Blood Policy and Technology

January 1985

NTIS order #PB85-234870
Recommended Citation:

Library of Congress Catalog Card Number 85-601151

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, DC 20402
Foreword

Posttransfusion hepatitis, inefficiencies in blood collection and distribution, payment for blood donations, and the cost of blood products are subjects that, from time

to time, have focused attention on the Nation’s blood services system. In response, tests

have been developed for detecting carriers of transfusion-related hepatitis. Transfusions

with the individual components of blood instead of whole blood have become accepted

therapy and also resulted in more efficient use of blood donations. Improved technologies

have extended the storage life of blood, and improved methods of collection have enabled

large-scale processing of plasma so that its component proteins could be extracted. One

result of this progress was increased availability of Factor VIII, the antihemophilic factor, which has allowed hemophiliacs to lead nearly normal lives.

In sum, improvements in blood banking and transfusion medicine in the late 1970s

and early 1980s have resulted in a stable and safer blood supply. Recent developments,

however, create uncertainties. Transfusion-related cases of acquired immunodeficiency syndrome (AIDS) have threatened the safety of the blood supply and the equanimity that has been the foundation of the voluntary blood donor system. Recombinant

DNA technologies are being applied to the production of plasma proteins, and other

technologies are under development for the production of the cellular components of

blood. Legislation of prospective payment by diagnosis-related groupings for Medicare

patients’ hospital care has begun to exert pressure on blood center revenues as hospitals

seek ways to pare costs. Organ and tissue transplants have been increasing, raising questions in the blood banking community about its role in these new types of tissue banks.

These developments led the House Committee on Energy and Commerce to request that

the Office of Technology Assessment (OTA) conduct an assessment of blood policy

and technologies.

In preparing this report, OTA staff drew upon the expertise of members of the study

advisory panel, chaired by Louanne Kennedy; members of the OTA Health Program

Advisory Committee, chaired by Sidney S. Lee; representatives from industry, academia

and the public; and experts in blood banking and transfusion medicine, blood research

and development, and health policy. Key OTA staff involved in the preparation of the

report were Lawrence Miike, Denise Dougherty, Jeffrey Stryker, and Anne Guthrie.

- JOHN H. GIBBON S

Director
Blood Policy and Technology Advisory Panel

Louanne Kennedy, Chair

Baruch College/Mt. Sinai School of Medicine

New York, NY

Alvin W. Drake

Professor of Systems Science and Electrical

Engineering

Massachusetts Institute of Technology

Cambridge, MA

Thomas C. Drees

Los Angeles, CA

Tibor J. Greenwalt

Director

Paul I. Hoxworth Blood Center

University of Cincinnati Medical Center

Cincinnati, OH

Sylvia Drew Ivie

Director

National Health Law Program

Los Angeles, CA

Aaron Kellner

President

New York Blood Center

New York, NY

Sidney S. Lee

President

Milbank Memorial Fund

New York, NY

James W. Mosley

Los Angeles County

Services

Los Angeles, CA

Sharon Perkins

Coordinator, Donor

Fairfax Hospital

Falls Church, VA

Department of Health

Program

Michael B. Rodell

Vice-President

Regulatory and Technical Affairs

Ethical Products Division

Revlon Health Care Group

Tarrytown, NY

Rosemary Stevens

Professor of History and Sociology of

Science

University of Pennsylvania

Philadelphia, PA

Scott N. Swisher

President’s Council

American Red Cross

Washington, DC

Martin J. Valaske

Medical Director

Medical Faculty Associates

George Washington University Medical

Center

Washington, DC

William D. White

Associate Professor

Department of Economics

University of Illinois at Chicago

Chicago, IL

Theodore Zimmerman

Professor

Departments of Immunology and Basic and

Clinical Research

Scripps Clinic and Research Foundation

La Jolla, CA

Wolf Zuelzer

Silver Spring, MD
OTA Project Staff–Blood Policy and Technology

Roger Herdman, Assistant Director, OTA

Health and Life Sciences Division

Clyde J. Behney, Health Program Manager

Lawrence H. Miike, Project Director

Denise M. Dougherty, Analyst

Jeffrey Stryker, Research Analyst

Anne M. Guthrie, Research Assistant

Virginia Cwalina, Administrative Assistant

Beckie Erickson, Secretary/Word Processor Specialist

Brenda L. Miller, Word Processor/P. C. Specialist

Contractors

Richard Kahn, Ph. D., Robert Allen, Ph. D., Joseph Baldassare, Ph. D., Pamela Cheetham,

M. P. H., American Red Cross Blood Services, Missouri-Illinois Region

Johanna Pindyck, M. D., Suzanne Gaynor, R. N., Robert Hirsch, M. D., Mercy Kuriyan, M. D.,

Robert Reiss, M. D., Theodore Robertson, M. D., Martin Stryker, Ph. D., Alan Waldman,

Ph. D., Kenneth Woods, Ph. D., New York Blood Center

Emily B. Rossiter, Regulatory Resources, Inc.

Elaine Power, University of California, Berkeley

Jerrold B. Grossman, New York Blood Center; Victor Schmitt, American Red Cross Blood

Services

James L. Tunis, M. D., New England Deaconess Hospital

Peter Tomasulo, South Florida Blood Services
Contents

1.

2.

3.

4.

5.

6.

7.

Introduction and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Overview

The Blood

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Services

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Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Blood Technologies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Current Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alternative Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendixes

A. The Blood Resources Program, Division of Blood Diseases and Resources,

National Heart, Lung, and Blood Institute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

B. Glossary of Acronyms

C. Acknowledgments and

References . . . . . . . . . . . . . .

and Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Health Program Advisory Committee . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1

Introduction and Summary
Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Blood Services Complex . . . . . . . .

Cost of Blood Products. . . . . . . . . . . . .

Availability . . . . . . . . . . . . . . . . . . . . . . .

Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Issues endpoints to Consider . . . . . . . . . .

AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cost of Blood Products . . . . . . . . . . . . .

Containment of Health Care Costs...

Alternatives and Substitutes for Blood

Appropriate Use . . . . . . . . . . . . . . . . . . .

Coordination of Blood Resources . . . .

Voluntary. Commercial . . . . . . . . . . .

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . .

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. . . . . . . . . . . .,.,

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Products . . . . . .

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. . . . . . . . . . . . . . .

TABLE

Table No.

1. Worldwide Demand for Plasma Fractions, by Product,

LIST OF FIGURES

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Page

1978 . . . . . . . . . . . . . . . 10

Figure No. Page

l. Collection of Whole Blood in 1971, 1979, and 1980 . . . . . . . . . . . . . . . . . . . . . . . 5

2. U.S. Transfusions of Blood and Components, 1971-80 . . . . . . . . . . . . . . . . . . . . 6

3. Disposition of Domestically Collected Plasma, 1983 . . . . . . . . . . . . . . . . . . . . . . . 7
1 .

Introduction and Summary

INTRODUCTION

A decade ago, national interest in assuring an

adequate and safe blood supply resulted in a pronouncement by the Federal Government of a National Blood Policy (NBP), with the four general

goals of improving supply, quality, accessibility,

and efficiency. Among the policies that were to

be implemented were the adoption of an all-voluntary blood collection system, resource sharing and

regionalization of blood collection and distribution, and programs to assure appropriate use.

In addition, information systems were to be developed on a continuing basis to monitor: 1) the

whole blood collection system for transmissible

diseases and transfusion mishaps to aid in improving the effectiveness of the blood banking system;

and 2) the source plasma and plasma fractionation sector to determine the sufficiency of domestic sources of plasma fractions, develop future

positions on the relationships between plasmapheresis and plasma fractionation and whole

blood banking, and determine the degree of interdependence between the United States and other

countries with respect to plasma and plasma products. Adherence to the highest attainable standards for blood products were to be achieved

through Federal regulatory authority, and research on all aspects of blood products was to be

supported.

Despite a flurry of legislative activity preceding

the announcement of the National Blood Policy,

no legislation was actually enacted. The announcement of the NBP by the Secretary of the Department of Health, Education, and Welfare (DHEW,

the precursor to the present Department of Health

and Human Services, DHHS) became the focal

point around which blood banking policy has

evolved over the past decade.

Following announcement of the National Blood

Policy, the Federal Government accepted, and

partially funded, a private sector plan to establish an American Blood Commission (ABC) to implement “the lion’s share” of the NBP. A number

of factors have inhibited the ABC’s effectiveness

in implementing the NBP: the Commission had

no enforcement power; its long-range financial

support was dependent on the blood resource

organizations which were already involved in the

functions that ABC was expected to influence; and

many of the factors that contribute to improvements in blood resources (e.g., development of

new technologies) were outside ABC’s reach.

However, ABC succeeded in providing a forum

in which blood banking issues could be openly

discussed, and much of the conflict among blood

bankers of a decade ago is gone today.

ABC, because it was initiated in response to the

call for a National Blood Policy, has been the

NBP’s most visible activity. Because the National

Blood Policy represented a pluralistic, private sector approach instead of a central, Governmentdirected approach, its primary contribution over

the past decade has been its acceptance as a general guiding principle by both the private and public sectors, infusing a sense of common purpose

into all contributors to our blood resources. The

Policy may have been sufficiently general in purpose so that few interest groups felt seriously

threatened by it. Whatever its real or imagined

impact, however, many of the problems areas

identified over a decade ago have shown substantial improvement.

Of course, other problems remain or have arisen since the NBP was announced, and, for the first

time, technologies are being developed that could

replace many, if not eventually all, of the products currently obtainable only from human blood.

Some of these new products, especially the major

derivatives (albumin and antihemophilic factor)

currently extracted from plasma, may be commercially available before the end of the 1980s.

3
4 ● Blood Policy and Technology

This study was conducted at the request of the

House Committee on Energy and Commerce. The

committee pointed out that questions remain concerning donor screening and selection, the appropriate Federal reaction to the changing pattern of

blood-related transmissible diseases, the efficiency

and coordination of blood banking systems,

emerging and future technologies for blood-function substitution, and whether there is a constructive role for a National Blood Policy.

Progress in blood resources over the past decade, and current and future technologies, are the

subjects of this report. The rest of this chapter

summarizes the major issues in blood banking policy and focuses on specific points within each issue

area that deserve continuing attention.

Chapter 2 presents a brief overview of Federal

interest in maintaining and improving the Nation’s

blood resources, the blood products used in therapeutic applications, the donors who provide

blood, and Federal activities in blood resources.

SUMMARY

The Blood Services Complex

The structure of the blood resources system remains nearly the same as it was 10 years ago, but

it is very different in terms of the products, services, and technologies offered. The system continues to consist of two essentially different sectors: 1) a largely voluntary whole blood and

components sector, and 2) a largely commercial

source plasma and plasma derivatives sector.

(Products separated from whole blood [red cells,

platelets, cryoprecipitate, and fresh-frozen, singledonor plasma] are usually referred to as “components,” while products derived from plasma [albumin, Factors VIII and IX, the immune globulins]

are called “derivatives.”)

Three types of facilities are involved in the voluntary sector: 1) community and regional blood

centers which collect and distribute blood to hospitals in circumscribed geographic areas, 2) hospital blood banks which both collect and transfuse

whole blood and components, and 3) hospitals

Chapter 3 describes the blood services complex:

the voluntary, whole blood and blood components sector; and the commercial plasma and plasma derivatives sector.

Chapter 4 describes the blood technologies:

technologies for blood collection and processing;

and plasma fractionation technologies.

Chapter 5 discusses current issues: the impact

of AIDS on blood collection and use; coordination of blood resources; the impact of health care

cost containment efforts on blood resources; and

issues of appropriate use of blood products.

Chapter 6 provides a look at alternative technologies: alternative sources and substitutes for

blood products. ‘

Chapter 7 considers future directions for blood

banking: voluntary v. commercial approaches;

and tissue and organ banking and blood centers’

interests in these activities.

which primarily store and transfuse blood but do

not collect it. These facilities are represented

by several organizations with overlapping memberships.

The American Red Cross (ARC) has 57 regional centers operating under a single Federal license.

These Red Cross regional centers cover about half

the geographic area of the United States and collect about half of the Nation’s whole blood. The

institutional members of the American Association of Blood Banks (AABB), including members

who belong to the Council of Community Blood

Centers (CCBC), collect another 45 percent of the

Nation’s blood. In 1980, seven ARC regional centers and all but two CCBC centers also belonged

to the AABB, as did 1,977 blood collecting hospitals. One hundred and one community blood

centers were members only of AABB and did not

belong to CCBC. Approximately 2 percent of

blood was collected through 16 unaffiliated blood

centers.
Ch. I—Introduction and Summary ● 5

The trend has been for hospital blood banks

to play less of a role in blood collections. In 1971,

69 percent of the blood collected came from regional and community blood centers (555). By

198o these centers collected 88 percent of the total,

increasing to 91 percent in 1981 (29). The increasing predominance of regional and community

centers has been attributed to their ability to collect blood through constant mobile collections.

In 1980, nearly 70 percent of whole blood collections was through mobile units.

Whole blood collections have been able to keep

up with increasing demand while paid whole

blood donations have decreased significantly (fig.

1). The ability to meet increased demand has

occurred through increased recruitment, improved

inventory management, technologies that have increased the storage life of blood and its components, and a large increase in the use of blood

components instead of whole blood. Between 1971

and 1980, whole blood collections increased from

8.8 million to 11.15 million units per year, while

whole blood and red cell losses decreased from

2.44 million to 1.15 million units, an improvement

in losses from 28 to 10 percent of blood collected.

Out of the 11.15 million units collected in 1980

(fig. 1), 14.8 million units of blood components

were transfused, exclusive of blood that was outdated or lost (fig. 2).

The source plasma sector, on the other hand,

is largely commercial and has two main components: 1) collectors, or plasmapheresis centers; and

2) fractionators. Not-for-profit blood banks and

blood centers also play a part in the commercial

plasma industry when they sell recovered or salvaged plasma (plasma recovered after components

have been removed from whole blood, or salvaged after whole blood has outdated) to fractionators; when they contract with commercial

firms to fractionate their plasma into derivatives

which they then market themselves; or, in one

case, when they fractionate and market their own

products. Approximately 45 percent of the Red

Cross’ recovered plasma is fractionated by commercial fractionation companies, and 17 to 20 percent of the plasma derivatives sold in the United

Figure 1 .-Collection of Whole Blood in

1971, 1979, and 1980

8,800,000 collected

364,00 0 491.00 0

1971 1979 1980

Years

Volunteer blood donor s Paid blood donors

States is sold by the voluntary sector (primarily

the Red Cross and the New York Blood Center).

There are 336 source plasma centers licensed

by the Food and Drug Administration (FDA), 317

of which are commercially operated, and 19 of

which are operated by community or Red Cross

blood centers. More than 90 percent of the source

plasma centers are owned by 30 companies which

market biological products. Some of these biological companies are in turn subsidiaries of larger

corporations (e. g., Sera-Tec Biological, owned

by the Rite-Aid Corp., operates nine centers in

the East and Midwest, most of which are located

near college campuses).

Plasma collected by commercial plasmapheresis

centers is either sold to U.S. fractionators who

separate it into a number of products (primarily

albumin, Factor VIII [antihemophilic factor] and

immune globulins), or exported to fractionators

in Europe, Japan, or South America. The way

plasma is provided from plasmapheresis centers

to fractionators varies. Four fractionation com-
6 ● Blood Policy and Technology

Figure+ 2.–U.S. Transfusions of Blood and Components, 1971-80

16

14

12

10

8

6

4

2

0

1971

Years

SOURCE: Surgenor and SchnitzerlABC, 19S3.

panics “self-source”; i.e., they run their own

source plasma centers. Ninety-eight U.S. source

plasma centers (30 percent) are owned by fractionation companies. In addition, most of the

other centers contract annually with fractionators

to provide a certain amount of plasma, although

there is some “spot buying.” Recovered plasma

(from whole blood) is either contracted for, or

marketed through the efforts of nine major brokers. Both the brokers and the for-profit source

plasma centers are members of the American

Blood Resources Association (ABRA), a nonprofit trade association organized in 1972 to represent

the interests of businesses engaged in the collection, manufacturing, or distribution of certain

biological products—in particular, plasma for further manufacturing.

The market for source plasma is largely controlled by four pharmaceutical companies (Hyland Therapeutics, Cutter Laboratories, Alpha

Therapeutics, and Armour), which are in turn

1979 1960

subsidiaries of major corporations (Travenol,

Bayer, Green Cross of Japan, and Revlon, respectively). Each commercial fractionator accounts for

about 1 million of the 4 million liters fractionated

commercially in the United States annually (459).

In addition, the nonprofit New York Blood Center operates its own plant, with a capacity to fractionate 300,000 liters per year from plasma recovered from its own donors and from a portion

of Red Cross donors.

The U.S. source plasma collection industry is

the most important contributor to worldwide

plasma fractionation. The approximate disposition of both source and recovered plasma collected in the United States at the present time is

shown in figure 3. About 1.3 million of the 6 million liters of source plasma produced is exported,

in addition to the export of plasma derivatives

manufactured in the United States. Some 5.5 million of the 12.5-million-liter worldwide manufacturing capacity in 1978 was in the United States.
Ch. I—Introduction and Summary ● 7

Figure 3.—Disposition of Domestically Collected Plasma, 1983

Diagnostic

Source plasma (commercial sector)

(non-ARC)

estimate (1983) = 6 million liters

75,000

Diagnostic (ARC)

50,000 liters

J

Estimates of 1983

U.S. recovered plasma

(estimate = 1.75 million

liters)

k

I

Estimate (1983) = 5.575 million liters

total domestic

fractionation

Of the 7. O-million-liter capacity outside the United

States, abouts million liters were in the commercial sector, and about 2.0 million liters in the

voluntary sector. But there were only about 77

plasma fractionation firms worldwide outside the

United States (439) and commercial plants outside the United States operate at about 60 percent

capacity, compared to about 85 to 90 percent in

the United States (459). Increasing amounts of the

albumin and antihemophilic factor (Factor VIII)

produced in the United States are used abroad.

In 1984, it is estimated that approximately onethird of the albumin and one-half of the Factor

VIII produced in the United States will be consumed in foreign countries (see table 19). The U.S.

fractionation industry currently supplies about 70

percent of Factor VIII, 70 percent of albumin, and

lesser amounts of the gamma globulin used in the

world. Thus, much of the plasma and plasma

derivatives used worldwide comes from U.S.

sources.

Costs of Blood Products

Blood collection and transfusion facilities have

not developed an industrywide uniform method

of allocating costs to each step in the collection

and transfusion process. Further, most of the

available data are on charges or prices, not on

costs.
8 ● Blood Policy and Technology

In 1980, the average cost to a community blood

center for the collection of one unit of whole blood

was nearly $46, but costs varied widely, with a

standard deviation of over $15. Most of these

costs are allocated to red cells (see, e.g., 142). In

1980, the average community blood center red cell

processing fee was about $32, while the average

total hospital charge for a unit of red cells was

about $89. Processing fees charged for whole

blood and packed red cells are less than the cost

per unit of blood collected because costs are also

allocated to other components.

There are wide variations in the fees charged

to hospitals by blood collectors and by hospitals

to patients. For example, in 1983, processing fees

for whole blood charged to hospitals by American Red Cross regions ranged from $28 (in San

Juan, PR) to $59 (in San Jose, CA). Some of these

differences can be explained by differences in costs

between geographic areas, but blood centers can

allocate more costs to one component than to

others (as in the case of red cells), and also factor

into their charges such program expenses as personnel training, research support, and capital

costs for new buildings and equipment. There are

also substantial variations in hospital charges for

red cells (the only component for which hospital

data are available), with standard deviations from

a quarter to a third of the mean (576).

In addition to the processing fee charged by the

blood center, hospital charges might include an

additional processing fee, a nonreplacement

charge if a replacement policy is still in effect, a

laboratory charge, an infusion charge, and other

charges. Total charges are usually higher at collecting than at noncollecting hospitals, with higher processing fees and nonreplacement fees accounting for the higher total charges (576). (Latest

available data on hospital charges are for 1980,

and such charges have undoubtedly risen since

then. )

Increases in blood costs have generally not exceeded increases in total health care costs. From

1980 to 1982, national health expenditures increased an average of 15 percent per year, while

blood center processing fees increased 7 percent

(for CCBC members) and 12 percent (for Red

Cross regions). Increases in hospital charges for

blood, on the other hand, appear closer to increases in hospital charges in general, although

it is difficult to draw conclusions with information from only 2 years.

As for costs of plasma derivatives, 1984 retail

prices for Factor VIII (including heat-treated products) ranged from $0.09 to $0.26 per unit in the

United States (99,464). Needs vary for mild,

moderate, and severe hemophiliacs, but assuming an average consumption of 50,000 units per

year (293), Factor VIII could cost the average

hemophiliac from $4,5OO to $13,000 per year. In

addition, from 10 (99) to 15 (76) percent of hemophiliacs have inhibitors to Factor VIII and require

a special form of coagulation product, anti-inhibitor coagulant complex, which can cost from

$0.70 to $1.00 per unit (99). Factor IX Complex,

used for hemophilia B patients, costs from $0.05

to $0.10 per unit. Products for hemophiliacs are

more costly in foreign countries.

In the United States, a 250-milliliter bottle of

albumin costs approximately $32. The price of

albumin has not been challenged per se, but its

use instead of less expensive crystalloid alternatives for volume restoration has been questioned,

and there have been other longstanding questions

over the proper use of albumin.

Availability

The trend in collection and distribution of blood

components has been toward centralization; i.e.,

toward the establishment of community and regional blood centers and away from hospital

blood banks individually providing for their own

needs. Blood components, especially the cellular

ones, still have relatively short storage lives;

whole blood and red cells have 35 days (with preservative solutions recently approved for 49 days),

and platelets up to 5 days (5-day storage bags have

recently been approved, increased from 3-day

bags). Thus, the regionalization of blood resources

has been primarily oriented toward maximum use

of a perishable product, and purchasers (predominantly hospitals) have been less concerned over

the price they paid than the assurance that they

could obtain blood components as needed. That

is, the cost to hospitals could be passed on to pa-
Ch. I—Introduction and Summary ● 9

tients and their insurers; so availability, and not

price, was the primary factor in purchasing blood

components. (The implications of present health

care cost containment measures and their effect

on price-consciousness are discussed below. ) Regionalization of blood resources has proceeded on

this basis, including the American Blood Commission’s regionalization recognition program.

Blood banks, whether as regional centers or as

part of a hospital, have also kept their stocks in

approximate balance with demand by sharing between banks with surpluses and those with shortages. There is apparently much undocumented ad

hoc sharing by blood banks both within regions

and between regions, and there are also two national sharing programs, one run by the American Association of Blood Banks, and another by

the American Red Cross.

Periodic attempts to combine these two systems

into a single system, with the American Blood

Commission as the mediator, have been unsuccessful. One reason is that, despite a Department

of Justice opinion that a resource sharing agreement would not violate Federal anti-trust legislation, the American Red Cross has expressed fear

that it would be liable to a civil suit if it were to

sign a formal nationwide resource sharing agreement. For example, representatives of the plasma

derivatives industry have objected to limiting a

resource sharing agreement to voluntarily collected blood. On the other hand, there are no systematic deficiencies which can be clearly identified

which would be resolved by a single sharing system. Blood banks have their own informal networks and use both of the national systems on

an as-needed basis. In addition, sharing can and

does take place on a regular, planned basis between blood banks with chronic shortages and

those which have a consistent surplus.

It is not possible to estimate what the minimal

amount of sharing should be between blood service regions to determine whether regions are collecting their “fair share” of the blood components

they need and use; i.e., whether they are adequately self-sufficient. Blood collection regions

have been established reflecting past blood collection organization efforts, the distribution of

hospitals in the region, as a compromise between

competing local collectors, etc. They have not

been established on the basis of assuring that the

population base from which blood is collected is

the same population as the users of those blood

products. Nor would that be possible, given the

widespread population that modern medical centers draw from. Similarly the majority of donors

are under 40, while the majority of users are older

people, and blood collected from small cities and

towns is used in large cities.

In conclusion, there do not seem to be systematic problems with availability in the voluntary

whole blood sector. Imbalances between supply

and demand have been met both within and between regions by a combination of ad hoc and

organized methods of sharing. Price has not

played much of a role, but indications are that

it is becoming increasingly important as purchasers come under prospective payment systems

and can no longer pass on all the costs of their

purchases.

Because the plasma derivatives sector is part of

the pharmaceutical industry its distribution networks are similar to those for the marketing of

prescription drugs. Thus, the commercial sector

presents a different picture from that of blood

components, although, as in the voluntary sector, availability of products does not seem to be

a problem. The national plasma derivatives market is intertwined with the international market,

and both profit and nonprofit companies and organizations are involved. Because of the increased

use of red cell concentrates instead of whole

blood, the voluntary sector has become a significant supplier of plasma and plasma derivatives,

accounting for about 20 percent of the plasma

derivatives sold in the United States. The American Red Cross (which contracts with commercial

fractionators to produce derivatives from Red

Cross plasma) markets its own products, as do

the New York Blood Center, and laboratories run

by the States of Michigan and Massachusetts. In

addition, both the Swiss and Dutch Red Cross sell

some albumin in the U.S. market. The New York

Blood Center and the American Red Cross also

sell Factor VIII, and the Massachusetts Biologics

Laboratory is the sole producer in the United

States of herpes zoster immune globulin.

38-647 0 - 85 - 2
IO ● Blood Policy and Technology

Following the establishment of the plasma fractionation industry in World War II to produce

albumin in mass volume, albumin for civilian use

became the principal product of the industry. This

“driving force” role was briefly taken over by the

immune globulins in the 1950s, then by the coagulation proteins (principally Factor VIII) toward

the end of the 1960s as techniques to extract

coagulation proteins in mass volumes were

perfected. At the present time, coagulation proteins, being the most profitable, are the principal

desired product of the fractionation industry, and

albumin is a “byproduct” although still the largest

in terms of volume and total sales (see table 1).

Hyperimmune globulins against specific diseases

have been developed in addition to general immune serum globulins that contain a mixture of

antibody types.

Albumin marketing is much like that for basic

commodities or generic drugs. The market is sensitive to price changes, a high level of competition exists, and product choice is related more to

the price, source of service, packaging, and other

inducements than to the quality of a particular

manufacturer’s product. All manufacturers’ products must meet FDA standards.

Distribution outlets for the coagulation proteins

vary from region to region, but most large urban

areas have at least one major hemophilia treatment center that routinely stocks them. As home

care of hemophiliacs increases, patients are beginning to be able to have these products supplied

directly to them on prescription. Packaging, auxiliary supplies (e.g., infusion sets), availability,

as well as price and brand name loyalty have

begun to determine which manufacturer’s products are purchased. In addition, some manufacturers provide financial assistance in the form of

Table I.—Worldwide Demand for Plasma Fractions,

by Product, 1978 (in monetary value)

Albumin/PPF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 0/0

Intravenous gamma globulin . . . . . . . . . . . . . . . . . . . . . 23

Hyperimmune globulins . . . . . . . . . . . . . . . . . . . . . . . . . 14

Factor Vlll concentrate . . . . . . . . . . . . . . . . . . . . . . . . . 13

Immune serum globulin . . . . . . . . . . . . . . . . . . . . ., . . . 8

All others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100°/0

SOURCE: International Federation of Pharmaceutical Manufacturers, 1980,

reduced prices for insured hemophiliacs. Product

availability may be an issue, however, for those

who are uninsured or live in remote areas.

Sellers of both albumin and the coagulation

proteins have central distribution or supply networks, and volume purchasing, often by organized groups of purchasers, on an annual bidding

basis, is fairly prevalent. Immune globulins are

routinely distributed by pharmaceutical distributors, hospital supply companies and blood centers, as well as directly by manufacturers to the

numerous hospitals, nursing homes, physicians,

and clinics that prescribe these preparations. Annual bidding is not as common as for albumin and

the coagulation proteins, but is increasing.

In sum, regional shortages and surpluses in the

voluntary sector have been handled through sharing programs between regions, but there is much

ad hoc sharing between blood banks outside the

organized intra- and interregional programs.

Technological improvements in storage methods

have also enhanced availability. Price and other

competitive aspects of supplying a product have

not been important factors but may become so

with the implementation of programs to contain

health care costs through prospective payment

systems.

In contrast, the major plasma derivatives are

marketed nationally and internationally, with no

apparent advantages in price and quality of the

nonprofit products over the commercial ones. Excess plasma from greater use of red cell concentrates instead of whole blood has led to nonprofits

becoming increasingly involved in the plasma

derivatives industry. Product availability seems

to be an issue only for hemophiliacs, as a consequence of inadequate resources or geographic inaccessibility to treatment.

Safety

Although recent attention on the safety hazards

of blood transfusions has focused on acquired immunodeficiency syndrome (AIDS), individuals

have a much greater chance of contracting some

form of hepatitis from transfusions of blood components and some plasma derivatives than they

do of contracting AIDS, despite a number of med-
Ch. I—Introduction and Summary ● 1 1

ical advances and the decrease in paid whole

blood donors. Laboratory tests for hepatitis B

have greatly increased in sensitivity over the past

decade; as a consequence, there has been a dramatic reduction in posttransfusion hepatitis B

cases. (Hepatitis A is rarely transmitted by blood

because the individual’s blood usually contains

the virus only during the clinical stage, during

which the individual is unlikely to donate blood

and which is easily detected during routine donor

screening procedures. ) However, by the late 1970s,

a new type of transfusion-associated hepatitis was

found.

This form of hepatitis has been named non-A,

non-B hepatitis, because it is distinctly different

from both hepatitis A and B. Five to eighteen percent of Americans who receive five or more units

of transfused blood develop non-A, non-B hepatitis (271a). Currently, approximately 90 percent

of all posttransfusion cases of hepatitis is due to

non-A, non-B hepatitis, and 10 percent due to

hepatitis B (558). No etiologic agent(s) has so far

been identified, although a retrovirus has recently

been implicated as the cause of non-A, non-B hepatitis. Therefore, there are no specific tests for

non-A, non-B hepatitis at present.

Efforts to prevent infection can occur at the

following stages of blood processing: 1) donor

screening, to prevent collection of potentially contaminated units; 2) laboratory testing of collected

units, to detect contaminated units; and 3) inactivation or removal of micro-organisms, to destroy infectious agents prior to use.

Screening of donors may begin by selection of

populations with a low prevalence of transmissible diseases. Preference for voluntary over paid

donors was based, in addition to ethical considerations, on the lower prevalence of hepatitis and

other transmissible diseases in voluntary donors.

The exclusion of intravenous drug abusers is based

on the same considerations, and recent decisions

to ask homosexual and bisexual men with multiple partners to refrain from donating, due to the

high incidence of AIDS in this group, were similarly motivated.

Individual donor screening is also carried out.

Each prospective blood or plasma donor, whether

voluntary or paid, is subjected to screening by

medical history and selected physical and laboratory examinations. Prospective donors are questioned for signs and symptoms of disease and a

history of exposure to disease. Laboratory tests

to determine whether or not the collected unit may

transmit infection may be specific or nonspecific.

Specific tests, such as the test for hepatitis B surface antigen, which is required of all blood and

plasma donors, detect the infectious agent itself

or some element of it. Nonspecific tests, such as

the screening for syphilis that is also required of

all blood and plasma collections, usually measure a response of the body which may occur in

several disease states, one of which includes the

disease in question. They have obvious limitations

but may be useful until specific tests can be developed. Other examples of nonspecific tests are

measurement of the liver enzyme, alanine aminotransferase (ALT), used by a few blood centers

to screen for carriers of non-A, non-B hepatitis,

and the T-lymphocyte helper: suppressor ratio,

which was initiated at the Stanford Medical Center to screen for AIDS. The presence of antibodies

to hepatitis B core antigen (as contrasted to the

presence of hepatitis B surface antigen, which is

indicative of the presence of the active virus) has

been used by some blood centers to screen donors

for AIDS, because it is believed that those individuals who have been exposed to hepatitis B may

also have a higher risk for exposure to AIDS.

To be useful, laboratory tests should be: 1) able

to be performed easily, rapidly, and on a large

scale to permit testing of the large number of units

collected to prepare perishable blood products;

2) sensitive enough to detect a large proportion

of contaminated units; 3) specific enough not to

have incorrectly positive reactions in most noninfected units; 4) able to detect a disease of health

importance to the recipient population; and 5) targeted at a disease which occurs frequently enough

to warrant screening of all donated units (434).

Of the tests mentioned above, the specific test for

hepatitis B surface antigen is the only test that

satisfies all these criteria.
12 . Blood Policy and Technology

Early attempts to prevent AIDS from entering

the blood supply were reminiscent of early methods oriented toward hepatitis B and current attempts to screen out hepatitis non-A, non-B carriers. One of the principal stimuli for a National

Blood Policy was the risk of hepatitis B. Donor

screening methods, directed both at groups with

high incidence of hepatitis and at individuals,

plus the labeling of blood as being derived from

“paid” or “voluntary” donors, were the principal

methods of screening for hepatitis B until very sensitive laboratory tests to detect the presence of the

hepatitis B surface antigen were developed and

applied to every unit of blood and plasma collected. In the case of non-A, non-B hepatitis,

donor screening remains the primary line of defense, with a few blood centers using the nonspecific ALT test in addition. This is similar to strategies to screen for AIDS; specific classes of donors

have been excluded, physical examinations in high

risk areas look for some of the preclinical signs

of AIDS such as general enlargement of the lymph

nodes, and a few blood centers have used surrogate tests for AIDS. (A specific blood test for the

presumed AIDS agent, human T-cell lymphotropic virus, type III (HTLV-III), will be available

in early 1985. )

In addition to screening through donor exclusion and laboratory testing, some transmissible

infections can be prevented by treatment of the

blood product to remove or inactivate infectious

agents. Currently, the most important of these

methods is pasteurization. (The cellular elements

of blood cannot withstand this treatment, which

is applicable only to some of the plasma derivatives. ) Albumin, which is widely used for blood

volume expansion and other medical purposes,

can be heated to 600 C for 10 hours, which inactivates hepatitis viruses and appears to inactivate

other viruses as well. Thus, FDA requires that

all albumin preparations be pasteurized in this

manner.

Prior to the AIDS problem, concentrates of the

clotting factors (e.g., Factor VIII) had not been

subject to pasteurization because of inactivation

of the clotting factors. However, recent advances

in heat processing of Factor VIII in the presence

of stabilizers have been accomplished, with evidence of inactivation of some type of viruses but

with some loss in potency of the preparations

(162). All four commercial manufacturers of Factor VIII have recently received FDA approval to

market these products. Claims of reduced hepatitis

transmission from heat-treated products, based

on chimpanzee studies, are currently under study,

with the hope that pasteurization will also inactivate other viral agents, such as the presumed

virus(es) for AIDS. (Current research suggests that

the presumed AIDS agent, HTLV-III, is inactivated by this process. )

ISSUES AND POINTS TO CONSIDER

Currently, three areas of primary concern in

blood resources development and maintenance are

at issue, none of which were major issues a decade ago when a National Blood Policy was enunciated. These issues are: 1) the impact of AIDS

on blood collection and use, 2) the impact of efforts to contain health care costs and the related

issue of the costs of blood products, and 3) alternative sources and substitutes for blood products.

AIDS is having an immediate impact, health care

cost containment portends possible fundamental

changes in the near future, and new and emerging technologies have the potential in the not too

distant future to profoundly affect the present

source plasma and plasma fractionation and voluntary whole blood industries.

In contrast, the primary issues a decade ago,

in addition to that of safety, were: 1) coordination of blood resources (including disagreement

over community v. individual responsibility for

blood donations, and the desirability of Federal

intervention in the blood supply); 2) appropriate

use; 3) voluntary v. commercial approaches; and

4) information systems to monitor blood resources. These are still issues today, although they
Ch. I—Introduction and Summary ● 1 3

been pushed into the background by AIDS, cost

containment, and alternative sources. Furthermore, continuing activities in these areas are likely

to be influenced by what happens in the three current primary issue areas.

AIDS

In some sense, the safety issues associated with

AIDS and blood products are but an extension

of the safety issues of a decade ago, when hepatitis

B was the primary disease that was transmitted

through blood. Hepatitis continues to be the primary blood-transmitted disease, with non-A,

non-B hepatitis replacing hepatitis B as the primary transmitted disease. The experience with

non-A, non-B hepatitis is very similar to that with

AIDS, with the difference that it has not captured

the public’s attention as AIDS has. Of the risks

associated with blood products, transfusion recipients and users of coagulation proteins are

much more likely to contract non-A, non-B hepatitis or hepatitis B than AIDS. Hemophiliacs, however, are a special class even though their rates

of hepatitis are higher than their risk of contracting AIDS, because of their great use of coagulation proteins and the high incidence of AIDS

among them.

Publication in January 1984 by Centers for Disease Control (CDC) researchers of their conclusion that there were cases of AIDS associated with

transfusions (143) caused consternation in blood

resources circles. But at a February 1984 meeting,

convened by CDC, of representatives of blood

banks and other groups interested in transfusion-associated AIDS, there was agreement that

the evidence that AIDS could and had been transmitted through blood products was conclusive

enough that no further studies need be conducted

to prove/disprove the association. Rather, studies

to quantify and clarify the risks were needed. Even

before this, however, AIDS was already suspected

as being due to some type of transmissible agent

such as a virus, and procedures had been adopted

in an attempt to reduce the risk of blood-related

AIDS. Furthermore, it was already known in 1982

that hemophiliacs were among the groups that

were at increased risk for AIDS, with their heavy

use of clotting factors as the suspected mode of

transmission.

In March 1983, the FDA, in consultation with

the major blood banking and plasma derivative

organizations, the National Hemophilia Foundation, the National Gay Task Force, the Centers

for Disease Control, and the National Institutes

of Health (NIH), issued recommendations to initiate: 1) educational programs to inform persons

at increased risk of AIDS to refrain from blood

or plasma donation, 2) expanded medical screening of blood and plasma donors to identify individuals with early signs or symptoms of AIDS,

3) examination of source plasma donors for lymph

node enlargement, and 4) measurement of body

weight of source plasma donors prior to each donation to detect unexplained weight loss. Some

blood banks began to introduce procedures which

allow donors to privately indicate whether or not

their blood donations should be used for transfusions, because such individuals may be especially

reluctant to acknowledge their homosexuality or

use of injectable drugs before their peers at school,

business or community blood drives.

As part of public information campaigns about

the risks of AIDS, the Public Health Service and

blood banking organizations included warnings

about who should refrain from donating blood

and also tried to allay groundless fears that AIDS

could be contracted by simply donating blood.

For source plasma collectors, FDA made additional recommendations that plasma collected in geographic areas of high risk for AIDS not be used

to manufacture coagulation proteins. And the National Hemophilia Foundation issued guidelines

for the use of cryoprecipitate, Factor VIII and Factor IX complex, including the preferential use of

cryoprecipitate in some circumstances.

As of May 1984, the FDA Blood Products Advisory Committee was also studying the issue of

whether specific surrogate tests should be instituted for all whole blood and plasma collections

and had also recommended that a pilot study be

conducted to measure the effectiveness of procedures by which plasma donors could privately indicate that their plasma should not be used in the

manufacture of coagulation products (as had been
74 ● Blood Policy and Technology

adopted by a number of blood banks for whole

blood donations).

All four commercial manufacturers, the Red

Cross, and the New York Blood Center withdrew

lots of Factor VIII (and related lots of Factor IX

Complex) upon being informed that a donor(s)

whose plasma had been used in the preparation

of those lots had developed AIDS. (Donor records

must be kept for at least 5 years, and matchups

of AIDS cases with donor lists had been made. )

The largest of these voluntary market withdrawals

involved enough Factor VIII to represent 500

patient-years of treatment (434).

As noted, all four commercial manufacturers

also subsequently developed heat-treatment (pasteurization) methods with claims of reduced infectivity of hepatitis viruses, the hope being that the

process would also affect the presumed AIDS virus. These pasteurization methods have reduced

the potency of the clotting factor preparations (the

reason why previous preparations could not be

pasteurized), but apparently not enough to markedly affect their efficacy.

Surrogate laboratory tests for AIDS have also

been extensively discussed, and some blood banks

have instituted them. The tests are of two types:

1) detection of abnormalities associated with

AIDS or the preclinical stages of the disease, and

2) evidence of past infections with diseases that

have a high incidence in the same population

groups that are at increased risk for AIDS. However, conditions other than AIDS can lead to abnormal test results in tests of the first type. For

example, Stanford University Blood Bank began

to test all blood donations for T-lymphocyte

helper: suppressor ratios (445). About 1 to 2 percent of collections have been positive, but such

individuals are not permanently deferred from

donating, since short-term virus infections can

also cause an abnormal ratio.

The Irwin Memorial Blood Bank in San Francisco instituted a test for antibodies to hepatitis

B core antigen (as did Cutter Laboratories for its

source plasma donors) which reveals past infection with hepatitis B and expects that donor deferrals will increase by 5 to 7 percent. (Cutter expected a positive test rate of 15 percent and

planned to use this plasma only for production

of albumin and immune globulins, which are not

implicated with AIDS. )

AIDS also kindled interest among patients and

physicians for autologous and directed donations.

Autologous donations, where a patient “banks”

his/her own blood prior to elective surgery, was

always considered the safest of transfusions. However, it could pose problems for the management

of blood if it were to be more widely applied.

Surgeons often prefer not to use it, medical personnel may be exposed to health risks because the

blood is not tested for hepatitis, and autologous

blood may outdate if surgery is postponed. Individual blood banks have allowed the use of directed donations either to ease patients’ fears or

in response to pressures from patients and their

physicians. Directed donations, however, have

been opposed by most blood bankers because of

the potential for disruption of the blood collection and distribution system if widely adopted,

and because of a lack of evidence that such donations are indeed safer than anonymous donations.

In April 1984, the Secretary of DHHS announced

that researchers had identified the AIDS virus and

developed technologies to mass-produce a blood

test which would become “widely available within

about 6 months, ” and would “identify AIDS victims with essentially 100 percent certainty” (256).

A few days later, DHHS announced a request for

applications to produce and distribute such a test,

with requests to be submitted within 10 days of

the announcement (181). Thus, whether the Secretary’s promise to provide a reliable test for AIDS

can be kept will be known soon, and if the test

is provided it should alleviate much of the pressure to adopt some type of surrogate test—and

may again turn directed donations into a nonissue

in the blood community.

But questions raised as a result of the donor

screening methods developed against AIDS, use

of surrogate tests, and interest in directed donation programs will not be completely moot even

if a highly specific test for AIDS is available soon.

Points to Consider

Evaluation of Donor Screening Criteria .-One

of the first steps taken by the blood community

in attempting to keep AIDS out of the blood
Ch. I—Introduction and Summary ● 1 5

supply was to exclude classes of people who were

deemed at high risk for AIDS. The impact of this

policy has been especially felt by the gay male

community. (Young males have always been

among the principal, if not the largest, groups of

blood donors. ) Intravenous drug abusers have

always been one of the excluded blood donor

groups, and exclusion of recent Haitian immigrants can be likened to policies which exclude

donors who have recently arrived from areas with

high incidence of infectious diseases which can

be transmitted through blood donations.

An evaluation of the exclusion of gay males is

needed, not only to confirm whether or not this

policy has indeed led to decreased AIDS transmission through blood, but also to confirm whether or not such an exclusionary, stigmatizing policy is justified by the results.

There are two measures of whether or not this

policy has worked. First is an assessment of the

process; i.e., whether or not the donor population has indeed changed, with fewer young to

middle-aged males in the donor base. This would

be especially significant in areas of high incidence

of AIDS, where the implementation of this policy has been actively pursued. This evaluation

would also include the effectiveness of providing

avenues of private communications by donors to

indicate whether or not their blood should be used

for transfusions.

Second would be an evaluation of whether or

not exclusion of gay males has in fact resulted in

a reduction of blood-transmitted cases of AIDS.

The time between transfusion and onset of illness

has ranged from 10 to 43 months, with an average of about 24 months (143). Cases of bloodtransmitted AIDS that were diagnosed through

the end of 1984, would have resulted from transfusions of blood which were donated prior to instituting the donor exclusion policies, which began

in early 1983. If donor exclusion policies have

made a difference, the effect should not begin to

appear until late 1984.

These evaluations could also be tied to the expected development of highly specific laboratory

tests for AIDS. As those expected tests are instituted and evaluated, a reassessment of current

donor screening policies could help determine

whether or not they should continue, be modified, or be eliminated.

These evaluations were discussed at the February 1984 meeting of blood bankers convened by

CDC, but no decisions were made. CDC sees its

primary role as risk assessment, not risk management. Therefore, thought was given to the role

of the blood banking organizations in the evaluation of donor screening.

Individual blood centers have instituted variations on the basic donor screening recommendations, such as different ways to allow donors to

withdraw their donations in private. Several of

these centers have ongoing evaluations of these

efforts, and the blood organizations (AABB,

ARC, CCBC) could coordinate these efforts or

mount a centralized research effort. Thus, blood

organizations could be encouraged to conduct

evaluations of donor screening and its impact on

blood-transmitted AIDS.

The alternative to a blood banking organization-directed evaluation is to direct Federal agencies to evaluate donor screening and its impact

on blood-transmitted AIDS. Federal agencies

could play the primary role in evaluating donor

screening, with cooperation and/or contracting

with the voluntary organizations or directly with

a consortium of blood centers to perform the actual study. A possible locus for this Federal role

could be the National Center for Health Services

Research instead of CDC, NIH, or FDA, since the

latter agencies are oriented more toward epidemiological field work and basic and applied biomedical research. It is conceivable that FDA could

sponsor the evaluation because of its regulatory

responsibilities.

Congress could advise the Department of

Health and Human Services as to its priorities in

this evaluation as against other evaluations of

blood-transmitted AIDS, or it could provide separate funds. The evaluation could also be expanded to address the broader question of the continued need for donor screening methods specific

to AIDS once a specific laboratory test for AIDS

is in place.
16 ● Blood Policy and Technology

Identification of Suspected AIDS-Carrying

Donors and Recipients of Their Blood Donations.—CDC has gathered and continues to accumulate information on AIDS cases in general and

on donors who have been implicated with cases

suspected to be blood transfusion related, although they are now doing so with a coded system, making donors anonymous even to CDC

until tracing is required. While some health departments have a policy to inform the local blood

center as new cases of AIDS are diagnosed in order to match their names with blood donor lists

(e.g., the San Francisco health department and Irwin Memorial Blood Bank), blood donations are

not necessarily limited to the current city of

residence, particularly with the mobility associated with modern life. One issue, then, has been:

should the names of AIDS patients be made available, to what extent, and to whom? For example, should all State health departments be notified? Should all blood banks be notified, so that

they can match the list of names with their donor

registries?

Finding donors who actually have had AIDS

has been the exception. Most of the “suspected”

donors have not been found to actually have

AIDS; they either belong to a high-risk group

(e.g., are gay males) or have nonspecific laboratory abnormalities (e.g., reversed T-lymphocyte

helper: suppressor ratios) or physical signs that

could be AIDS related (e.g., enlarged lymph

nodes). The use of a test for HTLV-III will also

identify persons who have been exposed to the

presumed AIDS agent and who may or may not

be carriers of the virus. Should these donors be

treated in the same way as confirmed AIDS patients, insofar as releasing their names is concerned?

An even more vexing problem has been in dealing with patients who received blood components

from donors who are suspected in the blood-transfusion AIDS cases. Should they be told, or should

that information be passed on only to the blood

bank which provided the blood, or to the patient’s

personal physician, leaving it up to his/her judgment to inform the patient? Since monitoring of

these recipients of suspected AIDS-contaminated

blood is important in determining the epidemiological characteristics of the disease-e. g., its rates

of infectivity, morbidity, and mortality—it does

not seem practical to design such monitoring

activities without informing the patients.

These issues were addressed at the February

1984 CDC meeting, a subsequent March 1984

meeting of the National Heart, Lung, and Blood

Institute’s AIDS Working Group, and another

meeting of the AIDS Working Group in late May

1984. This latter meeting also included medical

ethicists to see how such studies could be reconciled with the ethical problems. A previous assessment of “Confidentiality in Research on AIDS”

had been completed by The Hastings Center, but

the focus of that assessment was on assuring the

confidentiality of AIDS victims, and not to the

issue above—i. e., how to approach the question

of monitoring other recipients of suspected AIDScontaminated blood, and who should be informed.

Laboratory Tests for AIDS.—Current surrogate

tests lead to exclusion of far more donors than

are ever expected to actually have or develop

AIDS, and seem to have been instituted more to

allay patients’ and physicians’ fears rather than

in hopes of decreasing exposure to AIDS, Besides

increasing costs due to the expense of testing, discarding of blood after collection, lost donors, and

the need to recruit additional donors, the psychic

costs to donors labeled as suspect have been subordinated in order to reduce the psychic costs of

potential and actual recipients and their physicians. Given the public apprehension surrounding

AIDS, this situation can be expected to continue.

For example, testing for past infections with hepatitis B (anti-HBc) is expected to exclude about 6

percent of current voluntary donors and 15 percent of commercial source plasma donors, and apparently this cost is not viewed as too high for

the psychic benefit it is expected to produce.

The criterion used in decisions to institute these

programs appears to be whether the added costs

can be handled, not whether in fact AIDS will be

reduced. However, these decisions seem entirely

compatible with public reaction to the threat of

AIDS in the blood supply. The risk is very small,

but the fear is great, and the perception that

something is being done is important to public

confidence.
Ch. l—lntroduction and Summary ● 1 7

A highly accurate, AIDS-specific test should decrease the perceived need for adopting any of the

surrogate tests that have been proposed, but reassuring the public will probably mean that these

tests can also be expected to be applied far beyond

the application that would be scientifically justified, For example, hepatitis B testing is justified

on the basis of its incidence and severity, and the

search for a test for non-A, non-B hepatitis is also

justified on that basis. On the other hand, the continued requirement for testing for syphilis of all

whole blood and plasma collections has been

questioned because of its low cost effectiveness.

The syphilis testing example, however, points to

the fact that safety has been the primary concern,

and it can be expected to take priority once an

AIDS-specific test is available.

Thus, it can be expected that the test for HTLV111 will be a requirement for all blood and plasma

collections, regardless of the relative degree of risk

among blood banks and geographic areas. Even

if not required for all, blood banks and plasma

collectors will feel compelled to perform the test

anyway because of the public confidence factor

and the threat of lawsuits. It should also be reasonable to expect that plasma fractionators, because of the pooling of plasma from thousands

of donors, may be required to test for AIDS a second time when they receive plasma from blood

banks and source plasma centers (this is currently

being discussed in FDA for the test of active

hepatitis B, the HBsAg test, which is currently required only at the time of donation).

Such additional testing will further raise the

costs of blood and plasma products, but the advent of cost containment measures will exert pressures in the opposite direction; i.e., it can no

longer be assumed that blood testing (and other

processing) costs can be passed on to purchasers.

The circumstances surrounding AIDS will most

likely compel nationwide adoption of tests that

are developed, but the additional costs of such

testing should provide incentives to reassess all

of the tests that have been adopted over the years

to improve safety. Among these are the requirements for syphilis testing and for blood typing

each time a donor gives blood (blood types do

not change).

Directed Donations. —Interest in directed donations increased with AIDS and has been implemented in some of the areas with a high incidence

of AIDS (e.g., Los Angeles, San Francisco). Such

interest may diminish with the availability of an

accurate and sensitive test for AIDS, but individual blood centers-may maintain directed donations for individual patients indefinitely. A serious problem may arise, however, if organizations

press for directed donations. In this case, entire

sets of blood might be tied up and have the potential for disrupting the present, well-balanced

system of blood supplies. The potential scope is

great: a third of those who donate regularly do

so to contribute to a company blood drive (25).

Costs of Blood Products

Charges for blood products vary considerably

but are generally not considered to be a national

problem because they account for only about 1

percent of total health care costs and because increases in charges do not appear to have exceeded

increases in overall health care costs. However,

the costs of blood products may cause hardships

for two types of consumers: hemophiliacs and

public hospitals.

Points to Consider

Coverage for Hemophiliacs’ Care .—The situation for hemophiliacs has improved dramatically
18 ● Blood Policy and Technology

since passage of Public Law 94-63 in 1975. The

law provided funding for the creation of comprehensive hemophilia treatment centers, 23 of

which have since been created. A recent survey

of about half of those centers found that conditions had markedly improved for the 3,705 patients seen in the fifth year of the program. Compared to the year before the programs had started,

the costs of total care, including rates of hospitalization, had been reduced, and unemployment among hemophiliacs was lower. The proportion of patients with third-party coverage had

also grown, both because employment of hemophiliacs increased as a result of better treatment,

and because health care workers at the centers

have helped patients arrange for coverage. However, the survey of treatment centers represented

only those hemophiliacs with access to comprehensive treatment centers, probably half of the

hemophiliac population. In addition, third-party

payments may not cover the plasma derivatives

needed for prophylactic treatment, which can cost

$13,000 per year for a severe hemophiliac.

Medicare does not, and private insurers often

do not, cover the costs of the needed blood products on an outpatient basis, because plasma derivatives are considered to be pharmaceuticals.

Distributors of coagulation proteins sometimes

disregard copayment requirements for their hemophiliac clients. Coverage is further complicated

by the fact that unlike the End-Stage Renal Disease Program under Medicare, which recognizes

patients with end-stage renal disease as being

totally disabled and thus eligible for Medicare coverage for dialysis and transplants, hemophiliacs

can receive Medicare coverage only through a

case-by-case determination. State plans to cover

hemophiliacs exist but vary widely in comprehensiveness, and hemophiliacs have been known to

relocate in search of better benefits, disassociating

themselves from important family and community ties. Thus, opportunities exist for improving

health care provisions for hemophiliacs, if not by

creating a special program for them, then by providing coverage for blood products on an outpatient basis.

Costs of Blood for Public Hospitals.—As for

many other products and services the purchase

of blood is a problem for public hospitals. Blood

centers feel obliged to deliver needed blood products to public hospitals regardless of the fact that

they may not be paid, and public hospital bills

are often written off as uncollectible (420). Thus,

the costs of blood for public hospitals are partially

underwritten by hospitals which can pay the

prices that blood centers charge. This situation

is somewhat analogous to the sources and users

of blood itself-suburban, rural, and middle-class

urban residents already support inner cities by

providing much of the needed blood. As cost containment measures pressure hospitals to reduce

overall per patient costs, pressure on blood centers

to lower or not increase their charges may make

it difficult for them to continue absorbing losses

from their public hospital clients.

Containment of Health Care Costs

The diagnosis-related grouping (DRG) method

of payment for Medicare is now in the process

of implementation. Under previous cost reimbursement, there were few incentives for hospitals to be price-conscious in purchasing blood

products, reliability of sources being their primary

criterion.

Higher charges for whole blood and red cells

were associated with hospitals that collect part of

their blood requirements v. those hospitals that

did not (576). While no comparable hospital blood

bank cost data were available, it seems reasonable to assume that at least part of the higher

charges was due to higher costs. For example, regional blood centers have been found to have

economies of scale for total costs. Under cost

reimbursement, there was no incentive for hospitals to rely more on regional blood centers, but

under fixed reimbursement rates management will

have to reassess its arrangements for blood supplies. Even for hospital blood banks with costs

lower than those of regional blood centers, other

factors may lead to greater dependence on the regional center. These include the possibility of

duplication of services, competition for blood
Ch. I—Introduction and Summary ● 1 9

donors, inventory control and outdating, and

greater need for blood because of expanded and

new services (189).

Another factor is the trend in ownership in both

for-profit and nonprofit hospitals toward multihospital chains, which are introducing corporate

management practices and volume purchases,

thereby inserting hospital management more into

the traditional relationships between hospital

blood banks/transfusion services and regional

blood centers. These developments mean that hospital management will be taking a close look at

the cost effectiveness of purchasing blood from

regional centers versus maintaining complete

blood banking operations, although it has been

argued that because blood is such a small portion

of a patient’s bill, such reviews may not occur for

some time (534).

However, a move toward greater dependence

on regional centers maybe tempered by the need

to generate income to support remaining blood

banking activities. For example, with a fixed

overhead in running hospital blood banks, hospitals may look toward additional services to generate income, such as platelet collections and therapeutic apheresis. Another opinion is that it is

more cost effective for hospitals to collect their

own blood, but that it has been more convenient

to purchase it from a blood center (140).

Finally, one blood banker predicted that blood

centers would expand even more and hospital

blood banks would eventually close. The blood

center has freedom from hospital cost control, and

has a distinct advantage when it comes to research

opportunities, since the blood center does not

have the external controls that are found in hospitals (90).

Clearly, what will actually happen is still quite

speculative, but some indications of the influence

of cost containment measures are beginning to

emerge. Limits were placed on hospital payment

rates to provide them with incentives to be costconscious, including not only the services they

performed, but also the purchases they made.

While capital costs have been excluded from the

DRG payment system by the current legislation,

purchases of supplies have not. One blood center has been told by one of its hospitals that it

would not accept any price increases in 1984 (196).

In addition, the president of the ABC has expressed concern that hospitals are now shopping

around for blood supplies on the basis of price,

even using the AABB Clearinghouse at times in

preference to their usual regional blood center

sources (383).

Points to Consider

Financing of Blood Center Operations .-Blood

centers use their revenues for their operating, research, and capital costs. Predictability of demand

(and related revenues) for their products has been

made easier by the regional systems that have developed over the past decade. Ad hoc and formal

sharing of blood between blood centers with

shortages and surpluses have also contributed to

a fairly predictable stream of revenue. Furthermore, as availability/convenience has been the

controlling factor instead of price under previous

cost reimbursement for hospital services, the

prices that blood centers have quoted have generally been what they received.

Some price competition is now appearing for

blood products, either through requests to hold

prices level or through purchases from less expensive sources. Some blood bankers have already

suggested that the service (processing) fee b e

treated as a pass-through, leaving under DRGs

those costs of typing patients, cross-matching and

all of the other services provided by the hospital

for the patient (120). Whatever the merits of such

a proposal, it is premature at this point. Very

good reasons would have to be provided without opening the door for other health care sectors to clamor for such an exclusion. This does

not mean, however, that these concerns should

be dismissed. One area of concern is the research

and training programs conducted by blood

centers, and capital costs for new or improved facilities. The Red Cross, because of the large reserves it has accumulated from blood revenues,

could help some of its centers to maintain their

research and training programs, but independent

blood centers do not have this cushion to fall back

on.
20 . Blood Policy and Technology

One reason for proceeding with caution before

reaching the conclusion that cost restraints will

significantly affect the present supply system is

the underlying assumption that price competition

will (or could) develop into a significant purchasing factor. The system is, after all, based on a system of voluntary donations. While regions with

surpluses and those with shortages are part of the

system, and spot purchases at better prices than

available at the regional blood center may occur,

competitive purchases in the kinds of volumes that

would endanger a region’s blood center are not

highly probable. In order to do so, competing

blood centers and blood banks may have to collect blood far beyond their needs and would have

to justify to their donors why they are doing so.

Increased revenues would hardly be accepted as

a valid reason. Thus, hospitals may augment their

major purchases by “spot buying” on the basis

of price, and the real impact on blood centers may

be to make them more cost conscious in their

operations.

Current Supply and Distribution Systems.—

The same considerations apply to the effect of cost

containment measures on the collection and distribution systems that have been nurtured over

the past decade, with the blood center at the hub

(regionalization). If publicized, overcollection of

blood for the purpose of increasing revenues

would threaten the blood center/donor relationship. As long as voluntary donors are the basic

source of blood components, collection centers

should not be able to increase their supplies for

the purpose of competing for sales outside their

existing distribution channels without threatening the relationship that has been so carefully nurtured over the years. Thus, current indications of

price shopping may be a temporary phenomenon,

or an activity that will continue only at the margin.

Alternatives and Substitutes for

Blood Products

Recent advances in biotechnology, particularly

in the field of recombinant DNA technology, have

suddenly raised the prospect that alternative

sources for some blood products can be available

by the end of the 1980s. The gene for albumin was

cloned a few years ago, and many recombinant

DNA companies have publicly claimed to have

both recombinant yeast and bacterial strains carrying the human albumin gene. Most companies

appear to have this project on hold for the present, due to problems of scaleup to mass production, purification of the resulting product, and

questions over whether a recombinant albumin

could be priced competitively with albumin from

human sources. Many of the technical problems

facing commercialization of recombinant albumin

are unique. Not until those problems are solved

will recombinant albumin be capable of meeting

worldwide demand for albumin.

Developing recombinant DNA sources for Factor VIII was initially a much more difficult process, because the protein is much larger than albumin, and bacteria are incapable of producing

the entire molecule because of the complexity of

the gene. One company (Genetics Institute) announced in December 1983 that it had cloned part

of the gene for Factor VIII, and several other companies have given the impression that they were

close to testing recombinant Factor VIII in clinical trials.

These claims were met with skepticism, given

the complexity of the molecule and its gene, and

the instability of the biologically active protein.

However, in April 1984, Genentech announced

that it had succeeded in cloning the entire Factor

VIII gene, and used a mammalian cell to produce

the protein, thereby bypassing many of the problems inherent with bacteria or yeast as the cellular

host. Genentech also claimed that it had tested

the product and found it biologically active. Thus,

technologies for producing both albumin and Factor VIII, the foundations of the plasma derivatives

industry, are rapidly being developed. There are,

however, some hurdles to be overcome before

these products will be commercially available.

These include development of techniques for production on a commercial scale, completion of tests

of safety and efficacy, and approval by FDA for

marketing. There is also the danger that litigation

to resolve patent disputes maybe quite protracted,

delaying commercial availability of new products

until claims of priority are resolved.
Ch. l—introduction and Summary ● 2 1

Other potentially useful plasma proteins not

presently produced by the plasma derivatives industry or produced only on a small scale are also

under exploration or testing by recombinant DNA

companies. However, the activities necessary for

developing other useful protein products are different from those used to develop Factor VIII and

albumin. Small markets, and the unexplored clinical utility of these proteins, may mean that companies will not devote resources to their development.

True cellular substitutes for blood are much further away. Two products, perfluorochemicals and

hemoglobin solutions, have been under development for a number of years, but still face safety

and efficacy hurdles before they will become

available. Even if and when they do become available, however, they will not be true substitutes

for red blood cells, but will be only partial substitutes which can be used in place of red cells in

special circumstances. Platelet substitutes are

much further away, although there is growing interest in this field. White blood cell substitutes do

not seem to be needed, given the doubtful need

for them now from human blood.

The approach of developing cellular substitutes

on a synthetic basis maybe ultimately supplanted

by cell culture techniques. Both red cells and

platelets come from common progenitor “stem”

cells found in bone marrow (and a small amount

circulating in blood). If cell lines could be developed which both proliferate in massive amounts

and can be controlled to differentiate into the

desired cell types (red cells and platelets), a true

alternative source of blood cells will have been

accomplished. Given the rapid advances in cell

culture techniques (e.g., hybridoma technology

for the production of monoclinal antibodies) and

understanding of cellular functions, it is not science fiction to assume that production of red

blood cells and platelets from “stem” cells will

eventually become a reality.

Nearly all of the work on developing recombinant DNA sources of plasma proteins is being

conducted by biotechnology companies, some in

conjunction with the parent corporations of the

large fractionators of plasma (e.g., Green Cross

of Japan, Baxter-Travenol). Most of the work on

(partial) red cell substitutes has been performed

by academic investigators or at military research

institutes, although an array of commercial organizations has also been interested, ranging from

plasma fractionation companies and large industrial concerns to small biotechnology firms. Most

of the work on hemoglobin solutions has been

sponsored by the military in its search for a battlefield resuscitation fluid. The company most

closely associated with the other major class of

partial red cell substitutes, perfluorochemicals, is

Green Cross of Japan and its American subsidiary,

Alpha Therapeutics (purchased a few years ago

by Green Cross, and one of the four major plasma

fractionators in the United States).

Points to Consider

Impact on the Plasma Derivatives Industry.—

As an industry whose primary products are Factor VIII and albumin, the plasma derivatives sector is obviously vulnerable to inroads or eventual takeover of the market by recombinant DNA

sources of the two principal plasma proteins that

are marketed. Moreover, monoclinal antibodies

may also replace the third principal part of the

plasma derivatives market, the immune globulins.

In the past few years, the plasma derivatives market has shifted more toward collection of antibodies toward specific diseases, collectively

known as the “hyperimmune” globulins. Monoclonal antibodies would be more effective than

even these hyperimmune globulins, because they

would be composed of single antibodies, not a

mixture with a high titer of one antibody as is the

case for plasma from sensitized donors.

The large plasma fractionators have been positioning themselves so they will be able to switch

to the new sources of plasma proteins, and it is

likely that they will continue to be the major producers, or at least continue as the major marketers, of these new sources of plasma proteins.

However, some destabilization of the plasma

derivatives industry is inevitable, with possible

difficulties in providing other, less profitable,

derivatives such as Factor IX Complex. Source

plasma centers are especially vulnerable, since

their sole role is in providing the raw material,

human plasma, from which current plasma pro-
22 ● Blood Policy and Technology

teins are extracted. While the upshot for albumin

may be a desired decline in its use because of questions of its appropriateness, there is some concern

about how Factor IX will be provided to the relatively small population that needs it. In addition,

the clinical utility of other plasma proteins may

be harder to explore. Factor IX, for example, was

“discovered” in the process of fractionating plasma

for Factor VIII.

When and how this impact on plasma collectors and fractionation products will occur is not

predictable at this time, although some impact

seems inevitable. Even if recombinant DNA and

monoclinal antibody sources of plasma proteins

are phased in gradually, there could be large

dislocations in the plasma derivatives industry.

Many source plasma collection centers and some

fractionation plants could close. The price and

perhaps even availability of some of the plasma

proteins would also be affected, not only because

of competition from alternative sources, but also

because of the nature of the processes in the

plasma derivatives industry where the extraction

of marketable proteins from plasma is done in successive steps, linking the costs of each plasma fraction product to the costs of the others.

Impact on the Voluntary Whole Blood Sector.—The voluntary sector could also experience

negative consequences as a result of shifting

plasma protein production to nonhuman sources.

The whole blood and plasma sectors are now interrelated to a significant extent because of excess

plasma capacity in whole blood collections, which

has been sold to plasma fractionators or converted

to plasma derivatives independently (New York

Blood Center) or by contract (Red Cross). This

interrelationship is a direct consequence of the increased volume of whole blood that has been separated into components over the past decade. Currently, the voluntary sector accounts for about

20 percent of the plasma derivatives market, and

significant revenues would be lost. Possible consequences are increased prices for blood components because of lost income from plasma sales;

increased collection of specific components (i.e.,

red cells, platelets), or at least attempts to make

component-specific collections more cost effective;

and increased transfusion therapy activities by

blood centers to generate other sources of revenues.

Impact on Consumers. —Development of alternatives to human blood products has both positive and negative implications for consumers,

particularly hemophiliacs. While recombinant antihemophilic factor (and other nonhuman-derived

products) would be free of infectious agents,

nonhuman alternatives will be more expensive,

at least in the short run. In addition, less profitable

products such as Factor IX Complex may not be

produced, or may become exorbitantly expensive,

and the clinical utility of trace proteins may not

be explored by commercial firms. Thus, additional public support for hemophiliacs and for research on trace proteins in plasma may be necessary.

●

Appropriate Use

There is wide agreement that blood products

are overused, but little data exist by which to evaluate the extent of overuse, in many cases because

scientific precision is lacking as to when a component or derivative should be administered. Estimates of the extent of overuse are high: 20 to 25

percent for red blood cells (204), as much as 90

percent for albumin (8), and 95 percent for freshfrozen plasma (457).

Initially, the focus was on the use of whole

blood instead of red cell concentrates. Currently,

questions continue on overuse of red cells and

have focused especially on albumin, and freshfrozen, single-donor plasma.

One of the most controversial areas concerning red cells is the matter of the “transfusion trigger,” the hemoglobin level which is considered the

point at which transfusion is required. For example, women naturally have lower hematocrits than

men, but surgeons use the same support and ceiling hematocrit levels to indicate transfusions for

both sexes. Iron-deficiency anemia continues to

be among the leading reasons for transfusions

(202), even though it rarely warrants transfusions.

The dramatic increase in the use of fresh-frozen

plasma over the last decade has led to concerns

that its uses are often vague and without scientific basis and that other products are available

that are as effective and safer (567).

Even the growing use of platelets has been questioned; for example, their prophylactic use in pa-
Ch. I—Introduction and Summary ● 2 3

tients with malignancies (see, e.g., 481), the practice of treating the “platelet count” rather than the

patient, and the use of pheresis platelets over

platelet concentrates.

Despite workshops and the development of

guidelines for albumin use in the mid to late 1970s,

its use continues and production continues to increase. Per capita use of albumin differs markedly

from country to country, even in countries similar in levels of medical sophistication (388).

A key element of inappropriate use is that criteria for clinical use are often unclear. Past attempts to change medical practice in this area have

been largely educational, using such methods as

seminars, handbooks of suggested practices, and

textbooks. These attempts appear to have been

largely unsuccessful, although systematic data on

specific uses of blood products are lacking.

Points to Consider

Direct Attempts to Improve Use.—The NHLBI’s

Division of Blood Diseases and Resources has instituted a program of “Transfusion Medicine Academic Awards” through which recipients will

work with medical schools to incorporate transfusion medicine into the curriculum. Thus, one

method is to build up a specialty base in transfusion medicine,

Some blood centers have attempted to modify

the practices of physicians directly. For example,

at Puget Sound Blood Center in Seattle, requests

for more than eight units of a blood component

must be cleared through a blood center consultant before the blood is released. This is made possible because Puget Sound maintains a central

crosshatching laboratory, and all orders for blood

and blood products are received and reviewed in

that lab. Most blood centers supply blood in volume to hospitals and are not aware of individual

clinical practices. Thus, another method is for

blood centers to have more control over the use

of their products.

A third method is to monitor use through hospital transfusion committees and pharmacy committees (for plasma derivatives), but such committees have been largely regarded as ineffective.

Indirect Effects on Improved Use. —The threat

of AIDS has made patients and their physicians

more cautious in their use of blood products, and

perhaps this effect will outlive the current threat.

A more sustained limiting factor, however, is the

widely accepted need to curb health care costs and

the implementation of the prospective payment

diagnosis-related grouping system for Medicare

that was recently enacted. The prospective payment method is likely to have the effect of revitalizing hospital transfusion and pharmacy committees’ monitoring of physicians’ use of blood

products in attempts to stay within the limits of

payments on a DRG basis.

Coordination of Blood Resources

Regionalization is not acknowledged by all to

be the best approach to managing blood supplies,

and a recurring question is the benefit gained from

participation in the American Blood Commission’s

regionalization recognition program. Another recurring debate centers on the issue of centralized

blood services v. hospital-based services, or some

combination of the two. On the whole, within any

region of the country, a patient who needs blood

will receive it, but there still remain the questions

of efficiency and cost. There are many groups

operating within each region. Should the plurality

of the present system be left as is, because it produces acceptable products at a sufficient level, or

is there a better organizational framework for provision of blood at lower cost?

The need for resource sharing, on the other

hand, is not seriously debated. The need for a

single resource sharing system has been the issue,

given the existence of two parallel, though largely

successful systems, run by the American Association of Blood Banks and the American Red Cross.

Without a single national sharing system, regions

with blood shortages are able to meet their needs.

Individual blood centers contract with other blood

centers outside of the formal mechanisms of the

AABB or ARC, as well as within them. In some

regions, there are even local clearinghouses which

serve functions similar to the AABB.

Other issues concerning coordination of blood

resources revolve around the need for a blood
24 ● Blood Policy and Technology

credit system, and the need for the American

Blood Commission or some similar organization.

Points to Consider

Regionalization. —As discussed previously under

cost containment, there are some indications that

hospitals are shopping around for blood products

on the basis of price, going outside their usual suppliers and even using the AABB Clearinghouse.

Some blood bankers are concerned enough that

they have suggested that the service (processing)

fee for blood from blood banks be treated as a

cost pass-through. However, the observation was

made that it is hard to see how blood centers could

explain to their donors why they should greatly

increase their sales to hospitals outside their normal distribution channels, and why therefore donations should also greatly increase. Thus, sales

of excess capacity could be justified, but increasing capacity in the face of existing surpluses would

be hard to explain to the blood center’s donors,

assuming that blood center donors (or community representatives) are kept informed of the disposition of the blood they donate.

Sharing and the Blood Credit System.—One interesting aspect of AABB’s Clearinghouse is that

the blood credit/replacement system is alive and

well, at least among blood banks, and to a lesser

extent, for individuals. In addition to coordinating the movement of blood and blood components, the Clearinghouse transfers credits between

blood banks and between regions where such programs exist. In 1983, 47 percent of the transactions

coordinated by the Clearinghouse were for actual

shipments of blood, including blood shipped for

replacement. The remaining transactions consisted

of issuing and/or transferring blood credits (25

percent) and payment of nonreplacement fees (28

percent). Individuals giving blood in one region

may receive credit for their donation in another

area of the country, thereby canceling nonreplacement fees for themselves or in the name of another

patient. The American Red Cross may not want

to be involved in a single resource sharing system because it would mean participating in the

AABB’s system, which, although only partially,

involves a credit system. The American Red Cross

withdrew from the AABB Clearinghouse in 1976

in an attempt to put more fully into practice its

philosophy of “community responsibility.”

Cost-consciousness on the part of corporations,

many of whom are beginning to self-insure for

health care because of rising costs over the past

decade, and the costs that they incur for companysponsored blood drives which are usually conducted during business hours, may combine to

provide a continued stimulus for these corporations to maintain the blood credit system. Thus,

it is not unreasonable to ask whether or not costconsciousness may lead to increased demand for

a blood credit system or for discounts on blood

costs, such as on processing fees. Over the past

10 years, the use of blood credits has declined,

but an increase in their use is obviously not

viewed negatively by all. Payment of the nonreplacement fee goes to the blood bank, not to any

donor, and would be a welcome source of income.

Donors only benefit when they or their immediate families are treated in a hospital which is part

of a credit system, usually within a year of the

donation.

Discounts on processing fees, instead of maintenance/revival of a nonreplacement fee, would

benefit transfusion recipients directly, if only

modestly. However, there is a wide array of

health insurance plans, and they treat blood costs

in a variety of ways. Patients would directly benefit only if such costs were part of their deductible or coinsurance requirements. Moreover, administration of such a discount system could be

extremely complex. The blood credit system can

result in lack of coordination for individual patients who give blood at a center where no credits

are given, yet who receive transfusions at hospitals where replacement fees are charged. It may

be necessary for the blood banking community

to take a stand on whether blood credits should

increase again, or conflict between the representative organizations may be renewed,

American Blood Commission. —The impact of

the American Blood Commission on coordination

of blood resources is difficult to evaluate. ABC

was unable, for example, to get the blood collecting organizations to take a unified stand on the
Ch. I—Introduction and Summary ● 2 5

blood credit system, or to finalize a single resource

sharing agreement. Similarly, its attempt at establishing a National Blood Data Center met with

mixed reviews. However, many credit it with reducing the conflict between the AABB and ARC

which 10 years ago threatened to lead to Federal

takeover of blood collection and distribution.

ABC today receives no Federal funds, and is dependent on member fees and private donations.

Both membership and private donations have

recently declined, leaving ABC facing an annual

deficit for the first time since its inception. It is

not clear what could be done to stabilize ABC,

but many believe its demise would mean the attenuation of constructive dialog between the

blood collecting organizations.

Voluntary v. Commercial

A continuing issue in the use of blood-derived

products is that of voluntary v. commercial

sources. This was a critical issue in the whole

blood sector a decade ago, with the result that

commercial whole blood collections have been effectively eliminated. Currently, the distinction between voluntary and paid whole blood donations

has been maintained through the labeling of blood

components as being derived from a “paid donor”

or “voluntary donor. ” This labeling is applicable

to whole blood, red cells, platelets, single donor

plasma, and cryoprecipitate, but does not apply

to source plasma or plasma derivatives. Donor

and laboratory screening tests have been applied

over the last decade, with the result that there are

no substantial differences in the safety of plasma

derivatives whether they are derived from voluntary or commercial sources. One reason is the necessary pooling of large amounts of plasma from

individual donors for the efficient processing of

plasma into plasma derivatives.

But the availability of products that are derived

from human tissues may also be influenced by criteria other than whether or not the market has

resulted in a safe, readily available product. Canada, for example, in 1980, amended its national

policy of a voluntary blood supply by extending

its nonprofit policy to fractionation products.

Currently, the only major import is Factor VIII,

at the rate of 20 million to 22 million activity units

per year. Other products imported in relatively

small amounts are specific immunoglobulins to

varicella zoster, hepatitis B, tetanus and rabies,

and the activated Factor IX Complex. Canadian

Red Cross (CRC) meets all requirements for blood

and blood components, and CRC plasma sources

supply all albumin, normal Factor IX Complex,

pooled immune serum globulins, and about 20

million activity units of Factor VIII. Canada also

has developed a collection system oriented toward

maximum preservation of plasma coagulation

proteins so that 95 percent of its whole blood collections can be processed and the plasma frozen

within 12 hours (147).

The Canadian experience shows that a voluntary system can meet nearly all blood needs, but

other factors make it unlikely that a policy will

be pursued in the United States to make the voluntary sector the exclusive or even dominant collector of plasma as well as whole blood.

Points to Consider

Can the Voluntary Sector Provide All Blood

Products?—It has been estimated that voluntary

whole blood collections would have to triple to

meet U.S. production of plasma derivatives (165).

U.S. plasma sources, however, also supply a large

part of the world market, and not as much plasma

would be needed to supply the U.S. market alone.

But sales abroad have been claimed to help to

lower prices in the United States, whatever one’s

position is on the morality of this situation.

Whether the voluntary sector would want the

responsibility of serving the United States and part

of the world markets then becomes the question.

Aside from the problems of establishing and maintaining an adequate donor base, costs for starting

up or retooling plasma fractionation plants are

substantial.

New technologies make the future prospects of

the plasma derivatives industry sufficiently doubtful that no planned movement toward a voluntary system can be expected. By the end of the

century, there is a real chance that plasma as a

source of current biological proteins will be

replaced by recombinant DNA and monoclinal

antibody technologies. For the first time, there are

38-647 0 - 85 - 3
26 ● Blood policy and Technology

real prospects that the longstanding controversy Blood centers themselves do not see the plasma

over commercial plasma donors may be solved— sector as their future, but are instead looking

not through implementation of a deliberate, con- toward organ and tissue banking and their related

tested public policy, but through advances in tech- technologies, such as tissue typing, as their growth

nology which could make the voluntary v. com- areas.

mercial policy debate moot.

CONCLUSION

The past decade has been a contentious one for

the blood resources community, but the results

have been generally gratifying, and the blood

community’s internal conflicts have generally been

out of the public’s eye— perhaps indicating public satisfaction with and commitment to the informal system even while internal battles continued.

The “National Blood Policy” which has guided

development of our blood services complex over

the past decade was not codified in law but was

an expression of commitment, backed by specific

activities that used the Policy as a general guiding

principle. The establishment of a Blood Program

in the National Heart, Lung, and Blood Institute,

represented by the NHLBI’s Division of Blood Diseases and Resources, and the strengthening of

safety and efficacy standards through establishment of a blood products division in the Office

of Biologics Research and Review (previously the

Bureau of Biologics) provided the primary instruments through which Federal policy could be

formulated, implemented, and maintained. In the

initial years of the NBP, there was a direct fiscal

relationship between the Federal and private sectors through major support of the private sector

body, the American Blood Commission, which

was established in order to provide for continued,

decentralized management of blood resources.

Federal interest at the central policy level within

the Department of Health and Human Services

slowly faded away, leaving the Blood Division

at NHLBI and the Office of Biologics Research and

Review as the primary Federal participants in continuing with the objectives of the National Blood

Policy, and improving the biomedical base of

blood resources and the safety and effectiveness

of blood products.

OTA concludes from this broad review of

blood policy and technology that the policies implemented over the past decade have been successful in assuring a safe and available blood supply,

This has occurred despite continuing internal conflicts; e.g., whether or not to maintain a credit

system, other differences between the major organizations involved in blood collection, and commercial v. nonprofit operations. Conflicts of these

types seem inevitable in the pluralistic system

which evolved, should not come as a surprise, and

should not be the basis for judging whether or not

the policies of the past decade have been successful.

The current situation presents new challenges,

AIDS has shaken the public’s confidence in blood

supplies far beyond its actual risk to blood recipients, yet no widespread shortages have resulted,

and both donors and blood collection organizations have generally responded to the challenge.

It remains to be seen if AIDS will have a long-lasting effect on blood resources. In addition, blood

suppliers and users face additional pressures because of continually escalating health care costs

and recent economic policies instituted to deal

with them. And on top of all of this, truly new

technologies have emerged which have a high

probability of replacing some blood products by

the end of the 1980s, and if not yet making humanderived blood products obsolete, represent the

first real steps toward that event.

Given the overall success of the past decade and

the transitional nature of present circumstances,

the prudent course would be to continue with the

cooperative arrangements that have been established over the past years and to monitor key developments to anticipate when particular adjust-
Ch. I—Introduction and Summary ● 2 7

ments need to be made. In the previous section,

OTA has identified what it considers as the key

issues and enumerated some of the points that

need to be considered in determining future actions in these issue areas. The following chapters

provide background information and more detailed discussions of these and related issues.

Some of these issues involve actions in which

the Federal Government is expected to take the

leading role, such as in assurances of safety, although the private sector is also deeply involved

and needs and wants to participate in such actions. Other areas, such as use of the blood credit

or nonreplacement fee, involve differences in philosophy about how much responsibility individuals should have in providing blood resources and

what rewards they should have for doing so.

Thus, Federal participation involves resolving or

reconciling these differences among the different

collection organizations and their clientele, should

any decision be made to modify the course of developments in the blood field.

Still other areas involve consequences of Federal policies directed at even larger problems—

the continually escalating costs of health care and

recent legislation to “cap” these costs through prospective payment mechanisms—whose purpose

was to impose exactly the kinds of cost-saving

behavior which hospitals apparently are beginning to exhibit, and over which the blood community is so concerned. The architects of these

broader policy changes in health care financing

are aware of the negative consequences in particular circumstances—e. g., their effects on research and training programs and capital acquisitions. Such consequences also need to be explored

in the blood resources area, but simply shielding

blood products from these cost containment efforts is no answer. Federal action might also be

considered in the areas of support for biomedical research and studies to determine appropriate use of blood products, and improved coverage for hemophiliacs.

A decade ago, developing a data system for

blood resources was a major objective of the National Blood Policy. The efforts subsequently

undertaken under the sponsorship of the American Blood Commission and financed primarily by

the Blood Resources Program at NHLBI did not

meet expectations. In retrospect, one problem was

the general nature of the data and the inability

to find sponsors to continue the data collection.

In other words, the data may have been informative and useful in understanding the general contours of the blood services complex, but they were

not useful to organizations interested in information that could help them in their operations.

Thus, there is general agreement that future data

collections should be much more targeted.

The problem with collecting data which would

be useful to the operations of organizations is the

issue of who should be responsible for collecting

it, and the relevance of those types of data for

public policy illumination and formulation. Another problem is that, while specialized data sets

are the most useful, they also tend to be fragmented, and some type of coordination needs to

be arranged. For example, both the American Red

Cross and members of the American Association

of Blood Banks are involved in data collection on

a daily basis, and much of this data would be useful for public policy purposes. In fact, much of

this information is used for determining policy

within those organizations, and the organizations

are willing to share a large amount of this information, although as health care provision becomes more competitive as a consequence of cost

containment efforts, much of this information is

coming to be regarded as proprietary. Other information sources can be found in the data systems that are being organized to monitor the effects of the Medicare prospective payment system,

which have the potential to provide more specific

information on use and costs than have been possible previously.

Monitoring functions which include coordination of data sources require a capacity for sustained activities, and the problem is in identifying who can and should assume this function. The

Federal Government’s primary data collection organization in the health field, the National Center for Health Statistics, can collect comprehensive data on specific issues, but the kinds of data

needed to help formulate policy in the issue areas

identified above are of a different type. The National Center for Health Services Research can
28 ● Blood Policy and Technology

also conduct policy-relevant research, but it too,

lacks the capacity for sustained and coordinated

activities. The Office of the Assistant Secretary

for- Health is the logical choice for such data coordination and policy formulation, but it is preoccupied with immediate issues and functions more

as the receiver rather than as the gatherer of information. FDA and NIH, which are the primary

Federal agencies involved in blood resources on

a sustained basis, could be given that responsibility, but their primary responsibilities are in

circumscribed areas of the blood services area—

assuring safety and efficacy and resource building—and the net effect would be what has happened in the past; i.e., they can be required to

fund such activities, but would not be able to

assume the primary Federal role in determining

overall blood resources policy.

The private sector could conduct these activities, and in fact would argue that they are already

doing much of it. Federal funds could again be

provided, as it was for the data collection efforts

and early general support of the American Blood

Commission. Two problems would recur, however. First, is the question of whether any single

private sector organization would be recognized

by the diverse interests in the blood services complex as a legitimate policymaking body, instead

of serving primarily as a policy debating forum.

Second is the question of how sustainable Government funding could be.

If there are no obvious answers as to who could

assume both a monitoring and policy formulation

role, or on the even more limited role of monitoring developments in blood resources, perhaps a

different approach should be taken. Just as the

emphasis on data needs has shifted from the general to the specific, a more practical and useful

approach might be to have periodic appraisals

that monitor specific issues to see: I) what happens in these issue areas over time, 2) whether the

issues identified initially continue as the primary

ones, and 3) what new issues arise. Thus, one approach is to formulate a set of questions and use

them as guidelines for narrowing the issues, to see

how these questions are resolved, and how public policy can contribute to their resolution. The

issues and points to consider that have been

enumerated above represent one attempt to delineate those questions, based on the broad overview represented by this report.

Certain policies could be extracted from this approach. For example, oversight hearings could be

structured around the identified issues, with both

private organizations and Federal agencies contributing information to further clarify the issues

and to suggest approaches to their resolution.

Periodic hearings or other methods of followup

could then take place to follow the course of

events. For example, the National Academy of

Sciences could be requested to review these issues

periodically, or the Federal Department of Health

and Human Services could be required to reassess

them in reports to Congress as is often required

for other policy issues. Specific issues could be

examined in detail by any of the congressional

support agencies. A restatement of the National

Blood Policy could also be constructed to provide

general guidance—as its original formulation a

decade ago has done. Within any of these approaches, specific actions could be taken as the

need arises, either by legislative action, by administrative changes in the operations of Federal agencies, or by voluntary actions by the private sector.

In conclusion, in the decade since the National

Blood Policy was announced, blood resources

have become safer and more available, despite

continuing differences among participants in the

blood services complex. This should not be surprising, given the decentralized, pluralistic approach

that was continued under the NBP. Today, AIDS,

cost-consciousness, and radically new technologies have significantly affected the blood services complex and portend changes that will most

likely be even more significant. These changes are

occurring rapidly; over the short time that this

report was prepared, the cause of AIDS has been

apparently identified and tests for its detection are

under development, and the entire gene for Factor VIII has been cloned, adding to the already

available gene for albumin.

The transition that the blood services complex

is currently undergoing, as represented by these

events, calls for a policy of focused monitoring

and adjustments to particular circumstances as the
Overview
Contents

Page

Part 1: History of Federal Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Part 2: Blood and Blood products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Part3: The Blood Donor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Risk for Donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Part4: Federal Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Payment for Blood Products and Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

LIST OF TABLES

Table No. Page

2. Ten Policies and Six Critical Issues in Support of National Blood Policy

Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

3. Blood Components and Plasma Derivatives in Therapeutic Use. . . . . . . . . . . . . 37

4. FDA Statutory Authority to Regulate Blood Products and Blood Banking

Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5. Blood Products Recalls, June 1975 to November 1983 . . . . . . . . . . . . . . . . . . . . . 46

6. Significant Deviations Leading to Plasma Center Suspensions,

Oct.1, 1979 to Aug.31, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

7. Types of Numbers of Blood Processing Errors, 1981-82 . . . . . . . . . . . . . . . . . . . . 47

8. New Blood Products and Procedures Approved by FDA in the Past

Two Years (approx. 1982-83) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

9. Blood Products and Related Technologies in the Approval Process as of

Early 1984 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2

Overview

PART 1: HISTORY OF FEDERAL INTEREST

Federal interest in assuring an adequate and safe

blood supply has a long history. President Truman

called blood a “critical national resource vital to

the country’s well-being and security. ” The Federal Government regulates blood banking (as do

State governments), monitors the safety and efficacy of blood products, and promotes research

on blood diseases and resources.

In the 1960s, scientists recognized the correlation between high rates of posttransfusion hepatitis and blood obtained from paid donors. Cardiac surgery and other advances in medical care

increased the use of whole blood for transfusion,

and with this increased use came increased concern for the safety of blood transfusions. Separation of whole blood into components and the use

of platelets and plasma derivatives became increasingly widespread. One result of this heightened

interest in blood was the establishment of a National Blood Resources Program at the National

Heart and Lung Institute in 1967, In 1972, the program was reconstituted as the Division of Blood

Diseases and Resources in the expanded National

Heart, Lung, and Blood Institute (NHLBI), where

it still operates.

In the early 1970s, there was a surge of public

interest that prompted Federal policymakers in

both the executive and legislative branches to review the Nation’s blood program. This round of

debate was sparked largely by the publication of

The Gift Relationship by Professor Richard Titmuss, a British scholar and student of social welfare policy. Professor Titmuss excoriated the commercial market for whole blood in the United

States on both safety and ethical grounds. His

book received much attention in the news media

and inspired a television documentary which

highlighted the hepatitis problem and featured

pint after pint of blood being poured down the

drain to dramatize the wastage problem.

During this time period, over 40 bills designed

to regulate blood resources were introduced in the

92d Congress, including H.R. 11828, introduced

by Representative Victor V. Veysey, which proposed that a National Blood Bank Program be located in the Department of Health, Education, and

Welfare (DHEW, the predecessor to the current

Department of Health and Human Services, or

DHHS) (485). Simultaneously, the increasing input of private sector health organizations prompted

the executive branch to take a stand on the blood

issue.

President Nixon’s annual health message to the

Congress in March 1972 described blood as a

“unique national resource, ” and he subsequently

charged a DHEW task force with the assignment

of developing a safe, fast, and efficient nationwide blood collection and distribution system.

In May 1972, monitoring of blood resources

was transferred from the National Institutes of

Health (NIH) to the Food and Drug Administration (FDA). Since that time, FDA’s Bureau of

Biologics (currently renamed the Office of Biologics Research and Review) has been the principal regulator (States also play a regulatory role)

of blood collection, processing, testing, and marketing. As a result of this change, all blood banking in the country, not just interstate blood trade,

came under direct Federal regulation.

Following extended examination and debate, including the DHEW Task Force Report which

found that: 1) the supply of blood was sometimes

inadequate, 2) the quality of blood was uneven

and reliance on commercial blood was contributing to a high rate of hepatitis, 3) gross inefficiencies existed, and 4) the cost of blood therapy

was a burden to many people, a National Blood

Policy (NBP) was enunciated by the Federal Government in 1973. There were four goals underlying the National Blood Policy (180):

33
34 ● Blood Policy and Technology

1.

2.

3.

4.

Supply. A supply of blood and blood products adequate to meet all of the treatment

and diagnostic needs of the population of this

country.

Quality. Attainment of the highest standard

of blood transfusion therapy through full

application of currently available scientific

knowledge, as well as through advancement

of the scientific base.

Accessibility. Access to the national supply

of blood and blood products by everyone in

need, regardless of economic status.

Efficiency. Efficient collection, processing,

storage, and utilization of the national supply of blood and blood products.

The National Blood Policy was broken down

into 10 specific policies, along with six issues

which were to be examined critically. Prominent

among the policies were adoption of an all-voluntary blood collection system, coordination of

charges and costs for blood services, and regionalization of blood collection and distribution.

Critical examinations of the nonreplacement fee,

the plasmapheresis industry, and standards of care

for hemophiliacs and other special groups were

also recommended (table 2).

A number of Federal and private sector initiatives were undertaken in order to begin implementing the National Blood Policy. In 1974,

DHEW accepted the private sector plan to establish an American Blood Commission (ABC),

which was to implement “the lion’s share” of the

National Blood Policy (180). The National Heart,

Lung, and Blood Institute provided partial funding for ABC activities until recently, when the existing contract expired (ABC may still apply to

NIH for funding of specific projects, but on a competitive basis). ABC now depends on membership

fees and donations, and it has been experiencing

difficulty in retaining some of its organizational

members.

There were no direct government actions to ban

the sale of whole blood and plasma, although

steps were taken to regulate the safety of plasma

products and discourage the use of commercial

whole blood. FDA became increasingly involved

in regulating the plasma industry, building on its

initial involvement which had begun during the

late 1960s (506). In 1973, FDA’s Bureau of Biologics published additional standards for source

plasma and required all plasmapheresis operating facilities to file an application for licensure of

both their establishments and products; a formal

compliance program began in mid-1977. FDA

oversight over the plasmapheresis industry was

relaxed somewhat in 1977, when responsibility for

annual inspections was transferred from the Bureau of Biologics to FDA field investigators and

supervisors (506).

No Federal efforts were made to ban commercial plasma collections. Regulators realized that

the demand for plasma supplies could not be met

by the existing voluntary sector. Since the collection of whole blood and preparation of blood

components were largely in the province of the

voluntary sector, an FDA rule was implemented

in 1977 to identify the source of whole blood and

its components (red cells, platelets, single-donor

plasma, cryoprecipitate). This action was taken

on the basis that available data indicated a greater

risk of transmission of hepatitis with the use of

blood and blood components from paid donors.

Under this regulation (21 CFR sec. 606.120(b)(2)),

whole blood and its components are labeled as

collected from a “paid donor” or “volunteer

donor.” The regulations state that a paid donor

is a person who receives monetary payment for

a blood donation, while a volunteer donor is a

person who does not receive such payment. Other

benefits that are not readily converted to cash,

such as time off from work and cancellation of

nonreplacement fees, are not considered as monetary payment. These labeling requirements do not

apply to source plasma or plasma derivatives,

since plasma derivatives produced from plasma

obtained from paid or volunteer donors are considered to be equally at risk for transmission of

infectious agents.

Steps were also taken to assure that hemophiliacs were afforded access to care. The Public

Health Service Act of 1975 (Public Law 94-63):

1) established Federal funding for comprehensive

hemophilia diagnostic and treatment centers, and

2) authorized funds for projects to develop and

expand blood derivative operations in the event

the Secretary of DHEW found that there was an
Ch. 2—Overview ● 3 5

Table 2.—Ten Policies and Six Critical Issues in Support of National Blood Policy Goals

Ten policies:

1. Efforts toward an all-volunteer system for blood and blood

components were encouraged, fostered, and supported.

2. The establishment of a system for the collection and analysis of all relevant information concerning plasmapheresis, plasma fractionation, and the flow of plasma and

plasma products within the United States and other countries was to be encouraged, fostered, and supported. This

information was believed necessary to determine the sufficiency of domestic sources of plasma fractions; develop

future positions on the relationships between plasmapheresis and plasma fractionation and whole blood banking; and develop a degree of interdependence between

the United States and other countries with respect to

plasma and plasma products.

3. Continuing data and information collection and processing systems to describe all elements and functions in the

blood banking sphere on a continuing basis. The purpose

of this policy was to acquire fundamental information on

the nature and transmission of diseases by blood and

blood products and the occurrence of transfusion mishaps, as well as to design and create changes which

would enhance the effectiveness of the blood banking

system.

4. Resource sharing and areawide cooperation in the collection, processing, distribution, and utilization of blood.

5. Ample donations were to be assured through encouraging: a) improved accounting and reporting systems to

identify the relationship between costs and charges; and

b) public and health professional education.

6. Educational and other programs to assure appropriate

use.

7. Adherence to the highest attainable standards for blood

products, including plasma derivatives, through use of or

extension of Federal regulatory authorities were to be

employed.

8. Research, including systems analysis and other management approaches to extend shelf life, and to identify and

control diseases transmittable by blood.

9. Insurance benefits for the service aspects of blood components and both the acquisition and service aspects of

plasma derivatives. The acquisition costs of plasma derivatives were to be covered in recognition that commercial

acquisition may still be necessary.

10. The Secretary of Health, Education, and Welfare was to

be responsible for implementing this policy.

Sixa critical Issues to be examined:

1. The adequacy of any proposed implementation action in

meeting the extraordinary demands for blood that may

arise in national and regional emergencies.

2. The appropriateness of the replacement fee in an allvoluntary system.

3. Systems approaches to the integration of various functions and segments of the blood banking industry.

4. Regionalization of blood services management.

5. Appropriate inducements and authorities, whether existing or to be sought, necessary to exclude commercial

acquisition of whole blood or blood components.

6. Special problems of accessibility for hemophiliacs and

others with continuing or extraordinary needs for blood

or blood products.

SOURCE” Federal Register, Mar 8, 1974.

insufficient supply of blood derivatives available

to meet the treatment needs of hemophiliacs. A

contractor’s report to DHEW (554) projected that

sources of supplies of antihemophilic factor and

prothrombin complex were adequate to meet

hemophiliacs’ needs through and beyond the authorization period, so the treatment centers were

established but projects to develop and expand

blood derivative operations were not funded.

The nonreplacement fee became an issue when

the American Red Cross, in order to make its

practices conform to its philosophy of community responsibility, withdrew from the AABB National Clearinghouse system, which used blood

credits and nonreplacement fees. The lack of cooperation between the three major blood supply

organizations (American Red Cross, American

Association of Blood Banks [AABB], and the

Council of Community Blood Centers [CCBC])

led to concerns over the possibility of blood shortages in some regions, and to the introduction of

two bills in Congress (S. 1610, introduced by Senator Schweiker in 1979; and S. 140, introduced

by Senator Hatch in 1981). The Schweiker and

Hatch bills would have eliminated the nonreplacement fee and provided donors with a discount on

the charge for blood when they were patients.

The nonreplacement fee was also the focus of

concern that Medicare was overpaying for blood

(546). Medicare guidelines require that patients

pay a three-unit blood deductible by either replacing or paying for the first three units of blood

transfused. A General Accounting Office (GAO) investigation found that billing and replacement

practices of blood banks and hospitals had caused

substantial Medicare overpayments for blood and
-.

36 ● Blood Policy and Technology

blood products, that blood banks had prevented

the use of blood replacement credits to reduce

blood fees whenever Medicare would pay the fees,

and that hospitals charged nonreplacement fees

to Medicare patients for blood supplied by community blood banks that charged only processing fees.

In addition to improved monitoring practices,

one of GAO’s recommendations was that the

Health Care Financing Administration (HCFA)

undertake a study of the relationship between the

costs and charges for blood. Such a study has not

been conducted by HCFA. (In addition to a blood

replacement fee, there are fees for blood processing, typing and crosshatching, and for transfusion services, which are charged whether or not

a blood replacement fee is imposed. In 1980, for

example, average total charges for transfusing a

unit of red cells was $88.17, including an average replacement fee, when charged, of $27.98

(576).)

Other Federal interests in the issues surrounding blood services delivery have come in the form

of support for a variety of basic and applied research, principally from the Division of Blood

Diseases and Resources of the National Heart,

Lung, and Blood Institute (556). Most recently,

the same division has begun efforts to improve

the appropriate use of blood products (e.g., the

“Transfusion Medicine Academic Awards”). Current activities of the Federal Government with respect to blood services, policy and technology are

set forth in part 4 of this chapter.

PART 2: BLOOD AND BLOOD PRODUCTS

Blood is a mixture of specialized cells suspended

in plasma, which itself is a complex liquid containing proteins, nutrients, salts, and hormones.

Blood has many functions, including transport of

oxygen and nutrients to body tissues, removal of

carbon dioxide and other wastes, and transfer of

hormonal messages between organs. It also plays

a major role in the body’s defenses, inhibiting invasion and spread of organisms by transporting

antibodies and infection-fighting cells to the sites

of infection. Albumin, the principal protein found

in plasma, helps maintain blood volume by maintaining an osmotic gradient (oncotic pressure) between the vascular system and surrounding tissue,

and serves as the carrier molecule for fatty acids

and other small molecules (467). A complex clotting system to prevent blood loss involves both

cellular (i. e., platelets) and protein elements of

blood.

In blood banking terminology, “components”

refers to products separated from whole blood and

consist of the various types of blood cells, plasma,

and special preparations of plasma. Components

are usually separated from single whole blood

donations, using a sterile system of plastic bags

attached to the collection bag.

“Derivatives” refers to products derived from

the chemical fractionation of plasma to concentrate selected blood proteins. Plasma from many

donors is pooled prior to chemical fractionation

in order to yield sufficient amounts of the final

concentrated material for cost-effective production.

Blood components and plasma derivatives and

their general indications for use in medical therapy are listed in table 3.

Hazards associated with therapeutic use derive

primarily from immunologic incompatibility between donor and recipient and from transmissible diseases. Incorrectly typed and crosshatched

blood or mislabeled blood can lead to reactions

ranging from transient fever and chills to death.

More subtle incompatibilities that may not be uncovered in routine typing and crosshatching may

lead to sensitization of the recipient and hypersensitivity reactions from subsequent transfusions.

Infections of various types can occur through

collection of blood from donors whose blood contains the infectious agent or from contaminants

introduced in the collection, processing, or transfusing procedures. Syphilis was one of the first

bacterial diseases known to be transmitted through
Ch. 2—Overview • 37

Table 3.—Blood Components and Plasma Derivatives

in Therapeutic Use

Components and their therapeutic use:

Whole blood: Replacement of large volume blood loss.

Packed red cells: Anemia; provision of oxygen-carving

capacity.

Leukocyte-poor red cells: As for packed red cells; used in patients with reactions to leukocytes.

Frozen red cells: As for packed red cells; used in patients

with more severe reactions to leukocytes; provision of rare

red cells.

Platelets: Platelet deficiency; platelet function abnormalities.

Fresh-frozen plasma: Multiple coagulation factor deficiencies

(indications under review).

Single-donor plasma: Uncommon use.

Cryoprecipitate: Provision of Factor Vlll, von Willebrand’s factor, fibronectin, fibrinogen.

Leukocytes; Bacterial infections in immunocompromised patients (rarely used).

Derivative:

Albumin: Plasma volume expansion.

Immune serum globulin: Infection prevention (immunodeficiency states, travelers).

Hyperimmune gamma globulin (e.g., Varicella Zoster immune

globulin, Hepatitis B immune globulin): Prevention of

specific infections,

Factor Vlll (antihemophilic factor): Factor Vlll replacement

in hemophilia A.

Factor IX Complex: Factor IX replacement in hemophilia B.

Anti-inhibitor Coagulant Complex: Hemophilia A patients with

high levels of Factor Vlll inhibitor.

SOURCE: J. Pindyck, S. Gaynor, R. Hirsch, et al., “Prevention of Infection

Transmission by Transfusable Blood, Blood Components or Plasma

Derivatives.” 19B4.

blood, but in general, bacterial contamination is

not a problem in modern blood banking. Protozoa] diseases such as malaria and sleeping sickness can also be transmitted through blood, but

most of these diseases are not endemic to the

United States, and a history of travel to endemic

areas or exposure to the disease that is uncovered

during the medical screening of blood donors has

effectively kept these diseases out of the blood

supply.

Viruses are the major class of infectious agents

that are transmitted through blood. Of these,

hepatitis B and non-A, non-B hepatitis are the

most prevalent. Surveys of blood donors show

a frequency of hepatitis B of 5 to 7 percent. In

the 1970s, development of increasingly more sensitive laboratory tests for the detection of hepatitis

B that are now applied to every blood donation

resulted in a dramatic reduction of posttransfusion

hepatitis B cases. However, a new form of hepatitis (non-A, non-B) appeared, which, although

no agent(s) has been isolated, is presumed to be

a virus. * Currently, 5 to 18 percent of Americans

who receive five or more units of transfused blood

develop non-A, non-B hepatitis (271b). About 90

percent of all post-transfusion cases of hepatitis

are non-A, non-B, and about 10 percent are due

to hepatitis B (558).

Other viruses are relatively common in the general population and normally are of no consequence in transfusions. One exception is cytomegalovirus, which can cause infections in premature

infants and immunosuppressed recipients, such as

kidney or bone marrow transplant recipients.

Other viruses are fairly common but not known

to lead to transfusion-related disease (e.g., EpsteinBarr virus, the agent for infectious mononucleosis), while other, recently discovered rare viruses

could be theoretically transmitted through transfusions. AIDS, which is now accepted as being

transmittable through blood, is now considered

to be of viral etiology (i.e., the retrovirus-HTLV111) (256).

All blood components and some plasma derivatives are capable of transmitting viral infections.

Components are stored either at room temperature (platelets), in cold storage (whole blood, red

cells), or frozen (red cells, plasma), and none of

these processes inactivate viruses. Of the plasma

derivatives, only albumin (and a related product,

plasma protein fraction) and immune serum globulin (ISG) appear to be free of active viruses.

Albumin is heated for 10 hours at 60° C in the

presence of stabilizers to help maintain the structure of albumin, and this pasteurization inactivates viruses. Inactivation of viruses in immune

serum globulin appears to be due to two factors:

1) the cold ethanol fractionation method appears

to precipitate ISG in a fraction separate from the

fraction containing viruses (61); and 2) ISG contains many antibodies against many viruses,

which may diminish or destroy their infectivity

(217).

Until recently, virus inactivation for the plasmaderived clotting factors had not been available be-

*A retrovirus has now been implicated as the cause of non-A,

non-B hepatitis (493).
38 . Blood Policy and Technology

cause heat treatment caused loss of function. Heattreated clotting Factor VIII, however, has recently

been licensed by the FDA. It is not known how

much Factor VIII activity is lost in the heat treatment process, and, since a balance has to be maintained between loss of function and inactivating

viruses, the conditions under which these products are heated may not inactivate all viruses.

(Current research suggests that the presumed

AIDS agent, HTLV-III, is inactivated by this

process.)

PART 3: THE BLOOD DONOR

Approximately 8 million people, representing

about 3.5 percent of the population or about 10

percent of those eligible to give, donate blood in

a year. There are no nationwide sources of data

which profile blood donors. Nevertheless, many

individual blood banks and donor recruitment

centers have conducted studies to find out who

constitutes their pool of donors, by characteristics such as age, sex, race, socioeconomic and occupational status, as well as by geographical location (e.g., urban, suburban, and rural). From

these studies has emerged a picture of the “typical”

blood donor: a white, middle-class male family

member who gives at his place of work. The

prevalence of male donors is a worldwide phenomenon, and it has been estimated that between 60

and 70 percent of all those donating blood in the

United States are male (291).

Mobile blood collections have traditionally

taken place in corporate and institutional settings,

where relatively well-ducated, middle-class white

males are most likely to be found. This picture

may be changing. Women have entered the work

force in increasing numbers and hence are more

likely to be subject to recruitment and to have

convenient opportunities to donate.

Members of minority groups, and blacks in particular, may be harder to motivate (450), with

speculation that it may be due to mistrust of the

health care system in general, or existence of a

sociocultural gulf between donation officials and

potential minority donors. Blood bankers have

attempted to overcome some of these hurdles by

special recruitment tactics. These efforts include

Other methods of inactivating viruses include

heating the derivative in the dry state (529), using

detergents and organic solvents instead of heat

(447), or neutralizing viruses by the addition of

antibodies, a method which requires the use of

specific antibodies against each type of virus to

be inactivated (100). The Netherlands Red Cross

is reportedly producing derivatives containing

specific antibodies against hepatitis B virus (373).

involving leaders and spokespersons for minority groups in recruitment efforts and reaching out

to cohesive minority fraternal, social and civic

groups. Churches, which have long been a mainstay of recruitment drives, are particularly fertile

grounds for such efforts.

Lower socioeconomic status may also compromise the willingness to give, in view of the

finding that altruism is almost always at the top

of the list of reasons for donating. Donors invoke

altruistic reasons even when participating for the

purpose of blood credits/replacements or being

paid (49,71,409). Even scholars who have questioned the depth and the validity of altruism as

a motivating force have concluded that, because

it is a socially accepted motivation and one most

often verbalized, it should continue to form the

basis for appeals for donors (417,433).

There are certain physical limitations that are

applied to potential donors. In general, any

healthy person who weighs more than 110 pounds

and is between the ages of 17 and 66 can be a

blood donor. The upper age limits are imposed

by blood collection agencies and are subject to

some exceptions, while the lower age limits are

imposed by State law. Blood donors who weigh

less than 110 pounds are rejected because the

standard amount of whole blood collected (450

ml) amounts to too great a percentage of their

blood volume, a loss which could result in a serious hypotensive episode. Pregnant women are excluded from donating, as is anyone who has

undergone major surgery in the preceding 6

months.
Ch. 2—Overview ● 3 9

Many States have made statutory exceptions

to the age of majority (usually 18) by allowing

17 year olds to donate. This allows entry into high

school, which is not only a convenient donation

site, but also inculcates youngsters with an understanding of the need for blood donors. The cutoff for those aged 66 or older has attracted some

criticism. Critics argue that a more rational end

point would be based not on age alone, but rather

on health status, weight, and donation history.

By these measures, many older people can give

blood safely into their later 60s and 70s.

Physical limitations aside, most donations appear to be influenced by motivational and situational circumstances. Both donors and nondonors

are aware of the need for blood, and personal experiences with the need for blood is distributed

widely throughout the population (35). But many

who claim they intend to donate do not actually

follow through, and the “slippage” between those

who say they will donate and those who actually

do so maybe as high as 60 to 65 percent (192).

This general acknowledgment of the need for

blood and its contrast with those who actually

donate have led to criticisms of generalized appeals through the mass media to donate blood.

Much of the efforts of recruitment officials has

involved generalized announcements of the continued need for blood donors. These most commonly take the form of television or radio public

service announcements, often showing celebrities

in the act of giving blood or recipients whose lives

have been saved through transfusions. Such advertising campaigns, geared toward raising awareness of the need for blood, are ineffective in helping to overcome fears of donating, and suggestions

have been made that advertising dollars may be

better spent in allaying such fears.

More frequent and convenient donation opportunities, rather than knowledge of the need for

blood, are correlated with increased donation

rates (35). Observing others donating increases

the chances that a person will also donate. Social

and peer pressure can be an important force in

donor motivation, especially regarding first-time

donors, who often report to the donor site accompanied by friends (132,133). And the existence of

an identifiable patient in need heightens awareness and the feeling of an obligation to give, even

when the specific patient in need is identified

anonymously (e.g., “a young mother with children”) (489).

Most of the research on blood donors has

focused on the motivations and characteristics of

donors, not on factors involving the donation setting and the recruitment process. Research has

most often been undertaken in one location,

where a single donation ideology has motivated

recruiters. There have been few comparisons of

urban v. rural donors, fixed v. mobile sites, or

cross-cultural studies. Factors such as the length

of time it takes to donate and the donor’s perception of how he or she was treated by the staff and

peers may be better predictors of donor commitment than attitudes toward moral obligations, etc.

Little attention has been devoted to determining what forces convert a first-time donor into a

committed, repeat donor. Recruitment professionals play a key role in garnering first-time

donors and in converting them into repeat donors.

The personal convictions of the individual recruiter are important factors in motivating donors,

and donor recruiters are often active donors

themselves (236). Many large blood collection

centers have donor recruiters as full-time staff

members to organize local media efforts, to encourage and coordinate corporate and institutional drives, and to direct appeals to particular

individuals, such as former donors. The conversion of first-time donors into repeat donors is a

particularly important aspect, as the retention of

past donors may be considerably more efficient

than recruiting new donors (382).

Risks for Donors

The risks of whole blood donation are minor

and rarely result in serious complications. For virtually all blood donors the loss of 450 ml of blood

(up to 13 percent of total volume) is experienced

with no untoward effects. Potential risks include

local injuries such as bruises or reactions to antiseptics and dressings. The phlebotomy (needle

stick) can result in arterial puncture or air embolism. Infections also occur on occasion, but they

are usually infrequent and localized (577). The low

level of risk to blood donors is evidenced not only

by the medical literature and statistics kept by
40 . Blood Policy and Technology

blood donation centers, but also by the dearth of

activity in the courts. In contrast to the number

of lawsuits brought on behalf of recipients of contaminated blood products, there have been very

few court cases involving injuries to donors.

Vasovagal syncope (a transient reaction marked

by pallor, nausea, slow heartbeat, and a rapid fall

in arterial blood pressure which sometimes results

in fainting) is a risk for a small percentage of

donors. Although it is impossible to predict with

certainty which donors are at risk, certain factors,

such as age, weight, a history of fainting and inexperience in donating, may be predisposing.

Along with loss of blood volume from donating, other factors can influence the amount of

blood circulating to the brain. Vasovagal activity tends to pool blood in the skeletal muscles and

gravity tends to pool blood in the distal veins;

this is exacerbated if sitting erect. Eating and

drinking pools blood in the stomach and intestines. Vasovagal reactions can, on occasion, include a blocked airway or cardiac arrythmia.

Blood donor centers are advised to keep resuscitation equipment on hand. Donors are observed for

impending signs of fainting and are usually accompanied to a lounge for a brief period following donation. Obviously, part of the danger in

fainting is from resulting bruises, lacerations, or

other injuries. Yet, fainting following blood donation is uncommon; an acceptable level of such incidents is 0.3 percent, according to the Red Cross

(44).

Plasmapheresis donors undergo some of the

same risks as whole blood donors—for example,

those associated with phlebotomy (e.g., arterial

puncture or air embolism). Unlike conventional

blood donation, plasmapheresis involves the

removal of whole blood, separation by centrifuge

into its constituent parts and reinfusion of cellular

components into the donor. Thus, the plasmapheresis procedure entails the additional risk of

reinfusion of cells from another donor, which

could occasion a hemolytic reaction; Federal regulations specifically require that this risk be disclosed as part of the informed consent process (21

CFR pt. 640.61).

Labeling requirements have been adopted by

plasmapheresis centers to decrease the likelihood

of such an occurrence, and some centers use portable centrifuges by the donor’s chair, which

further reduces the chance of a mixup. New technologies being developed to speed up the plasmapheresis process and make it more efficient would

remove this risk, as these generally involve membrane or centrifugal separation of blood components in a self-contained system to which the

donor is attached continuously.

The greatest controversy regarding risk to plasmapheresis donors has involved limitations on the

volume and frequency of donation. The average

adult male of 175 lbs has a plasma volume of

3,OOO ml. Under Federal regulations donors in the

United States can give 1,000 ml of plasma per 48-

hour period up to twice a week. (Donors weighing

more than 175 lbs can give 1,200 ml per donation (21 CFR 640.65 (4-6). ) The regulations allow

plasmapheresis donors to give up to 50 or 60 liters

of plasma each year; this contrasts markedly with

limits set by other industrialized nations—generally 10 to 25 liters annually. Regulations require

that plasmapheresis donors undergo a serum protein electropheresis and a measurement of immunoglobulin every 4 months to determine whether

they are in normal range.

The effects of plasmapheresis on short- and

long-term levels of plasma proteins and other

blood components have been vigorously contested. Often the scientific debate has been overshadowed by social, ethical, and political questions concerning commercial plasmapheresis,

especially in developing countries. The relative

frequency with which U.S. regulations allow

plasmapheresis has been decried, especially by

European critics (347,348). One critic of U.S. policies regarding commercial plasmapheresis has

stated that, “It defies comprehension that the necessary quantities of plasma are not procured by

the simple expedient of increasing the number of

donors sufficiently to minimize the individual

risk” (346).

A group of experts convened by the World

Health Organization (WHO) and the League of

Red Cross Societies concluded that “no consistent clinical abnormalities have been detected during periods of up to 6 years in donors who have

undergone adequately controlled plasmapheresis”
Ch. 2—Ovetview Ž 41

(593). They concluded that plasmapheresis is generally safe when limited to 15 liters per year, and

called for retrospective and prospective studies because of “possible effects on lipid transports and

deposition, decreased resistance to infections

through frequent removal of immunoglobulins

and even changes in immune responses toward

oncogenic viruses cannot be ruled out . . . .

Disorders might arise out of too frequent

plasmapheresis, active immunization and frequent

restimulation” (595).

A number of studies have concluded that even

frequent plasmapheresis appears safe for both

short- and long-term donors who are otherwise

healthy and of good nutritional status (150,475).

Other studies of plasmapheresis donors over 3 to

4 years have shown small, but statistically insignificant decreases in albumin levels (206,244).

In the first 4 to 6 months there is a statistically

significant rise in the concentration of x and ß

globulins and a decrease in the concentration of

the immune globulins IgG, IgA and IgM. After

a few more months of continued plasmapheresis

IgG and IgA concentrations return to normal,

while IgM levels continue to be slightly depressed

but still within normal limits (206).

Many, including representatives of the plasmapheresis industry, have urged that further studies

be conducted “because there are questions about

frequency and all the answers are not in” (327).

PART 4: FEDERAL ACTIVITIES

Introduction

The Federal agencies with primary responsibilities in the blood resources area are the National

Institutes of Health (NIH) and the Food and Drug

Administration (FDA). NIH supports research and

development activities, and FDA is responsible

for regulating the efficacy and safety of blood

products and the technologies associated with

them. Other agencies such as the Centers for Disease Control (CDC) may be involved in specific

issues at any given time, such as in AIDS research,

where some of CDC’s investigations involve

blood-transmitted AIDS.

The studies done to date have been criticized for

looking only at donors who are least likely to be

at risk, excluding those in poor nutritional status

and those who may have stopped donating for

health-related reasons (429). Studies have also

been difficult to design because of variables such

as regularity of donation, volume donated at each

session and total cumulative volume (206). Although it is agreed that plasmapheresis can exacerbate problems associated with poor nutritional status and alcoholism, there is still some

controversy over whether such individuals continue to form any portion of the donor pool, in

spite of the Federal regulations and screening processes at work since the mid-1970s. Because of this

uncertainty, it has also been suggested that this

screening process should include tests of nutritional status (161).

Other suggestions for long-term studies include

assessments of the long-term risks to hyperimmunized donors who supply high-titer antibodies

after being immunized with tetanus toxoid or herpes zoster. One group of specially immunized

donors produces Rh immune globulin, a product

which has saved many lives by dramatically reducing the incidence of erythroblastosis fetalis

(hemolytic disease of the newborn). Experts have

questioned whether this process is safe for donors

over the long term (408a).

The Medicare program for the elderly (and

disabled) also makes the Federal Government a

major purchaser of blood products. Escalating

costs since Medicare’s inception in the mid-1960s

have led to a search for methods to restrain cost

increases, and in 1983 Congress passed the Social

Security Amendments of 1983 (Public Law 98-21),

which is based on prospectively paying for inpatient hospital care by diagnosis-related groupings (DRGs), instead of payment on a costincurred basis. The Health Care Financing Administration (HCFA), the Federal agency responsible

for operating Medicare, began to phase out the

cost-based hospital reimbursement system in Oc38-647 0 - 85 _ 4
.

42 • Blood Policy and Technology

tober 1983, and the DRG system’s phase-in is to

be completed by October 1986.

The activities of these three Federal agencies,

HCFA, NIH, and FDA, are briefly described in

the following sections. Payment for hemophiliac

care is also briefly described in the first section.

Payment for Blood Products

and Services

Health Care Financing Administration

The Medicare program consists of two parts:

Part A, the hospital insurance program, and Part

B, a supplementary medical insurance plan. Part

A is available without charge to those who are

eligible, while Part B is optional and requires payment of a monthly premium (about $15/month

in mid-1984). Enrollees must choose not to participate in Part B, since premiums are deducted

automatically from Social Security checks. In

1982, 99 percent of the elderly and 92 percent of

the disabled enrolled in Part A were also enrolled

in Part B (544).

The Medicare law has been amended through

the years, and various limits have been placed on

both hospitals’ and physicians’ charges; beneficiaries’ cost-sharing has also been modified. However, the situation is roughly as follows.

Medicare will pay for the first 90 days of hospitalization, minus a deductible ($356 in 1984).

After 60 days, a daily copayment ($89 in 1984)

is assessed until the 90th day of care. After the

90th day, a lifetime reserve of 60 days can be

drawn upon, but a larger copayment is required

($178 per day in 1984). A copayment of $45 per

day is also required for the 21st through the 100th

day in a skilled nursing facility.

Under Part B, there is an annual deductible ($75

in 1984) and a coinsurance of 20 percent for the

remainder of approved charges (certain limits

were placed on the actual level of reimbursement

to physicians, although payment is still related to

what they charge). Physicians can also accept the

level of payment that Medicare will approve on

a bill-by-bill basis. If they agree, Medicare will

pay them 80 percent of approved charges directly

(the patient’s coinsurance is 20 percent, which is

paid directly by the patient to the physician), but

they cannot charge their Medicare patients for the

difference between what they charged and what

Medicare has determined is the actual level of

reimbursement. If they do not agree to accept

Medicare’s payment as payment in full, Medicare

pays the 80 percent to the patient, and the physician has to collect the full amount from the

patient—the 80 percent from Medicare, the 20

percent coinsurance which is the patient’s responsibility, and the difference between what the physician charged and the amount Medicare determined would be paid.

Part A insurance pays for blood transfusions,

drugs, and biological when furnished as part of

services provided in hospitals or skilled nursing

facilities. Part B pays for blood transfusions and

drugs and biological that cannot be self-administered when provided by physicians or by outpatient hospital services. Part B payments are subject to the deductible and coinsurance payments

described earlier.

For both Part A and Part B, the patient is responsible for any nonreplacement fee charged for

the first three units of whole blood or packed red

cells (the fee applies only to these two blood products). After the first three units, Part A will pay

the nonreplacement fee in addition to the processing and transfusion charges, and Part B will

do the same subject to the annual deductible and

20 percent coinsurance (568).

Under the diagnosis-related grouping system of

prospective payment for Part A, which began to

be phased in during October 1983 and which is

to be completed by October 1986, 470 diagnosisrelated payment categories have been constructed.

Hospitals will therefore be paid a single price regardless of how much it costs to provide that care,

including the costs of collecting/processing or purchasing blood products. Hospital outpatient services and physicians’ services are still based on a

charge-based system, and there is no similar limit

on the amount of reimbursement that can be made

as was legislated for hospital and skilled nursing

home care. (Recent and proposed changes in

Medicare are discussed in detail in the OTA report on “Medical Technology and Costs of the

Medicare Program, ” July 1984. )
Ch. 2—Overview ● 4 3

Payment for Hemophilia Care

In 1975, Public Law 94-63 authorized funding

for two activities to aid hemophiliacs: comprehensive hemophilia diagnostic and treatment centers,

and development and expansion of blood separation centers. Both types of centers were to be administered by public and nonprofit private entities. Funding for blood separation centers was

predicated on finding that there was an insufficient

supply of coagulation products to meet the needs

of hemophiliacs, but it was determined that supplies would be sufficient through 1980 (554). As

a consequence, only funds for treatment centers

were actually appropriated.

The law required that funds establishing comprehensive hemophilia centers were to be granted

in geographic areas with the greatest need for services. However, it also required that programs be

established linking geographically designated

centers with other, more remote providers of services. Under the law, hemophilia care centers were

to provide programs for training of professional

and paraprofessional personnel in hemophilia research, diagnosis, and treatment; programs for

diagnosis and treatment of hemophiliacs being

treated on an outpatient basis; programs of social

and vocational counseling for hemophiliacs; and

individualized written comprehensive care programs for each individual treated by or associated with the center. Funds for the direct care of

patients were never provided. Only $3 million to

$4 million were authorized for the establishment

of the comprehensive centers for the first 2 years.

In 1982, $2.6 million was appropriated (401).

Since 1975, from 22 (504) to 24 (6) major comprehensive care centers, plus many satellites, have

been funded, serving about half of the Nation’s

estimated 15,000 hemophiliacs (6). The centers are

funded through the Department of Health and

Human Services’ Bureau of Community Health

Services/Office of Maternal and Child Health.

Unlike the End-Stage Renal Disease Program

under Medicare, which recognizes patients with

end-stage renal disease as being totally disabled

and thus eligible for Medicare coverage for dialysis and transplants, hemophiliacs can receive

Medicare coverage only on a case-by-case determination. Self-administered coagulation proteins

are also not covered by Medicare. Therefore, in

addition to providing for the distribution of

coagulation products and establishing a multidisciplinary hemophilia care team, hemophilia

care centers have engaged in efforts to establish

funding for individual hemophiliacs (504). A variety of State and third-party sources have been

used (see, e.g., 400), as, for example, to provide

home care coverage (478).

National Institutes of Health

The institute with primary responsibility for

blood resources is the National Heart, Lung, and

Blood Institute (NHLBI) and its Division of Blood

Diseases and Resources (DBDR). In 1948, the National Heart Institute was established under the

National Heart Act. In 1969, it was redesignated

the National Heart and Lung Institute, when

pulmonary diseases were added to its responsibilities. NHLBI was organized in 1976, when its

research responsibilities were to include “the use

of blood and blood products and the management

of blood resources. ”

The National Heart, Blood Vessel, Lung, and

Blood Act of 1972 (Public Law 92-423), however,

has most influenced NHLBI. The 1972 legislation

established separate funding and renewal periods

for the Institute, as had been established for the

National Cancer Institute in the previous year. In

contrast, other institutes at NIH fall under the general research authority of the Public Health Service Act, which places no specific disease category

allocations or time limits on their authorization.

The 1972 Act specified the following responsibilities:

research into the epidemiology, etiology, and

prevention of heart, blood vessel, lung, and

blood diseases, including the social, environmental, behavioral, nutritional, biological,

and genetic determinants and influences;

research in basic biological processes and

mechanisms of the heart, blood vessel, lung,

and blood;

development and evaluation of techniques,

drugs, and devices used in diagnosis and

treatment of these diseases;

programs to develop technological devices to

assist, replace, or monitor vital organs;
44 ● Blood Policy and Technology

●

●

●

●

●

●

programs for field studies and large-scale

testing, evaluation, and demonstration of approaches to these diseases;

research in blood diseases and the use of

blood resources;

education and training of scientists, clinicians, and educators in these fields;

public and professional education in these

diseases;

programs for research of these diseases in

children; and

programs for research, development, demonstration, and evaluation in emergency medical services.

The 1972 legislation also required that: 1) an

Interagency Technical Committee (IATC) be

established to coordinate Federal health programs

and activities in these diseases; 2) no less than 15

percent of appropriated funds be used for programs in lung diseases, and 15 percent in programs

for blood diseases and blood resources; and 3) annual reports be issued summarizing that year’s accomplishments and plans for the next 5 years from

the director of the institute and from NHLBI’s National Advisory Council.

The Director of NHLBI chairs the Interagency

Technical Committee, which includes representatives from all Federal departments and agencies

whose programs involve research in diseases of

the heart, blood vessels, lung and blood, and in

transfusion medicine. Three reports have been

issued, on 1977, 1979 and 1981 activities. The

functional arms of the IATC are its working

groups, such as those on smoking and blood resources; these meet separately. In 1979, NHLBI

provided over $71 million for programs directly

related to blood diseases and resources, while

other NIH agencies provided nearly $43 million,

and other Federal agencies, outside NIH, nearly

$21 million (557).

Research program interrelationships between

NHLBI and other Federal agencies are the result

of activities in similar areas but for different missions. For example, the Department of the Army’s

1983 research budget on hemoglobin solutions

was approximately equal to NHLBI’s (403). The

Army is interested in its military applications as

a battlefield and other emergency situation resuscitation fluid, and the NHLBI is more interested

in its civilian applications and its use in selected

circumstances in addition to its use as an emergency resuscitation fluid.

Another example is in research on AIDS. CDC,

FDA, and NIH have all been involved in investigations into the cause and treatment of the disease. CDC is conducting various epidemiologic

and laboratory studies on AIDS. At FDA, studies

of antiviral agents such as interferon and mediators of immunological function such as interleukin-2 were modified to permit interaction with

AIDS clinical protocols and to determine in vitro

efficacy in correcting immunologic defects. At

NIH, work is primarily concentrated in three

Institutes—the National Institute for Allergy and

Infectious Diseases (NIAID), the National Cancer Institute (NCI), and NHLBI—with AIDS patients also being treated at the NIH Clinical Center (508a). Officials of the various agencies also

regularly attend meetings convened by the other

agencies; for example, the AIDS Working Group,

consisting of non-Federal researchers, which advises NHLBI’s Division of Blood Diseases and Resources, has observers/participants from FDA and

CDC in attendance.

The Division of Blood Diseases and Resources

has four program areas: 1) bleeding and clotting

disorders, 2) red blood cell disorders, 3) sickle cell

disease, and 4) blood resources.

In 1982, NHLBI conducted a 10-year review of

its activities since passage of the landmark 1972

legislation and identified activities that should be

undertaken over the next 5-year period (556). Research needs and opportunities were identified in

the areas of: 1) blood bank management, 2) cellular elements, 3) plasma and plasma derivatives,

4) safety, 5) apheresis, 6) immunology, 7) blood

substitutes, 8) clinical trials, and 9) education. An

early 1984 “snapshot” view of the projects which

DBDR was supporting in these areas, categorized

by the study group’s recommendations, is summarized in appendix A. In addition to the laboratory, clinical, and management studies which

were being supported, Transfusion Medicine Academic Awards were instituted in 1983 for the integration of educational programs in transfusion

medicine into the medical school curriculum, and
Ch. 2—Overview ● 45

a study was to be funded in June 1984 to determine future blood data collection, analysis, and

reporting activities.

Food and Drug Administration

The Food and Drug Administration’s authority to regulate blood products and blood banking technologies derives from several statutory

acts (table 4). (The regulations interpreting these

statutes are contained in the Code of Federal Regulations, ch. 21, pts. 600 et seq. ) Regulation is

organized in FDA’s Center for Drugs and Biologics, with blood products and blood banking

technologies under the purview of the Office of

Biologics Research and Review. Within the Office of Biologics, the Division of Blood and Blood

Products is responsible for all new blood establishment and blood product license applications

and amendments, and for approval to market

blood products and related technologies, such as

products used in typing and compatibility testing

and in preserving and storing blood products. The

division has five branches: 1) blood products, 2)

immunohematology, 3) plasma derivatives, 4)

coagulation products, and 5) hepatitis testing

(162).

Scientific activities related to the Division of

Blood and Blood Products are based at NIH,

along with the Office of Biologics Research and

Review’s other scientific divisions. The Scientific

Director of the Center for Drugs and Biologics integrates the scientific and research activities of

these divisions with those of the NIH and serves

as a member of the NIH’s Scientific Directors’

Committee.

In 1978, FDA and HCFA signed a Memorandum of Understanding which was approved by

the Secretary of the Department of Health and

Human Services and published in the Federal Register on March 30, 1980 (45 FR 19316). The memorandum provided for HCFA to assume sole responsibility for inspecting all registered blood

establishments that did not perform routine collection, processing and transmission of blood and

blood products. These facilities were already being inspected by HCFA (including facilities inspected and accredited by the Joint Commission

on Accreditation of Hospitals (JCAH) and American Osteopathic Association (AOA) as well as

those inspected by the Medicare State survey

agencies) for approval to participate in the Medicare program.

As a result of the agreement and its extension,

there are approximately 5,000 facilities which are

no longer subject to dual inspections (252). HCFA

uses the good manufacturing practice regulations

and the compliance guidelines and checklists prepared by FDA. FDA inspects blood collection and

source plasma establishments biannually, as does

HCFA for the establishments for which it has

Table 4.—FDA Statutory Authority to Regulate Blood Products and Blood Banking Technologies

Statutory authority Group affected Mechanisms of control

Public Health Service Act and Food, Blood banks engaged in interstate Licensure of establishment, and

Drug, and Cosmetic Act—1902 and commerce. individual products. Inspection.

amendments Labeling review. Amendments to

original license applications for

nonstandard or new technologies

and new blood products.

Public Health Service Act—1902 Manufacturers of biological Licensure of establishment and

reagents for blood bank use. products. Lot release control.

Labeling review.

Food, Drug, and Cosmetic Act–1938 Developers of new anticoagulants, Investigational New Drug Application.

collection or storage systems or

new blood products.

Medical Device Amendments of the Manufacturers of other reagent Registration. Inspection. Premarket

Food, Drug, and Cosmetic Act—1976 solutions, supplies and notification or approval. Labeling

equipment used in blood review.

banking.

SOURCES: J. M. Solomon, “Legislation and Regulations in Blood Banking,” federa/ Le~islatlon and the C/inica/ Laboratory, Morris Schaeffer (cd.) (Boston, MA: G. K.

Hall Medical Publishers, 1981); and U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Working Relationships

Agree~err/ Among the Bureaus of h.fedica/ Devices, Radio/ogica/ Hea/th and Biologics, April 1982.
46 ● Blood Policy and Technology

assumed responsibility. Manufacturers of plasma

derivatives and diagnostic reagents used in blood

banking are inspected annually by FDA (252).

In regard to medical devices, the Division of

Blood and Blood Products performs some of the

review functions for blood-related devices for the

Office of Medical Devices of the National Center for Devices and Radiological Health. Medical devices are regulated through a three-tiered

regulatory structure, with only Class III devices

needing to undergo full premarket approval similar to that used in the process of evaluating drugs.

Other devices are essentially regulated by manufacturing controls and inspections, and manufacturers need only to notify FDA of their intent to

market these devices and to conform to the good

manufacturing practices regulations.

The Division of Blood and Blood Products in

the Office of Drugs and Biologics, through the interoffice agreement, reviews the notice of intent

to market new device products; applications for

clinical investigations of Class III devices to gather

the information needed to support a premarket

approval application; and the application itself

for premarket approval of Class III devices that

are used in blood banking (162). (The medical devices industry, including its regulation by FDA

under the Medical Device Amendments of 1976,

is the subject of another OTA report, “Federal

Policies and the Medical Devices Industry,” published in October 1984. )

Product recalls are voluntary actions and may

be taken as a result of FDA findings during inspections, reports from consumers, or new scientific data indicating risks. Although voluntary,

a formal procedure is invoked. After FDA is

notified, the potential hazard is classified as a market withdrawal (hazard unknown) or Class I, II,

or III recall in decreasing severity, and FDA

monitors the product recall. FDA may invoke its

seizure powers if the health hazard is definable

and voluntary recall is not made.

Table 5 summarizes individual recalls between

June 1975 and November 1983. Recall actions

have been classified since November 1978, and

of the 61 recalls since that time, only two (involving whole blood and albumin) have been listed

as Class I, considered to be an immediate, serious to deadly hazard. (Reasons for each recall

were not tabulated until 1983. )

Table 5.—Blood Product Recalls,a

June 1975 to November 1983

Product Number

Diagnostic reagents:

Reagent red cells . . . . . . . . . . . . . . . . . . . . . . . . 31

Typing antisera . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Hepatitis test kits . . . . . . . . . . . . . . . . . . . . . . . . 6

Plasma derivatives:

Normal human albumin . . . . . . . . . . . . . . . . . . . 12

Purified protein fraction . . . . . . . . . . . . . . . . . . . 2

Immunoglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Factor IX Complex. . . . . . . . . . . . . . . . . . . . . . . . 2

Source plasma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Recovered plasma. . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Whole blood and components . . . . . . . . . . . . . . . . 21

Blood containers and preservative solutions . . . . 6

aThe number of recalls IS not Indicative of the relatlve quality of these products.

A single unit of red cells would be Iieted as a recall, while a lot of albumin might

represent 20,000 donors, and 10,000 or more units of albumin.

SOURCE: D. Donohue, personal communication, 19S4.

Between 1974 and 1984, there were 175 voluntary suspensions and revocations. Fourteen involved establishments providing whole blood

and/or components; the rest affected source

plasma centers. Most suspensions are temporary,

and establishments are reinstated after corrections

are verified by reinspection. Deviations in whole

blood collections were for hepatitis testing and

recordkeeping, particularly in component preparation. Table 6 summarizes the types of actions

that led to suspensions of 13 plasma centers in

fiscal years 1980-81.

Table 6.—Significant Deviations Leading to Plasma

Center Suspensions, Oct. 1, 1979 to Aug. 31, 1981

Number of

Deviationsa

occurrences

Over bleeding (10°/0 or more), . . . . . . . . . . 1 lb

Donor suitability inadequately

determined . . . . . . . . . . . . . . . . . . . . . . . . 4

Four-month test requirements not met . . 3

Aseptic technique not used in

collection, separation, and/or

reinfusion . . . . . . . . . . . . . . . . . . . . . . . . . 3

Records incomplete . . . . . . . . . . . . . . . . . . 3

Personnel inadequately trained and/or

informed . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Unsuitable donors drawn . . . . . . . . . . . . . . 2

Units shipped before receipt of written

HBsAG test results . . . . . . . . . . . . . . . . . 2

Hazards of plasmapheresis not

explained . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Donors drawn after loss of red cells . . . . 1

Number of locations suspended. . . . . . . . 13

aMOrO than Orle deviation may have been incurred by a Piasma center.

bAt least five locations aiso had inaccurate recordings of whole blood weights.

SOURCE: D. Donohue, personal communication, 19S4.
The Blood Services Complex
Contents

Page

Part 1: The Voluntary, Whole Blood, and Blood Components Sector. . . . . . . . . . 51

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Blood Collecting Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Blood Collections in the Voluntary Sector . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Costs of Blood and Blood Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Costs and Charges for Blood Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Part2: The Commercial Plasma and Plasma Derivatives Sector . . . . . . . . . . . . . 63

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63,

Sources of Raw Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Finished Products Licensed for Use in the United States . . . . . . . . . . . . . . . . . . . . 67

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

LIST OF TABLES

Table No. Page

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

Whole Blood Collections by Type of Facility and Affiliation, 1980.. . . . . . . . 52

Activities of Three Major Voluntary Blood Service Organizations . . . . . . . . . 53

American Blood Commission Member Organizations and Its Board of

Directors, April 1984. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

American Blood Commission Statements of Support, Revenue, and

Expenses and Changes in Fund Balances for Years Ended Mar. 31,

1976-83 (thousands of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Blood Center Processing Fees for Blood and Components (1983) . . . . . . . . . . . 60

American Red Cross Blood Services Statements of Revenue and Expenses

and Statement of Assets and Liabilities, 1980-83 (or the year ended June 30)

(in thousands) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Blood Center Costs and Hospital Charges for Red Cells, 1980. . . . . . . . . . . . . 62

Changes in Processing Fees for Red Cells Compared to Changes in Total

U.S. Health Care Expenditures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Number of Plasma Centers Located in the United States (by owner,

fractionator, multi-operator single operator, and nonprofit) . . . . . . . . . . . . . . 63

Production and Consumption of Human Serum Albumin and

Antihemophilic Factor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Albumin and Plasma Protein Fraction Consumption unselected

Countries, 1976. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

21. Principal Producers of Human Plasma Derivatives for the U.S. Market . . . . . 66

22. Manufacturers of Normal Serum Albumin (NSA) and Plasma Protein

Fraction (PPF) Licensed for Use in the United States . . . . . . . . . . . . . . . . . . . . . 67

23. Manufacturers of Coagulation Factors Licensed for Use in the

United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

24. Manufacturers of Selected Immune Globulins for Use in the United States . . 71

25. Representative Blood Center Prices for Plasma Derivatives. . . . . . . . . . . . . . . . 73

LIST OF FIGURES

Figure No. Page

4.

5.

6.

7.

8.

Relationships Among Blood Collecting Facilities, 1980 . . . . . . . . . . . . . . . . . . . . 52

Increases in Red Cells Available for Transfusion As a Result of Improved

Inventory Management and Decreased Outdating . . . . . . . . . . . . . . . . . . . . . . . . 58

Recent Trends in Whole Blood and Components Distributed for

Transfusion( Red Cross data only) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

U.S. Production of Factor VIII (inactivity units) and of Albumin/PPF

(in 12.5 Gram Equivalents), 1971-82 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Flow of the Nation’s Blood Resources, 1980... . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3 .

The Blood Services Complex

PART 1: THE VOLUNTARY, WHOLE BLOOD, AND

BLOOD COMPONENTS SECTOR

Introduction

The whole blood sector is called “voluntary”

because it collects blood primarily from unpaid

donors. In 1980, only 2.2 percent of the 11,880,000

units of whole blood collected was collected from

paid donors (518), in contrast to the situation of

10 years ago when over 10 percent of whole blood

was collected commercially. Three types of facilities are involved in the voluntary sector: 1)

community and regional blood centers which

collect and distribute blood to hospitals in circumscribed geographic areas; 2) hospital blood

banks which both collect and transfuse whole

blood and components; and 3) hospitals which

primarily store and transfuse blood, but do not

collect it. In addition, the voluntary sector depends on the commercial pharmaceutical firms to

fractionate its recovered and salvaged plasma.

Community or regional blood centers generally

provide a full range of blood services to a surrounding geographic area. These services may include collection, testing, and labeling of blood,

and distribution of blood and blood products to

hospitals, physicians, and hemophilia care centers. In addition, blood centers often conduct research and training programs.

Hospital blood banks generally provide a

smaller range of services than regional blood

centers, usually limited to the collection and storage of whole blood and components. Some common laboratory tests may be available in-house,

depending on the size and scope of the blood bank

operations, while other tests must be sent out to

private laboratories or the regional blood center.

Often hospital blood banks orient donor recruitment efforts to the friends and relatives of patients; thus, many of the existing nonreplacement

fee programs are associated with hospital blood

banks.

The third type of facility involved in the voluntary sector is the hospital transfusion service,

which is responsible for the administration of

blood and blood components within the hospital. Some hospitals do not collect any blood but

obtain their blood and blood products through

an outside supplier, either a regional blood center or another hospital blood bank, thus making

the transfusion service the primary participant in

blood management and use in such noncollecting

hospitals. While transfusion services also serve as

blood banks, they are called transfusion services

to differentiate them from blood banks which collect, as well as store, blood.

Although blood collection began in hospital

blood banks, over time they have come to play

less of a role in blood collection. In 1971, 69 percent of the blood collected came from regional and

community blood centers (555). By 1980, regional

and community blood centers collected 88 percent of the total, and comparable, though less

reliable figures for 1981 indicate that 91 percent

of total whole blood collections were made through

blood centers (29). Surgenor & Schnitzer/ABC

(518) attribute the predominance of regional

centers to the centers’ ability to collect blood

through constant mobile collections. In 1980, 69.5

percent of whole blood collections was through

mobile units. There is some speculation that the

dominance of regional blood centers may be

reversed in the future as hospitals seek to gain control over costs in the face of such cost containment measures as the prospective payment system—although, as discussed below, there are

those who argue that cost containment may accelerate the trend toward more centralized collections

(see ch. 5, pt. 3).

51
52 . Blood Policy and Technology

Blood Collecting Organizations

As shown in figure 4 and table 10, blood collection and transfusion facilities in the voluntary

sector are represented by three organizations with

overlapping memberships: the American Red

Cross (ARC), the American Association of Blood

Banks (AABB), and the Council of Community

Blood Centers (CCBC). The American Red Cross

has 57 regional centers operating under a single

Federal license, and also maintains an affiliation

with the New York Blood Center (which is a member of CCBC). The Red Cross regional centers

cover about half the geographic area of the United

States, and collect about half the Nation’s whole

blood.

Another 45 percent of the Nation’s whole blood

is collected by institutional members of the AmerFigure 4.—Relationships Among Blood Collecting

L

(41 facilities)

1 57 I

\

ARC regions I

Other

fig. 8).

Table 10.—Whole Blood Collections by Type of

Facility and Affiliation, 1980

Number of Units

facilities collected

Regional and community

blood centers:

AABB only . . . . . . . . . . . . . . 101 2,163,614

CCBC . . . . . . . . . . . . . . . . . . 41a 1,866,586

ARC . . . . . . . . . . . . . . . . . . . . 57 5,434,783

Unaffiliated. . . . . . . . . . . . . . 16 208,421

Total for blood centers 215 9,673,404

Hospitals:

AABB affiliated . . . . . . . . . . 1,977 1,116,143

Unaffiliated. . . . . . . . . . . . . . 4,455 73,895

Total for hospitals 6,432 1,190,038

Other collections. . . . . . . . . . . 16,637

Total—U.S, collections 10,880,079

Euroblood imported . . . . . . . . 265,839

Grand total 11,145,918

ican Association of Blood Banks, including members who belong to CCBC. In 1980, seven ARC

regional centers and all but two Council of Community Blood Centers belonged to AABB, as did

1,977 blood collecting hospitals. There were 101

community blood centers that were members

only of AABB. Approximately 2 percent of blood

collections were through 16 unaffiliated blood

centers.

The AABB was formed in 1947 to protect the

interests of already existing hospital blood banks

in the face of a plan announced by the Red Cross

to attempt to collect and organize the Nation’s entire blood supply (307). Existing hospital and regional blood banks wanted to maintain their

established collection programs. Today, the

AABB represents over 2,OOO institutional (voting)

members, as well as about 7,OOO individual members, primarily blood bank personnel (e.g., administrators, medical technologists). Institutional

members include blood centers, hospital blood

banks, and transfusion services. While blood

centers account for two-thirds of the blood collected by AABB members (29), each institutional

member has a single vote regardless of its size.

In 1962, the Council of Community Blood

Centers was formed by six community blood bank

administrators who were dissatisfied with the

dominance of the AABB by hospital blood banks.
Ch. 3—The Blood Services Complex • 53

CCBC today consists of 27 institutional members,

i.e., community or regional blood centers. All but

two current CCBC members (New York Blood

Center and Puget Sound Blood Center in Seattle) are also members of AABB. CCBC as an organization has played a relatively minor role in the

politics of whole blood delivery, which has been

dominated by ARC and AABB. CCBC’S recent

move to the Washington, DC, area, where the

Red Cross, the AABB, and the American Blood

Commission are headquartered, was a move designed in part to make CCBC more of an active

participant in National Blood Policy deliberations.

Thus, three major organizations represent

almost all the blood collection organizations in

the United States. Although there is some overlap

in organizational membership and in function, the

three major organizations espouse different philosophies and are designed to serve different functions (see table 11). The AABB and CCBC are

organizations which represent individual blood

collection facilities. The Red Cross, as a corporation and a blood collector in its own right, provides a Federal license to collect and process blood

as well as an organizational framework to its

member centers, although each center operates

somewhat independently and is required to be

more or less self-sufficient. “

American Red Cross (ARC) Blood Services

Red Cross chapters choose whether or not to

engage in blood services and other services offered

by the Red Cross, except disaster services and

services to the Armed Forces, which are required

to be available from all chapters. In 1982, 1,873

of the 3,01.1 Red Cross chapters participated in

57 ARC regional blood services. Donor recruitment, blood collection, and processing are performed by volunteers and staff of the regional

centers. In addition to blood collection, regional

centers also provide diagnostic and other bloodrelated services. National headquarters provides

standards for its 57 regional blood centers and inspects them periodically. Interregional resource

sharing is accomplished by the use of a computerized inventory system. ARC

maintains a Rare Donor Registry,

its regions conduct research (so).

national also

and many of

Table Il.—Activities of Three Major Voluntary Blood Service Organizations

ARC AABB CCBC

Actual blood services:

Number of institutional members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 regions 2,176 27

1,873 chapters

Units of blood collected by organization or members in 1981a

. . . . . . . . . . . . . 5,799,024 3,395,854 b

2,320,750 C

Actual blood collection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

● ●

Formal resource sharing program. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Other activities or characteristics:

Management conferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Government liaison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Organ and tissue procurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

● *

Scientific programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Scientific and educational publications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Rare donor registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Blood bank procedures manual. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Standards published . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Institutional inspection and accreditation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Training for technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Incorporation as single entity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

Plasma products marketed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

Formal ongoing strategic planning activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

● Collected by members.

“ “Several members of these organizations are engaged in organ and tissue procurement.

ards of care.

SOURCE: Office of Technology Assessment.

x

x

● *
54 . Blood Policy and Technology

Red Cross Blood Services also maintains a

plasma products division operating out of its national headquarters, which is responsible for arranging contracts for fractionation of plasma from

Red Cross blood collections and marketing of the

products on a competitive basis with the commercial fractionation industry (see below). The Red

Cross recently entered into an agreement with

Baxter-Travenol which would give it more control over fractionation of the plasma it collects

(and the ability to develop new products), but Red

Cross does not fractionate its own plasma. In general, 85 percent of the plasma products sold by

the Red Cross (primarily albumin and Factor VIII)

is marketed by and within Red Cross regions; and

the remaining 15 percent is marketed outside the

regions (486). Eleven Red Cross regions are also

licensed as source plasma centers.

Other fairly new activities of the Red Cross include efforts at strategic planning and management, and involvement in organ and tissue procurement (see ch. 7, pt. 2). In the last year, Red

Cross Blood Services has created a Planning, Marketing, and Operations Research Division at National Headquarters. Blood services is one concern of an organization-wide planning group

called the President’s Council. The Red Cross is

concerned that particularly because of technological advances such as genetic engineering, blood

services as it exists today may be a declining industry. Currently, Blood Services accounts for

almost 60 percent of the Red Cross’s gross revenues (see “Costs and Charges for Blood Products” for further discussion of Red Cross Blood

Services finances).

The entire ARC organization holds a special

position in the national blood services complex.

ARC is the only one of the blood service organizations with a congressional charter, although the

charter is for disaster relief, not blood collections.

(The charter is dated 1905, and Red Cross blood

collections were not begun until the 1940s. ) The

President of the United States is ARC’s honorary

chair, and other cabinet members serve as honorary counselor and treasurer. The President appoints eight of the ARC’s Board of Governors,

and by an act of Congress ARC audit reports are

reviewed by the Department of Defense. For these

reasons, ARC is sometimes described as a quasigovernmental agency.

American Association of Blood Banks (AABB)

The American Association of Blood Banks characterizes itself as the only organization devoted

exclusively to blood banking and blood transfusion services (28). As a scientific and administrative association, AABB sets technical standards

which are followed by its members (see, e.g., 583),

inspects and certifies the operations of its institutional members, and serves as a liaison with the

Federal Government and with the other blood collection organizations. A major part of AABB’s

operation is its National and Regional Clearinghouse (see “Coordination of Blood Resources”

in ch. 5), which accounted for two-thirds of its

assets at the end of 1982 ($1.3 million of AABB’s

$2 million total) (20).

The basic standards in blood banking were first

formalized and published by the AABB. The Red

Cross and AABB have agreed to keep their standards essentially identical and even jointly publish

the “Circular of Information” which must be included with shipments of blood components as

required by the Food and Drug Administration

(FDA). The AABB also initiated the first formal

nongovernment inspection and accreditation system. All institutional members of AABB are inspected on a regular basis and are dropped from

membership if they are not in compliance. AABB

also conducts inspections of approved schools for

training specialists in blood banking to ensure that

the required educational standards are maintained.

Council of Community Blood Centers (CCBC)

The primary audience for CCBC activities is

blood center managers. (The AABB has recently

become more actively concerned about blood center administration; to date, the AABB has oriented

itself primarily to hospital blood banks and to the

day-to-day technological aspects of blood services. ) CCBC describes itself as serving as a forum

for blood center administrators, medical directors

and senior management. It publishes no technical or procedures manuals, and does not operate
Ch. 3—The Blood Services Complex ● 5 5

a formal resource exchange system, but holds two

meetings a year to discuss management issues.

CCBC is a relatively small organization which has

struggled financially in the past. It derived almost

all of its $207,000 income in 1983 from membership dues (136).

Each of the three organizations described above

also serves its members or chapters by representing them on the American Blood Commission’s

Board of Directors.

American Blood Commission (ABC)

The American Blood Commission is the one

formal mechanism enabling the AABB, ARC, and

CCBC to work together, along with other health

care providers (e.g., American Hospital Association, American Medical Association), consumer

groups (e.g., National Hemophilia Foundation,

National Kidney Foundation, American Legion),

and representatives from the commercial plasmapheresis industry (e.g., Pharmaceutical Manufacturers Association of America). A list of ABC’s

members and governing board is shown in table

12.

Given its unique position as a private voluntary association charged with implementing public

policy, ABC has been forced to influence blood

policy through nonregulatory channels. Its potential effectiveness was limited by its lack of enforcement powers. In addition, philosophical differences

persist among ABC’s member blood collecting

organizations, both voluntary and commercial,

and the organizations fear losing control over their

operations to the ABC. Many early attempts by

the commission to mediate a compromise between

the major blood collection organizations failed.

For example, while ABC’s Board adopted the recommendation of its 1977 Task Force on Donor

Recruitment that the nonreplacement fee be abolished, it was never acted upon by the full commission because of AABB’s opposition.

Some of ABC’s programs and initiatives are

widely credited for catalyzing change in the blood

industry-or at the very least, for maintaining

constructive dialog conducive to problem-solving.

It has been suggested that ABC may have succeeded in its role as conscience of the blood

industry (270) by providing a public forum for

discussion of blood policy issues. ABC has established standing committees on donor recruitment,

and regionalization, for example; both are issues

in which the exchange of information, and an

eventual consensus, are of value both to the industry and to those served by it.

ABC, and many others, see its regionalization

recognition program as having been fairly successful, with 44 regions, representing over 50 percent of the Nation’s blood supply, having achieved

full recognition status. ABC’s attempt at a more

far-reaching effort at resource sharing (which

would have overcome the discontinuities between

the AABB Clearinghouse and the ARC system)

was delayed when the commercial sector objected

to limiting resource sharing to noncommercial

blood, and the Red Cross withdrew in fear that

a civil suit would be filed. The Red Cross has substantial assets which it fears could be attached if

such a suit were filed and won.

In an attempt to get an agreement about resource sharing signed, the ABC Board contemplated, but never enacted, a motion to seek Federal legislation that would, in effect, exempt

participation in resource sharing from antitrust

action. The strategy now is to see whether the

move of the AABB National Clearinghouse operation to the Washington, DC, area will make resource sharing seem more feasible. The continuing failure of the blood collectors to agree on a

means of coordination has been frustrating to the

consumer representatives on the ABC Board, but

it is not clear that such coordination would contribute significantly to the efficiency of blood collection (see ch. 5, pt. 2).

ABC’s effort at coordinating an ongoing system of data collection and analysis was a mixed

success. While the 1979 and 1980 data collected

for the ABC’s National Blood Data Center represent the only systematic national data collection since 1972, ABC was unable to maintain data

collection on an ongoing basis, or to make it commercially viable, as had been hoped. The effort

was marked initially by heated debates among the

participating organizations (e.g., on the collection

of information on outdated blood, which was

defined differently by different organizations (270;

see also 547). Further, National Blood Data Center data do not include information on the com-
56 ● Blood Policy and Technology

Table 12.-American Blood Commission Member Organizations and Its Board of Directors, April 1984

Member organizations:

American Association of Blood Banks

American Association for Clinical Histocompatibility

Testing

American Association of Donor Recruitment Professionals

American Association of Retired Persons

American Association of Tissue Banks

American College of Physicians

American College of Surgeons

American Federation of Labor—Congress of Industrial

Organizations

American Heart Association

American Hospital Association

American Legion

American Medical Association

American Nurses’ Association, Inc.

American Osteopathic Association

American Red Cross

American Society of Anesthesiologists

American Society for Apheresis

American Society of Clinical Pathologists

American Surgical Association

College of American Pathologists

Communications Workers of America

Cooley’s Anemia Foundation

Council of Community Blood Centers

Health Insurance Association of America

Leukemia Society of America

National Association for Sickle Cell Disease, Inc.

National Association of Patients on Hemodialysis and

Transplantation, Inc.

The National Hemophilia Foundation

Pharmaceutical Manufacturers Association

United Way of America

Veterans Administration

Board of Directors:

Ray Andrus

American Federation of Labor—Congress of Industrial

Organizations

J. Newton Ashworth, Ph.D.

Pharmaceutical Manufacturers Association

Fred A. Barnette, at-large

Ortho Diagnostics, Inc.

Carl G. Becker, M.D.

American Heart Association

Hamp Coley

United Way of America

Margaret M. Diener, MPH

National Association of Patients on Hemodialysis and

Transplantation, Inc.

Suellyn Ellerbe, R. N., M.N.

American Nurses’ Association, Inc.

—

Ralph G. Golden, Ph.D.

American Association of Retired Persons

Charles R. Goulet

Blue Cross/Blue Shield Association

David Guri, at-large

Alpha Therapeutic Corp.

Douglas Holloway, at-large

James B. Hubbard, Vice President

American Legion

Alfred J. Katz, M.D.

American Red Cross

Roland H. Lange

American Red Cross

Paul McCurdy, M.D.

American Society of Hematology

Franklin D. McDonald, M. D., Secretary

National Kidney Foundation

Mary L. Mays

Communications Workers of America

Harold T. Meryman, M.D.

American Association of Tissue Banks

John D. Milam, M.D.

American Association of Blood Banks

William V. Miller, M. D., President, at-large

Gerald S. Moss, M. D., FACS

American College of Surgeons

Victor H. Muller, M.D.

American Society of Clinical Pathologists

Richard E. Palmer, M.D.

American Medical Association

Peter J. Quesenberry, M.D.

Leukemia Society of America

Randall H. Rolfe

American Hospital Association

Dale A. Smith, at-large

Baxter-Travenol Laboratories, Inc.

James M. Stengle, M.D.

The National Hemophilia Foundation

Bill T. Teague, B. S., M.T. (A. S. C.P.), S.B.B., Treasurer

American Association of Blood Banks

John L. Thornton, M. D., Vice President

Council of Community Blood Centers

Martin J. Valaske, M.D.

College of American Pathologists

Edward L. Wampold, at-large

Cooper Diagnostics

Charles F. Whitten, M.D.

National Association for Sickle Cell Disease, Inc.

Edward C. Zaino, M.D.

Cooley’s Anemia Foundation

SOURCE: American Blood Commission.

mercial plasmapheresis industry, which was col- Federal funding. A great blow was the withdrawal

lected and published separately by the American of the American Cancer Society, the American

Blood Resources Association. College of Emergency Physicians, the American

Osteopathic College of Pathologists, and the NaGovernment support for ABC has diminished tional Medical Association in 1983. Although

over the years, necessitating increases from pri- members are often delinquent in their dues, colvate funding (see table 13). ABC now receives no lections of membership dues for fiscal year 1984
Ch. 3—The Blood Services Complex ● 5 7

Table 13.—American Blood Commission Statements of Support, Revenue, and Expenses and

Changes in Fund Balances for Years Ended Mar. 31, 1976-83 (thousands of dollars)

1983 1982 1981 1980 1979 1978 1977 1976

Public support:

U.S. Government contracts . . . . . . . . . . . .

Private grants. . . . . . . . . . . . . . . . . . . . . . . .

Contributions . . . . . . . . . . . . . . . . . . . . . . . .

Total public support . . . . . . . . . . . . . . . .

Revenue:

Membership dues . . . . . . . . . . . . . . . . . . . .

Investment income . . . . . . . . . . . . . . . . . . .

Conference fees . . . . . . . . . . . . . . . . . . . . .

Publications and miscellaneous. . . . . . . .

Loss on sale of equipment . . . . . . . . . . . .

Total revenue . . . . . . . . . . . . . . . . . . . . . .

Total support and revenue. ., . . . . . .

Expenses:

Program services:

Technical advisory panel . . . . . . . . . . . .

Resource sharing . . . . . . . . . . . . . . . . . .

Policy operations . . . . . . . . . . . . . . . . . .

National Blood Data Center . . . . . . . . .

Regionalization . . . . . . . . . . . . . . . . . . . .

Management and Logistics

Conference. . . . . . . . . . . . . . . . . . . . . .

Plasma study . . . . . . . . . . . . . . . . . . . . . .

Utilization . . . . . . . . . . . . . . . . . . . . . . . . .

Long range planning. . . . . . . . . . . . . . . .

Commonality . . . . . . . . . . . . . . . . . . . . . .

Clearinghouse . . . . . . . . . . . . . . . . . . . . .

Donor recruitment. . . . . . . . . . . . . . . . . .

Planning and implementation . . . . . . . .

Total program service expenses. . . .

Supporting services:

Management and general . . . . . . . . . . .

Financial development . . . . . . . . . . . . . .

Total supporting services . . . . . . . . .

Total expenses . . . . . . . . . . . . . . . .

Excess (deficiency) of public support and

revenue over expenses . . . . . . . . . . . . . . .

Fund balances, beginning of year . . . . . . . .

Fund balances. end of year. . . . . . . . . . . . . .

$ 5 6 $296 $467 $337 $348 $526 $389 $129

12 42 100

126 123 46 51 61 46 7

$182 $419 $513 $389 $420 $614 $395 $229

$166 $169 $179 $179 $159 $144 $144 $141

20 19 9 8 3 1 4

10 8 23 10

22 6 3 2 2

(3)

$202 $219 $217 $200 $163 $147 $144 $145

$384 $638 $730 $589 $583 $761 $540 $374

3 3 16

12 8

93 137 142 173 149 139 169

73 240 277 191 165 237 106 29

57 84 103 70 87 88 72 36

8 3

2 4

5 7 4

1

46 107 39

5 5

44 63 20

35

$225 $475 $555 $440 $407 $565 $525 $158

$110 $157 $178 $141 $119 $172 $ 85 $ 4 0

7 4 13 2 21

$117 $161 $190 $143 $139 $172 $ 8 5 $ 4 0

$342 $636 $746 $583 $547 $737 $609 $199

$42 $ 2 $(16) $ 6 $ 3 7 $ 2 4 $ (69) $175

157 156 172 166 129 106 175

$199 $157 $156 $172 $166 $129 $106 $175

SOURCE American Blood Commission, 1983

exceeded ABC’s goal. Nevertheless, as a consequence of corporate contributions not meeting

ABC’s goal, ABC now projects a $20,000 shortfall in fiscal year 1985. Some believe that the decline in support indicates that there is no longer

a need for such an organization to resolve differences among blood collectors.

Blood Collections in the

Voluntary Sector

Whole blood collections have been able to keep

up with increasing demand at the same time that

paid whole blood donations have decreased sig38-647 0 - 85 - 5

nificantly (fig. 1 in ch. 1). This increase has

occurred through increased recruitment, improved

inventory management, and a large increase in

the use of blood components instead of whole

blood.

The most recent comprehensive data on whole

blood collections and transfusions are for 1979

and 1980 (518). Partial data are available from

blood collection centers (but not transfusion services) represented by ARC, AABB, and CCBC for

1981 (29) and from the American Red Cross

through June 1983. In 1980, out of 11.15 million

units of whole blood collected, 14.8 million units

of blood components were transfused, exclusive
58 ● Blood Policy and Technology

of blood that was outdated or lost (see fig. 2 in

ch. 1). Between 1971 and 1980, whole blood collections increased from 8.8 million to 11.15 million units, while whole blood and red cell losses

decreased from 2.44 million to 1.15 million units,

an improvement in losses from 28 to 10 percent

of blood collected (see fig. 5). (Solutions increasing the storage life of blood from 21 to 35 days

were introduced in 1980, and this effect is only

partially reflected in the 1980 data. Recent approval of a solution that allows a 49-day shelf life

for packed red cells should result in further improvement, although the additional cost of such

solutions may limit their widespread acceptance. )

Losses in Red Cross centers have remained

fairly stable in the years since 1980 but these data

do not include reports from hospitals and other

blood banks to which blood is shipped. Red Cross

data shown in figure 6 for products distributed

for transfusion (but not necessarily transfused) indicate that trends toward component therapy and

the use of blood components have continued.

Figure 5.—Increases in Red Cells Available for

Transfusion As a Result of Improved Inventory

Management and Decreased Outdating

1.21M

1.23M

1971 Years

m - l

19791980

Outdated units

Lost or unaccounted for units

Figure 6.—Recent Trends in Whole Blood and

Components Distributed for Transfusion

(Red Cross data only)

10

8

6

4

2

0

1981 1982 1983

Years

SOURCE: American Red Cross, Blood Services Operations Reports:

Red blood cells (including whole blood) continue to dominate use and are the driving force

behind collection efforts in the voluntary sector.

Platelet use rose from 0.41 million units in 1971

to 2.86 million units in 1980. (Approval in 1982

of platelet storage bags that extend the storage

period from 3 to 5 days is expected to increase

the availability and use of platelets, as well as to

decrease outdating, which is substantial.) Most

platelet concentrates are made from whole blood,

but platelets are also collected directly (plateletpheresis). Plateletpheresis collections have increased steadily in Red Cross regions since 1979

(45,46,47,48). The reported nationwide drop in

plateletpheresis collections between 1979 and 1980

(518) may be misleading because of a simultaneous increase in combined leukaplateletpheresis

procedures (47o).

Fresh-frozen plasma (FFP) production has also

increased, although indications for its use are

limited and have become the topic of private and

Federal scrutiny (see ch 5, pt. 4). In the Red Cross

alone, 3.2 million units of FFP were produced in

1983, a 27.2-percent increase over the previous

year. However, only 30 percent of the fresh-frozen

plasma produced was distributed for transfusions.

Two-thirds was used for fractionation.
Ch. 3—The Blood Services Complex ● 59

Use of the final product from voluntary whole

blood collections, cryoprecipitate, which contains

antihemophilic factor (AHF) and other coagulation proteins, remained constant from 1972 to

1980, primarily because of availability of a more

effective and stable way to inject concentrates of

AHF derived from pooled plasma. However, in

light of the AIDS crisis, and because new uses

have been found for the substance (see ch. 5, pt.

4), cryoprecipitate production has increased recently (23,48).

Costs of Blood and Blood Components

On the whole, the cost of blood and blood

products has not been a major factor in discussions of health care expenditures, probably because it has been estimated that the total valuation of collected and transfused blood and blood

products (including plasma derivatives) is only

about 1 percent of total health care expenditures

(31a). However, the National Blood Policy (NBP)

pointed out that costs could have an impact on

access to health care. Another issue addressed by

the NBP was the need for public confidence in the

reasonableness of service charges to encourage

voluntary donors. To this end, the National Blood

Policy encouraged development of accounting and

reporting systems to identify relationships between the costs and charges for all services and

materials associated with transfusion therapy

(180; see table 2 in ch. 2).

In 1979, the U.S. General Accounting Office

recommended that the Health Care Financing

Administration (HCFA) investigate the relationship between costs and charges for blood products to determine if Medicare was being overcharged by hospitals (546). Concern had also been

raised about whether nonreplacement fees constituted “profiteering,” especially when patients

were charged for nonreplaced blood that was

originally obtained from unremunerated donors

(e.g., see 511). The nonreplacement fee was also

viewed as causing problems of access to health

care for Medicare patients, who are responsible

for paying a three-unit deductible if they cannot

arrange to replace the blood transfused in hospitals charging a nonreplacement fee.

Costs and Charges for Blood Products

The costs associated with voluntarily donated

blood derive from donor recruitment, equipment

(hardware and software) and labor, testing, inventory management and distribution, and transfusion. When donors are paid, the costs of remuneration must be added. Blood collecting and

transfusing facilities in the voluntary sector have

not developed a uniform industrywide system for

allocating costs to each step in the collecting and

transfusing process. The American Red Cross and

some larger independent blood centers (e.g., the

New York Blood Center) have developed cost

accounting systems for internal use.

There is wide variation in the fees charged to

hospitals and patients by blood collectors and by

hospitals to patients. As shown in table 14, 1983

processing fees for whole blood charged by American Red Cross regions ranged from $28 (in San

Juan, PR) to $59 (in San Jose, CA). Charges in

some community blood centers can be higher,

e.g., $67 for whole blood in San Mateo, CA (including a replacement fee); $75 at the Irwin

Memorial Blood Bank in San Francisco. Similar

variations are found for other components. Production and sale of the several blood components

means that an average Red Cross blood center

could collect up to $105.54 from a single unit of

whole blood donated in 1983, not including revenues from recovered plasma (higher if red cells

are frozen or washed).

Increases in processing fees for blood components, as well as better inventory management,

have meant that blood suppliers have been able

to accumulate substantial fund balances. For example, as shown in table 15, Red Cross net assets

at year-end increased by 18 percent from 1980 to

1981, by 30 percent from 1981 to 1982 and by 32

percent from 1982 to 1983. Although apparently

substantial on a cumulative basis, Red Cross net

assets of $36,053,000 for the year ended June 30,

1983, amounted to only 8.5 percent of that year’s

entire blood services revenues, representing fewer

than 36 days of operating expenses, according to

the Red Cross (43). Some blood centers (e.g.,

Puget Sound Blood Center, Hoxworth Blood Center) have deliberately accumulated revenues over
60 • Blood Policy and Technology

Table 14.–Blood Center Processing Fees for Blood and Components (1983)

Average processing fees

Blood components ARC CCBC Rangea

Whole blood. . . . . . . . . . . . . . . . . . . . . . . . $ 41.83 $42.59 $28.00 (San Juan)–$ 59.00 (San Jose)

Red blood cells . . . . . . . . . . . . . . . . . . . . . 41.17 40.41 28.00 (San Juan)— 59.00 (San Jose)

Red blood cells deglycerolized. . . . . . . . 131.55 — 91.00 (Portland) – 225.00 (Atlanta)

Red blood ceils washed. . . . . . . . . . . . . . 86.00 NA 60.25 (Roanoke) — 160.00 (Atlanta)

Fresh-frozen plasma . . . . . . . . . . . . . . . . . 25.08 24.49 17.00 (Waco) – 38.00 (San Jose)

Cryoprecipitated AHF. . . . . . . . . . . . . . . . 12.28 12.68 8.00 (Great — 18.00 (4 centers)

Falls, Daytona)

Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.41 25.31 17.00 (Waco) — 40,00 (Boston)

aRed Cross data only.

NA = not available.

SOURCES ARC—American Red Cross (1983), fees shown are as of June 30, 1983, and do not include the NYBC; CCBC—Huitt, letter to OTA, 1964; fees shown are

as of July 1983.

those required for operating expenses in order to

provide for capital expansion (221,242). Red Cross

headquarters usually does not exercise direct control over blood services assets; such assets are used

at the discretion of individual blood services regions (141). A small portion of Red Cross revenues is devoted to research—less than 2 percent.

The difference between community blood center processing costs and hospitals’ charges to patients is shown in table 16. In table 17, the processing fee for red cells charged by blood centers

to hospitals is compared to hospital charges to patients. In 1980 the average community blood center red cell processing fee to hospitals was about

$32. (The average cost of $45.91 for collecting and

processing a unit of whole blood is offset by sales

of remaining blood components. ) The average

total hospital charge for a unit of red cells was

$88.97. In addition to a processing fee, hospital

charges might include an additional processing

fee, a replacement charge, a laboratory charge,

an infusion charge and other charges (table 16).

Data for processing fees for hospitals include hospitals which also collect their own blood. Wallace

& Wallace/ABC (576) found that total charges are

higher at collecting than at noncollecting hospitals, and that higher processing fees and replacement fees accounted for the higher total charges.

As might be expected, there is substantial variation in hospital charges for red cells (the only component for which hospital data are available), with

standard deviations from a quarter to a third of

the mean.

Increases in blood costs have not exceeded increases in total health care costs. As shown in

table 17, national health expenditures have increased on an average of 15 percent per year (for

1980 to 1982), while blood center processing fees

have increased 7 percent (CCBC members) and

12 percent (Red Cross regions). Increases in hospital charges for blood appear closer to increased

hospital charges in general, although it is difficult to draw conclusions with information from

only 2 consecutive years.

Access

Issues of access are more difficult to sort out

than issues of cost/charge relationships. It is currently unlikely that individuals will be denied hospital care because they cannot afford the cost of

blood to be transfused during their hospital stay,

but the issue may become more complicated as

prospective payment systems are phased in (see

ch. 5, pt. 4). At present the only real threat to

access posed by the cost of blood products seems

to be that uninsured hemophiliacs may receive less

Factor VIII than is optimal.

At present, there is wide variation in the way

third-party payers cover the costs of blood products. Since 1968, Blue Cross/Blue Shield national

policy has been to encourage voluntary donation

and replacement, and blood assurance programs

(79). Like Medicare, then, most Blue Cross/Blue

Shield policies have a three-unit deductible for

nonreplacement fees when they are charged. For

Federal employees covered by Blue Cross/Blue

Shield, however, replacement fees are partially

covered by the supplemental portion of the policy (i.e., 80 percent coverage for high option; 75

percent coverage for low option). Policies more

costly to patients are followed in at least one State.
Ch. 3—The Blood Services Complex • 61

Table 15.—American Red Cross Blood Services Statements of Revenue and Expenses and Statement of

Assets and Liabilities, 1980-83 (for the year ended June 30) (in thousands)

1983 1982 1981 1980

Revenues:

Blood Services processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Investment income . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Government and private foundation grants . . . . . . . . . . . . . . . . .

Other income . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

$418,962

5,389

177

73

1,292

$371,901

3,695

200

101

1,371

377,268

$301,685

2,252

$241,155

1,213

—

209

1,021

66

2,016

Total revenues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425,893 306,019 243,598

233,684

(10,633)

223,051

Expenses:

Blood Services expenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Less—expenses incurred by chapters funded from nonBlood Services support and revenue . . . . . . . . . . . . . . . . . . . . .

379,091 342,813 292,281

(9,821)

369,270

(9,469)

333,344

(9,673)

Net Blood Services expenses . . . . . . . . . . . . . . . . . . . . . . . . . . . 282,608

Excess of revenue over expenses before property and

equipment acquisitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Property and equipment acquisitions—net of proceeds from

sales of property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56,623

(20,570)

43,924 23,411 20,547

(9,577)

—

—

—

(17,927) (10,130)

Net Excess of Revenues Over Expenses and

Property Acquisitions:

Increase in designated balances approved by Board

action for:

Replace and improvement of buildings and equipment . . . . .

Other specific purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Net operating assets required . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9,271

6,193

20,589

—

—

—

.

36,053

111,364

$147,417

25,997

85,367

$111,364

13,281

72,086

10,970

Designated Net Assets, Beginning of Year . . . . . . . . . . . . . . . . . 61,116

$ 85,367 $ 72,086

$ 6,658

9,365

31,129

52,351

353

—

Designated Net Assets, End of Year . . . . . . . . . . . . . . . . . . . . . . .

Assets:

Cash and time deposits .., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Investments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Receivables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Inventories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other assets... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Due from undesignated funds . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

$ 14,392

46,415

47,745

55,116

1,084

8,172

172,924

$ 6,425

29,350

47,073

47,268

799

4,015

134,930

$ 5,982

15,181

41,458

51,975

541

—

115,137 99,856

15,136

602

12,032

Total assets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Liabilities:

Accounts payable and accrued liabilities . . . . . . . . . . . . . . . . . . .

Notes payable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Due to undesignated funds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20,018

494

9,258

25,480

27

23,132

434 — —

Total liabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25,507 23,566 29,770 27,770

$111,364 $85,367 $ 72,086

$ –

—

—

—

Net Assets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Net assets—as follows:

Replacement and improvements of building and equipment . . . .

Other specific purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Net assets required for operations . . . . . . . . . . . . . . . . . . . . . . . . . .

$147,417

$20,511

16,405

110,501

$147,417

$ 11,240

—

100,124

$111,364

$ 6,577

—

78,790

Net assets—as above, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $85,367

Notes: Compared to:

● Total ARC Public Support and Revenue . . . . . . . . . . . . . . . . . . . .

● *Total Net Assets of ARC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

$722,159

628,658

$637,059

559,949

$556,911

231,298

$484,300

214,647

SOURCE American Red Cross Annual Report, 1980-83.
62 ● Blood Policy and Technology

Table 16.—Blood Center Costs and Hospital Charges

for Red Cells, 1980

Average community blood center

cost per unit whole blood collected . . . $45.91 (15.34)’

Average total hospital charge for unit

of red cells . . . . . . . . . . . . . . . . . ., . . 88.97

Charges may include:b

Processing fee (average) . . . . . . . . . 37.94

Replacement fee (average) . . . . . . . . . 27,54

Laboratory fee (average).,..,..,,,. 40.51

Infusion fee (average) . . . . . . . . . . . . . 20.41

Other (e.g., blood delivery,

general administration), ............ 17.32

aFigure in parenthesis is standard deviation.

charge all types of fees. Of the 2,441 respondents to the survey conducted by

60 charged a fee related to some other service.

SOURCE: Wallace and Wallace/ABC, 1982.

Mississippi Blue Cross/Blue Shield has a threeunit deductible for all costs associated with blood

transfusions, including processing charges and

administration charges.

Some blood centers offer coverage incentives

to donors in addition to replacement credits. The

Gulf Coast Regional Blood Center in Houston has

two blood assurance plans. “Life Plan I,” for families and individuals covers the donor (and certain selected others) for all Gulf Coast Regional

Blood Center service fees for blood and blood

components transfused in the gulf coast region

served by the blood center. Hospital charges for

typing and crosshatching etc. are not covered,

and, as in most insurance plans, preexisting conditions are not covered. “Life Plan II” is a group

plan which fully covers participating donors and

their immediate families and also provides partial coverage (equal to one replacement donation)

for nondonors in the group, if there is 25 percent

participation. Gulf Coast also charges and covers replacement fees.

Mississippi Blood Services (MBS) has probably

the most generous coverage plan for donors. Its

“donor protection program” covers any out-ofpocket blood charges (including any hospital

replacement fees) up to $10,000 for any MBS

donor, without geographic restrictions. MBS itself

does not charge a replacement deposit fee. In

1983, MBS paid out-of-pocket blood charges

amounting to $51,163 for 393 patients. The largest

single payment for one patient was $3,759. MBS

acknowledges that such a system would not be

feasible for blood centers on a large-scale basis

because insurance companies might increase their

deductibles if such a plan were adopted nationwide, or even in entire regions.

Table 17.—Changes in Processing Fees for Red Cells Compared to Changes in Total U.S. Health Care Expenditures

Percent change Percent change

Processing fees charged by from previous year in national

community blood centers ARC CCBC3

ARC CCBC health expenditures4

1976-77 . . . . . . . . . . . . . . . . . . . . . . . . . . 22.19’ n/a — — 11.9

1979 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . n/a 32.30

1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30.232

34.14

1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.302

36.98

1982 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38.802

39.72

1963 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.47’ 40.41

Hospital charges5

Total Processing Fee

1979. . . . . . . . . . . . . . . . . . . . . . . . . 79.06 32.07

1980 . . . . . . . . . . . . . . . . . . . . . . . . . 88.97 37.94

Percent change 1979-80 . . . . . . . . 13% 18%

8.04

26.7

1.3

6.9

Replacement

28.31

27.54

– 3 %

5.7

7.7

7.4

1.7

Laboratory

33.94

40.51

19%0

13.5

15.8

15.1

12.5

n/a

Infusion Other

19.94 13.60

20.41 17.32

20/0 270/o

n/a = not available.
Ch. 3—The Blood Services Compiex ● 63

PART 2: THE COMMERCIAL PLASMA AND

PLASMA DERIVATIVES SECTOR

Overview

Demand for large amounts of plasma, principally for production of albumin, antihemophilic

factor (AHF, or Factor VIII), and immune serum

globulins, has led to what is known as the “source

plasma” industry, in which donors provide plasma,

not whole blood.

The source plasma sector is largely commercial

and has three main components: collectors, or

plasmapheresis centers; fractionators; and brokers,

all of whom operate on a for-profit basis. Notfor-profit blood banks and blood centers also play

a part in the commercial plasma industry when

they sell recovered or salvaged plasma (i.e.,

plasma recovered after components have been

removed from whole blood, or after whole blood

has outdated) to fractionators, or when they

contract with commercial firms to fractionate

plasma into derivatives which they then market

themselves.

Forty-five percent of the Red Cross’ recovered

plasma is fractionated by commercial fractionation companies (486). It is estimated that from 17

to 20 percent of the plasma derivatives sold in the

United States is sold by the voluntary sector (i.e.,

by the Red Cross and the New York Blood Center). These sales put the not-for-profit industry

in direct competition with the commercial plasmapheresis industry.

As shown in table 18, at present there are approximately 336 source plasma centers licensed

by the FDA: 317 U.S. centers are commercially

operated, and 19 are community or Red Cross

blood centers—i.e., they are not operated for

profit. The largest portion (90 percent) of source

plasma centers is owned by independently operated multi-location companies. These multi-location centers are owned by 30 companies marketing biological products. Some of these biological

companies are subsidiaries of larger corporations

(e.g., Sera-Tec Biological, owned by the Rite-Aid

Corp. in New York, operates nine centers in the

East and Midwest, most of which are near college campuses). The plasma collected by commercial plasmapheresis centers is either sold to U.S.

fractionators who separate it into a number of

products, primarily albumin, Factor VIII (antihemophilic factor) and immune globulins, or exported to fractionators in Europe, Japan, or South

America.

The way plasma is provided from plasmapheresis centers to fractionators varies. Four fractionation companies “self-source”; i.e., they run their

own source plasma centers. According to the

latest figures, 98 (30 percent) of the U.S. source

plasma centers are owned by fractionation companies. Most centers contract annually with fractionators to provide a certain amount of plasma,

although there is some “spot buying. ” Recovered

plasma (from whole blood) is not contracted for,

but is marketed through the efforts of nine major brokers. Both the brokers and the for-profit

source plasma centers are members of the American Blood Resources Association (ABRA), a nonprofit trade association organized in 1972 to represent the interests of businesses engaged in the

collection, manufacturing or distribution of certain biological products—in particular, plasma for

further manufacturing (437).

Table 18.-Number of Plasma Centers Located in the United States

(by owner, fractionator, multi-operator, single operator, and nonprofit)

Nov. 1979 July 1980 Mar. 1981 Apr. 1984 Percent change

Fractionator owned . . . . . 121 123 107 92 – 24%

Multi-operator. . . . . . . . . . 171 167 213 177 + 4%

Single operator. . . . . . . . . 98 104 50 48 – 51%

Non-profit . . . . . . . . . . . . . 9 9 11 19 + 110YO

Total . . . . . . . . . . . . . . . . 399 403 381 336 – 160/0

SOURCE: Plasma Ouarter/y, summer 1984,
64 . Blood Policy and Technology

The market for source plasma is largely controlled by four pharmaceutical companies (Hyland

Therapeutics, Cutter Laboratories, Alpha Therapeutics, and Armour), which are in turn subsidiaries of major corporations (Travenol, Bayer,

Green Cross of Japan, and Revlon, respectively).

Each commercial fractionator accounts for about

1 million of the 4 million liters of plasma fractionated in the United States annually (459). In

addition, the nonprofit New York Blood Center

operates its own 300,000-liter-capacity plant for

fractionating plasma recovered from its own

donors and from a portion of Red Cross donors.

(The States of Michigan and Massachusetts each

have small [approximately 50,000 liters each] fractionation capacities, with derivatives distributed

primarily in each State. )

The U.S. source plasma collection industry is

the most important contributor to worldwide

plasma fractionation. The approximate disposition of both source and recovered plasma collected in the United States at the present time is

shown in figure 3 in chapter 1. About 1.3 million

of the 6 million liters of source plasma are exported, in addition to the exportation of plasma

derivatives manufactured in the United States.

About 5.5 million of the 12.5-million-liter worldwide manufacturing capacity in 1978 was in the

United States. Of the 7-million-liter capacity outside the United States, about 5 million liters were

in the commercial sector, and about 2 million liters

were in the voluntary sector. But there were only

about 77 plasma fractionation firms worldwide

(439), and commercial plants outside the United

States operate at about 68 percent capacity, compared to about 85 to 90 percent of capacity in the

United States (459). As shown in figure 7, domestic production of AHF and albumin have increased

steadily. In 1971, 110 million activity units of Factor VIII were sold; in 1982 the figure was 528 million. Comparable increases have occurred for

albumin. Albumin accounts for the largest share

of total sales (see table 1 in ch. 1). It is estimated

that in 1984, approximately one-third of the

albumin and one-half of the Factor VIII produced

will be used in foreign countries (see table 19).

Figure 7.—U.S. Production of Factor VIII (in activity

units) and of Albumin/PPF (in 12.5 Gram Equivalents),

1971-82

6.0

5,5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

1971 1979 1980 1981 1982

Years

millions of activity units.

Thus, much of the plasma and plasma derivatives

used worldwide comes from U.S. sources.

The principal products of the source plasma industry that are used in this country are albumin,

AHF, and plasma protein fraction (PPF), which

is used much as is albumin. Other products include intravenous gamma globulin (IVGG), immune serum globulin and hyperimmune globulins.

Worldwide use differs from use in the United

States. For example, in 1978, at a time when

IVGG was not licensed in the United States, it accounted for 23 percent of worldwide demand for
Ch. 3—The Blood Services Complex ● 6 5

— —

Table 19.—Production and Consumption of Human Serum Albumin and Antihemophilic Factor

Forecast

1971 1976 1979 1984

Plasma processed in the United States (thousands of liters). . . . . . . . 1,950 2,910 3,950 6,920

HSA production in the United States (millions of grams) , . . . . . . . . . . 39 67 91 159

HSA consumption:

Domestic (millions of units) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9 4.6 5.8 8.5

Foreign (millions of units). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.3 0.7 1.5 4.2

Total (millions of units) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 5.3 7.3 12.7

Domestic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940/0 870/o 800/0 670/o

Foreign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60/0 13 ”/0 20 ”/0 330/0

HSA revenues:

Domestic (millions of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $58 $133.4 $168.2 $300

Foreign (millions of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 20.3 43.5 148

Total (millions of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 153.7 211.7 448

Plasma processed globally for AHF (thousands of liters) . . . . . . . . . . . 365 1,600 2,750 5,320

AHF units processed (millions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 400 688 1,330

Domestic consumption: ●

Millions of units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 300 412 648

Average price (cents/units) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 10 10 14

Sales (millions of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.8 30 41.2 91

Foreign consumption:

Millions of units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 100 275 682

Average price (cents/units) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 30 30 27

Sales (millions of dollars) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 30 82.5 184

Total AHF sales (millions of dollars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 60 123.9 275

SOURCE: Office of Technology Assessment, based on data and estimates in M M. Le Coney, “Who Needs Plasma?” Plasma Ouarterly 2:68-93, September 1980.

plasma fractions (see table 1). Table 20 summarizes differences in albumin/PPF consumption

between selected countries in 1976.

Sources of Raw Plasma

In the 1960s, the introduction of plastic bags

for collection of whole blood enabled component

separation to increase, and blood centers began

to address the need to more effectively utilize

plasma from whole blood. Today, plasma in excess of a region’s needs is supplied by blood

centers to plasma derivative manufacturers for

further processing. Plasma is supplied as freshfrozen plasma or liquid recovered plasma to

licensed processors (253).

Table 20.—Albumin and Plasma Protein Fraction

Consumption unselected Countries, 1976

Consumption in kilograms

Country 1 million population

West Germany . . . . . . . . . . . . 499kg

United States . . . . . . . . . . . . . 301

Austria . . . . . . . . . . . . . . . . . . . 259

Finland . . . . . . . . . . . . . . . . . . 213

France . . . . . . . . . . . . . . . . . . . 59

Japan . . . . . . . . . . . . . . . . . . . . 50

Brazil . . . . . . . . . . . . . . . . . . . . 14

SOURCE” Adapted fromT. Drees, Plasma Forum, 1979,

The American Red Cross, which has been involved in providing plasma for fractionation since

the pioneering work of E. J. Cohn, does not operate any facilities for production of plasma derivatives. One regional blood center, the New York

Blood Center (NYBC), has its own plasma fractionation facility. The Red Cross maintains a

number of contracts with domestic and foreign

plasma fractionation facilities to process Red

Cross plasma in accordance with Red Cross specifications, and the products are returned to Red

Cross regional blood centers for distribution to

hospitals and other users (319). Through its system of regional blood centers, the Red Cross collects more plasma for fractionation than any other

single entity in the world. As described earlier,

however, the vast majority of the plasma required

to meet the needs of the United States and other

parts of the world is provided by commercial

plasmapheresis centers. While some of the major

manufacturers operate their own plasma collection centers, many are operated by independent

multi-location companies.

Plasmapheresis has several advantages over

recovery of plasma from a single unit of whole

blood, First, the volume of plasma recovered per

donation is greater with plasmapheresis. Up to 600
66 . Blood Policy and Technology

ml of plasma can be taken per donation, versus

an average recovery of 200 to 250 ml per donation of whole blood. Second, under current FDA

guidelines, a donor can be plasmapheresed twice

each 7 days, while a whole-blood donor can contribute only once every 8 weeks and a maximum

of five times per year. Third, because plasmapheresis collections are specifically for fractionation

into derivatives, the plasma is frozen immediately

upon collection, thereby preserving more of the

labile protein fractions whose functional loss is

proportional to delays in freezing.

Finished plasma derivatives for the U.S. market are produced and supplied by several companies. Most manufacturing facilities that produce

human plasma derivatives are located in the

United States, but some are located in Europe and

Canada. The principal producers of human plasma

derivatives for the U.S. market are identified in

table 21. None of these licensed manufacturers

produce all of the plasma derivatives approved

for distribution in the United States. In addition

to those listed, numerous other manufacturers

produce plasma derivatives for use in other parts

of the world (319).

The cost of plasma is generally determined by

the number of products that can be made from

the plasma and the anticipated protein yield. Frozen source plasma, collected by plasmapheresis,

and fresh-frozen plasma obtained from whole

blood but frozen shortly after processing, have

traditionally provided the highest product and

protein yield. Although all plasma processing is

based on the basic Cohn process (described in ch.

4), modifications and improvements in methods

or equipment enable some fractionators to process plasma more cost effectively than do their

competitors.

The time from collection to processing into

licensed, finished products takes as much as 4 to

6 months, depending on the products produced

and the manufacturer. Temporary shortages and

surpluses can occur, with parallel increases and

decreases in price. In addition, such factors as

price variances between nations, due to prices

governments and insurance plans pay for a particular plasma derivative, affect where products

are distributed. Many manufacturers have distribution networks in numerous countries and direct their products to the markets where demand

is great and prices are higher.

Barriers to entry into the plasma fractionation

business are substantial, due to the need to develop cost-effective production techniques, construction of a capital-intensive facility, and stringent licensing requirements for biological products.

For these reasons and the volatile and competitive nature of the plasma derivatives market, no

new production facilities have been constructed

in the past 12 years by firms not already in the

business. In the recent past, except for continued

marketing of some immune globulins, several

firms have left the plasma derivatives market, including large pharmaceutical firms such as ParkeDavis, Squibb, Upjohn, and Merck Sharp &

Dohme.

Table 21.—Principal Producers of Human Plasma Derivatives for the U.S. Market

Company Manufacturing location Ownership

Alpha Therapeutics California Green Cross/Japan

Armour Illinois Revlon/USA

Connaught Canada Connaught/Canada

Cutter North Carolina Bayer/Germany

Hyland California Baxter Travenol/USA

Immuno Michigan/Austria lmmuno/Austria

Massachusetts State Laboratory Massachusetts State of Massachusetts

Michigan State Laboratory Michigan State of Michigan

New York Blood Center New York New York Blood Center

Swiss Red Cross Switzerland Swiss Red Cross

Netherlands Red Cross Netherlands Netherlands Red Cross

SOURCE: Grossman & Schmitt, 1984
Ch. 3—The Blood Services Complex • 67

Finished Products Licensed for Use

in the United States

Normal Serum Albumin and

Plasma Protein Fraction

Normal serum albumin (NSA) and its close

relative, plasma protein fraction (PPF), are produced from Cohn Fraction V, with PPF also containing proteins from Cohn Fraction IV-4. Under

FDA standards, greater than 96 percent of the protein in NSA must be albumin, while for PPF the

requirement is that only greater than 85 percent

of the protein in the solution must be albumin. The

production of PPF instead of NSA is economically

advantageous to plasma fractionators due to the

allowed differential in albumin concentration in

the final product.

Normal serum albumin is available in 5 and 25

percent concentrations in various vial sizes. PPF

is available ins percent concentrations in various

vial sizes. NSA and PPF are generally regarded

as generic products by users, and distributors and

hospitals often obtain these products from several sources (319).

Many of the major manufacturers of NSA and

PPF often contract to deliver their products to

users on a direct basis. The need for these products and the size of the market requires that numerous outlets be made available. Users include

hospitals, nursing homes, dialysis centers and

pheresis centers, as well as the local physician who

requires an occasional vial to treat a patient in

his office.

NSA and PPF account for approximately onehalf of the total dollar volumes of plasma derivatives distributed in the United States. In the last

5 years, there has been a steady decrease in the

use of PPF, with increasing use of 5 percent NSA

displacing PPF (486).

One liter of plasma processed into NSA will

yield approximately 25 grams of protein. Based

on market prices in mid-1984, the value of the

product would be between $2.50 and $2.80 per

gram, or between $62.50 and $70.00 per liter of

plasma. The manufacturers that operate FDAlicensed facilities for the processing of plasma into

NSA and PPF for the U.S. market are listed in

table 22.

Table 22.—Manufacturers of Normal Serum Albumin

(NSA) and Plasma Protein Fraction (PPF) Licensed for

Use in the United States

Alpha Therapeutics

Armour Pharmaceutical

Connaught Laboratories

Cutter Biological

Hyland Laboratories

Immuno

Massachusetts State Laboratory

Michigan State Laboratory

New York Blood Center

Netherlands Red Cross

Swiss Red Cross

SOURCE: Grossman & Schmitt, 1984

Although there are numerous distribution outlets, the vast majority of these products are supplied by the manufacturers and the Red Cross

directly to hospitals. Distributors are used to service the specialized needs and regional requirements

of other users.

Every institution that uses NSA and PPF independently determines the purchasing method that

provides it the most benefits. The various purchasing alternatives currently available are: 1) arranging an independent purchase contract with

a manufacturer, 2) participating in group purchasing contracts, 3) purchasing from local American

Red Cross centers, and 4) purchasing from a community blood center or distributor. Institutions

that have special requirements, in addition to negotiating prices, make these needs known to their

suppliers. Some of these special requirements

often preclude delivery of products in large shipments to one central warehouse facility. When this

occurs, the cost of servicing an account is greatly

increased, and manufacturers may lose the contract to smaller distributors or regional blood

centers.

One of the most common ways of pricing NSA

and PPF is by annual bidding from the various

manufacturers and suppliers. Some hospitals negotiate annual prices with a local blood center or

distributor that can provide supplies in quantities

that meet the hospital’s special needs.

Many not-for-profit hospitals have joined together to form joint purchasing groups. The concept of a joint purchasing program is that a supplier will bid a lower price if it can more easily

obtain a substantial and reliable quantity of busi-
68 . Blood Policy and Technology

ness. Member hospitals provide the joint purchasing programs with projected use figures. The information is consolidated, and bids are solicited

from approved manufacturers and suppliers.

Most purchasing groups operate as clearinghouses for information between their respective

members and potential vendors, and never actually take delivery of the products. Orders are

placed by each member institution directly with

the supplier. Delivery and supply arrangements

are coordinated between the hospital and the supplier. The purchasing group receives a rebate

directly from the supplier, based on the actual volume of business, and manufacturers supply monthly

reports to the purchasing groups.

Some purchasing groups or shared service corporations actually take ownership of the products.

These purchasing groups provide warehousing

and delivery services for its members as required.

Shared service warehouses offer the hospitals numerous advantages, such as ordering all supplies,

not only PPF and NSA, from one source. The

manufacturer benefits by reducing costs for shipping and billing, since an order will only have to

be sent to one location and billed to one account.

One of the problems arising from purchasing

group programs is that manufacturers or distributors who are awarded supply contracts are

required to rebate a specified percentage of the

revenue to the purchasing group to offset its costs.

Since these costs are paid by the supplier, they

must be factored into the bid price and are ultimately paid by the hospital. The issue is often

debated as to whether or not direct purchases

could be made for less, especially by the larger

hospital members.

The large chains of proprietary hospitals also

solicit annual bids from the major producers. In

many cases each hospital is given the opportunity

to negotiate a more favorable supply arrangement

with a local supplier. If a more favorable pricing

arrangement cannot be made, the hospital can

purchase from the vendor who has been awarded

the national supply agreement for the chain.

Dialysis centers and nursing homes requiring NSA

and PPF usually negotiate with local sources at

spot market prices because their requirements are

often very sporadic.

In all cases, however, supply is a major factor.

Reliability is often more important than saving

a few cents per vial. When an organization can

avoid having to carry a large dollar item in inventory, such as NSA and PPF, it often offsets

these costs by purchasing from local sources rather

than purchasing in large quantities from one of

the manufacturers.

Supply and availability of all plasma derivatives are dependent on both the availability of the

raw material (human plasma) and the prices obtainable for manufactured products. Prices as well

as supplies have traditionally had very large

“peaks and valleys.” To offset price volatility, suppliers and manufacturers often resort to product

transfer from one country to another.

Competition for business among the manufacturers and suppliers of NSA and PPF is very fierce.

Traditional emphasis has been for pricing to act

as the main element for differentiation. Purchasing groups which control a substantial volume of

the NSA and PPF market tend to treat these products as commodities. The market is sensitive to

price changes and thus maintains a high level of

price-competitiveness. Margins earned by manufacturers on the sale of NSA and PPF are substantially below those characteristically earned on

the sale of pharmaceutical products.

The second major determinant of consumer

preference in the purchase of NSA and PPF is confidence in the suppliers’s ability to fulfill its purchase obligation. Long production lead time, as

well as sudden pricing shifts, make it difficult for

suppliers to plan for and rapidly provide additional material. Some hospitals have encountered

supply problems with a particular vendor and are

often reluctant to purchase from that firm again,

even if the price offered is lower than that of a

competitor.

Other less significant determinants of purchaser

preference are items such as packaging, which

does affect sales to some accounts. Package size,

type of intravenous hanger, cap or stopper, as

well as the administration set used, have become

competitive opportunities.

Differentiations between NSA and PPF products have become more related to the source of
Ch. 3—The Blood Services Complex ● 6 9

service, packaging, and availability than to the

product itself.

Coagulation Factors

Approximately one-quarter of the total dollar

volume of plasma derivatives distributed in the

United States are represented by coagulation factors, which are used for treatment of individuals

with congenital deficiencies of Factor VIII or Factor IX. Antihemophilic factor, or concentrates of

Factor VIII, is distributed and prescribed by the

number of “activity units” desired. An “activity

unit” is defined as that amount of Factor VIII present in 1 ml of normal plasma. The protein is very

unstable and is therefore prepared as a lyophilized

powder, which is reconstituted with sterile water

prior to injection, AHF is available in reconstituted volumes of 10 to 40 ml, with associated

activity unit ranges from 250 or 400 to 1,250 or

1,500. Manufacturers licensed by the FDA for Factor VIII and Factor IX sales in the United States

are listed in table 23.

All major plasma fractionators in the United

States produce AHF (see table 23). Unlike other

plasma derivatives, coagulation factors are produced only from plasma frozen within 24 hours

of collection. The activity of these factors decreases rapidly unless the plasma is frozen and

stored at —18 o C or colder until used by a plasma

fractionator. Economics dictate that plasma be

frozen as quickly as possible after collection in

order to maximize product yields.

One of the major disadvantages of use of AHF

has been the inability to treat the product in a

manner that would reduce or eliminate the potential for disease transmission. Recently all four

Table 23.-Manufacturers of Coagulation Factors

Licensed for Use in the United States

Factor IX Anti-Inhibitor

Manufacturer Factor Vlll Complex Complex

Alpha. . . . . . . . . . x x

Armour . . . . . . . . x x

Cutter . . . . . . . . . x x

Hyland . . . . . . . . x x x

Immuno . . . . . . . x

New York Blood

Center. . . . . . . x

SOURCE: Grossman & Schmitt, 1984.

commercial manufacturers received approval

from FDA to begin marketing of heat-treated

AHF. Although some manufacturers have data

which indicate the process may reduce the transmission of viral diseases, there is no AHF product which has yet been proven to be entirely free

of risk.

One liter of frozen plasma processed for AHF

will yield approximately 200 AHF activity units.

Based on market prices in mid-1984, the value of

this product would be between $0.07 and $0.10

per activity unit, or between $14.00 and $20.00

per liter for non-heat-treated product. The heattreated product sold during the same period for

$0.11 to $0.16 per activity unit, or approximately

$22.00 to $32.00 for the yield from 1 liter of frozen plasma. (It has been reported that the yield

of heat-treated Factor VIII is slightly less than the

yield of non-heat-treated Factor VIII from 1 liter

of frozen plasma. )

The second major coagulation factor is Factor

IX Complex, which is a product consisting of

coagulation factors II, VII, IX, and X. Factor IX

Complex is used in treatment of hemophilia B,

as well as in treatment of some patients with inhibitors to Factor VIII. As with AHF, Factor IX

Complex is measured in activity units and is prepared as a lyophilized powder which is reconstituted prior to injection.

Most of the U.S. market for Factor IX Complex is shared by two plasma fractionators, Cutter and Hyland. The total U.S. consumption of

Factor IX Complex is estimated at approximately

130 million activity units per year. Based on a

yield of approximately 400 activity units per liter, it takes 325,000 liters of plasma to meet this

need. Based on market prices in early 1984, the

value of Factor IX Complex was between $7.8 million and $13 million.

The other coagulation factor product is “activated” Factor IX, or anti-inhibitor coagulant

complex, for treatment of patients with inhibitors

to Factor VIII. This part of the market is serviced

by two companies, Hyland and Immune.

In addition to the manufacturers listed above,

who distribute the products manufactured in their

own processing facilities, the American Red Cross
70 ● Blood Policy and Technology

has plasma fractionated into the various clotting

factors by selected manufacturers. These plasma

derivatives are returned to the Red Cross regional

blood centers for distribution to hospitals and hemophilia treatment centers. Numerous suppliers

and regional blood centers also purchase products for distribution to their local hospitals and

hemophilia treatment centers.

Distribution channels for the coagulation proteins vary from region to region. Availability is

often dependent on whether there is a hospital or

hemophilia treatment center in a particular region.

Most large urban areas have at least one major

hemophilia treatment center that routinely stocks

the various clotting factors.

Depending on the size of the region, patient requirements, and product preferences, numerous

purchasing channels can be encountered. The hospital may solicit bids for the various factors required through its Purchasing Office in conjunction with the Pharmacy or Blood Bank, but there

does not appear to be a standard as to which department should take responsibility for purchasing, inventory control, or distribution of coagulation factors within a hospital.

Depending on the institution, it could be assigned to the Blood Bank, Pharmacy, Purchasing Office, or Hemophilia Treatment Center. It

is not uncommon for one company to receive the

entire award for a l-year period for a particular

product at a hospital or hemophilia treatment center. When numerous patients are treated at a hospital, the treating institution may require products manufactured by several manufacturers. To

assist hospitals and reduce their inventory requirements, many institutions utilize the services of a

local distributor or regional blood center, which

maintains adequate supplies of each of the needed

clotting factors.

In recent years, home care treatment of hemophiliacs has increased. At least one manufacturer,

numerous distributors and pharmacies, and several regional blood centers have begun to supply

these products directly to the patient at home.

Orders are filled in response to instructions from

the treating physician, and home care treatment

has lifted the burden from the patient of having

to visit the hospital each time a treatment is required. The regional blood centers, manufacturers, distributors, and pharmacies that distribute clotting factors to home care patients often

provide the supplies needed to administer the clotting factors—which saves time, money, and effort in having to secure them from another source.

Some manufacturers will only supply end-users,

such as hospitals or blood centers, or directly to

patients. Other suppliers provide products to endusers, distributors, and other suppliers. Suppliers

of coagulation factors vary from region to region,

as does the availability of these products. Purchase and selection of a specific brand is often left

to the patient, unless the physician specifies a particular brand.

Packaging, supplies, and availability, as well

as price contribute to the numerous differences

in the supply and use of the various clotting factors. Brand awareness of the product on the part

of physicians, nurses, and patients often plays an

important role in sales of various coagulation

factors.

Brand loyalty is encouraged by manufacturers

by supplying information at educational seminars

and through direct communication with the physician and hemophilia nurse-clinician. Information is also provided directly to the patient by

company representatives at many of the various

national and local hemophilia meetings. Manufacturers provide a wide array of product sizes,

and product preferences and loyalty are often

based on the successful response a patient has had

with the product in past treatment episodes, not

on what manufacturers tell patients.

Immune Globulins

Immune serum globulins (ISG) account for approximately 10 percent of the total dollar volume

of plasma derivatives distributed in the United

States. A typical preparation of ISG will contain

multiple antibodies to a wide variety of infectious

agents.

ISG is available in either “normal” or “hyperimmune” preparations. The “normal” product is produced from the plasma of donors who have not

been stimulated to produce elevated levels of specific antibodies. “Hyperimmune” ISG products are
Ch. 3—The Blood Services Complex ● 71

obtained from donors with elevated levels of a

specific antibody. This elevation may occur naturally, as with antibodies to the Rh blood type

(Rho(D)) or hepatitis B, as a result of the donor’s

prior medical experience, or maybe obtained by

injection of materials designed to produce an immune response in the form of antibody formation

(319).

Specific types of ISG which are presently available in the United States include normal immune

serum globulin, and hyperimmune globulins

against hepatitis B, measles, mumps, pertussis,

tetanus, rabies, varicella zoster, and RHo(D). All

of these ISG products are available for intramuscular, not intravenous, injections. ISG is prepared as a 16.5 percent protein solution and distributed in vials ranging from 2 to 10 ml each.

In the United States, varicella zoster immune

globulin (VZIG) is manufactured only by the Massachusetts Biologics Laboratory and is distributed

primarily by the American Red Cross and other

regional blood centers. Since this limited market

drug was licensed, no other manufacturer has

begun to produce it for distribution within the

United States.

Intravenous gamma globulin is indicated for

maintenance treatment of patients who are unable

to produce sufficient amounts of IgG antibodies.

Use of this product may be preferred to that of

the intramuscular immunoglobulin preparations,

especially in patients who require an immediate

increase in intravascular immunoglobulin levels,

in patients with small muscle mass, and in patients

with bleeding tendencies in whom intramuscular

injections are contraindicated.

Intravenous gamma globulin (IVGG) is currently produced only by Cutter, and is available

directly from Cutter, regional blood centers, or

distributors for purchase by prescribing hospitals

and physicians. Immuno and Sandoz have applied

for licensing of their IVGG products. The products under review by FDA are prepared in a

lyophilized form, whereas Cutter’s IVGG is prepared in solution. Manufacturers of some of these

products are listed in table 24.

Manufacturers of the various immune globulins

distribute their products through many channels.

Table 24.—Manufacturers of Selected Immune

Globulins for Use in the United States

Manufacturer ISG IVGG RHoD HBIG VZIG

Abbott ., . . . . . x x

Armour. . . . . . . . . . . . . . . . X x

Connaught/BCA, . x

Cutter. . . . . . . . . . . . . . . . ., X X x x

Hyland . . . . . . . . . . . . . . X

Immuno ., . . X

a

KABI . . . . . . . . . . . . . . . . . . . x

Massachusetts

Biologics Laboratory. . . . x

Merck Sharp & Dohme . . . . x

New York Blood

Center . . . . . . . . . . . . . . . . X

Ortho . . . . . . . . . . . . . . . . . . . x

Sandoz. . . . . . . . . . . . . . . . . . Xa

%ppi(catlon for licensing pending before FDA as of May 1~.

KEY: ISG: immune serum globulin; IVGG: intravenous gamma globulin; RHoD:

anti-RH antigen immune globulin; HBIG: hepatitis B immune globulin; VZIG:

varicella zoster immune globulin.

SOURCE: Grossman & Schmitt, 1984.

While almost every hospital utilizes some or all

of the immune globulins, there is usually no central distribution or supply network as is available

for normal serum albumin or coagulation factors.

Some manufacturers, such as Ortho, have a large

share of a specific market such as for RHo(D),

but they do not sell other plasma derivatives in

the United States.

Immune globulin products are routinely delivered by pharmaceutical distributors, hospital

supply companies and blood centers, as well as

directly by manufacturers to the numerous hospitals, nursing homes, physicians, and clinics that

prescribe these preparations.

Many manufacturers have their own sales representatives, who contact individual physicians

to encourage the ordering of brand-specific products. Within the hospital, these products may be

ordered by the Pharmacy, Purchasing Office,

Blood Bank, or by a special user department. The

department requesting the product often specifies

which supplier or manufacturer should be used,

based on services and product results in the past.

Annual bidding for each immune globulin

product is not as prevalent as for other human

plasma derivatives, but is gaining. Usually, an

award is made for one company’s product, and

supply has not been a factor since all manufacturers usually have adequate inventories.
72 ● Blood Policy and Technology

Many other manufacturers of immune globulins

offer various products and numerous customer

advantages, including low prices, well-located distribution outlets, and ease of ordering. The two

most important advantages are availability at the

time the product is needed and pricing.

Reagent Products

Plasma not suitable for further manufacture

into injectable is available for use by reagent

manufacturers. Plasma for this market is available from a variety of sources, including regional

blood centers, hospital blood banks, plasmapheresis collection centers, and plasma fractionators.

The number of manufacturers within the United

States requiring plasma for reagents is quite large,

and each one has strict requirements for the

plasma that it obtains. Usually, human plasma

destined for reagent use is sold to plasma dealers

who routinely supply laboratory reagent manufacturers and are familiar with the necessary specifications. Many of these dealers also provide a

wide array of animal proteins to the same laboratory reagent manufacturers.

Each manufacturer of reagent products provides

its sources of human plasma with the requirements

that must be followed in the preparation of the

material. These strict manufacturing specifications

often limit the sources of plasma to a highly select

group of hospitals, plasma collection centers, and

bulk product manufacturers. Plasma suppliers

that specialize in meeting the reagent manufacturer’s specifications usually maintain a long-term

relationship with these manufacturers. Some collection centers specialize in preparation and segregation of plasma from donors with special or

rare characteristics for use by selected reagent

manufactures.

Other Plasma Derivatives

At the present time, many proteins found in

human plasma are being evaluated and studied

for their therapeutic value. Proteins such as Alpha

I Antitrypsin, Antithrombin III, Factor XIII,

Fibronectin, Tissue Plasminogen Activator, von

Willebrand Factor, and Interleukin-2, as well as

new immune globulin preparations, are being

evaluated by numerous commercial and nonprofit

research facilities. The American Red Cross and

the Michigan Department of Public Health are

jointly evaluating as a new plasma derivative a

Factor IX Concentrate depleted of Factors II,

VII, and X; and a concentrate of C1 Inactivator

(373).

Several new plasma derivatives have been

licensed for use in other countries and will, after

passing the necessary testing, be licensed in the

United States. Some of these products are: 1) Antithrombin III, currently marketed in Europe by

Behring (Germany) and Kabi (Sweden); 2) Factor XIII, currently available in Europe by Behring (Germany); and 3) Fibrin Tissue Sealant

(Tissell), currently marketed in Europe by Immuno (Austria) and projected to be available in

the United States in 1985.

Costs of Major Plasma Derivatives

As already discussed, the market structure for

plasma derivatives differs substantially from that

for whole blood. However, the voluntary collectors compete with the commercial sector when

marketing plasma products. Prices charged by

selected not-for-profit blood centers are shown in

table 25. Current retail prices for Factor VIII in

the not-for-profit centers range from $0.10 to

$0.147 a unit for non-heat-treated Factor VIII and

higher for heat-treated Factor VIII. Prices charged

by hospitals to patients are reported to range from

$0.09 to $0.26 per unit in the United States (99;

464). Assuming an average consumption of 50,000

units per year (293), Factor VIII could cost the

average hemophiliac from $4,5oo to $13,000 per

year, although “average” consumption can be a

misleading figure.

Hemophiliacs can require a large infusion of

Factor VIII for surgery, including minor surgery.

Needs also vary for mild, moderate, and severe

hemophiliacs. In addition, from 10 (99) to 15 (76)

percent of hemophiliacs have inhibitors to Factor VIII and require anti-inhibitor coagulant complex, which can cost from $0.70 to $1.00 per unit

(99).

Federal activities in support of hemophiliacs

were discussed in chapter 2. While provisions for

hemophilia care have improved in the last decade, coverage for coagulation proteins on an out-
Ch. 3—The Blood Services Complex ● 7 3

Table 25.—Representative Blood Center Prices for Plasma Derivatives

Blood Center

Goldman S.E. Central NYBCa

Major blood derivatives (Okla.) La. Sacramento (Pittsb.) List Actual

Serum Albumin 5°/0 250 ml

Serum Albumin 5°/0 500 ml

Serum Albumin 25°/0 20 ml

Serum Albumin 25°/0 50 ml

Serum Albumin 25°/0 100 ml

Plasma Protein F. 250 ml

Plasma Protein F. 500 ml

Factor Vlll

Factor VIII, (Heat-treated)

Factor Vlll Anti-Inhibitor

Complex 200-600 FECU

Factor Vlll Inhibitor

Complex 200-600 FECU

Factor ll, Vll, IX, X

complex 500 u vial

34.1OF

67.65F

35.20F

0.132iu C

0.165iu H

0.77iu FB

1.22H

57.20C

28.00

55.65

20.00

31.00 28.00

75.00 55.65

36.00 27.35

54,35

0.10iu

62.50 0.12iu

41.00

82.00

41.00

82.00

41.00

82.00

0.11 N

0.147A1

0.1 IAr

O.1O4C

O.1O8H

0.187A1b

0.145Ar

0.142C

0.129–

0.153H

0.75FB

1.01 H

0.066A1

0.057Ar

0.065C

0.113H

31.00

62.00

31.00

62.00

31.00

62.00

0.11

0.147

0.11

0.104

0.108

0.187

0.145

0.142

0.129–

0.153H

.75

1.01

0.066

0.057

0.065

0.113

Legend: Al =Alpha Therapeutics product; Ar=Armour product; C= Cutter product; F= Fenwal product; FB = FEIBA product; H = Hyland product, N = New York Blood

Center product.

Where no letter is given, product name was not specified.

and hemophilia home care service.

SOURCE: Grossman & Schmitt, 1964

patient basis varies widely, and they are often not expensive alternatives for volume restoration (see

covered because they are regarded as drugs rather ch. 5, pt. 4). A 12.5 gram dose of albumin, prethan biologics. When they are covered, copay- pared by a commercial fractionator and purchased

ment provisions can burden patients. Pharma- from a blood center, cost approximately $32.00

ceutical companies that distribute Factor VIII in 1984. In 1982, the cost from commercial mansometimes ignore the copayment requirement for ufacturers was $27.40 (464).

individual hemophilia patients.

The price of albumin has not been challenged

per se, but some have encouraged the use of less

CONCLUSION

U.S. blood resources consist of two distinct sec- blood collected, markets (domestic v. internators, a voluntary whole blood system and a com- tional), indications for use, and Federal policy atmercial source plasma industry (fig. 8). Human tention and directives. Even the acquisition and

blood is the common denominator, but there are use of the products of these two sectors differ.

distinct differences

donor populations,

between the two sectors in Whole blood and its components are ordered and

recruitment policies, type of monitored through blood banks and transfusion

38-647 0 - 85 - 6
74 . Blood Policy and Technology

Figure 8.—Flow of the Nation’s Blood Resources, 1980

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Blood Technologies;
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Blood Technologies;

PART 1: TECHNOLOGIES FOR BLOOD COLLECTION AND PROCESSING

Introduction

Modern blood bank technology began less than

100 years ago, when several technological obstacles were overcome. First, it was necessary to

arrest the blood clotting mechanisms which normally convert liquid blood into a gel in a matter

of minutes. Second, physicians needed tools by

which blood could be collected from one individual and infused into another with minimum risk

to donor and recipient. Third, there was a lack

of understanding of the immune system and the

potential for incompatibility between donor red

blood cells and red blood cell antibodies produced

by recipients.

The coagulation problem was solved by the addition of citrate into freshly collected blood (344);

citrate compounds are still the basis for stored

blood anticoagulants today. Preservatives such

as glucose were soon added to extend the shelf

life of stored red cells from several days to several weeks.

Devices used in collecting, storing, and administering blood have ranged from quill and tubing contraptions to syringes (used currently for

newborn exchange transfusions), to reusable

vacuum glass bottles, still the standard in parts

of the world today. In the United States, glass bottles have been replaced by flexible plastic containers with attached satellite bags to hold separate blood components.

Landsteiner’s description of ABO blood groups

in the early 1900s and other researchers’ elucidation of antigen/antibody relationships led to simple laboratory tests for compatibility between

donors and recipients, but 15 percent of transfusion recipients remained at risk until the Rhesus

or Rh blood types were discovered (331,342).

From that time to the present, determination of

the donor and recipient ABO and Rh blood types

has been the most important procedure in preventing potentially fatal hemolytic transfusion reactions.

In 1945, a new test was described (Coombs)

which made possible the recognition of previously

undetectable antigens and led to the identification

of more than 400 new red blood cell types over

the subsequent 30 years (284). However, probably fewer than 30 of these types are of clinical

concern in routine transfusion practice (220).

As the demand for blood increased, the larger

blood banks began to consider adaptations of clinical chemistry analyzers which could perform

multiple tests on a single blood sample to remove

some of the tedium and manual labor from mass

blood-typing. These systems have evolved into

computerized testing devices which deliver samples, interpret results, and flag any spurious findings for further investigation.

In the beginning, donor blood collection and

testing were conducted in the same setting as

blood transfusion; each hospital would screen

donors on the basis of specific patient needs, and

donors were often a patient’s family and friends.

World War II resulted in the creation of donor

centers across the United States to collect large

amounts of plasma for use in treating combat

casualties, and intensive research into improving

the storage life and function of red blood cells.

When the war ended, community blood centers

began to appear under the auspices of American

Red Cross chapters, community service clubs, and

local medical societies. These centers acted as staging areas from which mobile operations could be

sent for blood collections, after which the blood

was returned to the center for processing and

subsequent distribution to hospitals.

Blood collection and processing in a community blood center can function as an assemblyline operation because of the need for repeating

the same battery of tests on a number of donor

79
80 ● Blood Policy and Technology

samples, ranging from 200 per day in mediumsize centers to over 1,000 per day in large centers.

On the other hand, transfusion services repeat the

entire workflow upon receipt of physician orders

which, except in cases of standing orders for elective surgeries, are unpredictable and often urgent.

Therefore, batch or assembly-line processing is

not as feasible, except for verification of donors’

blood types and elective surgery workups.

Blood is inherently variable, with each collected

unit representing a unique “lot. ” Because it is impossible to test each unit for effectiveness before

transfusion, the use of scientifically proven protocols and regular checks on representative products are important.

The use of computers for donor resources and

inventory management at the community blood

center, and standard policies for surgical blood

needs at the transfusion service have improved

blood utilization, decreased outdating, reduced

charges to the patient, and improved management

of donor resources. Computer management of

discrete functions has been accomplished at many

U.S. blood centers, but often lack coordination

among donor recruitment, collection, laboratory,

inventory, and financial management departments. One comprehensive information system

has been designed as a joint venture between two

community blood centers (Blood Center of Southeastern Wisconsin and the South Florida Blood

Service) and Arthur Andersen & Co. The goals

of all such systems are to minimize manual documentation and subjective analysis, and provide

useful statistics for operational management and

planning.

A number of automated data management systems throughout the world utilize uniform bar

coding technology for the identification of donor

units and samples for production and inventory

management. This uniformity, which has the

advantage of standardized machine-readable as

well as simplified eye-readable features, is the result of a special task force of the American Blood

Commission, whose efforts were funded by the

National Heart, Lung, and Blood Institute and endorsed by the International Society for Blood

Transfusion.

Figure 9 shows an example of this labeling format. The labeling scheme has been endorsed by

FDA (182) and appears on 60 to 70 percent of

products distributed by U.S. blood banks. However, not all blood centers who label their products with bar codes have the equipment to make

use of the machine-readable information, and few

transfusion services have the capability. Nevertheless, eye-readable uniformity and simplicity are

universally appreciated aspects of the commonality

label, given a history of multiple color-coded label schemes and superfluous information on

earlier blood product label formats. The uniform

label has allowed developers of automated testing

systems and management information systems to

design equipment and software around a single

machine-readable format for use in the United

States and several countries in Europe and the Far

East.

As yet untapped, but applicable, technologies

include: recruiting by computerized telecommunications linkages, donor and physician education

via cable health networks, and robotics laboratories to perform certain repetitive tasks (209).

The feasibility of these alternatives is unproven,

but studies are under way.

Blood Collection

Technologies involved with collection of blood

from donors address three basic functions: 1) accurate identification of donors, 2) determination

of donor suitability, and 3) collection of blood.

Donor identification is accomplished in most

blood banks by the use of a cardboard or plastic

card embossed with name, address, permanent

identification number, and blood type. Most

blood banks also have rosters of “special” donors

against which the donor’s identification is compared. “Special” donors include individuals whose

blood is extraordinarily rare (for special needs),

as well as those whose blood is unacceptable for

transfusion due to laboratory findings on previous donations.

Donor suitability is determined by an assessment of current health status (temperature, blood

pressure, screening test for anemia, etc. ) and an
Ch. 4—Blood Technologies . 81

Figure 9.— Uniform Labeling Format for Blood Products

II I II

F 01255

I I

I I

\\ \\ \ 9

Unit Number EXPIRES

\

I

--------

1 hlrmd

LOT NO CODE

/

SOURCE: E Rosslter, “Technologies for Blood Collection, ” 1984

interview covering past and present illnesses, immunizations, hospital procedures, or other conditions (including travel outside the United States,

lifestyle, and exposure to other individuals) which

could make donating blood unsafe for the donor

or transfusion unsafe for the recipient. While some

of the donor acceptability criteria are straightforward, most are subject to varying degrees of interpretation at the time of screening, In the absence

of factual information to support all the decisions

that affect donor suitability, intuition is often used

EXPIRES

Form 7203 (1/81)

(598). There are also concerns among blood bank

physicians about the adequacy of current donor

criteria when used for frequent, long-term donors

(562).

Pre-donation cell counts or hemoglobin measurements generally assure that donating will not

be unduly risky for the donor and that an adequate number or volume of the desired component can be collected. Findings of diminished

platelet effectiveness in individuals taking aspirin
82 . Blood Policy and Technology

has led to deferral of such donors in plateletapheresis programs (565). (See ch. 2, pt. 3, for

a discussion of the risks to donors. )

One measure of the safety of the collection

process is the frequency of moderate to severe reactions in which donors faint or lose consciousness during or after donation. A rate of 0.3 percent or less is regarded as acceptable (44).

Collection of whole blood is accomplished by

the use of pre-sterilized collection sets which consist of a needle, tubing and container pre-filled

with anticoagulant/preservative solution. The

main collection bag may have one or more smaller,

satellite bags attached to it by tubing. After

venipuncture, blood flows by gravity into the

main container, mixes with the anticoagulant/

preservative and remains there until an internal

closure is opened to the satellite containers for

component preparation. Table 26 lists the usual

types of components that can be made from each

container configuration.

Underutilization of the multiple bag set can result when changes in blood orders or incidents

during the collection process necessitate preparation of fewer or different components than the

ones for which the configuration was designed.

For example, a bad (traumatic) venipuncture

results in decreased platelet and cryoprecipitate

yields; therefore, if a triple pack is assigned to a

Table 26.—Standard Blood Collection

Container Systems

Bag configuration Components prepareda Cost per packb

Single pack Whole blood $3.18

Double pack Red blood cells $6,52

Plasma

Triple pack Red blood cells $11 .04’

Cryoprecipitate or platelets

Plasma

Ouadruple pack Red blood cells $14.55C

Platelets

Cryoprecipitate

Plasma

Quintuple pack Pediatric doses of red $17.78

blood cells and plasma

aproduct$ listed do not include modified whole blood end resulting byproducts,

or components prepared by breaking original (sterile) seals.

bList prices for CPDA.I systems from Fenwal Division, Baxter-Travenoi, Deerfieid, iL.

cprice iS for 5-day piatelet product; 3-day platelet or Cryoprecipitate container

price is reduced by $1.44.

SOURCE: E. Rossiter, “Technologies for Biood Collection,” 1984.

donor who subsequently has a traumatic venipuncture in the collecting process, only red blood

cells and plasma may be prepared. The empty,

extra satellite container, which represents a cost

of $4.52 (based on differences in the price of double and triple packs with a 5-day platelet storage

container in 1984) is lost. The extent of this problem has been estimated by some to affect 7 to 10

percent of collected units (472).

Successful adaptation of sterile docking devices

to routine component production operations

could eliminate the need for multiple bag configurations; all blood could be collected into single

packs (at $3.18 each in 1984) and those units

needed for component production could be coupled

with separate transfer packs (at $2.25 each in

1984) via sterile docking technology (projected

cost of $0.50 per component) (3)0 Savings of $0.50

to $1.00 per component would be possible. Further savings could be realized on less expensive

storage containers for products designated for further manufacturing (e.g., plasma fractionation).

During the last 10 years, a new technology

originating in the United States called “apheresis”

has become popular for the collection of large

amounts of a specific component from a single

donor. (The therapeutic use of this technology

was reviewed in a July 1983 OTA case study, The

Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis. )

Plasmapheresis can be accomplished by manual techniques, which involve collection containers and techniques similar to those for whole

blood collection. After centrifugation and separation of the plasma, the red cells, white cells, and

platelets are reinfused into the donor. The entire

process is then repeated, resulting in two final

plasma products and involving a second reinfusion of the donor’s residual cells. The procedure

takes approximately 90 minutes. Plasmapheresis

is a relatively uncommon procedure in community blood centers and transfusion services; for

example, less than 0.1 percent of the total plasma

collections in the Red Cross in 1983 were by

plasmapheresis (48).

Plasma may be collected as a byproduct of

automated cytapheresis (cells) procedures for

platelets or white blood cells. Current automated
Ch. 4—Blood Technologies Ž 83

technologies are not cost effective compared to

manual methods for routine plasmapheresis (2),

but are useful nonetheless in collecting large

amounts of antibody-rich plasma from specially

immunized donors for reagent use or further manufacturing into injectable products, such as hyperimmune anti-Rh(D) for prevention of hemolytic

disease in the newborn.

Membrane filtration technology under development may provide a cost-effective alternative

to automated plasmapheresis. One developer projects a 20- to 35-minute procedure in which operator intervention is minimized by microprocessor

control.

All automated apheresis devices work on the

principle of centrifuging whole blood to enable

the separation of components, transfer of the

desired component to a storage container, and

reinfusion of the remaining components. The first

apheresis devices were largely mechanical processors, but later machines are microprocessorcontrolled with multiple modes for different component schemes. Operator experience and technique have been shown to substantially affect

equipment performance.

Collection techniques for plateletapheresis are

fairly new. Effectiveness and safety data show

some variation in end-products, mainly in platelet

yield and undesirable contamination by extraneous white blood cells and red blood cells (198).

Current plateletapheresis technologies are summarized in table 27. The costs of all systems are

comparable (1984 prices); hardware is approximately $30,000 and collection container systems

$65-85, except for the 5-day container system.

Platelets collected by apheresis (single-donor

platelets) have been proven to be as safe and effective as platelets prepared from whole blood

(random-donor platelets) (301, 501), but there is

controversy surrounding the extent to which

plateletapheresis products should be used in lieu

of platelets from whole blood collections. Critics

of “routine” plateletapheresis cite economic reasons (pheresis platelets costs ranged from $2OO to

$350 per dose; manually collected platelets, from

$125 to $200 in 1984), the higher prevalence of

donor complications, and lack of clinical data to

support widespread and indiscriminate use of

plateletapheresis technology (483). Nevertheless,

few blood bankers doubt that apheresis technologies could someday replace manual platelet collections.

The 24-hour shelf life of apheresis platelets

(compared to the 3- or 5-day shelf life of platelets

separated from whole blood collections, because

the collection system in apheresis is opened in the

separation and reinfusion of the donor’s cells) has

been a major problem in inventory management

with these products. But one company, Fenwal,

is now marketing a closed system for the production of apheresis platelets with a 5-day shelf life.

Table 27.—Plateletapheresis Technologiesa

Product

Manufactured Year dating

Technology model developed period Comments

lntermittentflow centrifuge . . . . . . . . . . . . . . Haemonetics 30 1973

Haemonetics V-50 1983

Continuous-flow

centrifuge . . . . . . . . . . . . . . . . . . Fenwal CS 3000 1979

1983

Dual stage continuousflow centrifuge . . . . . . . . . . . . . . IBM 2997 1977

24 hrs. First system approved by FDA. Requires

extra step to remove extraneous cell

contamination.

24 hrs. Produces platelet-rich plasma.

24 hrs. Fewer extraneous red blood ceils.

Lower extracorporeal volume.

5 days Sterile docking device technology and a

different type of storage container add

$40 to collection container costs.

24 hrs. Manufacturer plans no further development of product Iine.b
84 ● Blood Policy and Technology

Leukapheresis (for collection of white blood

cells) can also be performed (independent of or

concomitant with platelet collection) with the

same technology; costs and techniques are similar to those for plateletapheresis. Although the

safety, effectiveness and efficiency of leukapheresis technologies, and leukocytes as a transfusion

product have been under study for over a decade, use of the technology remains controversial

(90,405,468). Clinical data to support the use of

white blood cell transfusions are extremely difficult to obtain because of the morbidity of the recipients; white blood cells have generally been

used for individuals with overwhelming infections

unresponsive to antibiotics.

Blood Component Preparation

The proportion of whole blood donations that

are separated into components varies among

blood centers from around 50 to more than 99

percent, reflecting local medical preferences and

practices. The minimum yield from one unit of

whole blood is one unit of red cells and one unit

of plasma. Additional components which are

commonly separated are platelets and cryoprecipitate.

The plasma and cellular components of collected whole blood will separate by gravity over

Figure 10.—Derivation

Red blood cells

a period of about 24 hours. The most dense cells,

red blood cells, settle out to fill the bottom half

of a container. Less dense white cells settle in a

thin, visible layer on top of the red cell mass.

Platelets are distributed among the white blood

cells, with some platelets remaining suspended in

the plasma layer.

This separation process can be accomplished

in a matter of minutes using high-speed centrifuges. The flexibility of the plastic collection container allows removal of the top layer into a sterile

attached satellite bag.

The original collection container configuration

dictates the number and type of components

which can be prepared from whole blood (see

table 26). Through a scheme of primary and secondary processing steps, a variety of end-products

can be produced, either for direct transfusion or

for further manufacturing into other products (fig.

10). Secondary processing adds to product cost

and is generally limited to special applications.

On average, 80 percent of whole blood collections are processed into two or more components,

most commonly red blood cells and frozen or liquid plasma. Platelets are also prepared from over

30 percent of collections and have become the

“driving force” behind scheduling and planning

of component production. Platelet shelf life is the

of Blood Components

Further

manufacturing

Washed None

None

Rejuvenated None

Leukocytes removed Byproduct white blood cells

Whole

(

Platelets

(liquid)

Plasma

(liquid)

Fresh frozen

Frozen

None

Fractionating for plasma

protein products

factor concentrate

None
Ch. 4—Blood Technologies ● 8 5

shortest of all whole blood components, except

for granulocytes; the product must be prepared

within several hours of blood collection to preserve platelet function and survival. Because over

60 percent of blood collection operations are offsite periodic shuttles back to the blood center are

necessary throughout the day. Special collection

operations are scheduled over weekends and

holidays to avoid shortages.

The development in 1981 of new plastics for

storing platelets increased shelf life from 3 to 5

days and has alleviated some of the production

constraints. Initial studies show improved efficiency by an increase in product availability and

decrease in outdating (414b). Longer shelf life has

also allowed a reduction in the number of shuttles and weekend operations, further improving

component production efficiency. Notable increases in platelet demand and utilization were experienced in 1983 in the Red Cross, where 75 percent of the platelet production was in the 5-day

plastic containers (48,351).

The extended shelf life of platelets is possible

because of two different new plastics which allow

better exchange of oxygen and carbon dioxide

through the walls of the platelet storage container,

thereby preventing the buildup of acid (as metabolic processes continue in the stored product)

that is toxic to platelets. The new plastics have

an additional advantage over previous formulations in that they lack DEHP, a common plasticizer used in construction, home furnishings,

clothing, etc., which is known to leach into blood

during storage and therefore has caused concern

over potential toxicity (562).

The storage life of liquid-stored red blood cells

and whole blood was extended from 21 to 35 days

by the addition of adenine to the basic preservative solution in 1978. The improved efficiencies

from this change have resulted in 50 percent reduction in outdating, now at approximately 5 percent (48). Further extension of red blood cell shelf

life to 49 days is now possible. Red blood cells

are first suspended in CPD anticoagulant (one of

the standard preservatives), then an additive nutrient solution (AS-1, or ADSOLTM, from the

Fenwal Division of Travenol Laboratories) is

added after other components are separated. It

is not known whether the additive system approach (still in the introductory phase in 1984)

will allow appreciable further reduction in red

blood cell outdating, but there are other advantages to additive systems recognized from years

of use in Sweden and Australia (267,345). They

include increased plasma recovery (the additive

solution replaces the buffering function of plasma

during storage), better red cell survival in the recipient, and transfusion viscosity similar to that

of whole blood,

Potential disadvantages include the additional

cost of the collection container (approximately 13

percent more), extra manipulation during component preparation, and the potential need to

remove excess solution in patients subject to circulatory overload (392). Nevertheless, the additive solution approach represents a technology

designed to make possible specific preservative

solutions tailor-made for each blood component

(315).

Future component storage research is aimed at

further increases in platelet shelf life and the use

of ascorbate (vitamin C) to improve maintenance

of certain red blood cell functions.

Recent advances and commercial successes in

extending the shelf life of platelets are likely to

spawn further improvements in dating periods.

Use of additive solution systems, if widely accepted in the blood banking community, will

facilitate research into component-specific preservatives. There also is interest in automating

component production by the adaptation of

robotics systems used in the U.S. automobile industry. Such a system has been designed, and its

feasibility and potential impact are under study

(209).

Testing and Labeling of Blood

From Donors

With every donation, blood samples are tested

for selected red blood cell antigens and antibodies

and certain transmissible diseases (table 28). Test

methods, their scientific bases, and potential clinical relevance vary greatly.
86 ● Blood Policy and Technology

Table 28.—Testing of Blood Donor Samples

Test Test detects Reason performed Clinical significance

SOURCE’ U.S. Department of Health and Human Services, FDA Panel, 1979

Red blood cell tests determine the donor’s ABO

and Rh type. Mild incompatibility can result in

an ineffective transfusion due to reduced red blood

cell survival. Major ABO group incompatibility

can result in fatal hemolytic transfusion reactions.

Because of this danger, the donor ABO and Rh

type are confirmed by the transfusion service, and

ABO compatibility may be verified by crosshatching.

Standard tests for red cell antigens and antibodies are based on the principle of hemagglutination; i.e., the clumping of red blood cells that can

occur as a result of specific antigen-antibody reactions. When a red cell antibody comes into contact with its target antigen on the surface of red

blood cells, it combines with the antigen, forming antibody “bridges” between cells, which lead

to visible clumps. Some antibodies (e.g., A and

B) are very effective in bridge formation; others

need antiglobulin (Coombs) reagent to form visible antibody bridges.

Table 29 demonstrates the serological basis for

determining the ABO group of an individual. Because A and B antibodies are naturally produced

by individuals who lack one or both of the antigens, it is possible to determine the ABO group

by testing for either antigens or antibodies. Common practice is to perform both tests and check

for agreement.

Rh type is determined by testing for D antigen

on red cells; there is no naturally occurring anTable 29.—Determination of ABO Blood Group

Antigens

on donor’s Antibodies

red blood cells in donor plasma

Donor blood group A B A B

0 . . . . . . . . . . . . . . . . . . No No Yes Yes

A . . . . . . . . . . . . . . . . . . Yes No No Yes

B No Yes Yes No

AB : : : : : : : : : : : : : : : : : Yes Yes No No

SOURCE E. Rossiter, “Technologies for Blood Collection, ” 1984.
Ch. 4—Blood Technologies ● 8 7

tibody to D as with A and B antigens. Some blood

banks perform two different tests for D antigen

to provide an internal check. Blood banks also

perform additional, more sensitive antiglobulin

(Coombs) testing on samples giving negative

results for D antigen. This technique will detect

weak or suppressed D antigen, but its clinical significance is unclear.

ABO and Rh types are genetically determined

and do not change. For this reason, some European blood centers do not repeat ABO and Rh

determinations on donors who have been previously tested (sometimes multiple testing will be

conducted before subsequent testing is discontinued). This practice would significantly reduce

the testing workload in the United States, because

approximately 80 percent of blood donors have

donated before (48). However, Federal regulations

currently require ABO and Rh testing on every

donation. On the other hand, some blood banks

in Canada and Europe do more elaborate Rh typing than is done in the United States, testing for

C and/or E antigens (of the same family as D).

This practice has been discontinued in most U.S.

blood banks with no increased risk to recipients

(562).

ABO and Rh testing can be performed by manual or automated methods. Table 30 summarizes

the different manual techniques used for detecting red cell antigens and antibodies. All manual

techniques involve mixing of sera-containing antibodies and red blood cell suspensions, and visual

examination for clumping. Tube and microplate

techniques allow centrifugation of the test mixture for easier reading of the test reaction. The

predominant manual test technique is the tube

method, although use of microplates (actually a

miniaturization of the tube technique) has been

increasing since the late 1970s. In 1984, within the

Red Cross alone, 14 centers used manual microplate techniques as their primary method, and

another 7 used microplates as a backup to automated methods.

The Technicon AutoAnalyzer, introduced in

1967, was the first attempt to automate routine

donor testing. It used continuous flow technology already proven in clinical chemistry analysis, It automatically samples and performs ABO,

Rh, and STS (serological test for syphilis) tests,

but relies on the operator to identify samples, read

reactions, and interpret and record results. Nevertheless, the AutoAnalyzer was widely used (still

about 200,000 worldwide), easy to repair and

maintain, and, at about $30,000, within the price

range of a number of medium to large blood

centers; the largest of them often had two. The

AutoAnalyzer is no longer produced but is still

used in a number of centers.

Table 31 lists the fully automated testing technologies used in the United States in 1984. All

identify samples via bar-coded label, sample automatically, perform tests, read results by a photometer, and interpret results via dedicated computer. All systems also have some capability to

perform antibody screening and STS, but are not

generally used for these purposes in the United

States. Costs per donor sample range from $0.83

to $1.23 v. $0.53 for the AutoAnalyzer (208).

These systems are much more difficult to maintain

and repair. Overall costs of the fully automated

Table 30.—Comparison of Manual Technologies for Red Cell Serological Testing of Blood Donors

Type Advantages Disadvantages

Slide/tile testing . . . . . . . . . . Simple, fast, inexpensive.

Tube testing . . . . . . . . . . . . . . Allows the use of more sensitive

techniques than slide. Adaptable to batch

testing up to approximately 200 samples.

Microplate. . . . . . . . . . . . . . . . More sensitive than tube or slide. Uses

less sample, reagent and space. Easily

adaptable to large batch testing.

SOURCE E Rossiter, “Technologies for Blood Collect ion,” 1984

Less sensitive. Not adaptable to automation. Difficult to use in batch testing.

Coombs testing impossible without supplemental use of tubes.

Requires labeling and manipulation of

tubes. Uses larger amount of reagent and

sample than slide or microplate.

More dexterity required for sampling and

plate handling. May require new reaction

interpretation techniques.
88 ● Blood Policy and Technology

Table 31.—A utomated ABO/Rh Test Technologies in the United States, 1983

Number Price

System name Manufacturer Principle of centers (x1,000)

AutoGrouper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Technicon a Continuous flow analysis 11 $184

MiniGroupamatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kontronb Discrete analysis 5 $115

G-2000 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kontron Discrete analysis 8 $260

G-360 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kontron Discrete analysis 8 $460

aTarrytown, NY bEverett, MA

SOURCE:L Friedman, ’’Status ot Automated ABO/Rh Testing i n the US” ARC internal Report, 1983

systems are beyond the grasp of most community

blood centers (only 32 of 213 U.S. community

blood centers were using them in 1984).

The testing of blood donor samples for unexpected antibodies involves the use of reagent red

bloodcells selected on the basis of antigenic content. The test was originally designed to detect

antibodies in recipient plasma that might cause

difficulty in crosshatching, but it has become a

standard test for every sample entering the blood

bank. Tube or microplate testing is necessary to

detect clinically significant antibodies that react

only with Coombs reagent. Microplate techniques

are more efficient and more sensitive for this purpose (487).

Although traditional screening techniques have

included multi-phase testing with various enhancers

and potentiators, there is little justification for

elaborate procedures on donor samples. Regular

blood donors who have not been transfused or

pregnant since the last negative antibody screen

could be excluded from subsequent testing, but

the effort required to selectively exclude these

donors may negate the benefits of decreased

testing.

A new and abundant source of antibody production was developed in the 1970s and is being

applied commercially in the 1980s. Monoclinal

antibody technology (see ch. 6, pt. 2) allows largescale production of antibodies with selected specificity and potency (575). Production of antibodies

in this manner should eventually become less expensive and have the added advantage of reducing variability in test results that is inherent in

using naturally produced human or animal serum.

Monoclinal antibodies also can be easily labeled

with indicator substances (radioactive, fluorescent, etc. ) (436). Only a few monoclinal reagents

have been approved for blood bank products, but

many are under development.

Recent increase .. ss in the use of microplates for

manual ABO/Rh testing have led to renewed interest in automating that technique. Initial developmental work from at least three companies

indicates that “ELISA” readers, photometers currently used for reading enzyme-linked immunosorbent assays (an immunologic test) can be

adapted for reading hemagglutination reactions.

Coupled with dedicated computers for data analysis and interpretation, market projections indicate that these devices could be a more economical alternative for automated ABO/Rh testing

(table 32). The automated microplate system prototypes require more manipulation of test samples

than the current automated technologies, but the

techniques for manual and automated microplate

testing are the same, allowing easy conversion

from one technology to the other.

Still another technology under development for

several years by Gamma Biological, Inc. (Houston, TX) involves modified microplate technology (MicrotearTM), which offers visual or automated interpretation of hemagglutination by the

“streaming” of red blood cells after centrifugation.

All of the testing technologies described thus

far are liquid-phase tests; i.e., they involve the

mixing of sera-containing antibodies with red

blood cells in suspension, and the qualitative

reading of the presence or absence of agglutination. A solid-phase immunoadsorbance technique

has been patented by Rosenfield and Kochwa

(U.S. patent # 4,275,053, June 23, 1981), and similar developmental work has been presented by

Plapp and associates (1983), which offer quantitative evaluation of antigen-antibody interactions. Greatly increased sensitivity results from
Ch. 4—Blood Technologies ● 8 9

Table 32.—Traditional Automated Technologies v.

Automated Microplate Systems (AMS)

Tradition ala AMSb

Machine Costs . . . . . . . . . . . . . . . . $115K-$420K

—

$25K-$60K

Cost per sample ABO/Rh. . . . . . . $0.83-$1.23 $0.68

Operator intervention . . . . . . . . . . Minimal Centrifugation, resuspension, and loading of microplates required.

Backup technology , . . . . . . . . ., . Second machine, manual Standard manual microplate

tube, or microplate. technology is inherent

alternative.

Figures are based on estimates from developers

SOURCE Friedman, personal communication, 1983

affixing the reaction components to a solid surface (usually a microplate well), but the utility of

this technique in routine donor processing has not

been proven.

Except for the semiautomated AutoAnalyzer

techniques developed in the late 1960s, screening

technologies for syphilis have been unchanged for

the past 15 to 20 years. The tests are not specific;

approximately 90 percent of positive reactions are

due to causes other than syphilis. Questions have

been raised about the health status of false positive

reactors; some scientists believe the test may be

indicative of pre-disease states, the infectivity of

which is unknown (562). However, the overwhelming opinion of FDA expert panels, AABB,

and ARC is that the STS test need not be required

for donor samples. Federal regulations and most

State health departments currently require STS

testing, in spite of the lack of scientific evidence

to support its continued use.

Hepatitis testing technologies have undergone

rapid evolution since the discovery of Australia

antigen (80). The antigen so discovered was a

marker of hepatitis B virus and led to development of a succession of increasingly more sensitive

tests for hepatitis B surface antigen (HBsAg). Like

other tests on donor blood, it is repeated on every

donation, regardless of the donation frequency

and history, and once a donor has had a confirmed positive test, he or she is permanently disqualified as a donor. No confirmation of the (negative) test is performed by the transfusion service.

Current “third generation” technologies for

HBsAg testing are compared in table 33. Enzyme

immunoassay (EIA) are of equal sensitivity as

radioimmunoassay (RIA) techniques, but are increasingly preferred over RIA due to cumbersome

monitoring, licensing and waste disposal requirements for the radioisotopes used in RIA testing.

Both EIA and RIA have automatic reading of reactions and interpretation of results. Abbott Laboratories, the leading company in the field of

HBsAg testing, is developing a more complete

automated system which identifies samples by bar

code and can interface with other blood center

computers.

Once all testing is completed on donor samples,

blood components with unsatisfactory test results

must be disposed of and satisfactory units labeled

according to ABO, Rh and a statement of satisfactory test results (e.g., for HBsAg), and released

for distribution. This is a most crucial procedure,

since the mistaken release of a unit reactive to

HBsAg would go undetected, and blood labeled

incorrectly for ABO group could be transfused

into an incompatible recipient.

Labeling and release of blood components are

tedious and laborious tasks. They are usually performed in batches by a team of two or more persons, with one individual applying adhesive labels

and the other checking laboratory and donor

records. To minimize human error and facilitate

the process, computers storing laboratory and

donor suitability data can be used to print appropriate labels or to verify that a correct bar-coded

label has been applied, and that all testing on a

blood component has been satisfactory. Such systems, fully integrated with automated testing sys38-647 0 - 85 - 7
90• Blood Policy and Technology

Table 33.—Current Technologies for HBsAGa Testing

Agglutination test type Immunoassay test type

Latex Red blood cell Radio-plastic Enzyme-plastic

Test surface Slide/tile Micro plate Bead or tube Bead or tube

Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Good Good Excellent Excellent

Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fair Good Excellent Excellent

Interpretation of results . . . . . . . . . . . . . . . . . . . . . . . Subjective Subjective Objective Objective

Positive results indicated by . . . . . . . . . . . . . . . . . . . Clumping of Clumping of “Radioactive”b Colored

particles red blood cells bead solution

Automated reading . . . . . . . . . . . . . . . . . . . . . . . . . . . No Under Yes Yes

development

terns, are operational in probably not more than

10 community blood centers, and no onsite printers

approved by the American Blood Commission are

being used, but they are the ultimate goal of any

facility introducing computers into the laboratory.

Pre-Transfusion Testing Techniques

The purpose of test procedures in the transfusion service is to minimize risk of major serologic

incompatibility. The ABO/Rh type of the donor

unit is rechecked, the ABO/Rh type of the recipient determined, and a crosshatch performed between the recipient sample and selected donor

samples. Though not required by Federal regulations, AABB accredited transfusion services must

also perform a recipient antibody screen. Recipient antibody screening yields much the same information as the crosshatch, and there has been

increasing questioning of the need for both tests

since the antibody screen was required for accreditation by AABB in 1970. The next revision of the

AABB standards is likely to allow some options

in choosing between the tests.

The first crosshatch was a simple mixing of two

blood samples and observing for hemagglutination. The test eventually evolved into two distinct

procedures —mixing of recipient plasma with

donor red blood cells, and mixing of donor plasma

with recipient red blood cells (fig. 11). The former

is now regarded as the “major” crosshatch, because it is of prime importance in predicting the

likelihood of a hemolytic transfusion reaction (recipient’s antibodies would destroy the infused red

cells). The latter, “minor” crosshatch, is no longer

required by Federal or voluntary standards.

Figure 11 .—The Crosshatch

Donor Recipient

red blood red blood

cells cells

Donor Recipient

plasma plasma

SOURCE: Rossiter, E., “’Technologies for Blood Collection,” 1984.

In spite of the diversity of approaches taken in

testing, decisions about when to crosshatch and

how many units to hold available have become

increasingly standardized. Eighty-three percent of

responders to a recent survey (588) used a typeand-screen (T&S) procedure in which preliminary

testing (ABO, Rh, and antibody screen) is performed on low-risk surgical patients, and blood

is made available (though not crosshatched). The

T&S policy is implemented after each blood bank

reviews its own transfusion statistics across “surgery-related” groups and determines which elective surgical procedures seldom result in transfusion. In the rare instances in which blood is

needed during or after these surgeries, blood will

be released for transfusion with an abbreviated

crosshatch.
Ch. 4—Blood Technologies . 91

Studies of the safety of T&S practices indicate

that they are both safe (408b) and economical

(203). T&S and similar policies which establish

a standard number of crosshatched units for

surgeries that usually require transfusion, improve

blood resources management through lower inventory needs, improved utilization, and decreased outdating.

Conclusions

Technologies developed and put into use during the last 10 years have made blood products

more effective, and have increased their safety.

The biggest improvements have been in efficiency,

with increased availability and better utilization

of products.

Trends for the next 5 to 10 years in the use of

technologies will be continued increases in automation and computerization, and further improvements in blood preservation. These changes

are a natural result of technological changes made

since the late 1970s and reflect the dynamic climate

in which U.S. blood banks operate.

PART 2: PLASMA FRACTIONATION TECHNOLOGIES

Introduction

Plasma fractionation began in this country during World War II. At the onset of the war, liquid

human plasma was in use in the battlefields of Europe, but there was a need for a blood substitute

that was easy to transport and which could be

administered on the battlefield under widely varying climatic conditions.

At the request of the Medical Advisory Committee of the Red Cross and the National Research

Council’s Committee on Blood Transfusions, Edwin J. Cohn, head of the Department of Physical

Chemistry at Harvard University, agreed to

undertake an investigation to determine whether

or not the plasma of animals could be made safe

for transfusion. By mid-1940), Cohn notified the

Red Cross of the development of a system which

would yield not only albumin but other protein

components of plasma as well, but said he felt that

dependence should be placed on the use of human

plasma rather than that of animals. The Red Cross

then opened a blood donor facility at Peter Bent

Brigham Hospital in Boston to provide plasma to

support Cohn’s work. In April 1941, the first

human serum albumin produced by Cohn was

released for clinical trials, and by July 1941, pilot

production facilities had been expanded.

In December 1941, clinical studies had not yet

been concluded, but human derivatives from Harvard were rushed to Pearl Harbor for use in treatment of injured servicemen. By 1942, the Armed

Forces had authorized regular use of normal serum

albumin (NSA) and issued production contracts

to several pharmaceutical firms. Training of technical personnel from these firms was conducted

by Cohn and his staff. Cutter began to supply the

product in late 1942, and by 1943 seven U.S. companies were involved in fractionation and supply

of human plasma products. Following World War

II, these companies continued to process plasma

to meet the demand for various plasma proteins

for civilian use.

During the beginning of plasma fractionation

in the 1940s, albumin production and sale provided the economic support for the industry. Later

in the 1950s, the need for gamma globulin for prophylaxis against poliomyelitis, infectious hepatitis,

and childhood viral diseases provided financial

security for the industy. Subsequently, prevalence

of these diseases was markedly decreased, and at

about the same time methods for recovering Factor VIII were greatly improved, leading to increased treatment of hemophiliacs in the United

States and abroad. As a result, sales of Factor VIII

have been a significant source of revenues from

the mid-1960s to the present.

Plasma Collection

Three types of plasma are used to produce

plasma derivatives; liquid single-donor plasma,

fresh-frozen, single-donor plasma, and “source”

plasma, which is collected by plasmapheresis. Liq-
92 . Blood Policy and Technology

uid and fresh-frozen, single-donor plasma are primarily obtained through volunteer agencies as

“recovered” plasma from whole blood donations.

“Recovered” plasma is either fresh frozen within

6 to 24 hours of collection or is salvaged from outdated whole blood at the time the red cells are

discarded. Only fresh-frozen plasma is suitable

for Factor VIII fractionation. Increased use of

components has resulted in an increasing proportion of recovered plasma being frozen within a

few hours of collection to protect the labile coagulation factors. Single units of fresh-frozen plasma

are then shipped directly to the fractionators.

In plasmapheresis, 500 ml of whole blood is

drawn into a sterile container in which there is

anticoagulant solution (either ACD Formula A,

CPD, or Trisodium Citrate). The container is then

detached and the blood centrifuged in order to

separate the red cells from the plasma. During this

time the phlebotomy needle is kept open with

an infusion of isotonic salt (NaCl) solution. The

red cells are then reinfused into the donor, and

the process is repeated a second time. The 0.5 to

0.6 liters of collected plasma are then frozen. The

average elapsed time for such plasmapheresis is

90 minutes. Each donor is permitted to undergo

a double-bleeding of this type twice per week.

At least three systems for the automation of

plasmapheresis are currently undergoing research

and development: membrane filtration, continuous flow centrifugation, and intermittent flow

(batch) centrifugation. As yet, none is able to

compete economically with the traditional manual technique. Although the manual system is

labor-intensive, the total cost of a double pack

of plasma is in the range of $22 to $25 (277), including $7 to $10 for the donor fee, $8 for the

blood bag set and saline solution, $2 for donor

screening and testing, and $5 for labor. In the case

of automated centrifugal systems, the disposable

plastic bowls alone cost more than this; Haemonetics

$55, Fenwal $60, and IBM $65. However, these

costs could plummet if simplified to be used for

source plasma alone. The state of the art of the

automated centrifugal system has been developed

far beyond the needs for plasma collection because

the same basic hardware (with costs of approximately $20,000) and disposable plastic bowls can

be used to prepare platelet concentrates, buffy

coats (leukocytes), and washed red cells.

On a theoretical basis, filtration through membranes of appropriate pore size should be the

simplest way to separate liquid plasma from the

cells in whole blood. Earlier development of this

technology has been hampered by the fact that

filtration does not simultaneously yield cellular

components such as platelets to help amortize the

development costs. However, its potential value

in therapeutic plasmapheresis may catalyze its

evaluation in the collection of normal (source)

plasma. Membrane filtration at low temperatures

has also been attempted experimentally to isolate

Factor VIII-rich cryoprecipitate. Large-scale application of this new technology has not been attempted.

The estimated time required for a centrifugal

plasmapheresis separation is 30 to 40 minutes, and

for continuous flow membrane filtration, 50 to

60 minutes. When donor preparation time is

added in, the overall plasmapheresis time is slightly

longer than 1 hour. This compares with approximately 90 minutes for the traditional manual system (2). The interrupted flow centrifugal system

also requires only a single venipuncture, as opposed to the two needles or large, double lumen

needle necessary for continuous flow. The principal advantages of automated plasmapheresis

are: 1) the donor is always attached to his/her

own red cells or whole blood, thus preventing accidental administration of mismatched cells; and

2) the potential population of plasma donors may

be able to be expanded significantly throughout

the world. Automation also raises the possibility

of decentralized plasmapheresis, and, by shortening the overall procedure time, also enhances the

possibility of inclusion of volunteer donors for

source plasma. The remaining unanswered question is whether or not increased volumes of plastic

disposable will lower costs sufficiently to compete with a manual system in which labor costs

are only 20 percent of final production costs.

There are two types of plasmapheresis donors:

standard donors and specialized donors. Hightiter antibody preparations (hyperimmune globulins) are made from the plasma of specialized
Ch. 4—Blood Technologies ● 9 3

donors. Successful passive immunization is greatly

improved by use of gamma globulin fractions high

in specific antibody content against the individual diseases. The hyperimmunization of selected

(specialized) donors through repeated stimulation

of their immune systems with specific antigens

(noninfectious products made from the inactivated

protein of the underlying virus or bacteria) can

provide a pool of high-titer antisera. This technique has provided specific globulins for the management of such diverse disorders as rabies, herpes zoster, and hepatitis B.

In a similar manner, individuals who inadvertently have been immunized through prior

blood transfusions or pregnancy, or who elect to

become donors of blood group antibody sera, can

have their titers restimulated over a period of

years and maintain their role as specialized plasmapheresis donors for the production of anti-A,

anti-B, or anti-Rh immune globulin for blood

group typing, or, in the case of anti-Rh, for the

prevention of Rh hemolytic disease of the newborn (erythroblastosis fetalis).

Some overlap occurs between standard and specialized plasmapheresis donors. Immunization

against tetanus, for example, is so commonly

practiced and easily accomplished that it is common for standard donors to receive occasional

booster doses, making possible the recovery of

a high titer of tetanus antibodies from routine

gamma globulin fractionation.

Fractionation Methods and Products

The principal method used for the isolation of

the different plasma proteins continues to be the

cold-ethanol precipitation technique of Cohn and

collaborators (127). This method employs a fourvariable system of temperature, ionic strength,

ethanol concentration, and pH to precipitate:

●

●

●

●

Fraction I—chiefly Factor VIII and fibrinogen,

Fraction II—the gamma globulins,

Fractions III and IV—other coagulation proteins and trace components such as ceruloplasmin and iron-binding globulin, and

Fraction V—the albumins.

Fraction VI, the residue remaining, is currently

discarded due to lack of known therapeutic usefulness.

Method XII, the final technique evolved by the

Cohn group (128), gave promise of considerable

simplification by using metallic precipitation of

the globulins with zinc diglycinate, but this method

was never commercially adopted due to preliminary evidence of contamination of the albumin

fraction with hepatitis virus. It also was impractical in its requirement for decalcified plasma

(through ion-exchange treatment) rather than the

usual citrated plasma.

Due to a shortage of industrial sources of alcohol in England following World War II, the

principal fractionation facilities which were constructed at the Lister Institute were modified to

permit use of ether rather than ethanol. The basic

principle of the four-variable Cohn system was

nonetheless used, and this method was continued

for a period of approximately 20 years, following which the ethanol system was again employed.

Nevertheless, many minor modifications of the

basic alcohol precipitation technique have been

introduced successfully with improvement in

yield, cost effectiveness, and stability of individual products.

Factor VIII

In the original alcohol fractionation method,

Factor VIII precipitated with fibrinogen in Fraction 1-.. The yield of Factor VIII by this method

was similar to that developed by cryoprecipitation, but contamination of the final product with

other proteins was considerably higher with the

original alcohol fractionation method. These concentrates were used to treat hemophilia during the

1940s and 1950s, and were marketed primarily for

their fibrinogen content. After the development

of the cryoprecipitate technique by Pool, et al.

(442), Fraction I-o was abandoned as too crude

a preparation to use for its Factor VIII content.

The fibrinogen, which the recipient received as

a side effect of the Factor VIII replacement, led

to problems in red cell crosshatching. Contamination with hepatitis virus was also so prevalent as
94 ● Blood Policy and Technology

to no longer justify its commercial preparation,

and approval of Fraction I-0 (fibrinogen) as a

plasma product was withdrawn by FDA in the

late 1970s.

“Cryoprecipitate” was discovered by Pool and

associates (442,443) to trap a significant portion

of Factor VIII, and thus provided a simple physical step to harvest it. Currently, cryoprecipitate

is either prepared as a single unit in a plastic bag

during the routine collection and processing of a

single unit of plasma in a blood bank, or the

plasma is frozen and shipped to the fractionation

industry.

The concentration of Factor VIII in cryoprecipitates varies widely, depending on such factors as

the size of the ice crystals which form and the local

salt concentrations left behind when water crystallizes into ice (419). Federal regulations require

that the average Factor VIII potency of a single

unit of cryoprecipitate be greater than 80 units

as determined on four representative containers

each month (21 CFR pt. 640.56). (The Factor VIII

content of any single unit that is being used therapeutically cannot, of course, be measured. ) For

example, the average content of a bag of cryoprecipitate as determined by one Red Cross blood

bank was assayed as containing: 1) 120 units of

Factor VIII (range of 105 to 130), 2) 46.6 mgm

of fibronectin, 3) 326 mgm of fibrinogen, and 4)

present but not quantified amounts of von Willebrand factor (420).

With commercial preparations of Factor VIII

concentrates, a higher concentration of Factor VIII

can be achieved with less volume of infusion

needed to administer it, and an exact Factor VIII

content of each preparation can be assayed rather

than assumed. Moreover, the stability and packaging of the concentrates is more suitable for

home therapy.

When large pools of frozen material are processed, thawing is carefully controlled to improve

yield and stability. The best yields of Factor VIII

from cryoprecipitate are approximately 25 percent of the starting material. (As mentioned in ch.

3, heat-treated Factor VIII concentrates are now

available. )

Gamma Globulins

Essentially all gamma globulins are recovered

from Cohn Fraction II using the classic coldethanol technique. Immune serum globulin (ISG)

is dispensed as a 16 percent protein solution for

intramuscular injection in amounts up to 10 ml,

or as a solution for intravenous injection (Intravenous gamma globulin, or IVGG).

Albumin

The production of albumin from fraction V-o

utilizes pH, ionic strength, and ethanol concentration to precipitate a highly purified concentrate

of this principal oncotic agent of plasma. The

powdered albumin is then resolubilized as either

a 5 percent solution, with the same oncotic pressure as normal plasma, or as a 25 percent concentrate of salt-poor albumin. The 25 percent concentrate is marketed as a hyperoncotic concentrate

which draws water from the extravascular tissues

to restore blood volume and circulatory competence in a recipient suffering from hypovolemic

shock.

An alternative method of albumin production

is the elimination of the subfractionation steps

which precipitate Fractions IV and V and reconstitution of these pooled fractions as an albumin

solution. This material, plasma protein fraction

(PPF), contains 83 to 90 percent albumin, no more

than 17 percent of the total protein as alpha or

beta globulin, and no more than 1 percent as

gamma globulin. Currently, after the preceding

fractions are removed, 30 percent of all fractionated plasma goes into PPF production and 70

percent into albumin production.

Albumin (and gamma globulin) can also be prepared from human placentas. Such processing is

different from plasma because of the large amount

of connective tissue, free supernatant hemoglobin, and other extraneous material which must

be removed by filtration, adsorption, and centrifugation, but the final products are of high

purity. The average yield of albumin by this technique is 5 gin/kg of placenta.
5 m

Current Issues
Page

Part l: Impact of Aids on Blood Collection and Use . . . . . . . . . . . . . . . . . . . . . . . 99

Part 2: Coordination of Blood Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Regionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Resource Sharing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

American Association of Blood Banks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

American Red Cross.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Volume of Sharing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Part 3: Impact of Health Care Cost Containment . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Part 4: Appropriate Use of Blood Products. ....,.. . . . . . . . . . . . . . . . . . . . . . . . . 121

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Whole Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Red Cell Concentrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Granulocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Cryoprecipitate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Fresh-Frozen and Single-Donor Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Albumin and Plasma Protein Fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Factor VIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Methods to Change Usage Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

LIST OF TABLES

Table No, Page

34.

35.

36.

37.

38.

39.

40.

41.

Centers for Disease Control’s Characterization of Groups at Increased Risk -

for AIDS in the United States (percent of total reported AIDS cases as of

Dec. 19,1983). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Resource Sharing Inventory Shipment Fees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

AABB Clearinghouse Transactions by Type ........, . . . . . . . . . . . . . . . . . . . 114

Utilization of AABB Clearinghouse, 1973-83 . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Blood and Blood Components Moved by American Red Cross Regional

Blood Centers in 1982 and 1983 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Movement of Blood and Components Through the American Red Cross,

1979-83 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Total Movement of Blood and Blood Components in the United States,

1979-83 (including both the AABB and the American Red Cross) . . . . . . . . . 117

Blood Utilization by Major Disease Categories Ranked by Total Units

Transfused and Percent of Units Transfused: Operated Males,

Nonoperated Males, Operated Females, Nonoperated Females, and

All Patients in Each Category . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5

Current Issues

PART 1: IMPACT OF AIDS ON BLOOD COLLECTION AND USE

Acquired immunodeficiency syndrome (AIDS)

is a disease now shown almost conclusively to be

of viral origin, with a high mortality rate ( >40

percent of all diagnosed cases), and which is apparently transmitted through body fluids (e.g.,

semen, blood) through such means as sexual contact and intravenous drug abuse.

The disease is characterized by a profound

disturbance of the immune system, with death

usually due to extreme susceptibility to infections

by organisms which rarely cause disease in persons with normal immunity (e.g., pneumocystis

carinii pneumonia) and/or the development of a

type of cancer (Kaposi’s sarcoma) that is usually

seen only in elderly or severely immunocompromised individuals.

The probable agent for AIDS attacks a type of

white blood cell, T lymphocytes, which help to

mediate the body’s immune system through helping or suppressing the production of antibodies.

It appears related to another virus which has been

recently identified as the cause of human T-cell

leukemia. The probable agent for AIDS apparently selectively infects and kills T-lymphocyte

“helper” cells, whereas the T-cell leukemia virus

infects T cells and, instead of killing them, turns

them into cancerous leukemia cells (211,444,

476,488). (AIDS is examined in an OTA Technical Memorandum, “A Review of the Public Health

Service’s Response to AIDS” (in press).)

In the United States, the early AIDS cases were

concentrated among homosexual and bisexual

men, intravenous drug abusers, and persons of

Haitian origin. As time passed, however, cases

began to show up in hemophiliacs, and investigations of cases of unknown origin appeared to

show a relationship between blood transfusions

and subsequent development of AIDS (143).

There was initial skepticism toward the conclusion that some AIDS cases were due to blood

transfusions, but at a February 1984 meeting of

blood banking representatives convened by the

Centers for Disease Control (CDC), there was

agreement that the evidence was conclusive enough

that AIDS could be and had been transmitted

through blood products, that no further studies

need be conducted to prove/disprove the association, and that studies to quantify and clarify

the risks were needed.

Table 34 summarizes the percent of AIDS cases

according to groups at risk as of January 1984.

The “other” category includes some cases of

apparent transfusion-related AIDS in infants,

whose immune status is sufficiently different from

adults so that CDC has classified these infant cases

separately from adult cases. Some of these infants,

however, either had transfusions or were children

of known AIDS patients.

In an April 1984 telephone conference call with

representatives of blood banking organizations,

CDC reported that there were: 1) 43 adult cases

of AIDS associated with blood transfusions, with

an additional 10 cases in children; and 2) 33 cases

of AIDS in hemophiliacs. CDC had completed its

investigations of 13 adult and 7 pediatric transfusion cases. In 12 of the 13 adult cases, at least one

donor was identified who was either in a highrisk AIDS group (e.g., homosexual or bisexual

Table 34.—Centers for Disease Control’s

Characterization of Groups at Increased Risk for AIDS

in the United States (percent of total reported AIDS cases

as of Dec. 19, 1983)

Percent of total

reported AIDS cases

Homosexual and bisexual men . . . . . . . . 71

Intravenous drug abusers . . . . . . . . . . . . . 17

Haitians living in the

United States . . . . . . . . . . . . . . . . . . . . . 5

Heterosexual contacts of persons

at increased risk for acquiring

AIDS ... , . . . . . . . . . . . . . . . . . . . . . . . . . 1

Hemophiliacs . . . . . . . . . . . . . . . . . . . . . . . 1

Recipients of blood transfusions . . . . . . 1

Other (unknown) . . . . . . . . . . . . . . . . . . . . . 4

Total . . . . . . . . . . . . . . . . . . . . . . . . 100%0 (3,000 cases)

SOURCE: CDC, Morbidity and Mortality Weekly Review, Jan. 6, 1964

99
100 . Blood Policy and Technology

men) or who had an abnormal T-lymphocyte

helper: suppressor ratio. At least one high-risk

donor was identified in five of the seven pediatric

cases with completed investigations.

The incidence of transfusion-related cases of

AIDS is difficult to estimate because CDC traced

blood donations as far back as 5 years in their

search for a possible cause. CDC’S first report of

an association of transfusions with AIDS, for example, stated that the first 18 cases they reported

on were diagnosed during approximately a 12-

month period (to August 1983), when over 3 million persons in the United States received transfusions. But most of these cases were transfused between 1979 and 1982, when the prevalence of

AIDS was much lower than during late 1982 and

early 1983 (143). An incidence rate based on the

time of diagnosis would be 18 per 3 million persons transfused, or 6 cases for every million persons transfused. At a rate of approximately 10

million units of blood components transfused per

year (518), there would have been approximately

2 cases of AIDS for every million units transfused.

Cases in hemophiliacs have occurred at a much

higher rate. Estimates are that there are 15,000

moderate to severe hemophiliacs in the United

States (6), and 5,000 more mild hemophiliacs

(173), or a rate of about 1/500 for the 37 AIDS

cases diagnosed as of June 1984.

Hemophiliacs have been at highest risk of all

blood group recipients, probably through the use

of Factor VIII (and Factor IX) concentrates. If

AIDS is indeed a virus, and based on the histories of the transfusion-related AIDS cases (143),

all blood components—whole blood, red cells,

platelets, cryoprecipitate, and plasma—are also

capable of transmitting the agent.

Several methods have been employed to screen

out AIDS from the blood supply. These include:

1) donor screening in addition to those methods

which were already employed, 2) laboratory tests

to identify donors at risks for AIDS, 3) product

recalls, and 4) attempts to inactivate the AIDS

agent.

FDA, in consultation with the major blood

banking and plasma derivative organizations, the

National Hemophilia Foundation, the National

Gay Task Force, the Centers for Disease Control,

and the National Institutes of Health, issued a recommendation in March 1983 to initiate the following procedures (566):

1.

2.

3.

4.

Educational programs to inform persons at

increased risk of AIDS to refrain from blood

or plasma donation. Persons at increased risk

of AIDS were defined as follows: persons

with symptoms and signs suggestive of

AIDS, sexually active homosexual or bisexual men with multiple partners, Haitian en--

trants to the United States, present or past

abusers of intravenous drugs (such intravenous drug abusers were already excluded

by prior regulations), and sexual partners of

persons at increased risk of AIDS.

Expanded medical screening of blood and

plasma donors to identify individuals with

early signs or symptoms of AIDS, with revision of standard operating procedures to include questions to elicit a history of night

sweats, unexplained fevers, unexpected weight

loss or signs of lymph node enlargement or

Kaposi’s sarcoma.

Examination of source plasma donors for

lymph node enlargement by a physician (initially and annually), and by an adequately

trained individual at each donation.

Measurement of body weight of source

plasma donors prior to each donation to

detect unexplained weight loss. If loss was

detected, a physician’s examination was recommended prior to continued plasma collection.

The sensitivities involved in screening high-risk

donors are obvious; homosexual or other sexual

activities and the use of injectable drugs are activities associated with a high degree of social stigma

and illegal in many States. In negotiations surrounding the adoption of screening policies,

spokespersons for the gay community have expressed fears about what the “stigma of bad

blood” would do to a group already vulnerable

socially, politically, and economically (66,322).

To compound matters, it appears that the risk of

contracting and transmitting AIDS is linked to the

degree of sexual activity and number of sexual

partners. Leaders of the gay community have ob-
Ch. 5—Current Issues • 101

jected to the use of the value-laden term, “promiscuity” (368). Gay physicians have cooperated

and urged the adoption of a more restrictive definition of what constitutes a degree of sexual activity sufficient to contraindicate blood donation.

It has also been recognized that, while AIDS

has been linked with male homosexual practices,

women contracting the disease have been in other

risk categories—e.g., sexual partners of bisexual

men, intravenous drug users, or recent Haitian

immigrants. Thus, gay women have continued to

be safe prospective donors, and the blood banking community has continued to include them in

appeals for blood donations.

As part of generalized public information campaigns about the risk of AIDS, the Public Health

Service has included warnings about who should

refrain from donating blood. Blood banking organizations such as the American Association of

Blood Banks (AABB) have also waged their own

public information efforts, aimed at both increasing awareness of high-risk donors and allaying

groundless fears that AIDS could be contracted

by simply donating blood (which involves a sterile

needle that is disposed of after a single use).

In addition, many blood banks have introduced

procedures which allow donors to privately indicate whether or not their blood donations

should be used for transfusions, because such individuals may be especially reluctant to acknowledge their homosexuality or use of injectable drugs

before their peers at school, business, or community blood drives. The New York Blood Center,

for example, initiated a confidential form in

February 1983 on which donors could indicate

whether their blood could be used for transfusions

or only for laboratory studies. A more common

mechanism is to inform donors that they can call

the blood bank after donating to indicate whether

or not their blood should be used for transfusions.

The Red Cross formally adopted such a mechanism on January 1, 1984.

For source plasma collectors, an additional recommendation from FDA was that plasma collected in geographic areas at high risk should not

be used to manufacture the coagulation proteins.

Manufacturers have ceased to accept plasma for

Factor VIII and Factor IX products from prisons

and the cities of New York, San Francisco, and

Los Angeles (Hollywood area) (162),

A number of commentators have expressed

concerns that any system aimed at screening highrisk donors, rather than the blood itself, will be

imperfect. In the early debates over whether potential benefits from screening questions outweighed the dangers of invasion of privacy, an

AABB Transfusion Transmitted Diseases Task

Force resolution stated, “In fact there is evidence

that such questions, no matter how well-intentioned, are ineffective in eliminating those donors

who may carry AIDS. ”

While it maybe too early to gauge the success

of the screening procedures, some tentative initial assessments indicate that there has been a

drop-off in donations by males between the ages

of 18 and 35. Spokespersons for the New York

Blood Center, for example, have reported a high

degree of cooperation from the gay community,

with whom they initially forged ties during the

years of studies concerning transfusion associated

hepatitis, when thousands of gay men were recruited as subjects (230). Blood bank recruiters

have said that the same sense of civic responsibility that led to donating in the first place has

convinced gay men to refrain from donating or

allowing their blood to be used in transfusions

(144).

On the user side, the National Hemophilia

Foundation (NHF) (399) recommended that cryoprecipitate be used to treat newborn infants and

children under age 4, newly identified patients

never treated with Factor VIII, and patients with

clinically mild hemophilia who require infrequent

treatment. Similar recommendations have been

made for Factor IX deficient patients when freshfrozen plasma can be used instead of Factor IX

Complex. No specific recommendations have been

made between cryoprecipitate and Factor VIII for

the treatment of severe hemophiliacs because of

controversy over their advantages and disadvantages. Thus, the NHF recommends the continuation of early and appropriately intensive replacement of Factor VIII or Factor IX in the form of

Factor VIII or Factor IX Complex at each hemorrhagic episode, for the approximately 90 percent

of severe and moderately severe hemophiliacs

now so treated in this country.
102 ● Blood Policy and Technology

These recommendations came in the wake of

a number of anecdotal reports that hemophiliacs

were reducing the amount and frequency of administration of coagulation concentrates, foregoing treatment when indicated, or using smaller

doses for bleeding crises. Such practices risk increasing the long-term morbidity associated with

the disease, especially the orthopedic problems occasioned by bleeding into the joints, one of the

most vexing problems of hemophilia. There have

also been accounts of hemophiliacs declining necessary dental treatments or elective surgery, procedures which can require massive doses of coagulation products as a precautionary measure (s).

Plasma from a few donors subsequently diagnosed as having AIDS, or even from a single

donor, has led to uncertainty over the safety of

all the Factor VIII (and IX) concentrates derived

from the thousands of plasma units containing the

plasma from donor(s) with AIDS. All four commercial manufacturers of coagulation proteins, as

well as the Red Cross and the New York Blood

Center, have voluntarily withdrawn lots of Factor VIII or Factor IX upon learning that an AIDS

victim had donated plasma used in their preparation.

The potential dimensions of this problem are

enormous. Because of the preclinical, asymptomatic phase of AIDS, donors could give many

times before becoming aware of having contracted

the disease. In one recall case, an Austin, TX, man

had sold plasma to a commercial center 50 times

before being diagnosed as having AIDS. The process of pooling thousands of products also contributes to the need to quarantine a great deal of the

product; the largest of the voluntary withdrawals

involved enough Factor VIII to represent 500

patient-years of treatment (434).

All four manufacturers of coagulation factors

have also recently received FDA approval to market heat-treated Factor VIII. These preparations

have been shown to reduce the infectivity of

hepatitis viruses and a variety of marker viruses

added prior to the treatment process, with the

hope that viruses from other heat-sensitive classes

such as the retroviruses (in which the proposed

AIDS organism belongs) may be similarly affected. The heat treatment is also estimated to decrease potency of these preparations by about 10

to 20 percent (162).

While donor screening has been most controversial among the affected donor groups, the

methods that have raised the most controversy

among blood bankers have been attempts to

screen out AIDS from the blood supply through

the use of laboratory tests. No specific test for

AIDS is available, although one may become

available in the relatively near future if the tentative identification of an AIDS virus is confirmed

and tests can be devised to be used on a mass scale

as promised (256). In the absence of a specific test

for AIDS, attempts have focused on “surrogate”

tests. These are of two types: 1) detection of

abnormalities associated with AIDS or the preclinical stages of the disease, and 2) evidence of

past infections with diseases that have a high incidence in the same population groups that are

at increased risk for AIDS. Both of these types

of surrogate tests will be positive in a much higher

number of people than actually have the AIDS

agent.

The total costs associated with surrogate tests

include the cost of testing each individual unit,

the loss of blood which tests positively, and higher

recruitment costs associated with seeking donors

to replace those excluded. Moreover, tests purporting to reveal abnormalities implicated in the

preclinical stages of the disease raise questions

about what kind of information to share with

those who test positively. Conditions other than

AIDS can lead to abnormal test results in tests

of the first type. For example, the Stanford University Blood Bank now tests all whole blood

donations for the T-lymphocyte helper: suppressor

ratio. About 1 to 2 percent of collections are

positive and discarded, but donors are not deferred permanently, since short-term virus infections can also cause an abnormal ratio (445).

In the second type of surrogate test that tests

for past infections with other diseases, the diseases

tested for have much higher incidence than

known for AIDS. For example, in May 1984 Irwin Memorial Blood Bank in San Francisco initiated the test for antibodies against hepatitis B core

antigen (anti-HBc)(indicating past infections with

hepatitis B) and expects that deferrals will increase
Ch. 5—Current Issues ● 103

by 5 to 7 percent because of positive tests (445).

(Irwin expects that the test will also help to prevent non-A, non-B hepatitis transmission, another

infectious agent that so far has not been identified

specifically, although current research indicates

it is a virus.) Cutter, one of the four fractionators of plasma, also announced at approximately the same time that it also would use the

anti-HBc test and expects that approximately 15

percent of its donors will have positive tests. Cutter plans to use their plasma only in producing

albumin and immune globulins, which have not

been implicated in AIDS (137).

A study group of the Food and Drug Administration’s (FDA) Blood Products Advisory Committee has also been studying whether surrogate

tests, specifically, the anti-HBc test, should be instituted for all whole blood and plasma collections, with the majority believing that the test was

not appropriate as a means of identifying AIDS

high-risk group members. This group also recommended in March 1984 that another surrogate test

be studied in pilot tests. This test would be for

beta-2 microglobulin, a cell surface protein component of the immune system that has been found

to be elevated in patients with AIDS. Finally, the

study group also recommended that a pilot study

be conducted to measure the effectiveness of procedures by which plasma donors could privately

indicate that their plasma should not be used in

the manufacture of coagulation products.

Pressure to adopt some type of surrogate test

may have been temporarily alleviated by the announcement on April 23, 1984, by the Department

of Health and Human Services of its claim to identifying the AIDS virus, and its promise that a

blood test would become “widely available within

about 6 months, ” which should “identify AIDS

victims with essentially 100 percent certainty”

(256). Whether or not this expectation will be

realized should be known soon.

Pressure to institute some type of laboratory

screening test reflects the preoccupation with

safety with blood resources, with costs a secondary consideration. This is manifest in the decision

by some blood banks and plasma fractionators

to use surrogate tests, despite their high “false

positive” rates for AIDS, loss of donors, and the

increased recruitment effort needed to replace excluded donors. Blood bankers have also noted

that costs and benefits must be weighed in the balance and that, moreover, the potential costs of

not performing surrogate tests include those associated with the treatment of additional AIDS cases

and the potential for lawsuits arising from transfusion associated AIDS.

Assurances of safety from surrogate tests, whatever their validity, can also become factors in

competition for patients. For example, an additional reason for San Francisco’s Irwin Memorial

Blood Bank’s adopting the anti-HBc surrogate test

was Stanford University Blood Bank’s use of

another surrogate test, the T-lymphocyte helper:

suppressor ratio test. Apparently, the use of a surrogate test by Stanford and not by Irwin was

perceived by some patients and doctors as reflecting a “safer” blood source at Stanford (445).

For the longer term, costs may become a more

prominent factor in decisions to adopt additional

safety measures because of prospective payment

systems that are currently being implemented (discussed in a subsequent section of this chapter).

Even if a “guaranteed” screening test for AIDS

becomes available, the question still remains

whether it should be required of every whole

blood and plasma collector, or limited to highrisk whole blood collection areas and to plasma

supplies, the latter because of the pooling of

thousands of units prior to fractionation into

coagulation products.

The impact of AIDS has had other effects on

the blood supply besides the search for good methods to screen out AIDS. Interest in autologous

donations, where a patient banks his/her own

blood prior to elective surgery, has increased

dramatically. Autologous donations have long

been supported by the blood banking community

as the safest method of transfusion, and indeed,

a substantial portion of requests for autologous

transfusions probably originate with physicians

rather than patients, since in many institutions

physicians must give their written permission for

such a request and in many cases must point out

to the patient that it is an option (445). Nevertheless, their potential application is limited when

contrasted against the total number of transfusions.
104 ● Blood Policy and Technology

Predepositing one’s own blood requires knowledge in advance of the nature and extent of the

elective surgery anticipated and, furthermore, the

patient must be healthy enough to withstand the

blood donation process (often entailing the donation of three units of blood in the month prior

to surgery). The blood bank, for its part, must

be prepared to meet the logistical requirements

necessary to make the patient’s own blood available at the time of the operation. And even when

these steps are successfully undertaken, the process can be undermined should the patient require

more blood products than he or she was able to

predeposit.

Use of the patient’s own blood has also been

achieved through means other than deposits in advance. These efforts have primarily been undertaken for those, such as Jehovah’s Witnesses,

whose religious beliefs preclude them from accepting transfusions of blood products (121). Intraoperative salvage and postoperative collection of

shed blood have been used in surgery following

traumatic injury and in vascular, cardiac, and orthopedic surgery. Devices have been developed

for collecting salvaged blood for reinfusion as

whole blood or as “washed” red cells. The AIDS

crisis has given new impetus to development of

such techniques.

Fear of AIDS has also led to an increasing number of requests for “directed donations”; i.e., the

transfusion of blood from specific individuals,

usually family members or friends, rather than

using a product from a general inventory. Directed donations were the standard mode of operation until technological advances in this century

made storage and preservation of blood products

possible through maintenance of a constant inventory, and typing and crosshatching of blood

enabled safe exchange of blood between strangers

with the same blood type. The director of one of

the Nation’s first blood banks described the importance of these advances in a 1938 article. “The

advantage of the ‘blood bank’ over the previous

method is obvious. [It] dispenses with the commotion occasioned by calling to the hospital a

horde of excited relatives before a suitable donor

can be found” (176).

Today, directed donations are viewed negatively by most blood bankers because of the potential for disruption of the blood collection and

distribution system and because of lack of evidence that such donations are indeed safer. Opponents of directed donations have argued against

setting up a two-tiered system of blood, one

allegedly safer than the other. Furthermore, there

has been concern about the effect on the donor

pool; will prospective or regular donors refrain

from giving in order to be eligible to give should

an emergency arise for a friend or family member? Reflecting these concerns, the American Red

Cross, AABB, and the Council of Community

Blood Centers have issued a joint statement counseling against the establishment of directed donation programs (14) which was echoed by the

College of American Pathologists (129) and the

American Medical Association (38).

Individual hospitals and blood banks have had

to grapple with the question of whether or not

to allow requests for directed donations, either

as a matter of institutional policy or on an ad hoc

basis. Many hospitals have tried to discourage the

practice either through scientific or moral suasion

or bureaucratic intransigence. However, a few individual blood banks have instituted directed

donation programs under pressure from patients,

donors, and clinicians (445). In Philadelphia,

Thomas Jefferson University’s blood bank established a directed donation program at the urging

of cardiac surgeons (whose patients commonly receive multiple units of whole blood or red cells).

Irwin Memorial Blood Bank, located in San

Francisco, where AIDS has been a particular concern, adopted a program in June 1984 to allow

directed donations as a matter of formal institutional policy to be made known to all prospective transfusion recipients. Irwin’s somewhat

grudging acceptance of the directed donation concept is reflected in its advice to patients and in

procedural barriers it erects before allowing such

donations to proceed. Patients are advised “that

blood from directed (family and friend) donors

is at best no safer than blood from other volunteer

donors (and) there is actually a danger that directed donations may be less safe. ”
Ch. 5—Current Issues Ž 105

If patients insist on a directed donation, their

physician must place the request at least a week

prior to the anticipated transfusion and the patient’s friend or relative must undergo an initial

screening and testing procedure at the cost of an

additional $15. If the potential donor passes the

screening test, he or she must then return on a

separate occasion to actually make the donation.

The donor is told of the importance of forthright

answers to screening questions and told that if use

of the blood turns out not to be warranted for

the particular individual, it will be turned over

to the general inventory. Designated donors are

encouraged to return and donate with no strings

attached.

Special concerns about safety have also arisen

in the pediatric context, especially with treatment

of neonates in the intensive care setting. Blood

replacement is a frequent occurrence in this population. In addition to such reasons for transfusions as hemorrhaging, arterial blood gas evaluations and other laboratory tests require the

frequent withdrawal of blood for monitoring. Although this may be in small amounts of 5 or 10

ml at a time, in the aggregate it can amount to

a significant proportion of the blood volume of

tiny neonates. Particularly poignant cases of the

deaths of very young children from transfusionassociated AIDS have received a great deal of

media attention (325). As mentioned, the response

to pediatric AIDS cases is complicated by problems in defining what actually constitutes AIDS

in young children because of their naturally immature immune systems.

Some of the parents involved have emerged as

articulate proponents of more vigorous donor

screening methods, surrogate tests and limiting

the number of donors for multiple transfusions

when pediatric patients are involved. They have

also criticized what they perceive as the dilatory

response of the blood banking community (especially the voluntary sector) in adopting screening

procedures, and an inadequate and delayed response in funding studies related to transfusionassociated AIDS, especially in pediatrics.

The impetus for directed donations from physicians or patients has also resulted from concerns

that whatever the actual risks of contracting AIDS

from a blood transfusion may be, the perceived

risks may be no less important. A review of the

directed donation program at Cedars-Sinai hospital in Los Angeles concluded that “[w]e function with a philosophy that incorporates a concern for the patient’s psychological responses to

illness, as well as his need for blood. . . . [B]y providing these very frightened patients with the

knowledge that the blood to be received is from

their chosen donors . . . [we] enhance their general well-being and eventual recovery” (452).

Directed donors have also been described as an

additional source of donors; they may not have

been active donors in the past. Family and friends

can sometimes meet the majority of the patient’s

need for blood, thereby reducing the demands on

the general inventory. And because the patient

effectively supplies the donors, there is little or

no cost associated with recruitment.

While directed donation programs may not be

disruptive if limited to individual blood banks and

for individual patients, a more serious case is one

in which a donor gives blood but specifies that

it may be used only for another member of one’s

organization. In this case, entire sets of blood

might be tied up, which is somewhat reminiscent

of the nonreplacement fee or blood credit system—

but with the additional feature of restricting physical access to the blood and raising the specter of

greatly increased outdating and wastage. According to the administrative director of the Greater

New York Blood Center, “If people start to set

up separate pools . . ., we’d see little packets of

donors and eventually the blood banks would be

destroyed” (341).

One example of blood banking’s response to

such suggestions was triggered when the president

of a country club civic association in Long Island,

NY, sent a letter soliciting members to join a

special blood donor registry so that the risk of

contracting AIDS might be reduced by “obtaining blood directly from people you know. ” When

accounts of this effort appeared in the newspapers,

local blood banking officials contacted the organizers, concerned about their basic idea of “establishing a registry of ‘pedigreed donors’ without

knowing anything about the donors’ actual medical background and history. ” When representa38-647 0 - 85 - 8
106 . Blood Policy and Technology

—

tives of the civic association were given a tour of

the local blood bank and apprised of the donor

screening policies, they withdrew their suggestion

and instead sponsored a conventional blood drive

with no strings attached (432).

Directed donations built up around organizations instead of individual patients have great potential for disrupting the present, well-balanced

system of blood supplies. In a recent AABB survey

on public perceptions of AIDS and the blood

supply, the largest percent of those who donated

regularly did so to contribute to a company blood

drive (33.6 percent). Currently, companies

allow employees to donate blood during working hours, and many firms give additional time

off as a reward. Thus, the potential is present on

the part of the company or even its employees

to demand a directed donation program.

Legislators in several States (Florida, Georgia,

Kentucky, Washington) have also introduced bills

requiring blood banks to accept directed donations, but, in the face of concerted opposition by

blood bankers, none of these legislative initiatives

has progressed very far. (One related and similarly unsuccessful proposal from a New Jersey

State senator would have made it a criminal offense to misrepresent one’s health status or membership in a high-risk group. ) The development

and availability of a specific screening test for

AIDS, however, should do much to alleviate the

safety concerns that underlie much of the current

interest in directed donation programs.

But while awaiting confirmation of the identification of the viral agent associated with the

transmission of AIDS and the development of a

definitive screening test, there remain a number

of practical and ethical questions for blood bankers—and particularly for researchers tracking

down the blood connection. Perhaps the most intractable questions involve how to deal with medical information which is riddled with uncertainty

or information which fails to point up any possible therapeutic responses. Gerald Sandier of the

Red Cross put it this way: “I have had 10 years

of explaining tests to people. I want to know how

you will deal with those 5 percent of the normal

population who will be positive for anti-HBc. . . .

How can you convince people that their blood

is no good, but they’re healthy?”

Questions of confidentiality and the need to balance privacy interests against public health concerns, while not unique to AIDS, are raised in

sharper relief than in any other area of medical

practice and research. Recent scientific breakthroughs may give these questions a new twist.

In May 1984 the Red Cross announced plans to

conduct pilot tests of donated blood for antibodies

to the HTLV-III virus—the presumed agent of

AIDS. Development of such a test carries with

it immediate concerns about scale-up and availability, specificity and sensitivity, as well as ethical questions about the use of information revealed by the test. It remains to be seen whether

the test will be simple and cheap enough to be

readily available on a scale massive enough to obviate questions about who should have priority

among potential users. In addition to blood banks

generally, blood banks in high-risk areas and commercial plasmapheresis centers, additional millions of potential test users include members of

groups at risk of contracting AIDS—male homosexuals, intravenous drug users, and Haitians.

Also unclear are the implications of a positive

test. Red Cross officials have predicted that

positive findings of an AIDS screening test will

be dealt with much as hepatitis B findings have

been in the past. Donors who tested positively

would be informed by a letter, which would include an offer to make the information available

to the donor’s physician. The donor’s name would

then be added to a registry of permanently deferred donors, with the reasons for the deferral

encoded in a format strictly limiting their availability. Additional questions arise because in a

number of States, AIDS, like some other communicable diseases, must be reported by physicians to public health officials. Should these same

reporting requirements apply in similar fashion

to positive results of an AIDS test even if it is not

a definitive diagnosis of the disease? These are

among the issues confronting those who seek to

develop, market, and implement an AIDS screening test. When announcing its plans for pilot

testing, the Red Cross also stated that it was convening an ethics advisory panel to help sort

through this thicket of questions.

Related dilemmas concern how to divulge information uncovered in the course of epidemio-
Ch. 5—Current Issues Ž 107

logical investigations by public health officials.

What should high-risk donors be told once they

have been implicated in an AIDS case? Should

other recipients of blood products from these same

high-risk donors be told that they, too, are at risk

of contracting AIDS (or as a way to prevent unwarranted fear, should the information be divulged only to their treating physicians)? Local

public health officials have shared the names of

AIDS victims in high-risk areas with local blood

banks, so that it might be confirmed whether or

not they donated and, if so, who received their

blood products (e.g., the San Francisco Health Department and the Irwin Memorial Blood Bank).

(Federal regulations require that records of blood

donors who donate products for human use be

kept for 5 years. )

Is this practice being conducted with the necessary degree of regard for the protection of patient confidentiality? Should it be expanded in

scope? Do the proper authorities have access to

names and other patient identifiers? Should social

security numbers ever be used in this process? Are

public health officials doing enough to assure that

AIDS victims have not failed to mention if they

were blood or plasma donors, either because they

did not recall when and where they donated or

because they fear further stigma?

These are representative of the kinds of ethical

issues confronting blood bankers, public health

officials, and especially researchers. (A task force

of the bioethics research group, The Hastings Center, has recently completed a set of guidelines for

confidentiality in AIDS research. These guidelines

specifically eschew consideration of concerns specific to blood banking. These questions are being

addressed by CDC and the National Heart, Lung,

and Blood Institute in the course of designing protocols to test research hypotheses. )

Finally, while many areas experienced a decrease in blood donations in 1983, there does not

seem to have been major or systematic shortages

of blood supplies. The Red Cross, for example,

had been experiencing yearly increases in collection of about 5 percent prior to 1983, but in 1983,

no increase was noted. However, demand was

about equal to supply, and Red Cross analysts

noted that supply was dependent on demand, and

that most of the decreased demand could be attributed to reduced hospitalization and surgery

(302).

This decrease in demand was also noted elsewhere. The Gulf Coast Regional Blood Center

reported a 5-percent decrease in red cell use and

a 3.5-percent decrease in overall blood component use in 1983 compared to 1982. The single

largest contributing factor was a severe economic

recession in the gulf coast area, with decreased

insurance coverage and elective surgery. But

many patients were questioning physicians about

transfusions, and AIDS played a large role in reduced use (527). Similar conclusions were made

for the hospitals supplied by San Francisco’s Irwin Memorial Blood Bank. Hospitals supplied by

Irwin transfused 3 percent fewer whole blood and

red cells in 1983 than in 1982, and there was no

serious problem with supplies even though donations dropped 4.6 percent in the same period.

Some of the decline in demand probably reflected a tendency for patients to postpone elective surgery while the economy was poor. However, the steady decline in red cell use throughout

all four quarters of 1983, when the economy was

improving, suggests that fear of contracting AIDS

may also have been a contributing factor in the

decision to postpone surgery and in encouraging

physicians to be slightly more conservative when

ordering blood for transfusions (445).

PART 2: COORDINATION OF BLOOD RESOURCES

Coordination of blood resources is complicated aspects of blood delivery. One is the coordinaby the pluralistic system of blood services that has tion of all blood services within a given geographic

developed in this country since World War II. To area; this effort has been termed regionaliztion.

date, efforts at coordination have focused on two The second area of coordination involves provid-
108 ● Blood Policy and Technology

ing excess blood to other blood providers who are

occasionally or chronically deficient; this phenomenon of cooperation is called resource sharing.

Regionalization is not acknowledged by all to

be the best approach to managing blood supplies.

One of the recurring questions is the benefit gained

from participation in the American Blood Commission’s regionalization recognition program.

Another recurring debate centers on the issue of

centralized blood services v. hospital-based services, or some combination of the two. In addition, there are external forces, such as health care

cost containment efforts, which are just beginning

to have an effect on regionalization efforts.

The need for resource sharing is probably the

single aspect of blood delivery which is not seriously debated within the blood services community. Rather, the need for a single resource sharing system has been the issue, given the existence

of two parallel, though largely successful, systems—run by the American Association of Blood

Banks and the American Red Cross.

Regionalization

Essentially, regionalization is a term used to describe the local coordination of all facilities and

organizations involved in blood collection, distribution, or use in a given geographic region.

Generally, regionalization includes provisions for

cooperation with other regions, thus linking regional blood programs into a national resource

sharing program.

Many regions have been able to meet their own

blood needs completely, relying exclusively on

volunteer donors and satisfying the demand for

blood from local practitioners. While some areas

of the country are still concerned about meeting

local blood needs, other regions are concentrating

on the centralization of blood services within regions (i.e., the consolidation of small-scale blood

banking operations into a central blood center).

On the whole, within any region of the country, a patient who needs blood will receive it, but

there still remain the questions of efficiency and

cost. There are many groups operating within

each region. Should the plurality of the present

system be left as is, because it produces acceptable products at a sufficient level, or is there a

better organizational framework for the provision

of blood products at lower cost?

Since the formation of the American Blood

Commission in 1975, the ABC has supported

regionalization as the most logical way to improve

blood services in the United States. The ABC recognized that there were effective, high-quality, regional blood programs in a few areas of the country, but felt that a national program was needed

to improve the fragmented and uncoordinated

blood services in other areas. From the start, the

ABC regionalization program was conceived and

implemented so as to preserve the roles of the

many participants in blood banking. It has improved relations in regions in which a strong central blood service needed more formal and effective communications with its clients, and in doing

so, maintained the autonomy of all participants

with respect to management of the regional blood

resources (507). But in less centralized regions,

changing the roles of the participants or closing

small operations have often been opposed.

Since the ABC has no enforcement mechanism,

participation in the regionalization program has

always been voluntary. In order to support the

regionalization program, the ABC charges application and recertification fees to regions desiring to receive recognition.

The regionalization program sets forth criteria

for regional associations which distinguishes regional associations from regional blood programs

and provides a mechanism for areas wishing to

be recognized to form such cooperative arrangements. The recognition criteria contain specifications in the following areas:

●

●

●

●

●

●

●

For

governance,

management,

donor recruitment,

inventory control,

service area,

interregional relationships, and

range and quality of services.

instance, the criteria require that the governance of a regional association shall provide for

active participation of five interest groups:

1. donors;

2. blood centers, or the facility (ies), in the re-
Ch. 5—Current Issues ● 109

3.

4.

5.

gion which perform the functions of collections, processing, storage, and distribution

of blood;

hospital transfusion services;

physicians who provide direct patient care;

and

the patients who receive blood.

Participation by these five groups is in contrast

to a regional blood program, which usually involves only blood collection and distribution programs and perhaps hospital transfusion services.

Participation of all these groups is often considered to be the essential difference between a recognized region and other regional blood programs.

Among other goals, the criteria state that the

regional association should take an active role in

inventory control and the redistribution of blood

according to need within the region, and provide

for cooperation with other regions in cases of

unexpected need. Also, rather than require a particular approach, the criteria specify that donor

recruitment should be philosophically coordinated

within a region (i. e., either individual or community responsibility, ) so as to prevent donor confusion. The regions are also required to provide

a specific range of services within acceptable

quality limits (e.g., the provision of a physician

available for consultation on difficult blood problems on a 24-hour basis) and to do as much as

possible to promote good transfusion medicine

(34).

In order for a region to receive official ABC

recognition, it must pass through a four-phase application procedure evaluating a variety of operational and organizational criteria. In addition to

an application fee of $1,500, regions must supply

application materials—including bylaws, financial statements, operating reports, etc.—and host

a site visit by members of the ABC regionalization committee. Once recognized, a region must

be recertified every 5 years (30).

As of October 1983, the ABC had fully recognized 43 regions, with 29 additional regions somewhere in the application process. These regions

are located all across the country, and the ABC

estimates that 50 percent of the Nation’s blood

supply is collected through regions participating

in the regionalization program (31b). Despite these

accomplishments, however, there are questions

as to the need for and the effectiveness of the ABC

regionalization program.

Many criticisms of the ABC regionalization

program stem from ABC’s lack of power. ABC

was conceived as a “private sector” organization

“charged with carrying out public policy but lacking enforcement powers. ” The ABC never received a Federal charter. As a result, ABC programs are voluntary, and ABC recognition carries

with it no legal status. The fact that “recognition”

rather than certification is used to achieve compliance testifies to the difficulties of the ABC as

an unofficial body in exerting its influence (601).

Nevertheless, the ABC contends that the program

provides an incentive to regions who voluntarily

choose to regionalize and provides the technical

assistance and advice to complete the project successfully.

The New York Blood Center (NYBC), one of

the largest blood centers in the country, has opted

not to pursue ABC recognition. In 1958, the New

York Academy of Medicine Committee on Public

Health realized that there were serious deficiencies in the safety of the blood supply and transfusion practices. Foremost among their recommendations were the steps which resulted in the

NYBC. Years later, when the ABC was beginning

its regionalization program, the NYBC was thriving and chose not to participate.

Few would argue that the NYBC is in any way

inferior as a result. However, in 1978, the same

committee of the New York Academy of Medicine examined the progress made toward the goals

enunciated 20 years earlier. The main problem

which remained to be solved was attainment of

a good cooperative working relationship between

the Blood Center and the hospital transfusion

services; hospital blood bank directors felt that

they did not have any voice in the operation of

the blood center. Despite the appointment of advisory committees to the Blood Center, the NYBC

management tended to accept only advice with

which it agreed. Thus, hospital blood bank directors felt obliged to form their independent incorporated Council of Blood Bank Directors.

In an attempt to resolve this problem, the same

New York Academy of Medicine committee con-
110 . Blood Policy and Technology

vened a subcommittee to explore the possibilities

for developing a regional association more or less

in accordance with ABC regionalization recommendations. Over the course of the next year, a

compromise proposal, introduced by the representative of Blue Cross/Blue Shield of Greater

New York, was finally approved by all participants, excepting the representative of the NYBC.

The Blood Center objected to the portion of the

proposal which called for a Council with its governance independent of the NYBC. To date, the impasse remains.

In the meantime, the New York Academy of

Medicine Committee on Public Health has appointed a subcommittee to observe and report annually; this committee’s charge is sufficiently

broad to monitor all aspects of blood supply and

transfusion services. This situation provides an

example of a region which functions effectively

in most respects but lacks a mechanism to resolve

problems between the blood bank and its users

(360).

Further, due to the cumbersome and expensive

four-phase application procedure, some regions

with strong regional blood programs had little incentive to gain ABC recognition, given the costs

and effort required to acquire it. Some strong regional systems, such as the Puget Sound Blood

Program, have not seen a need for such formal

recognition, while other areas have not applied

but have benefited from the information made

available through the program and the knowledge

gained from activities, successes, and failures of

other regions. Because of this latter fact, perhaps

the ABC regionalization program deserves more

credit than the statistics indicate; and perhaps the

program has provided assistance to those who

needed it most (517).

Others have criticized the inconsistency with

which the ABC confers recognition. For instance,

in some places, autonomous functioning of small

local blood banks which refused to be integrated

into larger regional programs continued, but the

regions were “recognized” nevertheless (601). In

other areas, regions were allowed to apply for

recognition without the participation of many of

the users of blood.

In one notable instance, a region was allowed

to apply for ABC recognition without the inclusion of the region’s major blood supplier, the Red

Cross, in the formal regionalization plan. The

Washington, DC, Metropolitan Region has largely

resolved its blood supply problems. Now, the Red

Cross supplies the majority of blood in the area,

supplemented by the Metropolitan Washington

Blood Bank (MWBB), and some hospitals continue to be largely self-sufficient in the collection

and processing of whole blood, red blood cells

and platelets, as well as basic laboratory services.

Only 2 percent of the area’s blood supply is imported from outside the region. Several groups

in the Washington area have applied for ABC

recognition in an attempt to solve the problem

of local coordination, but have reached an impasse as the major area supplier, the Red Cross,

sees itself as a successful regional blood program

(509).

In other instances, attempts at obtaining ABC

recognition have stalled because of continuing territorial battles between blood programs. For instance, both the South Florida Blood Service and

the Broward County Blood Center have expressed

interest in the ABC regionalization program, but

the two blood centers are still in the midst of a

dispute over blood collection within Broward

County. The competition for donors between the

two blood centers has attracted the concern of the

community, and efforts are under way to encourage a compromise. As a result, attempts at

recognition have been tabled until the dispute is

resolved (465; 532).

A report completed in 1981 under contract to

NHLBI, evaluating the first 2 years of ABC’s

regionalization program, arrived at a much more

positive conclusion. The analysis concluded that

the regionalization program did provide incentives

to improve, and the associations recognized by

the ABC did meet the regionalization criteria,

which were consistently and fairly applied. It concluded that the regional associations demonstrated

evidence of both interregional resource sharing

and regional self-sufficiency, and that “most regional associations include a high proportion of

the total number of blood service establishments
Ch. 5—Current Issues . 111

in the region. ” Generally, the regions do not conform to political divisions, but rather are built

around existing blood center operations. The report also noted that plasmapheresis centers do not

participate, although they may conduct substantial operations within a region (32).

Finally, there have been some concerns about

possible antitrust allegations of “price-fixing” or

“restraint of trade” on the local level as a result

of regionalization (364), although there has been

no litigation on this issue to date. The problem

of antitrust action on a national level as a possible consequence of the Resource Sharing Agreement is currently being addressed by the ABC and

its legal counsel. (See subsequent discussion. )

In conclusion, now that supply has been largely

stabilized and inventory is not the central concern, efficiency and participation in decisionmaking by more than representatives of blood banks

have become primary goals in regionalization efforts. The role of ABC’s regionalization program

has been to provide the catalyst and information

for such regional efforts. It appears that each region will solve its problems on an individual basis,

gaining from the experience of other regions and

not necessarily pursuing ABC “recognition” as an

end in itself.

Resource Sharing

Over the past 30 years, there have been several attempts at interorganizational resource sharing. The first system has operated under the

auspices of the AABB since its beginning in 1951

and is called the Clearinghouse Lifeline Program.

In essence, the Clearinghouse serves as a facilitator

in the exchange of blood or blood credits between

blood banks, blood centers, and hospital blood

banks or transfusion services. For the most part,

the Clearinghouse serves regional blood centers,

although it serves any AABB accredited facility

which agrees to the conditions of participation,

including facilities which are not members of the

AABB.

In 1955, the Joint Blood Council, a short-lived

group formed by the AABB, American Red Cross,

American Medical Association, American Hospital Association, and the Society of Clinical

Pathologists, attempted to develop a cooperative

interorganizational reciprocity blood program between the AABB and the ARC. The committee’s

proposal was never enacted, as the Red Cross representative indicated that the ARC Board of

Governors would not approve the plan (18). The

Red Cross then instituted its own national reciprocity plan for Red Cross blood centers, the Central Exchange Program, based in Washington,

DC,

In 1958, negotiations reopened between the

AABB and the ARC in another attempt to reach

a sharing agreement. Finally, in 1960, an agreement for an interorganizational reciprocity program was reached between the AABB and the

ARC. The agreement became effective May 27,

1961, and the two organizations operated under

a series of sharing agreements which differed only

in terms of fees, until 1976, when the Red Cross

withdrew over concerns about nonreplacement

fees. Upon the withdrawal, ARC formalized its

sharing program, which acquired the name “Compass. ”

Most recently, the major collectors of blood in

the voluntary sector, and the American Blood

Commission, attempted to arrive at a comprehensive resource sharing agreement. The Resource

Sharing Agreement (RSA) was a proposal for a

coordinated blood distribution arrangement between the American Blood Commission (ABC),

the American Association of Blood Banks (AABB),

the Council of Community Blood Centers (CCBC),

and the Red Cross.

In late 1979, the Red Cross requested a Business Review from the Department of Justice for

the proposed Resource Sharing Agreement (328).

The antitrust considerations relevant to the RSA

were price-fixing and illegal boycotting. The

agreement contained provisions for shipping,

processing, and other charges involved in the

movement and sale/exchange of blood and blood

products. Further, the system included an indemnification account and replacement deposit fee

(responsibility fee, or nonreplacement fee). As a

result, the Red Cross was concerned that a civil

suit might be brought against it.

Representatives of the Justice Department’s antitrust division expressed the view that the RSA
112 • Blood Policy and Technology

would not be challenged because it contained no

enforcement mechanism for violation of the agreement. Litigation would be difficult, and a plaintiff would be forced to prove a boycott (330).

The boycotting concern was raised by ABRA

in a letter from its general counsel to the general

counsel of the American Blood Commission. The

letter of May 3,1983, charged that the RSA would

implement a group boycott against producers of

nonvolunteer blood products (meaning source

plasma collected and/or fractionated by ABRA

members). ABRA’s argument was that as long as

the FDA licensed these products, any contract

limiting their purchase would be in violation of

the antitrust statutes. The February 19, 1982, draft

of the RSA stated that “only blood obtained from

voluntary donors and labeled in accordance with

applicable law will be shipped.” The December

15, 1982, draft replaced the volunteer clause with

. . . (blood) procured and processed in conformity with the National Blood Policy . . .“ However, ABRA maintained that the National Blood

Policy was and is synonymous with volunteer

blood and that the result would be the same.

Because of the threat of civil litigation, the Red

Cross refrained from joining in the RSA during

the May 3, 1983, meeting at which the agreement

was to have been signed. The December 1982

draft of the agreement was signed by the ABC,

the AABB, and the CCBC but has not been implemented, although individual members of the

AABB and the CCBC utilize the Clearinghouse.

In addition, the Resource Sharing Council, under

the auspices of the ABC, continues to meet in an

effort to continue the dialog between the organizations on resource sharing. Despite the Red

Cross’ decision not to participate, the Resource

Sharing Council invited them to attend as observers, if they so desired, but the invitation was

declined. Most recently, representatives of the

ABC and the CCBC attended a regular meeting

of the AABB Clearinghouse committee as observers.

Even without implementation of the Resource

Sharing Agreement, and without a single coherent

national sharing system, regions with blood shortages are able to meet their needs. Individual blood

centers contract with other blood centers outside

of the formal mechanisms of the Clearinghouse

or the Red Cross, as well as within them. For instance, the South Florida Blood Service (SFBS) has

been undergoing a huge transition over the past

5 years in its switch from paid to volunteer

donors. As part of the transition, the region began

importing exclusively volunteer blood from other

regions in order to supplement the growing local

collections from volunteer donors.

Over the years, the SFBS has decreased its percentage of imported blood, completely eliminated

the use of paid blood, and increased its local collections from volunteer donors. The management

of the SFBS managed to meet the region’s blood

needs through a combination of contracts with

both Red Cross centers and independent regional

blood centers, use of the AABB Clearinghouse,

and supplementation via ad hoc shipments.

In some regions, there are even local clearinghouses which serve functions similar to the

AABB’s. For instance, the Metropolitan Washington Blood Bank (MWBB) was formed by hospitals over 20 years ago to receive daily inventory

reports and to coordinate blood movement between the hospitals. Today, the MWBB continues

to serve that function; in addition, it imports

needed blood from outside the region and participates in the AABB Clearinghouse. In August

1983, the MWBB, after deciding that the region’s

blood needs were still not being met locally, as

evidenced by the net import of blood into the region, began its own blood collection program.

The Metropolitan Washington region continues

to be dominated by the American Red Cross,

which controls approximately 90 percent of the

local blood supply.

American Association of Blood Banks

In 1979, the AABB National Committee on the

Clearinghouse developed its current program,

whereby blood banks may participate on a blood

credit-debit and/or fee-only basis. The Clearinghouse Lifeline Program consists of two alternative plans for members: the Blood Replacement

Exchange and the Blood Cooperative Programs.

Participants in the Blood Replacement Exchange

Program ship and receive blood under a debit/
Ch. 5—Current Issues ● 113

credit accounting system, and accept and issue

blood credits, if applicable. Routine inventory

surpluses and shortages are reported daily to the

District Clearinghouses, which match up compatible blood banks for inventory adjustment shipments.

Also, members who charge nonreplacement fees

may transfer credits through the Clearinghouse.

In addition, the resources of the Clearinghouse

are available to alleviate emergency shortages.

Transactions are settled via monthly statements,

which yield a net debit or credit balance owed by

the participant. In 1982, 96 percent of the Clearinghouse transactions were through the Exchange

Program, as opposed to the Cooperative Program. In the Blood Cooperative Program, blood

banks operate on a fee-only basis.

The Clearinghouse also coordinates payment

for any exchanged blood or credits. The Clearinghouse charges a $0.40 fee for each transaction

to both the shipper and the recipient of the blood

(or credits) in order to cover the costs of operating the service (16). Payments for blood are made

directly between the shipping and receiving blood

banks, although the Clearinghouse maintains

records of all transactions and provides monthly

statements which summarize the amount of blood

credits or money owed by individual participants.

The Clearinghouse sets a standard fee for blood

obtained through it, unless both parties to a transaction agree to another fee (usually the slightly

higher regular unit charge of the shipping blood

center). Transportation costs, as of fiscal year

1984, must be split between the parties of a transaction. This change was instituted by the AABB

Board of Directors on the premise that both facilities benefit from the shipment. The shipping

bank is able to outlet surplus blood that may

otherwise outdate on their shelves, and the receiving bank is able to obtain type-specific blood

needed to meet a blood shortage (259). The Clearinghouse will also arrange for long-term inventory shipments to provide assistance to regions

who need time to build their donor recruitment

programs toward the goal of self-sufficiency.

The Clearinghouse has a national office (relocated from Irwin Memorial Blood Bank, San Francisco, CA, to AABB National Headquarters, Arlington, VA, in June 1984) which oversees five

districts/regions covering the whole United States.

Requests are first referred to the regional offices,

and only referred to the national office if the region is unable to comply with the request. The

1984 American Association of Blood Banks budget allocates $459,000 for operation of the Clearinghouse, including $39,000 for the move of the

national office (21).

In addition to coordinating the movement of

blood and blood components, the Clearinghouse

transfers credits for blood donation between blood

banks and between regions where such programs

exist. Individuals giving blood in one region may

receive credit for their donation in another area

of the country, thereby canceling nonreplacement

fees for themselves or in the name of another patient. Blood banks settle their accounts in one of

two ways, depending on which program they participate in. (All payments for platelets, cryoprecipitate, and fresh-frozen plasma are handled on

a cash basis; replacement fees only apply to whole

blood or red cells. )

Members of the Blood Replacement Exchange

may settle a debit balance by paying a $15 replacement fee per debit or by shipping the appropriate unit(s) of blood. Centers choosing to settle via

actual blood shipments also receive $30 compensation per unit from the receiving center for processing expenses, raised from $25 in January 1984

by AABB Board of Directors, effective in May

1984. Conversely, centers with blood credit balances either receive cash compensation (at $15 per

credit) or replacement blood shipments (and pay

the $30 processing fee). Blood replacement shipments must be type-specific and in the same type

proportion as the general population. An approximately equal number of credit balances are settled

by replacement blood shipments and cash payments.

Participants in the Blood Cooperative Program

may outlet and receive blood and blood components on a fee-only basis (as opposed to maintaining a debit/credit balance sheet) to or from any

member of the Clearinghouse. Accounts are

settled monthly based on the net total of fees

owed. Cooperative banks do not exchange blood

credits, but may make a replacement shipment or

remit the $15 replacement fee in the name of a

specific patient. (Members of the Replacement Ex-
114 ● Blood Policy and Technology

change Program may accept blood or credit on

behalf of a specific patient, but they may not ship

blood in the name of a patient, as the mechanism

already exists to transfer credit) (16).

In both the Blood Cooperative and Replacement

Exchange Programs, blood banks are charged or

credited for blood receipt or shipment according

to a standard fee schedule set by the AABB Board

of Directors. Cooperative members are charged

a straight monetary fee according to the applicable fee schedule, while Exchange members are

charged/credited according to the current breakdown between replacement and service fees. The

Clearinghouse fee schedule covering inventory

shipments effective January 1984 is provided in

table 35.

In 1983, 47 percent of the transactions coordinated by the Clearinghouse were for actual shipments of blood or blood components. The remaining transactions consisted of issuing and/or

transferring blood credits (25 percent) and payment of nonreplacement fees (28 percent). The

relative proportions of the different types of transactions have changed very little in recent years

[table 36]. Similarly, the volume of blood moved

through the Clearinghouse has changed very little over the years, with the most noticeable change

occurring in 1977, after the withdrawal of the Red

Cross from the Clearinghouse [table 37].

Table 35.—Resource Sharing Inventory Shipment Fees

Shipment to a Shipment to an

cooperative bank exchange bank

Replacement Service

Unit fee fee fee

Whole blood and red

blood cells. . . . . . . . $40.00 $15.00 + $25.00

Washed and frozen red

blood cells. ., . . . . . . . . . $65.00 $15.00 + $50.00

Deglycerolized red blood

cells ., ., ., $90.00 $15.00 + $75.00

Platelets, cryoprecipitate,

or fresh-frozen plasma . . $20.00 $20.00

NOTE: The fee and replacement ratio for other components shipped under the

Blood Replacement Exchange are based on mutual agreement between

the shipping and receiving blood banks.

SOURCE: AABB, Guide for the National Clearinghouse Lifeline Program of the

Amer/can Association of B/ood Banks, July 1964.

Table 36.-AABB Clearinghouse Transactions by Type

Year Blood Shit) merits Replacement fees Credits

1983 . . . . 47%0 280/o 250/o

1982 . . . . 41 28 31

1981 . . . . 38 28 33

1980 . . . . 42 24 33

1979 . . . . 36 25 33

1978 . . . . 33 30 37

1977 . . . . 34 29 3a

1976a . . . 35 13 52

1975 . . . . 33 13 54

1974 . . . . 28 12 47

1973 . . . . 32 11 56

SOURCE: AABB Clearinghouse Transaction Reports, 1973-63.

American Red Cross

In addition to the AABB Clearinghouse program, which is available to any user or provider

of blood, the Red Cross has its own “Compass”

system for resource sharing. Based on past surpluses or shortages, and predictions for future demand, the American Red Cross annually coordinates the exchange of blood between its regions

on a contractual basis. The majority of the Red

Cross sharing is internal; i.e., between Red Cross

regional centers. In addition to contracted exchanges, the Red Cross arranges some sharing on

an ad hoc basis, some with blood banks outside

of the Red Cross.

Each Red Cross region contracts to buy from

or sell to a given center a certain amount of blood

on a weekly basis. That blood is committed to

the contracted recipient (after the needs of the collecting region are met). Although all contracts are

reported and monitored by the American Red

Cross Blood Services headquarters, many agreements are initiated and completed directly between the regional centers, without the intervention or assistance of the national office.

For the 1983-84 fiscal year, the Red Cross had

contracts with 33 regions for the provision of

6,729 units on a weekly basis (349,908 units annually) to 31 different recipients, both Red Cross

regional centers and non-Red Cross blood banks,

at a total estimated value of $14.2 million (based
Ch. 5—Current Issues • 115

Table 37.—Utilization of AABB Clearinghouse, 1973-83

Shipments of blood Percent change Total Percent change

Year and blood components previous year transactions previous year

1983 . . . . . . . . . . 278,032 units +31 .60/0 587,679 + 15.0%

1982 . . . . . . . . . . 211,296 +22.5 510,853 + 13.7

1981 . . . . . . . . . . 172,426 – 15.9 449,397 – 8.0

1980 . . . . . . . . . . 205,263 +21 .0 488,300 + 4.8

1979 . . . . . . . . . . 169,668 + 2.3 466,074 – 5.8

1978 . . . . . . . . . . 165,905 –11 .7 494,982 – 10.6

1977 . . . . . . . . . . 187,930 –28.2 553,859 –25.6

1976. . . . . . . . . . 261,696 +11.6 744,583 + 4.9

1975. . . . . . . . . . 234,448 +19.5 709,571 +15.2

1974. . . . . . . . . . 196,176 – 5.0 615,915 – 4.5

1973. . . . . . . . . . 206;536 — 617,779 —

1 percent annually)

SOURCE: AABB Clearinghouse Transaction Reports, 1973-83.

on the contracted weekly volume and the fee

schedule for whole blood provided by each supplying region). Of the total contracted blood

supply, approximately 65 percent, or 4,344 units

per week (225,888 units annually at an estimated

value of $9.25 million), are committed to 10 other

Red Cross regions. Thirty-five percent (124,000

units annually) will be provided to 21 non-Red

Cross blood banks.

In addition to the weekly contracts, 20 centers

had an additional weekly surplus estimated at

1,500 to 1,700 units, and 5 regions had consistent surpluses (approximately 500 units/week) for

which they desired exportation contracts. Both

types of noncontracted weekly surpluses amount

to approximately 100,000 units annually. These

noncontracted surpluses are provided on an ad

hoc basis.

Red Cross regional centers report any daily

surpluses or shortages to the national headquarters of the American Red Cross Blood Services.

If a region needs blood, the American Red Cross

will match up a request with a surplus. However,

regional centers often know from experience who

might have a surplus and will contact another center directly. All blood exchanged through the resource sharing plan is shipped prepaid. All blood

is provided at the cost of the processing and no

credits for donation or blood replacement are

given or exchanged. All fees are paid directly between blood centers; the American Red Cross does

not handle any billing or paperwork for exchanges

of blood or blood components.

The vast majority of blood or blood components moved through Compass is whole blood or

red blood cells, although there is some movement

of fresh-frozen plasma and cryoprecipitate, and

an increasing demand for platelets. Through both

the contracted and ad hoc arrangements, 71,682

units of whole blood, 469,640 units of red blood

cells, 43,885 units of platelets, 21,728 units of fresh

frozen plasma and 91,805 units of cryoprecipitate

were actually moved in 1982-1983 (table 38).

These amounts represented a decrease of 3 percent from the 1981-82 movement.

Volume of Sharing

In describing the movement of blood in this

country, it is useful to know what proportion of

the total blood supply is involved. In 1980, 17.1

million units of blood or blood components were

produced in the United States (518). In that year,

the AABB Clearinghouse coordinated the movement of 205,263 units of blood or blood components, while the American Red Cross moved

445,433 units, yielding a total of 650,696 units,

or 3.8 percent of the total available supply. This

percentage represents only those units that were

moved through the formal mechanisms of one of

the two systems. It is impossible to estimate how

much blood is moved on a local level, or through

informal networking, locally or long distance.

Judging from the existence and expansion of local

clearinghouses such as the Metropolitan Washington Blood Banks, and the success of temporary

programs such as the informal network of sup-
116 . Blood Policy and Technology

Table 38.—Blood and Blood Components Moved by American Red Cross

Regional Blood Centers in 1982 and 1983

Moved in 1983 Moved in 1982 Increase

Whole blood:

to other RC centers. . . . . . . . . . . . . . . 21,653 45,763 –53%

to blood banks . . . . . . . . . . . . . . . . . . . 50,029 73,021 –31 “/0

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 71,682 118,784 –40%

Red blood cells:

to other RC centers, . . . . . . . . . . . . . . 318,365 307,992 + 3%

to blood banks . . . . . . . . . . . . . . . . . . . 151,275 137,051 + 10 ”/0

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 469,640 445,043 + 60/0

Platelets:

to other Recenters. . . . . . . . . . . . . . . 24,493 21,742 +13%

to blood banks . . . . . . . . . . . . . . . . . . . 19,392 19,018 + 2%

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 43,885 40,760 +18%

Fresh-frozen plasma:

to other Recenters. . . . . . . . . . . . . . . 6,029 8,537 –30%

to blood banks . . . . . . . . . . . . . . . . . . . 15,699 18,334 –14%

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 21,728 26,871 –19%

Cryoprecipitated AHF:

to other Recenters. . . . . . . . . . . . . . . 74,313 67,068 +11%

to blood banks . . . . . . . . . . . . . . . . . . . 17,492 21,995 –20%

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 91,805 89,063 + 3%

All blood and blood components:

to other Recenters.. . . . . . . . . . . . . . 444,853 units 451,102 units – 1 %

to blood banks . . . . . . . . . . . . . . . . . . . 253,887 269,419 – 6%

Total . . . . . . . . . . . . . . . . . . . . . . . . . . 698,740-

720,521 – 3%

SOURCE: American Red Cross Blood Services Operating Reports, 1982 and 1983.

port for the South Florida Blood Service, it appears that there is a substantial amount of blood

which moves “off the record.”

In addition, the charging and payment of nonreplacement fees, and the issue and exchange of

blood credits, continue at a strong rate. In 1983,

over half of the Clearinghouse transactions were

for the exchange or issue of credits (25 percent)

or for the payment of nonreplacement fees (28percent). While the individual responsibility philosophy is not universally accepted, it is still widely

used in this country.

The figures of the American Red Cross for the

past s years indicate an absolute increase in the

amount of blood and blood components which

were produced but fail to suggest a trend toward

or away from increased blood movement (table

39). The lack of a pronounced increase in the percentage of blood moved denies a widening gap

between surplus and shortage areas. Similarly, the

net volume of blood and blood components

moved through the AABB and the ARC has continued to rise (table 40), although the pattern

Table 39.—Movement of Blood and Components

Through the American Red Cross, 1979-83

Volume moved Total production Percent total

Year through ARC by ARC production moved

1983 . . . . . . 698,740 units 14,331,858 units 4.9%

1982, 720,521 13,045,189 5,5

1981 ...., 562,431 12,052,017 4.7

1980, 445,433 11,233,274 4.0

“1979 332,971 10,465,129 3.2

SOURCE: American Red Cross Blood Services Operating Reports, 1980-83,

seems to reflect the influence of variables such as

the change in number of members in the Clearinghouse, and the amount of sharing arranged

outside of either formal network, rather than an

increasing demand for imported blood within deficient regions.

Conclusion

The blood collection organizations are largely

in agreement about the need for resource sharing. The current lack of cooperation between the

AABB and the Red Cross appears to be due to

concerns about antitrust violations. There is lit-
Ch. 5—Current Issues . 117

Table 40.—Total Movement of Blood and Blood Components in the United Statesj

1979-83 (including both the AABB and the American Red Cross)

. — .

Percent change from

Year Clearinghouse Red Cross Total previous year

1983 . . . . . . . . 278,032 units 698,740 units 976,772 units + 4.80/o

1982 . . . . . . . . 211,296 720,521 931,817 +26.8

1981 . . . . . . . . 172,426 562,431 734,857 + 12.9

1980 . . . . . . . . 205,263 445,433 650,696 +29.5

1979 . . . . . . . . 169,668 332,971 502,639 NA . 

SOURCE AABB Clearinghouse Transaction Reports, 1979-83; and American Red Cross Blood Services ‘Operating Reports.

tle evidence

1980-83,

to support the notion that the Red

Cross, or any of the other blood collecting organizations, sought to block the most recent resource

sharing agreement in hopes of retaining organizational control over its blood supply. Concerns

about nonreplacement fees remain to a lesser extent but are superseded by concerns for a wellmanaged blood supply. The nonreplacernent fee

continues to be supported for recruitment reasons

in selected areas of the country; in other areas,

the fee is adamantly opposed. The trend, however, is away from the nonreplacement fee, and

it will likely become a nonissue in terms of logistics and sharing of blood resources. The philosophical objections to cooperating with organizations operating under different recruitment

strategies have subsided.

Even without a single coherent national sharing system or the implementation of the Resource

Sharing Agreement (the one attempt at formalized

resource sharing between the major organizations

in the voluntary sector: the AABB, ABC, CCBC

and the ARC), regions with blood shortages are

generally able to meet their needs, either through

long-term contracts for blood provision or ad hoc

arrangements to compensate for unexpected demand or shortages. Individual blood centers often

contract with other blood centers outside of the

formal mechanisms of the Clearinghouse or the

Red Cross, as well as within them. For instance,

in 1983, the South Florida Blood Service received

70 percent of its imported blood through longterm contracts, 21 percent through ad hoc arrangements, and only 9 percent through the formal mechanisms of the Clearinghouse.

Contrary to the situation in past years, the

supply of blood in the United States is no longer

a critical concern. Blood is managed and shared

effectively, as witnessed by low outdate rates and

consistent interregional movement of blood. Efforts at coordination by the private sector have

been largely successful.

On the local level, many areas have coordinated their blood services, either through the ABC

Regionalization Program or through individualized approaches. In the remaining areas, discussion has at least been initiated on the means for

regional coordination. Nationally, the two voluntary sharing systems provide an effective means

for moving blood from “place of plenty” to “place

of need. ” In addition, blood bankers are predisposed toward assisting in times of blood supply

emergencies and temporary shortages, so many

ad hoc arrangements are made between individual blood service facilities. Thus, the combination of formal and informal sharing works, though

it might be more efficient in individual instances.

PART 3: IMPACT OF HEALTH CARE COST CONTAINMENT

The rising cost of health care has been a per- ample, greater use of health maintenance orgasistent and growing problem for a number of nizations and home health care services and more

years. In the past several years, a number of cost extensive coinsurance requirements, Perhaps the

containment efforts have been adopted; for ex- most far-reaching effort at health care cost con-
118 ● Blood Policy and Technology

tainment was Medicare’s introduction in October

1983 of a new system for hospital reimbursement

based on a prospective per-case payment using

diagnosis-related groups (DRGs). Under this form

of payment, hospitals will be paid a specific

amount for each patient treated in a particular

group, regardless of the number or types of services provided.

Until October 1983, Medicare employed a retrospective cost-based reimbursement approach

whereby hospitals could recover from Medicare

most of what they spent for Medicare beneficiaries. Any costs incurred in treating Medicare patients, including costs of blood products, were effectively “passed through” to Medicare (or to

patients and any other insurance they may have

had). Similar cost-based reimbursement systems

covered many non-Medicare patients. There was

little incentive for hospitals to control costs. Under

the new system, however, hospitals will be rewarded for reducing the cost of treating a patient

over the entire course of the hospital stay. The

new system is likely to have an effect that reaches

far beyond the Medicare system if it is adopted

by other third-party payers. Per-case payment encourages the hospital and its physicians to consider explicitly the benefits of any services against

their added costs. Thus, Medicare’s prospective

payment system is likely to affect all health care

suppliers, including the blood services complex.

Per-case payment systems such as DRGs provide a number of incentives to hospitals which

are not present under cost-based systems. Two

general incentives to hospitals in any per-case payment system are: 1) to reduce the cost to hospitals of each inpatient stay, and 2) to increase the

number of inpatient admissions. Cost per case can

be reduced by decreasing the number of inpatient

days, but it can also be reduced by using fewer

technological services or attempting to provide

them at lower cost. In addition, because outpatient care is excluded from the current DRG system, hospitals may be encouraged to arrange to

provide more services, including ancillary services, on an outpatient basis. Finally, hospitals may

seek to increase profitable admissions by manipulating case load.

The direction and strength of these incentives

for any particular hospital will be altered by key

features of the DRG payment system (e.g., the

proportion of the hospital’s case load covered by

DRG payment, the treatment of costs as passthroughs), as well as by other system constraints

(e.g., physicians’ incentives to practice highquality medicine, community pressure to provide

certain services), so that specific outcomes of implementing the DRG system for any part of the

health care system, including blood services, are

difficult to predict.

One result of hospital efforts to contain costs

that is already being felt by some blood suppliers

is a tendency for transfusion services to “shop

around” for blood products. Although there are

some indications of product preference (e.g., 308),

the safety and efficacy of blood products are for

the most part standardized. Thus, the only factors differentiating blood products are cost and

availability. As shown in chapter 3, fees for blood

services vary widely among blood suppliers; thus,

it is possible for blood users to compare costs. The

use of preservative systems for blood components,

and the computerized communications systems

now in place, make availability less of a problem, except perhaps for components with short

shelf lives, such as platelets.

Assuming that availability needs can be met,

comparative shopping may lead to increased use

of the AABB Clearinghouse, greater price competition among blood suppliers, and a breakdown

of regionalization programs (383). At a minimum,

competition should result in more contract negotiation between blood suppliers and transfusion

services. In the long run, the result could be either lower prices across the Nation or more negotiation about prices among blood suppliers—

resulting, perhaps, in a standard price for blood

products. DRGs may have little effect on the

plasma derivatives market, which is already

highly competitive (see ch. 3).

One manifestation of hospitals’ comparative

shopping on the basis of price may be increasing

questioning of the cost structure of blood suppliers’ processing fees. As discussed in chapter 3,

blood suppliers have not devised a uniform in-
Ch. 5—Current /ssues • 119

dustrywide system to account for the costs of their

blood products. Blood suppliers have recently experienced steady increases in the excess of revenues over expenses, often attributing such increases to needs for capital expansion or research.

Where competition is not a viable option, hospitals may exert pressure on blood suppliers to bring

down costs by limiting or seeking other avenues

for funding research projects or capital expansion.

Demands for price concessions may have particular adverse effects on independent (i.e., non-Red

Cross) blood centers which have built part of their

reputations on research.

DRGs are most likely to have the effect of

revitalizing hospital transfusion and pharmacy

committees’ monitoring of physicians’ use of

blood products. This effect may not be limited

to the whole blood sector. In general, hospital utilization reviews and quality audits are likely to

increase under DRGs (550). As discussed in part

4 of this chapter, the appropriate use of blood

products has been a topic of concern, primarily

because of safety considerations, but sometimes

(e.g., albumin), for reasons of cost. The implementation of DRGs will give hospitals both an

added incentive to monitor individual physicians’

use of blood products and a systematic means for

monitoring hospitalwide use. The implementation

of DRGs is expected to increase the reliability of

patient discharge data, because payment will rely

on the accuracy and timeliness of discharge

abstracts (550). It will also provide a systematic

way to match blood use to specific diagnoses, an

area in which national blood data are particularly

lacking.

Methods to correlate patient outcome with

aspects of hospital care are also being devised

(551), and these may be useful for studies of efficacy of blood components. Studies of the relationships between use and patient outcome will

be important because utilization reviews have

often focused on cost containment to the exclusion of concerns about quality of care (545), although such studies will add to administrative

costs.

The cost of blood products may come to affect hospitals’ case mix, and as a result, blood suppliers’ production schedules. There is speculation

that for certain patients (e.g., post-heart surgery,

post-vascular surgery, oncology patients), DRG

allocations may be depleted on blood demands

alone (see, e.g., 12). For example, in a bleeding

patient the cost of platelet concentrates alone may

be as high as $360 for 1 day. Under the DRG system, hospitals may become more specialized in

their care, treating only certain groups of patients.

Presumably, the rise of specialized care centers

will make for more rational adjustments in percase reimbursement rates, rather than affecting

patient access to care—although this may be a

short-term effect. Patients may have to travel farther to specialized care centers.

The net long-term effect of these changes may

benefit patients, assuming the appropriate adjustments in DRG reimbursement rates are made

so that specialized care hospitals are not adversely

affected by serving large-volume blood users. Recent research has shown that patients treated in

hospitals serving large numbers of specific diagnoses have better outcomes (188). Blood suppliers,

however, may have to adjust collection and production schedules as client hospitals change their

case load mix. For example, regions with transplant centers may require increased donations.

It is difficult to determine whether DRGs will

affect the present balance between hospital blood

bank and community blood center collections.

Community blood centers have come to dominate

blood collections (see ch. 3). There is speculation,

however, that hospitals may set up their own

donor rooms in an attempt to contain and control costs of blood services. Although the question of economies of scale in community blood

centers remains open, it is doubtful whether hospitals would enjoy any economies of scale from

collecting and processing their own blood products. For example, Wallace and Wallace/ABC

(576) found that collecting hospitals charged more

for blood (although it is difficult to determine

whether higher charges actually reflected higher

costs of collection).

Small-volume hospitals would find it particularly difficult to maintain the necessary levels of

expertise in donor recruitment, collection, and

processing, in addition to being unable to make
120 ● Blood Policy and Technology

the necessary space available. What may happen

is that a selected number of highly specialized hospitals may begin to provide for their own special

needs (e.g., for platelets and granulocytes from

pheresis; see 372). Because outpatient services do

not currently come under DRG regulations, DRGs

may temporarily favor transfusion services that

are independent blood centers. For example, all

Red Cross blood services have applied for Medicare provider certification.

The extent to which blood centers will be able

to be reimbursed as Medicare providers is limited,

however. The Health Care Financing Administration (HCFA) recently rescinded the Medicare provider certification of a blood bank, noting that,

“as the law now stands, a blood bank cannot be

paid directly for services it renders” (412). The

intermediary had originally considered the blood

bank in question as eligible for direct Medicare

payment on the assumption that the blood bank

would be considered a physician-directed clinic.

According to HCFA, under current law the blood

bank is only allowed to bill for physicians whom

the blood bank employs or has a contractual arrangement with, and who administer blood, but

not for services rendered by paramedical personnel.

Similarly, HCFA refused to make an exception

to the Medicare provision limiting therapeutic

apheresis procedures to inpatient or outpatient settings (172). The blood bank in question wanted

to be granted an exception on the basis that it was

a physician-directed clinic. Thus, a move by blood

centers to be considered comparable with outpatient units and increase their service base, as

well as help hospitals take advantage of anomalies

in the current reimbursement system, may meet

resistance from HCFA. It is expected that eventually outpatient care will also be covered by a

prospective payment system.

Multi-hospital chains, both profit and nonprofit, are another response to government scrutiny of health care costs. Such chains are believed

to provide more efficient management (98). There

was some speculation that multi-hospital chains

might find it in their interest to take over functions such as blood services, but apparently blood

services were not considered profitable enough to

get involved in (270), and blood collection and

distribution will be left to the largely not-for-profit

sector.

Apart from DRGs, private efforts at cost containment may result in changes in the blood services system, such as an increase in the use of

nonreplacement fees, or similar credits applicable to processing fees. Self-insurers (and participants in corporate donor programs), such as Wells

Fargo Bank in California, have expressed concern

that the cost of blood may be inordinately high

because donors effectively subsidize nondonors

(259). It may be that such corporations will request some form of credit for their employees in

exchange for holding mobile collection drives.

To summarize, the effects of DRGs and other

cost containment efforts are difficult to predict.

A special commission has been established to

monitor the effects of the DRG system and devise

necessary modifications. Health care providers,

including those in the blood services complex, are

watching and hoping to influence developments

in the Medicare reimbursement system (e.g.,

24). It is unlikely that there will be a significant

change in the organizational structure of blood

collections—i.e., blood center collections should

continue to predominate and perhaps increase

their influence. However, hospitals may exert

pressure on blood collectors to reduce charges for

blood products, and blood centers in some areas

may have to change their product mix. The greatest impact of DRGs may be on the ability of independent blood centers to conduct research and

expand their facilities. DRGs will certainly provide an opportunity for more stringent monitoring of blood product utilization.
Ch. 5—Current /ssues . 121

PART 4: APPROPRIATE USE OF BLOOD PRODUCTS

Introduction

Both blood suppliers and users agree that blood

is overused and used inappropriately, but they differ about the extent to which it is misused and

about the means to promote more appropriate

use. Estimates of the amount of blood products

which are inappropriately used are high: 20 to 25

percent for red cells (204); up to 90 percent for

albumin (8); and 95 percent for fresh-frozen

plasma (457). However, data by which to evaluate

the overall appropriate use of blood products do

not exist, in many cases because of lack of scientific precision concerning when a component or

derivative should be administered.

In addition, while some data exist on the number of patients transfused with particular blood

products (e.g., 518), national data on the reasons

why transfusions were given are harder to come

by. Studies such as Friedman’s (204) of the diagnostic categories for which red cells were transfused (as well as the relationship between such

transfusions and geographic location, patient age

and gender) have not been conducted for other

blood products.

Perhaps as important as overall trends in the

use of blood products are instances of bad transfusion practice which are believed to occur (19). As

with appropriate use, national data on the extent

of such bad practices do not exist.

What is known is that there are wide geographic

variations in the rate of transfusions. For example, transfusion rates for red cells and whole blood

varied from a high of 15.3 patients per thousand

population in the Mid-Atlantic States to 12.9 per

thousand population in the Mountain States. Hospitals in the New England region transfused 50

units of red cells per thousand population, compared to only 36 units per thousand population

in the Mountain States (518). The reasons for

these variations are not known. Although general guidelines exist (e.g., 17), in many cases

transfusion decisions, like many other medical

decisions, rely on clinical judgment. In addition,

handbooks widely used by physicians (e.g., 425)

may contain information which is inconsistent

with guidelines written by experts in transfusion.

There are wide variations across the United States

in other areas of medical practice, such as lengths

of hospital stays, that are not adequately explained by demographic differences or differences

in health outcomes (553).

Concerns over misuse have focused on different

blood products over time. Initially, questions centered on the widespread practice of infusing whole

blood instead of packed red cells. Current questions involve albumin solutions, fresh-frozen and

single-donor plasma. For example, a National Institutes of Health Consensus Development Workshop on fresh-frozen plasma indications and risks

was held in September 1984.

Whole Blood

Whole blood transfusions decreased from 67.4

percent of total blood component transfusions in

1971 to 13.0 percent in 1980, and from 78 percent of transfusions involving red cells to 19 percent (see fig. 6 in ch. 3). More recent nationwide

information on transfusions is not available, but

Red Cross data indicate that production of units

of whole blood continues to decrease: by 12.2 percent between 1980 and 1981; by 11.6 percent between 1981 and 1982, and by 20.7 percent between 1982 and 1983. For the year ended June 30,

1983, only 893,791 units of whole blood were produced in the Red Cross system, compared to

5,328,403 units of red cells.

In addition to the normal range of transfusion

hazards, risks specific to the use of whole blood

are circulatory overload as a result of rapid and

excessive infusion, and immunization to platelets

and granulocytes. Circulatory overload can result in pulmonary edema and congestive heart failure, especially in patients whose cardiovascular

status is precarious or compromised (273,388).

Transfusions of whole blood are also viewed as

not cost effective. Two or more components can

be made from every unit of whole blood. Recovered or salvaged plasma can be sold by the blood

center for additional revenue.

38-647 c) - 85 - 9
122 “ Blood Policy and Technology

For some physicians, the only valid indication

for the use of whole blood is when a patient needs

red blood cells and plasma simultaneously; i.e.,

for the active, massively bleeding patient (e.g.,

some surgical procedures and major trauma with

continuing hemorrhage) (407, 500). Others (e.g.,

395) see no need for either fresh or stored whole

blood in clinical practice, and believe that all uses

of whole blood should be replaced by a “threetiered” combination of: 1) volume expansion with

a fluid; 2) red blood cell replacement; and 3)

replacement of clotting factors, if necessary.

There are also different guidelines on the percentage of blood loss indicative of transfusion

with either whole blood or a combination of other

components (e.g., 17,500); the type of fluid replacement to use if whole blood is not used (see

discussion of albumin below); and the amount of

whole blood to transfuse, in particular the requirement for a single unit of whole blood (e.g.,

202,369).

Aside from the misuse of whole blood to restore volume and oxygen-carrying capacity,

whole blood is also believed to be transfused inappropriately when used to provide “general support,” to treat hypoproteinemia with some degree

of concomitant anemia, or to prepare a nutritionally deficient patient for some form of stressful

treatment. According to one textbook of transfusion medicine, the latter represent “serious misconceptions about the efficacy of blood transfusion, the dynamics of blood cell protein turnover

in disease and malnutrition, the optimal management of the undernourished patient, and even

more serious misconceptions about the risks of

transfusion.” In addition, transfusion to promote

wound healing is “usually a florid example of poor

medical practice” (407). The idea that whole blood

is preferable to other blood products because it

contains all components is also believed to be

mistaken. Whole blood stored over 24 hours contains few viable platelets and granulocytes, and

levels of Factors V and VIII are reduced (17).

Red Cell Concentrates

Red cell concentrates are seen as preferable to

whole blood in many instances, because red cells

have the same oxygen-carrying capacity as whole

blood, but are without some of its dangers. Risk

of circulatory overload is reduced, as are risks of

citrate and ammonia intoxication; metabolic

acidosis; acid/base imbalance; and some forms

of allergic and febrile reactions (369). Another important clinical advantage of red cell concentrates

is their use in situations where donor blood identical with the recipient’s ABO type is unavailable,

and use of the universal type O is indicated (407).

In such circumstances, the use of whole blood has

the risk of infusion of large amounts of donor

plasma containing antibodies directed against red

blood cells, which may result in severe hemolytic

transfusion reactions (171). In addition, a volume

of red cells provides twice the increment in hematocrit as does infusion of an equal volume of

whole blood (17). However, red cell concentrates

carry all the infectious risks of whole blood, and

the use of multiple components exposes the patient to multiple risks of hepatitis (17).

Use of red cell concentrates has been found to

vary considerably by geographic location, age,

gender, operative status (i.e., operated v. nonoperated), diagnostic category, and even by

month of transfusion (see 202,203,204; and, for

a more limited analysis, 518). In studies of 1974

and 1977 hospital data, Friedman and his associates found that women, particularly surgical patients, receive more red cell transfusions than men

do, apparently because of their lower hematocrit

levels (204). However, for all diagnostic groups

except one, males received a higher mean amount

of units.

Not surprisingly, surgical patients were transfused more often than nonoperated patients, and

older patients more than younger patients. Patients over 65 years of age constituted 44.3 percent of transfused patients, and received 43.7 percent of all units transfused (204). The major

disease categories accounting for most units

transfused in Friedman’s study of 1977 data were

malignant neoplasms ,cardiovascular disease,

nonmalignant diseases of the gastrointestinal tract,

fractures and traumatic injury, and anemia (see

table 41). The largest single group of units transfused were those transfused to operated males for

cardiovascular disease, which Friedman, et al.,

attributed to coronary bypass surgery.
Ch. 5—Current Issues “ 123

m

0

c-c”

, F ,

- 0
124 . Blood Policy and Technology

Stored red cells, whether packed or in whole

blood, do not contain functional platelets or

granulocytes. However, the nonfunctional platelets and granulocytes contained in red cell concentrates (and whole blood) can result in alloimmunization. Thus, for patients who have already

indicated reactions to transfusions—in particular,

urticarial reactions—or for patients likely to be

receiving frequent transfusions, washed or, less

frequently, frozen-thawed-deglycerolized red cells

are indicated (17). These prepared components are

1.5 to 3.5 times as expensive as unprocessed red

cells. They account for very little of total red cell

production. In the Red Cross only 46,802 units

of frozen red cells and 50,952 units of washed red

cells were produced in 1983.

A major textbook of transfusion medicine notes

that: “Despite a large and longstanding experience, the indications for transfusion of red blood

cell products are not always easy to delineate. ”

There is a wide variety of available transfusion

products, wide variation in the homeostatic capabilities of patients, and a multiplicity of clinical situations. Thus, while providing some general

principles, the textbook suggests that “rules of

thumb about when to transfuse, optimal hematocrit levels, and other such notions are unrealistic”

(407). Others (e.g., 201) suggest that more objective clinical criteria for blood transfusion can and

should be developed.

One of the most controversial areas concerning red cells is the matter of the “transfusion trigger, ” or the hemoglobin level which indicates to

physicians that a patient will be injured by oxygen deprivation, requiring a transfusion of red

cells. Patients vary considerably in their tolerance

of anemia. For example, women naturally have

lower hematocrits than men, but surgeons appear

to use the same support and ceiling hematocrit

levels to regulate blood transfusion for both

genders (202). Similar practices exist for patients

in diagnostic categories such as chronic renal failure and chronic obstructive pulmonary disease

(232). A hemoglobin of less than 10 g/all has been

the traditional “transfusion trigger” most often

used by physicians (204).

Recently, alternatives have been suggested. While

clinical judgment of the patient’s condition is suggested most often (e.g., 17,407), Gould (232) suggests combining clinical status with an evaluation

of a patient’s ratio of oxygen consumption to oxygen delivery (“oxygen extraction ratio” or ER)

rather than a hemoglobin count,

Red cells are sometimes used instead of a more

appropriate nonblood therapy. For example,

Friedman and his associates found that iron deficiency anemia was the fifth leading blood-user

diagnosis group in the United States among nonsurgical patients (204). This condition rarely warrants blood transfusion (201). Rather, it is treatable with dietary change or iron supplements.

Platelets

Patients most likely to require platelet transfusions are those suffering from malignancies involving the bone marrow (e. g., leukemia and

lymphoma), those suffering from bone marrow

depression as a result of chemotherapy, drugs,

infection or other causes (e. g., 481), and those

suffering from drug-induced thrombocytopenia

(platelet loss). Deaths due to leukemia have significantly declined since the introduction of

platelet therapy. Surgical patients suffering from

thrombocytopenia may also require platelet transfusions (199,533).

The risk of hepatitis and other transmissible infectious diseases from platelets is the same as for

whole blood. As with whole blood transfusions,

circulatory overload can occur, especially in

children. In addition, because platelets are stored

at room temperature, the risk of bacterial growth

is greater than that of whole blood. Risks specific

to random-donor platelet transfusions include

alloimmunization resulting in a refractory state,

transfusion reactions as a result of incompatibility

between antibodies in the platelet concentrate and

red blood cell antigens of the recipient, and graft

v. host disease as a result of the collection of lymphocytes along with the platelets. When sensitivities develop, single-donor transfusions are substituted for random-donor platelet concentrates,

although these are not without their problems

(533).

It is generally recognized that there are large

gaps in knowledge of the proper use of platelets

(481). There is general agreement that platelet

transfusions are of limited benefit in patients suf-
Ch. 5—Current Issues ● 125

fering from idiopathic thrombocytopenic purpura

and other forms of rapid platelet destruction

(264,533). There are different opinions concerning the use of platelet transfusions when other

forms of platelet dysfunction (thrombocytopathy)

are present. For example, the AABB Physicians

Handbook indicates that platelet transfusions are

indicated for thrombocytopathy. Daly (145) indicates that such transfusions are rarely necessary.

As with other components, the proper dosage

of platelets is a matter of unresolved clinical concern. Aster (55) notes that treating the “platelet

count” rather than the patient may result in waste.

Other questionable uses of platelets are for open

heart surgery, irrespective of a patient’s own

platelet level and clinical status (on the assumption that a qualitative platelet defect exists), and

in patients who develop a hemorrhagic diathesis

after renal transplantation (55).

Most significantly, some question the prophylactic use of platelets in patients with malignancies.

Clinical trials investigating this question have led

to different conclusions (481); another clinical trial

is currently under way (533). The resolution of

this question will have a major effect on the blood

supply and economics of blood services (520).

Granulocytes

Granulocyte transfusions maybe indicated for

patients who have an inadequate supply of white

cells (granulocytopenia) and a life-threatening infection which is unresponsive to antibiotics. Candidates for granulocyte transfusions include patients with acute leukemia, aplastic anemia, solid

tumors and auto-immune diseases, and transplant

recipients. Granulocytopenia can result from

chemotherapy or primary bone marrow depression.

Granulocyte transfusions carry the same risks

of infectious disease as whole blood. In addition,

immunosuppressed or immunodeficient recipients

may be at risk of developing graft v. host reactions. Allergic, febrile or hemolytic reactions,

HLA and red cell antigen immunization, and

severe pulmonary insufficiency can occur (17,

369). Granulocyte transfusions are expensive because of the complexities of cell procurement, storage and administration and the requirement for

close day-to-day cooperation between clinicians

and the transfusion service. For example, granulocytes must be obtained, crosshatched, and administered within 24 hours of donation, putting

enormous pressure on blood banks and transfusion services. Granulocyte donors may be particularly at risk because granulocytes must be obtained via pheresis and alloimmunized patients

may rely on a small pool of donors.

Indications for use of granulocytes are perhaps

the least clear of all the components, with the exception of fresh-frozen plasma (199,481). As a result of several clinical investigations, including

clinical trials (e.g., 191,482,590), the prophylactic use of granulocyte transfusion has been judged

to be of questionable therapeutic value, at a minimum (17). Some say the use of prophylactic

granulocytes should be considered a strictly investigational procedure not to be utilized outside

of research settings (e.g., 481). The therapeutic

value of granulocytes has been difficult to judge

because of the seriously compromised clinical

status of candidates for granulocyte transfusions

(e.g., 190). The use of granulocyte transfusions

has been declining nationwide. In general their use

to combat infections seems to be a therapy of last

resort.

Cryoprecipitate

Cryoprecipitate contains large amounts of Factor VIII and von Willebrand’s factor, in addition

to concentrated amounts of fibrinogen, fibronectin, and Factor XIII. The major clinical disadvantage of cryoprecipitate is the individual variation

in Factor VIII from bag to bag, resulting in unpredictability of the required therapeutic dose

(397). Cryoprecipitate has all the infectious risk

factors of whole blood. Other risks include febrile and allergic reactions, and hemolysis as a consequence of incompatibility between antibodies

in cryoprecipitated AHF and antigens of recipient red blood cells.

Indications for cryoprecipitate vary. It is recommended for the treatment of Hemophilia A and

von Willebrand’s disease, congenital fibrinogen

deficiency, and other conditions associated with

consumption of fibrinogen (e.g., obstetrical com-
126 . Blood Policy and Technology

placations, disseminated intravascular coagulation) and Factor XIII deficiency (e.g., 17,282).

Others do not mention Factor XIII deficiency

(369). The most recent use of cryoprecipitate has

been for fibronectin replacement in infection or

shock. This use has been questioned, because clinical indications have not been adequately tested,

and administration of excess fibronectin may be

harmful to the recipient (497).

The major controversy surrounding the use of

cryoprecipitate is its use in preference to lyophilized Factor VIII concentrate. Preparation of

cryoprecipitate is a labor-intensive process. Administration is more difficult because, unlike

lyophilized Factor VIII, cryoprecipitate must remain frozen to retain its therapeutic value. As

already noted, the Factor VIII content of cryoprecipitate varies from unit to unit and is largely unknown. While the conventional wisdom is that

cryoprecipitate is less likely to transmit infectious

disease because fewer donors are involved, in fact

a severe hemophiliac treated with cryoprecipitate

would be exposed to 500 to 1,000 donors a year.

If one of the units is contaminated with a lowprevalence virus, the hemophiliac receives all of

it. In a commercial pool, a low-prevalence virus

would be diluted and might be inactivated by antibody in the pool.

Fresh= Frozen and Single= Donor Plasma

Single-donor plasma, fresh-frozen (usually

called fresh-frozen plasma, or FFP) contains all

the coagulation factors found in native plasma.

Single-donor plasma (not frozen) contains all of

the stable coagulation factors but reduced levels

of the labile coagulation Factors V and VIII. Both

fresh-frozen and single-donor plasma have all the

risks of infectious disease that whole blood has,

as well as the risk of allergic or febrile reactions

and incompatibility between plasma antibodies

and recipient red cell antigens. Transfusion of

plasma to correct for coagulation deficiencies carries with it the risk of fluid overload (17).

The dramatic increase in the use of fresh-frozen

plasma over the last decade has prompted concerns that the uses of it “are often vague and without scientific basis, ” and that it is “likely that other

products are available that are equally effective

as and safer than fresh-frozen plasma” (567). Most

FFP is administered as replacement for deficient

coagulation factors in postoperative patients and

in a variety of medical bleeding disorders. Some

also is used as a replacement for fluid and colloid loss in patients with burns and shock. As with

other components, systematic data on the purposes for which fresh-frozen plasma is used are

not available.

Recommended indications for FFP and singledonor plasma vary. The most frequently cited indication for fresh-frozen plasma is the situation

in which a specific factor deficiency has not been

established (17,282,369,397,497). Harrison’s Principles of Internal Medicine (425) indicates that

fresh-frozen plasma (“and cryoprecipitate”) is necessary for treatment of coagulation disorders,

especially hemophilia, a suggestion that most experts in transfusion do not agree with. There is

disagreement over the use of FFP and single donor

plasma in other situations, in particular for the

treatment of low plasma volume (17,282,369,397,

497). The use of other solutions for fluid replacement would obviate the risk of infectious disease.

Other indications on which there is disagreement include the use of FFP: as a protein-containing medium (282); as a source of Factor IX

(282); for disseminated intravascular coagulation

and when deficiencies of multiple clotting factors

exist, as in liver disease (397; 497); the preparation of hemostatically deficient patients and intraand postoperative correction of bleeding problems

(497).

Albumin and Plasma

The primary indication

Protein Fraction

for administration of

albumin (and a similar product, plasma protein

fraction [PPF]) is for plasma volume expansion

in shock and trauma. Because albumin and PPF

are heat-treated, they are safer than whole blood

with respect to transmission of infectious disease.

Most adverse reactions are due to technical accidents during manufacture (520) or to inappropriate or incorrect administration (494,538). Recipients of albumin run the risk of fluid overload.

Like fresh-frozen plasma today, the overuse of

albumin was once a topic of great concern. Al-
Ch. 5—Current Issues . 127

though its use remains controversial (see below),

public concern about the use of albumin appears

to have subsided. Cost was a major element in

the controversy. Albumin is considerably more

expensive than crystalloid solutions such as saline

and Ringer’s lactate. A liter of Ringer’s lactate

solution costs approximately $1; an amount of

albumin required to produce a comparable result

costs $130 (394). One estimate is that as much as

10 percent of the total drug budget for an acute

hospitalization may be related to use of albumin

and other blood products (112).

In 1975, indications for the use of albumin were

the subject of an NIH Workshop (494). Following the workshop, guidelines for the use of albumin were published (538), and a number of attempts were made to modify physicians’ use of

albumin (e.g., 8). As late as 1977, however, Alexander, et al. (8), found that albumin was being

used inappropriately in 71 percent of surgical cases

and 41 percent of nonsurgical cases. Worldwide

U.S. production and consumption continues to

rise (see ch. 3). A recent international study (including the United States) found that clinical uses

of albumin covered many uses not recommended

by health and regulatory agencies—e.g., for

nephrosis, in detoxification, and as part of the

treatment of malignancies (260). An indication of

the confusion about the amount of albumin that

is needed in clinical practice is the significant

variation among countries, even countries similar in levels of medical sophistication (388).

Despite the guidelines published as a consequence of the NIH workshop, textbooks continue

to disagree on some of the uses of albumin; e.g.,

in adult respiratory distress syndrome (17,112,

349,520) and coronary bypass pump priming

(388,520). The latest edition of Harrison’s Principles of Internal Medicine (425) cites the use of

albumin in severe malnutrition, nephrosis, and

certain gastroenteropathies. Use of albumin for

malnutrition is not advised in manuals written by

blood bankers (e.g., 17). The international study

referred to above suggested that the needs of patients were reflected better by clinical use than by

agency recommendations. Thus, use of albumin

remains controversial.

Factor Vlll

Until the AIDS crisis, there was little controversy in this country concerning the appropriate

use of Factor VIII, particularly since it is readily

available. There is now some movement from use

of lyophilized Factor VIII to use of cryoprecipitate, at least for less severe hemophiliacs. Use of

lyophilized Factor VIII has reportedly decreased

substantially in the past year. In countries where

Factor VIII is less available, prophylactic use of

Factor VIII is an issue. Mollison (388) reports the

results of a randomized clinical trial conducted

in Great Britain (54) which showed that reducing the incidence of bleeding in severe hemophiliacs by 15 percent would require the use of

73 percent more Factor VIII than would be used

by simply treating episodes of bleeding. Reduction of bleeding by 66 percent would involve an

increased usage of approximately 160 percent.

Methods to Change Usage Patterns

To some extent, then, controversy surrounds

the appropriate use of all blood products. A key

element in the controversy is that criteria for clinical use are often unclear. Thus, practice at the

bedside relies on anecdotal reports and evidence

from inadequate trials (567). However, even when

medical guidelines are generally accepted, local

practice varies and may sometimes be inappropriate. Past attempts to change medical practice

have relied largely on educational efforts. Although systematic data do not exist to adequately

test their effectiveness, these attempts appear to

have been largely unsuccessful. Currently, a number of new efforts to curb the misuse of blood

products, described below, are under way. Perhaps the most effective push in the direction of

more appropriate use will be the impact of Federal cost containment efforts.

Education

As noted above, past attempts to change medical practice have relied largely on educational efforts such as seminars and textbooks. For example, the American Association of Blood Banks has

published a series of books based on seminars and
128 • Blood Policy and Technology

workshops at their annual conventions. Three

textbooks are available (Huestis, Bove, and Busch

[three editions]; Petz and Swisher, 1981; and,

Mollison [seven editions 1951-83]). It is unclear,

however, to what extent these efforts have reached

practicing physicians. Medical schools devote little

attention to transfusion practice. The result is that

medical students and residents learn most of what

they know about blood transfusion by the practice of “chaining” (520): “The chief resident passes

along what he has learned, gathered in an entirely

unsystematic way, to the assistant residents, who

then in turn teach the interns and medical students

as they rotate through the various clinical services. ” Results of formal teaching exercises such as

having blood center personnel speak at grand

rounds, staff meetings, or in-service training programs, have been varied (262). As discussed with

respect to fresh-frozen plasma and albumin, textbooks in general use by physicians do not always

follow the guidelines promulgated by blood

bankers.

The rise of component therapy has exacerbated

the need for clinicians to become more sophisticated about the use of blood. As a consequence,

several books of guidelines directed at practicing

physicians have been published. A pocket-sized

book published by AABB seems the most accessible (i.e., in addition to being pocket-sized, it has

brief chapters, is indexed, and costs only $3). An

AMA guide, General Principles of Blood Transfusion (39), has gone through several editions (1970,

1973, 1977) and is being revised. Currently, the

AABB is engaged in a more active attempt at physician education. Its Physician’s Handbook is to

serve as the basis for a new physician self-assessment program, the Transfusion Medicine SelfAssessment Program (26). Other attempts at continuing medical education include the American

College of Surgeons’ recent postgraduate course,

Pre- and Postoperative Care: Blood and How to

Use It (36).

Perhaps the most encouraging trend in physician education is the institution by the National

Institutes of Health of “Transfusion Medicine Academic Awards” (403; see app. A), and other efforts concerning appropriate use. Recipients of

Transfusion Medicine Academic Awards will

work with local medical schools to incorporate

transfusion medicine into the curriculum. Currently, five such awards, at $50,000 per annum

for 5-year periods, have been granted. The program will be announced each year until needs in

transfusion medicine are fulfilled. Perhaps as important as the awards themselves is the fact that

current transfusion medicine award recipients are

communicating with each other about their experiences in inculcating local changes (534). In addition, applicants for National Research and Demonstration Center in Transfusion Medicine (NRDC)

awards are encouraged to design projects directed

at testing and evaluation of strategies to affect

health management practices and physician and

health-professional knowledge.

As encouraging as these attempts at more physician education are, a limiting problem is that

many indications for transfusion are based on

“soft” scientific data. Thus, guidelines conflict and

experts conclude by saying that it is impossible

to provide rules of thumb. There is a need for

more objective evidence, but few randomized clinical trials have been conducted. For example, even

though NIH has stressed the need for clinical trials

and applicants for NRDC and Specialized Centers

of Research in Transfusion Medicine (SCOR)

awards are encouraged to conduct controlled,

carefully monitored trials, support for such trials

alone is explicitly prohibited by the awards. Currently, however, clinical trials are under way on

the appropriate uses of platelets (at Puget Sound),

Factors VIII and IX (at the San Francisco Veterans

Administration Medical Center), and fibronectin

(Albany, NY) (532).

Blood Center and Hospital Controls

Attempts to educate physicians and blood bank

personnel as to the appropriate uses of blood

products, while useful, typically have had limited

impact. Accordingly, some blood centers and hospitals have made more direct attempts to modify

the use of blood products. At Puget Sound Blood

Center, for example, requests for more than eight

units of a blood component must be cleared

through a blood center consultant before the

blood is released. This consultation process is an

example of the extent to which blood center physicians have gone from laboratory to clinical

aspects of transfusion (532).
6

Alternative Technologies
Page

Part 1: Alternative Sources of Blood Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Stem Cell Culturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Red Blood Cell Substitutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Platelet Substitutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Part 2: Alternate Source for P1asma Products–Use of Recombinant DNA

Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Application of Recombinant DNA Technology to Large-Scale Production of

Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Other Applications of Recombinant DNA Technology. . . . . . . . . . . . . . . . . . . . 172

LIST OF TABLES

Table No. Page

42. Composition of Fluosol-DA (20)% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

43. rDNA Companies That Are Working on Cloning the Gene for Serum

Albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

44. Companies Working on Cloning the Gene Coding for Factor VIII . . . . . . . . 164

LIST OF FIGURES

Figure No. Page

12. Schematic Diagram of Cell Replication and Differentiation . . . . . . . . . . . . . . . 134

13. oxygen Dissociation Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

14. Perfluorochemicals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

15. Crosslinked Hemoglobin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

16. Liposomes . . . . . . . . . . . . . , ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

17. Structural Map of the pBR322 Plasmid DNA Molecule . . . . . . . . . . . . . . . . . . 153

18. Common Methods for Inserting Foreign DNA Into the pBR322 Plasmid . . . 155

19. The Filter Hybridization Technique of Grunstein and Hogness, 1975 . . . . . . 156
6

Alternative Technologies;

PART 1: ALTERNATIVE SOURCES OF BLOOD PRODUCTS

Introduction

Substitutes and alternative sources of therapeutic blood components are likely to eventually

make the entire spectrum of human blood products obsolete, but it will be at least 3 to 5 years

before any one of these new products becomes

commercially available. Within the next decade,

virtually all plasma derivatives will be synthesized

using recombinant DNA technology. Substitutes

for blood’s cellular elements such as red blood cells

(RBCS) and platelets will be much more difficult

to develop, but present research activities, although in their infancy, suggest that all of the

problems are likely to be resolved. The most probable order of availability is that alternative sources

of plasma derivatives will be developed first, followed by red cell substitutes, and eventually by

platelet substitutes.

As in the current blood industry, there is a division within the development process of alternative blood sources and substitutes. Most work in

cellular substitutes has concentrated on an RBC

substitute, with the recognition that such a product may really be an additional transfusion product or adjunct solution, rather than a replacement

for RBCs. Most of the research is being performed

by academic investigators or at military research

institutes, although commercial organizations are

also involved, ranging from plasma fractionation

companies (e. g., Alpha Therapeutics) and large

industrial concerns (e. g., Monsanto Corp.), to

small biotechnology firms which have focused on

specific preparations (e.g., hemoglobin synthesis).

In contrast, nearly all of the research on new

sources of plasma derivatives is being conducted

by biotechnology companies. There is substantial R&D in progress, in which the goal is to clone

clinically useful plasma proteins utilizing recombinant DNA technology.

Impetus to develop blood substitutes and alternate sources comes from several factors. First,

there has been increasing use of component v.

whole blood therapy, which means that blood

substitutes need only duplicate the specific property of the desired blood product. Second, recent

advances in biotechnology, particularly in the

field of recombinant DNA technology, have suddenly raised the prospect that alternative sources

for blood products, particularly plasma proteins,

can be attained. There is therefore a new technology which can be exploited for its potential

for profitable commercialization.

Another major impetus to develop these products lies in their anticipated safety. Frequent blood

recipients, such as hemophiliacs, invariably develop viral hepatitis, and nearly 10 percent of all

blood recipients develop some posttransfusion viral hepatitis. Blood-transmitted AIDS is the most

recent safety problem, and substitutes and alternative sources would avoid the problem of bloodtransmitted infectious diseases.

The costs of transfusion may also be lower, because such requirements as special storage conditions and compatibility testing may be avoided.

Although the price of a unit of blood currently

ranges from about $35 to $60, this charge does

not include a hospital crosshatch and/or transfusion fee, which can often double the total charge

for a blood transfusion. “Artificial blood” offers

the hope that the direct cost of transfusions will

be less. And with the plasma derivatives, current

R&D activities are in many cases based on the

hypothesis that these products can be produced

at far less cost then the blood-extracted products

they would replace.

Current availability of blood products also

varies considerably as a function of the supply

of donors. Shortages still occur in the summer

133
134 ● Blood Policy and Technology

months and around the Christmas holidays. Onsite, resuscitative solutions in large quantities are

needed for civil disasters and battlefield casualties.

Although U.S. hemophiliacs now have access to

adequate supplies of Factor VIII, very few hemophiliacs in developing countries receive or have

access to this treatment.

Blood substitutes may also be preferred over

blood-derived products, such as for patients who

for various reasons will not or cannot receive

blood from other individuals; or in organ or tissue

perfusion, where the greater oxygen delivery capacity of a blood substitute may better maintain

tissue viability.

In sum, most of the impetus to develop alternate blood sources and substitutes is based on economic, safety, and availability considerations.

None of these products has yet reached the marketplace, and developmental efforts are still at the

stage of laboratory investigations or animal testing; clinical trials with humans have not begun

except for oxygen-transport substitutes. Thus, it

should probably be at least 3 to 5 years before

the first of these products will be approved for

human use.

Stem Cell Culturing

Red blood cells, platelets, and granulocytes are

mature blood cells that have a limited lifespan and

Figure 12.—Schematic Diagram of

are incapable of self-replication. Replacement of

these cells takes place in the bone marrow, where

less differentiated cells exist with capabilities to

differentiate into different cell types. These “’stem

cells” in the marrow possess both the ability to

replicate (multiply) as well as to differentiate into

specific hematopoietic cell lines (commitment).

Figure 12 is a schematic diagram of stem cell

replication and differentiation.

It is conceivable that stem cells could be grown

in culture so that a continuous supply of cells for

transfusion would become available. But at this

time, stem cell culturing for the production of

mature, transfusable blood cells is not possible.

Although it has been known for over a century

that mature blood cells were derived from the

bone marrow, it was not until 1961 that an assay

was developed which proved that bone marrow

cells are capable of forming colonies of hematopoietic progenitors (530). Other studies have

conclusively shown that the colonies are derived

from a single cell and that the responsible cell was

a true multipotential stem cell (596). Having an

extensive capacity for self-replication, stem cells

comprise only 0.1 percent of the total cell population in the bone marrow. Stem cells also circulate

in the blood stream, albeit in much lower concentration than in marrow. Thus, it is possible

to obtain stem cells from two sites (marrow and

Cell Replication and Differentiation

Progenitor cells Mature cells

stem cells

stem cells

(fragments into platelets)

Other “blood cells”

SOURCE: R. Kahn, et al., Alternate Sources, 1984
Ch. 6—Alternative Technologies • 135

blood), and their self-replicative capacity obviates

the need for large numbers of cells to initiate a

culture.

Stem cells have also been shown to differentiate and form colonies in tissue culture (92).

Mouse stem cells that produced granulocyte progenitor cells and pluripotent stem cells have been

cultured (159), and mouse bone marrow cultures

have been induced to generate stem cells for more

than a year (358), with documented red cell,

granulocyte, and megakaryocyte (precursors to

platelets) production.

The specific conditions needed in maintaining

a long-term bone marrow culture vary with the

species from which the cells are derived, but in

general they include an optimum cell density, the

proper nutrient medium, regular maintenance

(i.e., changing the medium), and a specific incubation temperature. A number of investigators have

successfully established long-term cultures of

human bone marrow cells (135,213,266), but the

culture methods developed are clearly suboptimal.

The cultures survived for only 2 and 6 months;

while hematopoietic differentiation was observed,

it is uncertain whether there was significant stem

cell replication. Differentiation also did not proceed along all cell lines. For example, mature, even

functional, granulocytes have been produced

(239), but mature megakaryocytes have not been

seen.

The list of culture supplements is long and

varies significantly between investigators (e.g.,

some use vitamins and others do not). Such culture supplements as fetal bovine serum, horse

serum, and steroids have been used with very little

knowledge of the active ingredient(s) or mechanism of action. The optimal temperature for

growth is also unresolved. Some cultures require

330 C, while others are maintained best at 37o C.

Last, cultures of human stem cells have properties that cultures of mouse stem cells (which live

far longer) do not, and it is uncertain whether the

differences represent suboptimal conditions or are

unique to the species used. For example, bone

marrow cultures usually consist of a layer of cells

adherent to the culture dish as well as a nonadherent layer. In the mouse system, stem cells

are released from the adherent layer into the nonadherent layer, where they differentiate (158).

This progression of stem cells from the adherent

to the nonadherent phase is absent or significantly

impaired in human cell cultures (135).

Future Directions

A considerable number of unresolved issues and

problems must be addressed before stem cell

culturing becomes an attractive method to produce transfusable blood cells. At the very least,

much more needs to be learned regarding hematopoiesis in general. For example, there is little

knowledge of the factors that tell the uncommitted stem cell to differentiate into progenitor cells,

and then into the mature blood cell (124). At the

very least, a complex series of cellular and environmental interactions govern the differentiation

process (399,411). Some are known, such as the

hormones erythropoietin for RBC production and

thrombopoietin for platelet production, once progenitor cells have developed. Control mechanisms

must be known in order to provide confidence

that the cells produced are indeed normal, rather

than products of an uncontrolled bone marrow

malignancy. It will also be essential to determine

those factors that govern stem cell replication as

opposed to commitment, if mature blood cell production is to be sustained.

Even with greater understanding of the events

governing hematopoiesis, several major problems

remain. First, how will production be amplified

from culture flasks producing millions of cells to

production of sufficient numbers (101

° to 1012) for

transfusion? For example, the cumulative production of granulocytes in primary mouse marrow

cultures reaches a maximum of 6 x 107 cells over

a period of a year (106 cells/culture/week) (358),

and therefore about 10,000 cultures would be necessary to generate 101

° granulocytes, or the number of cells found in one granulocyte transfusion

product. It is conceivable, however, that maintenance of a culture for longer periods, accompanied by secondary culturing of the primary

culture as well as by the addition of growth

enhancement factors, could shorten production

time considerably.

Second, how will the mature cells be harvested

so that unwanted contaminants are eliminated?
136 ● Blood Policy and Technology

—

Blood cells derived from a cell culture must be

free of nutrient media, which contains proteins

that can elicit an immune response in the recipient. Other supplemental factors (e.g., steroids)

may also cause adverse reactions.

Third, will end-products of the culture be functional cells? It is likely that compatibility testing

between “donor” and recipient will have to continue, thus negating the advantage of a universally compatible product, which other blood substitutes are likely to be. Last, there is evidence that

long-term cultures will sometimes contain malignant cells (354). This would, at the least, require

stringent precautions to purify the transfused

product; it might prohibit use of those products

altogether.

Stem cell culturing offers the potential of producing transfusable blood cells in a laboratory

environment rather than from routine blood

donations. This approach to blood cell production, however, is in its infancy; much more research is needed before an accurate assessment of

its usefulness can be made.

Red Blood Cell Substitutes

Most of the research on substitutes for the

cellular components of blood have focused on

RBCs, with some research on platelet substitutes.

Of the many different white cell populations, only

the granulocyte is currently used for transfusion.

As granulocyte transfusions are now used primarily for combating bacterial infections in an immunocompromised patient, the most practical

substitute has been to administer antibiotics. The

increasing availability of new, potent, and specific antibiotic preparations has contributed to the

decline of granulocyte transfusions over the past

few years, and development of other antibiotic

preparations should obviate the need for granulocyte transfusions.

Function of Red Blood Cells

Red blood cells are biconcave discs that are, for

all practical purposes, bags filled with hemoglobin. Each molecule of hemoglobin contains four

polypeptide chains: two alpha chains and two

beta chains. Each alpha chain has 141 amino acids

and each beta chain 146 amino acids, and all four

molecules comprise the globin portion of hemoglobin. Each of the four chains contains an iron

atom to which oxygen binds in a reversible fashion. Thus, a hemoglobin tetramer binds four

molecules of oxygen.

The four chains, which form a loose tetrameric

structure, can readily dissociate to form two

dimers. The formation of tetramers is favored

when hemoglobin is contained within the red cell.

When hemoglobin is free in solution, dimer formation is favored, which has poor oxygen binding characteristics.

The interaction between oxygen and hemoglobin in erythrocytes can be described by what is

called an oxygen dissociation curve (fig. 13),

which depicts the degree to which hemoglobin is

saturated with oxygen. At so percent saturation

(i.e., P50), and under normal physiological conditions, the y-axis of the curve is near 26 mm of

mercury, or 26 torr. When the affinity of hemoglobin for oxygen is increased and oxygen is therefore less able to dissociate from the hemoglobin

molecule, the oxygen dissociation curve is shifted

to the left and the P50 decreases. In other words,

Figure 13.—Oxygen Dissociation Curve

o 20 40 60 80 100

P02 in mm of Hg or torrs

Kahn, R., et al, Alternate Sources, 1984.
Ch. 6—Alternative Technologies ● 137

less oxygen is needed for 50 percent of the hemoglobin to be saturated, but oxygen is less able to

be released from hemoglobin. Alternatively, if hemoglobin’s affinity for oxygen is decreased and

oxygen can more readily dissociate from hemoglobin, more oxygen will be needed for 50 percent of the hemoglobin to be saturated. This is

represented by a shift in the oxygen dissociation

curve to the right and an increase in the pressure

of oxygen needed to saturate 50 percent of the hemoglobin with oxygen. A shift of the oxygen

dissociation curve in either direction is unwanted,

because the ability of hemoglobin to pick up oxygen in the lungs and to unload it in the tissues

will be adversely affected.

The affinity of hemoglobin for oxygen is influenced by many factors. For example, pH, carbon

dioxide levels and the intracellular molecule 2,3-

DPG affect the position of the oxygen dissociation curve and hence the P50 value. A decrease

in pH reduces the affinity of hemoglobin for oxygen and shifts the oxygen dissociation curve to

the right. This change is referred to as the “Bohr

effect” and is seen following substantial muscular

action, which is associated with production of lactic acid. The decrease in pH helps in delivering

oxygen to the exercising tissues. Carbon dioxide

also binds to hemoglobin and, by displacing oxygen in the hemoglobin molecule, results in reduced affinity of hemoglobin for oxygen and a

shift of the oxygen dissociation curve to the right.

Physiologically, however, the molecule 2,3-

DPG has the most important influence on P50

levels. It decreases the affinity of hemoglobin for

oxygen (right shift) by shifting the equilibrium between the deoxygenated and the oxygenated forms

of hemoglobin, It stabilizes the deoxygenated

form, causing oxygen to be released. However,

when the oxygen concentration is high—as it is

in arterial circulation— the equilibrium is shifted

toward the oxygenated form of hemoglobin,

thereby negating the influence of 2,3-DPG. At low

oxygen pressure (e. g., in tissues), 2,3-DPG displaces the oxygen on hemoglobin, causing oxygen

to be released.

The function of hemoglobin can be altered in

many ways that ultimately reduce its ability to

transfer oxygen. For example, the iron of the heme

group can be oxidized from the ferrous to the ferric form, producing methemoglobin, which is incapable of combining with oxygen. Such oxidization readily occurs to hemoglobin in solution, but

protective effects within RBCs prevent this alteration from happening. Hemoglobin function also

decreases when RBCs are stored, mainly because

of a reduction of 2,3-DPG, thereby causing the

P50 to decrease (left shift). Fortunately, 2,3-DPG

levels are largely regenerated through metabolic

processes within the first few hours following

transfusion.

Although a left-shifted oxygen dissociation

curve indicates a decreased capability of hemoglobin to unload oxygen, its occurrence does not

necessarily mean that tissue oxygenation will be

adversely affected. The body can effectively compensate for decreased oxygen availability by increasing cardiac output, heart rate, or the efficiency with which tissues can extract oxygen.

While oxygen is chemically bound to hemoglobin, it also is physically dissolved in plasma, but

the concentration of oxygen in plasma is far less

than in oxygenated hemoglobin, and plasma is

normally an inefficient medium for oxygen delivery to tissues.

The ideal RBC substitute should have six properties: 1) an oxygen dissociation curve and oxygen-carrying capacity similar to that of intact

RBCs; 2) be nontoxic and nonantigenic; 3) have

good flow characteristics; 4) remain in the circulation for a long period of time; 5) have a long shelf

life; and 6) be cost effective in comparison to

present RBC transfusions.

While no substitute as yet fulfills all of these

criteria, four approaches to achieving the ideal

substitute have been explored. One approach is

to utilize a class of synthetic compounds called

perfluorochemicals. Purified hemoglobin has also

been chemically modified to prolong its circulation and enhance its oxygen binding/dissociation

properties. A third approach has been to synthesize analogs of hemoglobin that, as in the

native molecule, chemically bind oxygen. Last,

investigators have attempted to assemble a red cell

by encapsulating hemoglobin in lipid vesicles

called liposomes.
138 ● Blood Policy and Technology

Each of these substitutes has problems and

drawbacks, some in common with one another

and some unique to a particular substitute. Nevertheless, at least one clinically useful RBC-like

preparation should become available by the close

of this century.

Perfluorochemicals

Perfluorochemicals (PFC) are compounds in

which all the hydrogen atoms have been replaced

by fluorine atoms (fig. 14). They are chemically

inert and not metabolized by the body. Unlike

other RBC substitutes, PFC transports oxygen

only in solution. Because the molecules of PFC

do not strongly interact with one another, they

have more room for gas to occupy the spaces between each atom and molecule. Thus, PFC can

dissolve 40 to 70 percent oxygen per unit volume,

almost three times the oxygen-carrying capacity

of blood. It is this relatively high volubility of

gases that make these compounds attractive as red

cell substitutes.

Figure 14.– Perfluorochemicals

SOURCE: R. Kahn, et al., Alternate Sources, 1984

The concentration of physically dissolved oxygen in a PFC solution is linearly related to the

concentration of the PFC in the solution. As the

PFC concentration increases, its contribution to

oxygen delivery and consumption also increases

(235). However, the oxygen-carrying capacity of

a PFC is also directly proportional to the concentration of oxygen in the environment. At room

air oxygen levels, PFC will hold little oxygen; it

therefore must be given in a high oxygen environment in order to be effective.

Pure PFCs, however, are immiscible with blood,

and, without any alteration, would act as an embolus when injected into the bloodstream. Since

PFCs are not easily converted to finely dispersed

stable emulsions, they must be emulsified to produce a very low viscosity and surface tension.

PFCs can be emulsified with surfactants known

as Pluronics, and in this form they can be mixed

with blood. Because PFC must be used in an

emulsified form, formulation and preparation of

emulsions are at the center of studies on these

blood substitutes. The emulsifying agent most

widely used in dispersing PFC is Pluronic F-68.

The preparation has the appearance of either a

clear solution or a suspension resembling diluted

milk, and the size of the particles can be as small

as 0.1 to 0.2 microns, or 1/70 the size of an RBC.

The emulsification process and the size of the

particles produced are important for stability and

potential toxicity. PFCs that are rapidly eliminated from the circulation do not form stable

emulsions, and conversely, those PFCs that can

be easily emulsified have been found to have long

body retention times. Since the body does not

metabolize PFC, those particles not excreted have

been shown to aggregate in the liver and spleen.

In an effort to find a PFC that is both stable

in emulsion and rapidly cleared from the body,

there has been a systematic effort to screen a great

number of PFCs for their utility as blood substitutes. In 1973, a combination of two PFCs were

formulated, one with a short half-life in the body,

and the other with a much longer half-life. It was

this new PFC combination that was distributed

by the Green Cross of Japan to its American subsidiary, Alpha Therapeutics, and used in the

United States in recent patient studies. Called

Fluosol-DA, it consists of 20 percent (weight to
Ch. 6—Alternative Technologies ● 139

volume) PFCs; perfluorodecalin (14gm/dl), with

a half-life in the body of 7.5 days but with only

a moderate emulsification capacity, and perfluorotripropylamine (6gm/dl), with a half-life of

65 days but with excellent emulsification.

Among perfluorocarbon preparations, FluosolDA is the most thoroughly studied and received

the widest publicity. Besides containing the two

PFCs and the emulsifying agent Pluronic F-68 in

a balanced salt solution, hydroxyethyl starch is

added to maintain blood volume and to enhance

the flow characteristics of the solution (table 42)

(219). The preparation has a circulation half-life

of about 13 hours and a tissue half-life of 9 days

as measured in animals (218).

Because they are biologically inert, PFCs contain no antigens, and therefore typing or crosshatching is unnecessary. The emulsions may be

frozen and refrozen, and they can be autoclave

for sterility. They are also easily synthesized from

readily available materials.

Other than as a substitute for red blood cells,

PFCs have advantages in other areas of medicine.

For example, carbon monoxide interferes with oxygen transport because hemoglobin’s affinity for

carbon monoxide is 250 times greater than its affinity for oxygen. In contrast, PFCs do not carry

carbon monoxide at all, and PFC administration

could provide oxygen to a carbon monoxide victim until the patient replaced his abnormal red

cells. Another potential use for PFC relates to their

small particles, which can easily penetrate vessels

Table 42.—Composition of FIuosoI-DA (20°/0)

that have been constricted, such as in cerebral

ischemia, myocardial infarction, or by abnormal

blood cells (e.g., sickle cell crisis).

Uptake of oxygen by PFC in the lung depends

entirely on the concentration of oxygen in the

alveoli. PFC does not preferentially extract oxygen from the air as hemoglobin does, and the

oxygen level in a PFC solution equilibrates with

the oxygen level in the atmosphere. Since PFC

preparations at ambient oxygen levels (air contains 21 percent oxygen) will carry very little oxygen, PFC therapy requires that the patient be

given concurrent administration of 60 to 100 percent oxygen in order to deliver enough oxygen

to the tissues.

PFC administration in a high oxygen environment is required because the highest achievable

concentration of PFC in blood is about 20 percent; higher concentrations are unstable. Consequently, in order to efficiently utilize the oxygen

carrying/delivery capacity of PFC, the patient

must be exposed to the risks of a high oxygen

environment, which can result in highly reactive

oxygen metabolizes that can in themselves inactivate cellular enzymes, damage DNA, and destroy cell membrane architecture (195). The concentration of oxygen in inspired gas (i.e., the FiO2

)

at which significant damage after short-term exposure (24 hours) is first seen is about 70 percent,

which is only slightly greater than the minimal

concentration of 60 percent oxygen that has been

successfully used for PFC administration (233).

Thus, the advantages of PFC must be weighed

against the potential toxicity of the high oxygen

environment in which they must be given. This

cumbersome and costly requirement for PFC

administration may prove to be the limiting factor in its use as a substitute for blood transfusion.

Animals have also been known to survive a

total exchange transfusion if they inspired 100 percent oxygen without PFC infusion (233). This

demonstrates that plasma can be a very effective

oxygen carrier at high oxygen concentrations, and

questions whether the benefits seen with PFC infusion resulted from the use of this material or

were merely due to the animals’ breathing a high

concentration of oxygen.
140 . Blood Policy and Technology

Another disadvantage of PFC emulsions relates

to the need to freeze them for storage because of

the emulsion’s instability. A surfactant that will

make stable emulsions at room temperature with

a variety of PFCs has recently been studied (123).

The new emulsifier also enabled the PFC concentration to be increased to over so percent, compared to current PFC concentrations of 20 percent.

Clinical studies. —The first human volunteers

were given the PFC emulsion, Fluosol-DA, in

1979. Initial clinical studies were performed in Japan and reported a high degree of safety and efficacy (272,384,413).

In April 1980, Alpha Therapeutics Corp., the

American subsidiary of Green Cross of Japan,

began clinical trials of Fluosol-DA in California.

Seven severely anemic patients were given FluosolDA before surgery to determine its effectiveness

in supplementing oxygen transport. When the patients breathed low levels of supplemental oxygen

(slightly more oxygen than ambient air levels) the

PFC carried only a small amount of oxygen, as

expected, and had virtually no benefit. When patients received pure oxygen, their arterial oxygen

content rose significantly and the PFC provided

24 percent of the oxygen consumed (537).

Japanese experience with Flurosol-DA and

reports from some American investigators have

generally given the substitute high marks for

safety and efficacy. But the frequency of such reactions from Fluosol-DA administered to Japanese

patients has been significantly less than reported

in Americans. This could be due to a number of

factors such as racial differences (e.g., lipoprotein levels differ between Japanese and Americans), different patient populations, medical practices, or monitoring procedures. Nevertheless,

there is a definite reluctance to extrapolate the Japanese experience with Fluoso1-DA to American

usage. Moreover, in the last 2 years an increasing number of reports have begun to document

a variety of toxic affects attributed to its administration.

Adverse effects. —PFCs are chemically inert and

do not appear to be degraded biologically. Their

principal avenue of escape from the body is via

the lungs and to a small extent through the skin.

Because of the particulate nature of the emulsion,

however, it was suspected, and later confirmed,

that clearance also involved the reticuloendothelial

system (RES). Both animal and human studies

have shown that some of the material is retained

by the liver and spleen for at least 2 years after

a single administration (312). Small PFC particles

coalesce intracellularly, but with time these larger

particles undergo further change to become smaller

again. Most droplets of PFC eventually disappear.

The exact mechanism(s) by which PFCs move

from the RES to the lung, or from the lung to the

airway, is unknown at present. Macrophages (a

type of scavenger white blood cell) may play a

role, since they readily take up PFCs and could

carry the material to the lungs.

Because the RES is involved in PFC clearance,

it was anticipated that saturation of the RES

would reduce the body’s ability to clear other

foreign substances, notably bacteria or viruses.

This hypothesis was confirmed in mice challenged

with a bacterial toxin simultaneous with PFC

administration, in which the lethality of the toxin

rose nearly eightfold (350). These results suggested

that PFC administration would be contraindicated

in patients who are likely to have infections (e.g.,

trauma patients) or a weakened resistance to infection.

Of greater concern, however, and as yet unaddressed, is the possibility of chemical carcinogenesis as a result of the long retention time. Although there is no data that would support such

a hypothesis, the fact that these chemicals remain

in the body for some time is disturbing, and the

issue will have to be addressed before general use

is permitted (197).

Early studies on the effect of PFC infusion occasionally noted pulmonary reactions, which were

attributed to a variety of physical properties of

the chemicals (122,218,502) that affected either

platelets or plasma proteins (334). Recent evidence, however, suggests that alterations in the

immune system may be the triggering event. The

transient hypoxemia and pulmonary congestion

seen upon Fluosol-DA infusion (537) is similar to

the effect of infusing activators of the body’s complement system. Stimulation of white blood cells

is also often associated with pulmonary reactions.

Thus, it seems likely that PFC emulsions cause
Ch. 6—Alternafive Technologies ● 141

pulmonary dysfunction by activating complement

and/or white cells. Release of a substance(s) from

damaged leukocytes may then result in both

leukocyte and platelet aggregation.

The first patient treated in the United States

with Fluosol-DA developed a pulmonary reaction

after receiving 30 milliliters of material over 15

minutes; no reaction occurred with a subsequent

infusion after premeditation with steroids (572).

Laboratory studies indicated that Fluosol-DA activated the complement system, thereby resulting

in microphage aggregation, which was a reasonable explanation for the pulmonary reaction (chest

tightness, shortness of breath) that was seen upon

infusion. Further studies suggested that the component of Fluosol-DA responsible for the effect

was the emulsifying agent, Pluronic F-68. This

finding is not unexpected, since PFCs are very

unreactive and, in emulsified form, are probably

coated with the surfactant. It is therefore likely

that any interaction with blood components involves the surfactant rather than the PFC itself.

The recent effect of another commercially available PFC emulsion on macrophages was studied

and the material found to be cytotoxic to these

cells (101b). Although the study was performed

on cells kept in culture, where exposure to PFC

is likely to be higher than in actual use, it reinforces concern over the effect of these compounds

on the body’s immune system. More evidence of

toxicity is the finding that PFC emulsions can disrupt the phagocytic function of peripheral blood

neutrophils and monocytes (574). These reports

clearly suggest that further studies are needed to

clarify the mechanism and consequences of the

leukocyte dysfunction that are seen upon exposure

to PFC preparations, and that more detailed

evaluations of the effects of PFC on host immune

defenses are also needed.

Concerns surrounding use of PFCs as blood

substitutes prompted the Blood Products Advisory Committee of the FDA to disapprove FluosolDA for human use at one of its recent meetings

(561). The committee heard presentations from

the manufacturer of the product, including a summary of the results obtained from approximately

100 patients in the United States and Canada who

were given Fluosol-DA under an Investigational

New Drug (IND) permit issued by FDA. Although

few reactions were noted in these patients, all of

the subjects were premeditated with relatively

high doses of corticosteroids.

The committee’s concerns over the possible

masking of immune reactions by steroid administration, the potential toxicity of the high oxygen

environment in which the PFC was administered,

the relative paucity of data regarding the effect

of Fluosol’s emulsant (Pluronic F-68) on the recipient’s own blood cells and tissues, and the lack

of convincing data that PFC administration to

anemic patients was efficacious, were the key factors that led to the committee’s decision (197,383).

Other emulsions having more favorable characteristics than Fluosol-DA (599) are being developed. Current PFC emulsions appear unsatisfactory for use as a blood substitute; their safety is

far from established and their utility is hampered

by the high oxygen environment in which they

must be given, and a PFC that is stable as an emulsion at room temperature and that is quickly excreted needs to be developed.

Even if these issues can be resolved, it seems

unlikely that clinicians will choose daily infusions

of a PFC emulsion until the patient’s red cell mass

returns to normal over a red cell transfusion. The

high oxygen environment requirement precludes

use of PFC transfusions in the battlefield or at the

site of an accident and would even discourage its

use in a hospital setting. Resolution of the safety

and efficacy issues may lead to use of PFCs for

specific indications such as in patients with religious objections to blood transfusion, in carbon

monoxide poisoning, sickle cell crisis, or cerebral

ischemia. If its use is limited to these clinical situations, PFC emulsions will never have a significant effect on the blood transfusion industry.

Hemoglobin Solutions

Early studies on the use of unpurified hemoglobin solutions were disappointing in that their

administration to animals and man were often

associated with renal abnormalities and coagulation defects (10,56,93,251,453,454,498), although

the effects appeared to be dose-related (175,224,

381,418,492).
142 . Blood Policy and Technology

Removal of RBC membrane fragments (i.e.,

stroma) from hemolyzed RBCs to produce “stromafree” hemoglobin eliminated many of the renal

and coagulation problems (74,75,125,455).

Stroma-free hemoglobin is produced by slowly

lysing washed RBCs with a buffered solution of

water (rather than unbuffered water), followed

by high speed centrifugation and micropore filtration (424,454,455).

To further purify a hemoglobin solution, other

investigators have altered the conditions of hemolysis, or the centrifugation and filtration steps

(95,155,240,257,396,490).

Although it is possible to prepare at least limited

quantities of a hemoglobin solution that has no

known contaminants, questions regarding the

safety of the preparation still remain. Coagulation abnormalities, renal dysfunction and alterations in cardiovascular function appear to be the

most common effects (83,197), but do not always

appear together. Liver necrosis is sometimes observed.

Severe hematologic alterations have occurred

in the first few hours after infusion of purified hemoglobin in dogs, but not in monkeys and pigs

(82). These results have raised many disturbing

questions. Is it possible that contaminants below

detectable levels can still cause adverse reactions?

If so, how will the safety of a clinically useful

preparation be determined prior to its infusion?

Second, what animal species should be used for

extrapolation to humans? Differences in response

between species make interpretation of safety data

confusing and the choice of animal model for experimentation extremely important. Variations in

response within animal species have also been

seen. For example, infusion of a presumably pure

hemoglobin solution into a group of rabbits has

caused severe, acute toxicity (even sudden death)

in some of the animals, but no adverse effect in

others.

Variations in the response to infusion of a hemoglobin solution into eight normal volunteers

have been reported (477), and other investigators

have noted unexplainable variations in the toxicity seen between preparations that were made

using the same recipe (83). Such findings have

recently prompted the Army Research and Development Command, the sponsor of the vast majority of research on hemoglobin solutions, to

issue a request for proposals to obtain a supply

of hemoglobin solution in sufficient quantity to

study the nature of the interspecies variability,

and to determine those factors which result in

batch-to-batch variability.

If presumably “pure” hemoglobin can cause

adverse reactions, is it possible that hemoglobin

itself can be toxic under certain conditions? Hemoglobin has been shown to activate the body’s

immune system (i.e. complement system), although it was possible that the preparation used

was impure (589). It is also possible that the configuration of hemoglobin in solution is conducive

to binding bacterial endotoxins, either in vitro

(during preparation of the solution) or in vivo as

the molecule passes through the gastrointestinal

circulation (357). Unpublished observations (83)

suggest that endotoxin may indeed be the primary

factor contributing to the toxicity seen.

The fact that inter- and intraspecies variability

exists emphasizes the need for standardization and

complete documentation of the methods used to

prepare the hemoglobin solution. Careful selection of the species used for testing and attention

to the conditions of the experiment are also key

issues. Unfortunately, the literature on this subject is, in general, much less thorough and exact.

A wide variety of species under an equal variety

of experimental settings have been utilized, with

hemoglobin solutions whose preparation and

properties are incompletely described.

Fate of infusion. —In addition to obtaining a

nontoxic solution, other significant problems have

been that: 1) free hemoglobin normally persists

in the circulation only a short time with a halflife of only 2 to 4 hours (75,87,455,477); 2) free

hemoglobin has a significant oncotic effect; and

3) its affinity for oxygen is unacceptably high.

The short circulation time of free hemoglobin

is due to the tetrameric form of the molecule easily

dissociating into dimers and monomers, with

rapid clearance of these subunits by the kidney.

Hemoglobin also readily binds to the plasma protein, haptoglobin, which is then rapidly cleared
Ch. 6—Alternative Technologies ● 143

by the reticuloendothelial system, primarily the

liver (101a,212). If the amount of hemoglobin

transfused exceeds the haptoglobin binding capacity, unbound hemoglobin is filtered through the

kidney, where it is reabsorbed. If the filtered

amount exceeds the reabsorptive capacity of the

kidney, hemoglobin then appears in the urine.

Free hemoglobin’s significant oncotic effect

severely limits the maximum amount that can be

given. While the concentration of red cell enclosed

hemoglobin in blood is 14g/dl, only 7g/dl of free

hemoglobin can be administered without exceeding the normal oncotic pressure of plasma. Increasing the amount infused to achieve the oxygen-carrying capacity of the blood lost will raise

the risk of volume overload in the recipient.

Therefore, significantly less oxygen transport capacity is attainable with hemoglobin in solution

compared to an equal volume of blood, and it

cannot be used as a 1:1 replacement fluid.

Several approaches have been taken to stabilize

the hemoglobin molecule and thus slow its disappearance from the circulation, as well as to decrease its oncotic effect so that more can be given.

One way is to crosslink (or “modify”) hemoglobin molecules (386) either intermolecularly or intramolecularly (fig. 15). The former type of crosslinking produces hemoglobin of high molecular

weight, while the latter stabilizes the tetrameric

form of the molecule. Although the intravascular

half-life using either method is prolonged (to 15

to 30 hours) and the oncotic effect of the polymer

becomes similar to that of hemoglobin in RBCs,

the oxygen affinity of modified hemoglobin remains extremely high, and therefore its ability to

deliver oxygen is still greatly impaired.

Another potential problem with many modifying agents is that hemoglobin molecules become

crosslinked both intra- and intermolecularly,

resulting in a wide assortment of hemoglobin

polymers of different sizes. Thus, batch-to-batch

reproducibility of a preparation is extremely difficult, and the ability to determine which polymers,

if any, are undesirable is a difficult task. Recently,

however, crosslinking agents have been found

that result in well-characterized, reproducible

polymers of hemoglobin. One such agent is the

adenine nucleotide, adenosine triphosphate (479).

Figure 15.-Crosslinked Hemoglobin

Intermolecula r

SOURCE: R. Kahn, et al., Alternate Sources, 1984

Another new crosslinking agent is the chemical

3,5 dibromosalicyl-bis-fumarate (540), which is

nontoxic, inexpensive, and capable of crosslinking hemoglobin at specific sites in a reproducible

manner, and thus is attractive for high-volume

production of a modified hemoglobin solution.

Another approach to stabilize hemoglobin is to

attach it to a larger molecule which persists in the

circulation for longer periods (113,525,526). Hemoglobin has been attached to the sugar, dextran,

with longer circulation times, but the relatively

high viscosity of the complex severely limits the

amount that can be given (113,525,526).

Another major drawback of native hemoglobin is its high affinity for oxygen. Hemoglobin

itself has a P5O of 13 to 18 torr, whereas the red

cell P50 is 26 to 28 torr (234,396). This difference

is mainly due to the intracellular molecule 2,3-

DPG, which modulates oxygen affinity by binding to hemoglobin. This binding stabilizes hemoglobin’s conformational state and enhances oxygen delivery (67,423).
144 . Blood Policy and Technology

Much research has centered on the search for

molecules that could substitute for 2,3-DPG. Unfortunately, 2,3-DPG itself cannot be used because

of its reduced binding efficiency to hemoglobin

in solution (238). The most widely used, and most

successful, attempts to normalize the P5O of hemoglobin solution have made use of the chemical, pyridoxal 5’-phosphate (P-5-P). This compound is an organic phosphate analog of 2,3-DPG

(67,241,377) and has been shown to decrease the

oxygen affinity of hemoglobin to essentially the

P5O of RBCs (i.e., 26 to 28 torr). P-5-P functions

by irreversibly binding to the beta chains of

hemoglobin near the binding site of 2,3-DPG

(68,69).

To achieve a P5O approximating that of RBCs

and a longer circulation time, many investigators

have both pyridoxalated and crosslinked hemoglobin. Pyridoxalated-polymerized hemoglobin

does not have the oncotic pressure restrictions of

unmodified hemoglobin, and it can be administered in a concentration of 14 to 15 gm/dl, the

same hemoglobin concentration as in whole

blood. The solution could be administered as a

one-for-one replacement of blood, and the oxygen

content per unit volume of circulating fluid would

be unchanged. Because of these features, pyridoxalated crosslinked hemoglobin has been widely

adopted as the preparation of choice, and it is the

formulation currently being tested in animals and

being proposed for future scale-up studies.

However, the P50 of such a preparation is really

a composite P50, since not all the hemoglobin will

be pyridoxylated and crosslinked in a given preparation. Polymerized hemoglobin and unmodified

hemoglobin are also eliminated by different mechanisms (89), and the contribution of each to any

toxicity that is seen is difficult to resolve. Future

studies are likely to focus on methods to prepare

homogeneous preparations of modified hemoglobin, which could then be used to more easily determine the etiology of any toxic effects. The true

benefits of transfusing a hemoglobin solution are

difficult to assess, because, as mentioned previously, cardiovascular and tissue compensatory

mechanisms occur when the concentration of hemoglobin in blood is moderately decreased. This

does not imply that hemoglobin solutions are of

little value, but rather that the clinical efficacy of

one preparation over another will be very difficult to prove, and testing in animals will have to

closely simulate the clinical condition in humans,

for which its use is intended.

Other problems. —Three other potential problems with hemoglobin solutions as a blood substitute are related to the source of the hemoglobin, how it will be stored, and whether the infused

material will invoke an immune response with the

formation of antibodies in the recipient.

Hemoglobin solutions are currently being made

from outdated human blood. If all the outdated

blood in the country could be channeled into hemoglobin solution production, only approximately

600,000 units would be available (or 5 percent of

the 12 million units collected).

An alternate source for hemoglobin is through

recombinant DNA technology. The hemoglobin

molecule has been cloned (see later discussion) and

therefore it is possible that sufficient amounts

could be prepared to satisfy all hemoglobin solution production requirements. Alternatively, it is

conceivable that an animal hemoglobin could be

substituted for the human molecule. Crosslinked

and pyridoxalated bovine hemoglobin has the

equivalent circulation time and oncotic pressure

as its human counterpart and has a more favorable P5O than does human hemoglobin (156).

Injections of bovine hemoglobin into rabbits

have resulted in antibody formation (185), and

it seems likely that antibody formation would occur in humans. Even if only one “unit” were given,

the ability to track such recipients and insure that

they would not receive another unit at a later date

would be very difficult. Whether human hemoglobin given to humans will be proven non-immunogenic is also unknown, and it is possible that

modifying the configuration of the molecule upon

crosslinking may enhance its immunogenicity.

A final concern regarding hemoglobin solutions

is their stability during storage. Refrigerated or

frozen storage may be suitable in a hospital environment, but is not satisfactory for use as an

emergency resuscitative fluid, particularly in the

battlefield. The most suitable form of the product for this purpose is as a freeze-dried powder

that could be kept at room temperature. It is not

certain that long-term storage of clinically suitable
Ch. 6—Alternative Technologies ● 145

freeze-dried hemoglobin can be achieved. But

other equally complex, large proteins have been

successfully freeze-dried and reconstituted without loss of function, and there is no reason to

assume that the ability to freeze-dry and reconstitute a functional hemoglobin preparation will

be any more difficult to resolve.

Clinical studies. —Although nearly all the work

done on hemoglobin solutions has utilized animal

models, there have been published reports in

which no more than a few milliliters of a hemoglobin solution was transfused into humans (10,

93,109,175,212,224,333, 381,415,418,430,477,

492). All but the most recent report (477) used

a crude preparation of hemoglobin that was uncharacterized. All of the studies were performed

on volunteers who had normal cardiovascular parameters, and in all of the reports adverse effects

were noted.

In the most recent study (477), a microporefiltered hemoglobin solution was administered to

eight volunteers, all of whom experienced cardiovascular, renal and coagulation abnormalities

lasting several hours. Another unpublished study

using presumably pure hemoglobin was sponsored

by the Biotest Corp. (88). The study began in the

late 1970s but was terminated prematurely after

the first two volunteers who received the unmodified preparation developed severe side effects

and had to be hospitalized. Although the etiology

of the reactions was thoroughly investigated, no

explanation was uncovered.

Since 1978, no clinical trial has been initiated

in the United States. The Army Research and Development Command hopes to initiate a clinical

study in 3 to 5 years, but the starting time is dependent on whether the present safety issues can

be resolved (83). Ability to reproducibly prepare

large batches of a homogeneous hemoglobin solution is a fundamental requirement for such a study

to begin.

As a substitute for blood, the major shortcoming of hemoglobin solutions is their failure to circulate for an appreciable period. Current research

so far appears unlikely to generate a molecule

whose circulation time anywhere near approaches

that of an RBC. Thus, hemoglobin solutions may

be limited to use as an emergency resuscitative

fluid.

The anticipated cost of the product will also be

an important consideration. It is impossible to reasonably predict at this time what the dollar cost

will be, since scale-up beyond laboratory use has

not been accomplished. However, it has been estimated that preparing a unit of hemoglobin (equivalent in function to a unit of blood), may cost as

much as $100 (83). If this estimate proves correct,

the price would be significantly greater than the

present price of a unit of whole blood. Thus, cost

might be a drawback to its acceptance for civilian use. (The military is inclined to be less concerned with cost because of the emotional/ emergency circumstances in which such hemoglobin

products would be transfused. )

If the hemoglobin used in the preparation were

derived from recombinant methods, the final cost

of the product might be far less than if the starting material were human blood. This is because

the purification of human hemoglobin from whole

blood is a multi-step process with a 30 to 40 percent loss of starting material. However, cost issues

at this point remain secondary, since the major

hurdles of safety and efficacy have not been

passed. Whereas the newer hemoglobin preparations have adequate retention times and oxygen

transport properties for their intended use, the

etiology of the sporadic adverse reactions seen in

animals remains an enigma. The antigenicity of

the solutions will have to be evaluated and, at

worst, restrictions on the frequency of infusion

may have to be put in effect.

Successful large-scale reproducible preparation

and storage of these solutions have yet to be accomplished. The fact that polymerized preparations are composed of many molecular species

poses major obstacles to characterizing just what

will be transfused, how reproducible each batch

will be, and what properties of a hemoglobin

preparation are undesirable. Nevertheless, it

seems likely that a hemoglobin solution will become available for transfusion eventually, and the

Army’s Medical Research and Development Command hopes to begin clinical trials of a hemoglobin solution in 3 to 5 years.
146 ● Blood Policy and Technology

Synthetic oxygen binding chemicals. -Rather

than use hemoglobin as an oxygen-carrying blood

substitute, attempts have been made to synthesize

organic chemicals that reversibly bind oxygen.

Some compounds have been synthesized that do,

indeed, bind oxygen reversibly (9,58,59). However, none of the compounds demonstrate a P50

that is appropriate for clinical application, nor

have they been used in a biological system. If,

however, one such compound should show promise, its small size would necessitate binding it to

a larger molecule in order to achieve adequate circulation time.

It is likely, however, that availability of recombinant-made human hemoglobin will obviate the

use of an organic analog. Moreover, it seems certain that the former development will succeed

before a synthetic compound can be made and

successfully complete all testing. Hence, research

in this area is unlikely to yield a blood substitute

of practical significance

practical span of time.

(A)

within the confines of a

Liposomes

Another approach to preparing an RBC substitute involves encapsulation of hemoglobin into

liposomes. Liposomes are closed spheroidal vesicles

which contain an aqueous phase. The internal volume is separated from the outside by a thin matrix composed of lipid molecules arranged in a

bilayer structure as in a normal cell membrane

(fig. 16). The composition of the aqueous internal compartment reflects the solution in which the

liposomes are formed and can provide for entrapment of a wide variety of substances if so desired.

Liposomes can be prepared from a single type of

phospholipid, a mixture of phospholipids, or mixtures of phospholipids and neutral lipids; e.g.,

phosphatidylcholine plus cholesterol. Since these

molecules are found in all mammalian cell membranes, liposomes are usually non-immunogenic

to the host.

The properties of liposomes can be somewhat

controlled by utilizing different lipids and/or different methods of preparation. For example,

Figure 16.—Liposomes

(B)
Ch. 6—Alternative Technologies . 147

whether the liposome will be multilamellar (i. e.,

vesicles composed of a series of alternating lipid

layers separated from each other by an aqueous

compartment) or unilamellar, or whether they are

large or small, can be determined by the method

of preparation. The net surface charge of the

liposome can also be manipulated by the types

of phospholipids used.

As an alternative to liposomes, vesicles can also

be formed from synthetically made organic molecules (183). Since these vesicles contain only manmade molecules, their functional groups can be

easily altered. They can be made to remain stable

for months and have an extremely long shelf life.

The size and permeability of small molecules can

also be designed in the manufacture of the vesicles.

The ability to control these properties make synthetic vesicles an attractive alternative to lipid containing vesicles but, at present, little work has

been done with synthetic vesicles as biologically

relevant macromolecules.

Preparation techniques. -Liposomes have been

used in a variety of ways, such as model membrane systems for studying the mode of action of

certain membrane-bound proteins, as carriers for

enhancing the pharmacological activity of drugs,

or to study the functional incorporation of macromolecules into cells. In all liposome preparations,

special attention is given to the following characteristics: 1) captured volume (volume enclosed

by given amount of lipid); 2) efficiency of the

liposomes to encapsulate material; 3) ability to

reconstitute cell membrane derived proteins; and

4) control of vesicle size.

Liposomes as synthetic red blood cells.–Although the overwhelming majority of research

and development on liposomes has focused on

their utility as a research tool to study cell membrane function, or as carriers of drugs, there has

been a limited amount of work using liposomes

as a blood substitute preparation. Hemoglobin has

been successfully encapsulated into lipid vesicles

at concentrations equal to that found in RBCs

(160,177,276,285). The general approach has been

to encapsulate concentrated hemoglobin solutions

into liposomes made by mixing phospholipids and

cholesterol. The liposomes contained no proteins

(either inside or within the lipid bilayer) other than

the encapsulated hemoglobin and, therefore, did

not cause immune reactions (285).

The functional characteristics of the liposomal

RBC substitutes were very similar to those of

native red cells. In studies in which 2,3-DPG was

also encapsulated, incorporation of 2,3-DPG

resulted in an oxygen dissociation curve similar

to that of whole blood (160,276). Liposomes with

2,3-DPG typically showed P5O values equal to 28

torr in one study (160,285) and 26 torr in another

(276). Thus, with respect to their ability to carry

oxygen from the lungs to the tissues, liposomes

appear to be at least equal to other artificial blood

substitutes. Unfortunately, they disappear rapidly

from the circulation, with a half-life of only 5

hours (177).

Although data on storage of these liposomes

are not extensive, they suggest the potential value

of this technique. Suspensions of encapsulated hemoglobin were stable when frozen and stored at

–20° C. (160). The liposomes showed very little

lysis and had P50 values similar to those before

freezing.

Many investigators have performed exchange

transfusions with rats using liposomal suspensions

(160,276,285). However, it should be noted that

a less than 95 percent exchange transfusion in

animals can be tolerated simply by administering a colloid or crystalloid solution.

A different approach to preparation of vesicles

has been taken by Davis and Asher (149). They

recently patented a process whereby stroma-free

hemoglobin was encapsulated in a polymerized

hemoglobin membrane. The crosslinked hemoglobin membrane was permeable to oxygen and impermeable to hemoglobin. The vesicles were

capable of reversibly binding oxygen and had diameters of less than 4 microns. Moreover, they

were reported to be stable under conditions of

normal blood flow. However, data supporting

these claims have not been published, and the

physiology of this liposomal preparation is

unknown.

Although the above studies are certainly encouraging, many problems remain. First, the

problem of rapid liposome removal from the circulation must be resolved before this substitute
148 . Blood Policy and Technology

will find widespread acceptance. Several factors

which govern removal of lipid vesicles from the

circulation are: 1) irreversible binding of vesicles

to tissues; 2) lysis of vesicles by plasma lipoproteins; and 3) clearance by the RES. Of these,

removal by the RES (i. e., liver and spleen), is by

far the dominant process (310,541). All studies

reporting on the distribution of liposomes after

intravenous injection have found that the liver is

the site of liposome retention (111,309,449,514).

Approximately 50 percent of the injected dose is

found in the liver within a few hours after administration. The mechanism of uptake is not completely understood but may be related to the fact

that the liver contains capillaries which allow

small molecules to penetrate.

The rapid uptake of liposomes not only results

in shortened liposome lifetime but also can saturate the RES and result in reticuloendothelial

blockage. Thus, before liposomes can function as

RBC substitutes, methods for limiting their uptake by the RES must be developed.

Recently, natural and synthetic glycolipids have

been inserted into the liposomal membrane and

tested for their ability to alter the final disposition of the liposomes. Incorporation of these

glycolipids decreased uptake by the RES (lo4,

292,359,597). However, many glycolipids are antigenic and thus would not be suitable for insertion into a liposome that will be transfused. Alternatively, there are non-antigenic glycolipids that

may also retard rapid liposome clearance. Hunt

and Burnette (1983) have attached inert carbohydrates to lipids and incorporated the glycolipids

into liposomes. They claimed to have reduced RES

clearance and binding of liposomes to tissues, although complete studies were not published.

Thus, it would seem that addition of inert carbohydrates may be one way to retard rapid liposome clearance.

The potential toxicity of a liposomal preparation is also of great concern. Initial studies (160,

177,276,285) indicated that hemoglobin-filled

liposomes were non-toxic when infused into rats

or rabbits. However, these studies did not address

the long-term effects of the liposomal preparation,

and toxicity of liposomes could potentially arise

either from impurities present in the hemoglobin

preparation, the lipids themselves, or impurities

introduced in the encapsulation procedure.

Acute toxicity following administration of

liposomes may not be seen, but adverse reactions

may arise if the contents of the liposomes escape.

Encapsulation of a toxin will essentially hide the

entrapped material until the liposomes degrade,

either by storage for long periods of time prior

to use, or when they are exposed to destructive

elements in the circulation (e.g., lipoproteins).

There are, however, several approaches to prevent this potential problem. The most direct is to

identify the impurities in the liposome preparation and eliminate them, which could be difficult

and costly. A second approach is to design liposomes which retain their encapsulated material

when stored or injected into the circulation. These

approaches are not mutually exclusive but will

likely have to be engineered into the liposomal

preparation.

Lipids used in construction of the liposome are

another source of potential toxicity. Although in

vivo toxicity of liposomes is thought not to be

a concern if proper care is taken in isolation and

storage of the lipids, one study has shown that

liposomes caused damage to the central nervous

system in mice (4).

Another potential source of concern is contaminants in the lipids that can affect liposomal integrity. Changes in the structure of lipid molecules

inevitably occur with time and can result in accumulation of lipid breakdown products in the

preparation. These contaminants can facilitate

liposomal degradation and loss of their encapsulated contents. To avoid this problem, the lipids

will have to be purified prior to use. There does

exist, however, a naturally occurring class of

lipids (branched-chained dialkyl ethers) that are

not subject to such breakdown (324). Another

alternative would be to use synthetically made

molecules that are not subject to these effects

(183).

It will also be important to examine the effects

of blood and blood constituents on liposomal disruption. It is known that serum lipoproteins can

interact with phospholipid vesicles (393) resulting

in their disruption (427,458,524). Since the loss
Ch. 6—Alternative Technologies • 149

of liposome integrity appears to be due both to

the binding of plasma components to the liposomes and to exchange of vesicle components with

plasma lipid constituents, any modification of

liposomes that will prevent these events should

increase their ability to retain entrapped material.

One such modification is the addition of cholesterol, which has been shown to dramatically

decrease the permeability of liposomes in the

presence of serum, plasma, or whole blood (311).

Inclusion of specific, naturally occurring phospholipids has also been shown to increase the

stability of liposomes in the presence of plasma

proteins (261). These results are encouraging, but

no detailed study has yet been carried out to determine the effect of plasma or whole blood on

the long-term stability of modified liposomes.

As is desired for all RBC substitutes, red celllike liposomes should have a long shelf life. Many

investigators have examined the stability of several liposome preparations for their ability to entrap and hold drugs (361,522). All preparations,

however, show some disruption after liquid storage, and storage of liposomes for extended periods is likely to result in some loss of membrane

integrity.

A possible solution to many of the problems

discussed above (e.g., toxicity, stability, and storage) may lie in the use of synthetically made

vesicles, or so-called “membrane mimetic systems”

(183,184) formed from synthetic surfactants. They

can be stabilized by polymerization, which effectively seals the membrane surface. The polymerized vesicles are appreciably more stable than

liposomes and have a shelf life of several months.

Moreover, the size of the vesicles and their permeability properties can be engineered as desired.

Although utilization of these vesicles has become

a significant area of research in chemistry, biological applications have not been explored.

Last, scale-up to prepare large amounts of a

liposomal preparation for transfusion using existing technology could be a formidable task. First,

it will require isolation of large quantities of lipids

and hemoglobin. The latter will undoubtedly be

obtained by recombinant DNA technology (see

following section). The majority of lipids could

be isolated from crude preparations of egg lipids

at a reasonable cost. However, it is known that

liposomes which contain only these lipids would

be cleared rapidly, and thus special masking lipids

would have to be included in the final product.

Because the relationship between liposome

composition/structure and clearance is not fully

understood, it is very uncertain what the final

product will contain and cost. But from the studies

reviewed above, it is likely that some type of synthetically constructed lipid will be necessary. For

example, a single synthetic surfactant may eliminate the need for purification and storage of lipids.

Production of surfactants is also easier and less

costly. Although no data have been collected concerning the potential toxicity of these preparations, it is entirely conceivable that the desired

properties of stability and safety could be engineered into the surfactant’s structure. This approach, however, is speculative; many years of

basic research will be required before testing in

humans can begin.

The second major problem in scale-up relates

to preparation of the vesicles. Many of the methods for encapsulating materials were developed

for drug delivery. Applications involved in drug

therapy require relatively small amounts of vesicles

compared with the large volume requirements for

a blood substitute. In fact, difficulty in obtaining significant amounts of liposomes is likely to

be the reason that extensive animal studies have

not yet been reported with existing preparations.

At the outset, therefore, only those preparative

techniques which can be easily scaled-up are likely

to be considered. However, at the present time

no suitable large-scale encapsulation procedure

has been devised or tested to provide confidence

that mass production of liposomes (or synthetic

vesicles) can be achieved.

In sum, the use of encapsulated hemoglobin as

an RBC substitute has received relatively little attention, particularly in comparison to the work

on PFCs and hemoglobin solutions. While the

technology is still in its infancy, encapsulation appears to be the approach most likely to lead to

a blood substitute that has all the properties of

an RBC. Certainly, major obstacles remain—

particularly the toxicity, stability, and storage of

such a preparation. But studies on liposomes or
150 ● Blood Policy and Technology

synthetic vesicles, while relatively new, are accelerating at a rapid rate, and technological advancements in this area will undoubtedly find

solutions to the problems that remain. Even so,

it is clear that many years of laboratory research

will be required before clinical studies will be

appropriate.

Platelet Substitutes

Under normal conditions platelets circulate in

the blood for approximately 10 days as diskshaped, formed elements, and do not adhere to

other cellular elements, the vascular endothelium,

or to themselves. But within a few seconds after

injury to a vessel, platelets adhere to the exposed

collagen surface. Such platelets become “activated”

and release their internal constituents, resulting

in a growing aggregate of platelets, and the simultaneous occurrence of clot formation. This growing mass literally plugs the hole in the damaged

vessel wall. Thus, platelet function can be described in terms of the following reactions: 1) attachment at the site of the injury (adhesion); 2)

aggregation of platelets to each other; and 3)

release of substance(s) that facilitate blood coagulation.

Adhesion to a cut vessel wall is a complicated

process that has been shown to require plasma

factors as well as key platelet membrane molecules. Aggregation of platelets to each other is

mediated by numerous exogenous platelet agonists

such as thrombin and adenosine diphosphate

(ADP). Each of these agonists has one or more

receptors on the platelet surface. Binding of the

agonist unmasks specific sites for plasma fibrinogen on the platelet membrane (70,355), which

is thought to somehow serve as the “bridge” between platelets. Platelet secretion is also initiated

by binding of agonists to the platelet membrane.

Last, platelets have been implicated in the activation of several coagulation factors such as factor

IX, factor X, and prothrombin (298,380,602).

Because of the complex role of platelets in the

arrest of bleeding, it follows that the biochemistry

involved in platelet function is also quite complex,

and the mechanism(s) by which collagen, ADP,

thrombin and other agonists result in platelet

adhesion, aggregation and secretion are not completely understood. Thus, it is impossible at this

time to fashion an artificial platelet which will

mimic the entire physiology of the platelet. Nevertheless, two approaches have been explored as

means to develop a suitable platelet substitute.

Platelet Fragments

The fact that platelets will clump to each other

to form a plug and thereby seal broken vessels

has been known for some time. Although the

mechanism for this effect is still being unraveled,

it might be hypothesized that intact platelets are

unnecessary to achieve plug formation. Thus, it

is not surprising that some early investigators examined the efficacy of transfusing platelet fragments. In one study (314) freeze-dried platelets

were given to children who required platelet

transfusion. Although substantial improvement

was noted in certain coagulation tests, the clinical efficacy of the preparation in controlling

bleeding was equivocal.

Another study by the same group utilized

platelets disrupted by freezing and thawing, and

again a transitory control of bleeding was seen

(313). These somewhat encouraging results, however, were challenged by animal studies in which

irradiation was used to create a clinical condition

that warranted platelet transfusion. Three independent, well-designed studies employing this

model showed that neither freeze-dried nor fragmented platelets were of value in control of

bleeding (187,263,288).

These studies seem to have put to rest the notion that platelet fragments could adequately substitute for the intact cell. But in 1983 McGill and

colleagues (365) examined the ability of platelet

fragments to prevent bleeding in platelet-deficient

rabbits. Their studies found that fragments appeared to have the same adhesive qualities as did

intact platelets. In studies directed toward understanding platelet function in general, others observed that platelet membranes would interact

with “activated” platelets in vitro but not with

unstimulated platelets (446). Many investigators,

however, remain skeptical that these recent observations warrant reopening this approach to obtaining a suitable platelet substitute. No clinical

studies in humans using platelet fragments have
Ch. 6—Alternative Technologies • 151

begun or are even contemplated, and further

studies by McGill in this area have been discontinued (366).

Even if such platelet fragments were effective,

there would remain the question of the utility of

such a preparation. The fact that platelet outdating is substantial in this country (i.e., greater

than 10 percent of the units collected) implies that

there is no chronic shortage, and the recently improved shelf-life of the component (from 3 days

to 5) has greatly alleviated inventory problems

that arise over weekends and holidays. Moreover,

platelet fragments would still carry the risk of infectious disease and other adverse effects associated with traditional platelet transfusions. Thus,

it is very unlikely that this substitute will ever see

clinical use.

Liposomes as Platelets

Because of our understanding of the role many

surface membrane constituents play in platelet

function, it maybe relatively easy to reconstitute

one or two of these functions into liposomes. In

fact, some progress in this area has very recently

been achieved.

One of the platelet membrane glycoproteins

which is thought to play a critical role in platelet

adhesion has been reconstituted into lipid vesicles

(499). When liposomes containing this protein

were incubated with a plasma factor that is also

important in platelet adhesion, liposome agglutination occurred, although the reaction did not

entirely mimic that seen with normal platelets. In

other studies the platelet membrane glycoproteins

required for fibrinogen binding to intact platelets

have been reconstituted into phospholipid vesicles

(57,421). Both of these studies incorporated isolated platelet membrane glycoproteins into phospholipid vesicles and showed that the vesicles

bound specifically to intact platelets in vitro.

These data show that it is possible to reconstitute

at least part of the platelet membrane constituents necessary for platelet function in vitro, although in no sense are the liposomal preparations

used in these studies suitable for clinical use.

The fact that individual activities can be reconstituted, at least in this primitive fashion, offers

promise that many activities can be reconstituted

in a single liposome. All the necessary proteins

would have to be reconstituted correctly. Since

many platelet functions are interdependent, and

since a completely reconstituted artificial platelet

must also function in a similar fashion, the interactions between molecules must also be reconstituted. Although this might appear to be an impossible task, several cooperative membrane

activities have been reconstituted in a stepwise

fashion (294,456). Therefore, at least in theory,

it should be possible to reconstruct many platelet

functions.

However, virtually all of the problems discussed in relation to liposomes as artificial red cells

are also relevant for development of liposomes

as platelet substitutes. In addition, these liposomal

preparations could be highly antigenic, since the

reconstituted membrane proteins will be exposed

on the liposome surface. Of concern is the observation that some cell membrane proteins have

been found to be more antigenic when reconstituted into liposomes than they are in their native

state in the cell membrane (300,495). However,

the antigenicity of certain proteins can be modified by the lipid composition of the liposome (81),

and it may also be possible to modify the reconstituted glycoproteins (e.g., remove the glyco- or

carbohydrate portion) in such a way that they are

no longer antigenic but still carry out their normal function. Neither of these approaches, however, has been studied so far.

It is impossible to estimate all of the difficulties

that may arise for mass production of such a preparation. Very few of the membrane proteins critical to platelet function have been identified, much

less isolated. However, when this information becomes known, production of significant amounts

of the required proteins will no doubt make use

of recombinant DNA technology. The rate-limiting step, however, as in the case of liposomal red

blood cells, may be in the ability to generate significant quantities of liposomes.

Since membrane proteins will have to be incorporated into the lipid bilayer, the only suitable

method known is the detergent removal procedure (57,421,499), which is very time-consuming

and likely to be too expensive for mass production. New preparation procedures will likely need

to be developed. Thus, it will be several years,

at least, before a serious attempt will be made to

construct a liposomal platelet substitute.
152 ● Blood Policy and Technology

PART 2: ALTERNATE SOURCE FOR PLASMA PRODUCTS–

USE OF RECOMBINANT DNA TECHNOLOGY

Introduction

Except for the oxygen-carrying function of

RBCs, the physiological functions performed by

the cellular and humoral components of blood are

mediated largely through proteins. These proteins

may act in a relatively specific and independent

fashion, as in the case of antithrombin III and C1

esterase. Alternatively, a single species such as

albumin may play a number of roles, alone or in

conjunction with other factors, in maintaining

homeostasis. Finally, a variety of proteins can interact in complex patterns to collectively carry out

a function (e.g., coagulation).

All plasma proteins of therapeutic value have

the potential of being produced by microorganisms carrying the genetic coding for the primary

structure of the specific protein. The ability to

construct a microorganism that can produce a

useful product is possible because of recombinant

DNA techniques that allow specific segments of

DNA to be isolated and inserted into a bacterium,

or other host, in a form that will allow the DNA

segment to be replicated and expressed as the

cellular host multiplies. The DNA segment is said

to be “cloned” because it exists free of the rest of

the DNA that, with it, constituted the genome of

the organism from which it was derived.

A DNA clone can be prepared in a number of

ways, but generally the process involves linking

the desired DNA segment to a second piece of

DNA known as the vector. The one feature all

vectors have in common is that they are replicated

independently inside a cell. The vectors commonly used for gene cloning in bacteria are of

three basic types: 1) plasmids; 2) derivatives of

the bacterial virus known as lambda; and 3)

genetic hybrids constructed from plasmids and

lambda, called cosmids. The vector chosen to prepare a gene clone will depend upon two primary

considerations: 1) the size of the DNA segment

to be cloned; and 2) whether or not the protein

coded by the DNA is to be expressed (produced).

Plasmids used in cloning technology represent

modified forms of DNA molecules that occur naturally in bacteria or yeast and generally confer

a selective advantage to a cell harboring them

(146). In the common bacterium E. coli, naturally

occurring plasmids conveying resistance to antibiotics such as penicillin and tetracycline have

been described (343,379,523). Another naturally

occurring E. coli plasmid, known as Col E1, carries a gene coding for a protein that is secreted

into the environment and inhibits the growth of

other bacteria.

All plasmids have certain features in common.

For example, their presence in a cell confers a

selective growth advantage. In addition, they

carry a specific sequence of DNA nucleotides that

serves as a recognition signal for the host enzymes

responsible for DNA replication. These enzymes

will therefore not only replicate the chromosome

as the cell multiplies, but will also replicate the

plasmid molecule (and any foreign DNA linked

to it).

The most commonly used plasmid for cloning

foreign genes in E. coli is a derivative of the Col

E1 plasmid known as pBR322 (84,85,86,91,519).

The characteristics of pBR322 have been selected

to optimize the plasmid for cloning DNA fragments up to approximately 5 kilobase pairs (kb)

in length. The plasmid is efficiently replicated in

the commonly used laboratory strains of E. coli,

with multiple copies of the plasmid being present

in a single bacterial cell (91). The pBR322 plasmid

is diagrammed in figure 17 and can be seen to contain separate genes that confer resistance to the

antibiotics penicillin (e.g., ampicillin) and tetracycline for the host cell.

The penicillin resistance gene codes for an enzyme known as beta-lactamase, which alters the

structure of the penicillin molecule so as to inactivate it (11). The gene conferring resistance to

tetracycline codes for a membrane protein that

blocks transport of the drug to the interior of the
Ch. 6—Alternative Technologies • 153

once and have been used routinely for inserting

pieces of foreign DNA. In addition to the single

cleavage sites for restriction enzymes such as Pst1, Barn H1 and Eco R1, pBR322 has numerous

sites for a wide range of other enzymes that “cut”

the plasmid molecule more than once (519).

Although pBR322 has been used extensively for

cloning, a number of plasmids that are customtailored for a specific purpose have been constructed from pBR322 and other segments of DNA

derived from a bacterial and/or bacteriophage

genome. A modified plasmid may be desirable for

a number of reasons, but most often they are used

so that the information encoded in a cloned gene

will be expressed by the bacteria carrying the gene.

in a circell, where it exerts its inhibitory effect (523).

Thus, E. coli cells harboring pBR322 will multiply

on nutrient media containing penicillin and tetracycline, whereas cells not carrying the plasmid will

die under these conditions. This difference is exploited in the cloning process.

One of the hallmark. discoveries that has enabled

molecular geneticists to splice DNA in a precise

and premeditated fashion was the discovery of enzymes called restriction endonucleases (352,385).

These enzymes recognize specific sequences of

nucleotide bases in DNA and cleave the molecule

within that sequence. To date, numerous restriction endonucleases have been identified from a

large variety of sources, each with its own nucleotide base recognition sequence (352,385). Thus,

a desired segment of DNA can be specifically excised from a larger piece of DNA if sites for particular restriction enzymes are known to flank the

desired segment.

As shown in figure 17, pBR322 has several restriction enzyme sites that cleave the molecule

Several “expression vectors” have been constricted

which are custom-tailored to express the protein

product encoded in any piece of DNA inserted

into the vector in a specific way (94,258,441,

573,581).

Other commonly used vectors for cloning foreign DNA are genetically modified derivatives of

the lambda virus. As was stated previously for

plasmids, lambda is a naturally occurring bacterial

virus that infects E. coli cells (513). Once the cells

are infected, their capabilities are commandeered

by the virus such that viral particles are synthesized to the exclusion of other host macromolecules. Mature viral particles accumulate inside

the cell until it finally lyses, at which time a large

number of phage particles are released into the

environment to repeat the process upon contact

with other bacteria.

The modifications of lambda phage necessary

to make it a useful cloning vector primarily require excising from the phage that part of DNA

which is not involved in its growth cycle (586).

The DNA excised from the natural genome is then

replaced with fragments of foreign DNA. Replication of the cloned DNA is achieved by infecting

a culture of E. coli cells with the modified lambda.

The one significant advantage to the use of a

lambda vector for gene cloning is that very large

DNA fragments can be cloned. Whereas most

plasmids can accommodate only 3 to 5 kb of

foreign DNA, lambda vectors can accommodate

up to 20 kb of it (77,338,586). The main disadvantage to cloning with lambda is that the expres38-647 0 - 85 - 11
154 . Blood Policy and Technology

sion of the protein encoded in a eukaryotic (higherorder organism) gene is generally not efficiently

expressed.

A third cloning vector, known as a cosmid

(131,268,269) is actually a genetic hybrid between

lambda virus and a plasmid. As with lambda, the

primary advantage of cloning with cosmids is that

very large pieces of foreign DNA (up to approximately 30 kb) can be cloned (269). Cloning in

cosmids also suffers from the same disadvantages

as cloning with lambda.

Choice of a particular vector to be used to clone

a desired DNA fragment will depend ultimately

upon what the investigator wants the cloning system to do. If the goal is to study the structural

organization of a gene on a chromosome, the vector of choice would probably be one of the derivatives of lambda phage or a cosmid. Cloning

with these systems would enable a large segment

of a chromosome containing the entire gene and

possibly flanking DNA to be studied in a single

isolate. If, however, the aim of a cloning procedure is to engineer a cell to produce a protein

product, cloning with a plasmid designed for expression of foreign DNA is the system of choice.

Since the goal of cloning genes coding for therapeutically useful plasma proteins is to produce

those proteins, the discussion that follows will

focus upon cloning with plasmids rather than with

the other vectors mentioned.

Eukaryotic genes, as they exist in the chromosome, are generally fragmented into regions of

coding and non-coding DNA called exons and introns, respectively. In bacteria, genes do not consist of exons and introns but rather of a single

coding sequence of DNA. If mammalian chromosomal DNA is cloned into a bacterial cell, the information will not be properly expressed, because

the bacterium cannot decipher the complex exon/

intron code of the mammalian DNA. In order to

resolve this problem, messenger RNA is used to

enzymatically synthesize a complementary DNA

copy.

During the expression of a chromosomal gene

in a mammalian cell, the information encoded in

the separate exons is ultimately spliced together

into a messenger RNA (mRNA) molecule, The

mRNA is then transported from the nucleus to

the cytoplasm, where it is translated into the

amino acid sequence of the protein molecule (579).

Messenger RNA occupies a unique position in

the flow of information from the nucleus of a cell,

since it contains the entire coding sequence of the

gene. Messenger RNA isolated from a mammalian

cell can be used to program the synthesis of a

double-stranded complementary DNA copy of

itself in vitro, In many cases, cloning a complementary DNA (cDNA) copy of mRNA is the

method of choice when cloning a gene that is to

be expressed by a bacterial host. Since the cDNA

form of a mammalian gene lacks the complex

exon/intron organization of the nuclear DNA, it

can be deciphered by a bacterium as if it were a

bacterial gene.

The synthesis of cDNA from mRNA relies on

use of an enzyme, isolated from avian tumor

viruses, known as reverse transcriptase (60,528).

This enzyme, under proper conditions, will synthesize a single-stranded DNA molecule that is the

complement of an mRNA template. The singlestranded cDNA product can then be used in conjunction with another enzyme, DNA polymerase,

to make a double-stranded cDNA molecule (353,

471), which can then be inserted into the vector.

One method of insertion can be accomplished by

chemically modifying the vector DNA and the

cDNA so that the ends of both molecules are

“sticky” (375,480). If the vector and modified

cDNA are mixed, the sticky ends of both species

can bind together, and the result will be the formation of a single, circular recombinant molecule

(fig. 18) (126).

Another way to link cDNA to the vector is to

attach a series of guanosine residues to the free

ends of the vector DNA. Cytosine residues are

also attached to the ends of the cDNA; when the

vector and cDNA are mixed, the base pairing

property of guanosine with cytosine allows the

molecule to anneal into a single recombinant

plasmid (573) (fig. 18).

The procedures for inserting foreign DNA into

a plasmid do not yield a uniform product. When

sticky ends of plasmids are generated, a certain

percentage of the plasmids recircularize and thus

do not recombine with the DNA to be cloned. It

therefore becomes important to be able to dis-
Ch. 6—Alternative Technologies ● 155

Common Methods

Anneal

Replication

@

●

●

-

2. -

+ b ccc ccc

4. +

SOURCE: R. Kahn, et al., Alternate Sources, 1984

criminate between plasmid molecules that have

cloned inserts and those that do not. A sensitive

method to screen for plasmids with inserts involves exploiting the presence of restriction enzyme sites located in the middle of the plasmid

genes that code for resistance to the antibiotics

penicillin and tetracycline (fig. 17). In general,

when a piece of foreign DNA is inserted into a

gene coding for resistance to an antibiotic, the

gene is inactivated. Thus, foreign DNA inserted

into the gene coding for penicillin resistance will

inactivate that gene, and a penicillin-resistant

bacterium will become sensitive to the drug. However, under these conditions the gene coding for

tetracycline resistance will continue to function

unaffected.

Inactivation of a gene following the insertion

of foreign DNA provides a quick way to screen

a large number of bacteria for those that harbor

plasmids with foreign DNA inserts. If the DNA

has been inserted into the gene coding for penicillin resistance, recombinant plasmids will no

longer be resistant to penicillin but will continue

to be resistant to tetracycline. Plasmids which do

not contain DNA inserts should have resistance

to both antibiotics. In practice, the plasmid mixture is added to bacterial cells that have been made

permeable to DNA molecules and, following a

brief incubation, the cells are plated on medium

containing tetracycline. Under these conditions,

bacteria that did not take up any DNA will not

grow because they have no resistance to tetracycline, whereas bacteria that took up plasmid, with

or without a DNA insert, will give rise to colonies.

An inoculum from each colony that grows on

the tetracycline-containing plates is then tested for

its ability to give rise to a colony on medium containing penicillin. Only those colonies that orginated from bacteria that took up plasmid without inserts will grow on penicillin, and thus are

discarded. In this example, colonies that grow
156 ● Blood Policy and Technology

only on tetracycline and not penicillin represent

bacteria that received recombinant plasmids harboring a foreign DNA insert.

Uptake of recombinant DNA molecules by

competent E. coli bacteria (or other organisms)

results in the appearance of colonies on agar plates

within 24 to 48 hours of incubation. The collection of colonies (known as a library) will contain

a representation of the cloned genes to which the

bacteria were originally exposed, and therefore

one or more screening protocols must be devised

to identify the colony(ies) harboring the DNA sequence of interest.

In some cases, identification of the desired clone

can be easily accomplished, as in the cloning of

cDNAs coding for hemoglobin (353), or albumin

(336). In these cases, the cDNAs were synthesized

from mRNA extracted from the cell type primarily responsible for synthesizing the protein (i.e.,

reticulocytes and liver cells, respectively). In

reticulocytes, most of the message present in the

mRNA code is for hemoglobin; thus most of the

bacterial colonies of the library will harbor cDNA

that codes for hemoglobin. The result is that relatively few colonies will have to be screened before

a cloned hemoglobin gene is identified. In most

cases, however, the cDNA library will contain

cDNA clones synthesized from a heterogeneous

mixture of mRNAs, and thus the colony harboring the desired gene clone will be identified only

after a large number of colonies have been screened.

Many methods are available to screen a library

of colonies. Colony hybridization (247) is one

method capable of examining hundreds of bacterial colonies quickly and easily. This method

essentially involves growing colonies on nitrocellulose filter paper soaked in medium, lysing the

cells and fixing the released DNA to the filter paper (fig. 19). Thus, a collection of DNA spots the

exact size and shape of the colonies from which

they were derived is left on a baked filter. The

filter is then incubated with a buffered solution

containing a nucleic acid probe that has been

radioactively labeled.

Since the recombinant clones on the nitrocellulose are denatured, (i.e., the two strands of the

DNA molecule have been separated) the single

strands are immobilized on the filter and are capable of pairing to labeled complementary nucleic

acid molecules present in the hybridization buffer.

Colonies that hybridize to the probe can be easily

detected by exposing the filter paper to X-ray film;

positive colonies will appear as black dots on the

developed film (fig. 19).

Maniatis et al (353) purified the mRNA coding

for hemoglobin from reticulocytes and then hybridized labeled mRNA to a cDNA library. The

success of this particular approach was due to the

large amount of hemoglobin mRNA that was

easily purified from reticulocytes. Success in identifying cDNA clones coding for albumin have also

been reported using this technique (542). Once

again, purification of the mRNAs was possible because of their large abundance in a particular

tissue.

Identification of cDNA clones synthesized from

less abundant mRNAs has also been possible using

hybridization techniques. One approach that has

repeatedly proven effective in identifying clones

involves hybridization of a gene library to a chemFigure 19.-The Filter Hybridization Technique of

Grunstein and Hogness, 1975

(c)

2. Bake filter >

1. Hybridize to

labeled probe

2. Wash filter and>

expose to film

(B)

(D)
Ch. 6—Alternative Technologies ● 157

ically synthesized oligonucleotide probe (516b).

Synthetic oligonucleotides of virtually any length

and of a predetermined sequence can be easily and

reliably synthesized by a variety of chemical

means (516b). The longer the probe, the more specific it will be in hybridizing only to the clone of

interest.

If the amino acid sequence of a limited part of

a protein is known, a nucleotide sequence that will

translate into that amino acid sequence can be

deduced. Synthetic oligonucleotides have been

used to identify gene clones for several plasma

proteins. Edlund et al. (170) and Prochownik et

al. (448) identified the genes coding for plasminogen activator and antithrombin III, respectively,

using this methodology. The successful cloning

of these and other genes emphasizes the effectiveness of synthetic oligonucleotides as hybridization probes for clone identification.

If the amino acid sequence of the desired protein is not available and its messenger RNA is in

short supply, an antibody that reacts with the protein may be used for clone identification. In this

technique, the antibody reacts with the antigenic

site(s) on the protein synthesized by the bacterial

colony harboring the clone gene. Immunological

screening involves growing colonies on nitrocellulose filter paper and lysing the cells in a manner that will allow the cellular proteins to stick

to the paper (258). The filter is then incubated with

radiolabeled antibody and exposed to X-ray film.

Any colony synthesizing immunoreactive protein

will show up on the film as an exposed spot and

thus presumably harbors the gene of interest. Immunological screening has been used to identify

recombinant clones coding for the proteins proinsulin (94,573) and tropomyosin (258).

The advantage of the immunological screening

approach to clone identification is that antibodies

are more easily generated than oligonucleotides.

Furthermore, colonies identified with this protocol

are synthesizing the protein from the cloned gene

in a correct fashion. The disadvantage to this approach relates to the requirement that the bacteria must express the cloned genetic information

correctly and must synthesize enough of the protein to be easily detected by an antibody. These

requirements may not be met by some colonies

harboring the correct gene sequence, but not expressing the protein correctly or in sufficient

amounts.

Once the desired gene clone has been isolated,

it can be used in a number of ways. Since the gene

is cloned, it can be produced in virtually any

amount and in a pure form for study or further

modification. For example, if the colony harboring the gene does not express the protein coded

by it, the gene may be excised from the vector

and reinserted into another vector that will allow

the protein to be expressed.

Of all the applications of gene cloning technology, perhaps the most widespread use is destined

to be in mass production of useful proteins. The

hope is that existing protein products can be made

more efficiently, more cheaply, and more cleanly

by gene cloning than by current methods. Before

these ambitions can be realized, however, several

hurdles must be passed. The first involves applying the techniques discussed previously to identify the desired gene clone and to get the product

of the gene expressed by the cellular host. As will

become apparent, this step is probably the easiest

task to surmount. Second, depending upon the

product, some modification may be required to

convert a precursor form of the protein, which

may be inactive, into the activated form. The

third requirement involves putting the recombined

gene into a host that will be suitable for growth

on an industrial scale. Finally, the protein product must be purified to meet safety and efficacy

standards set by Federal regulatory agencies.

Insulin is a protein that has undergone all of

these steps and is now marketed by Eli Lilly (Indianapolis, IN). It was one of the first pharmaceutically useful proteins for which the gene has

been cloned and the protein expressed. Since the

A and B polypeptide chains which comprise insulin are relatively short and the complete amino

acid sequence of each was known, it was a straightforward task to chemically synthesize oligonucleotides that would separately code for each

chain (227). The oligonucleotides were linked to

the E. coli gene for an enzyme, beta-galactosidase,

using a modified form of the pBR322 plasmid. The

beta-galactosidase gene facilitated the expression
158 . Blood Policy and Technology

of the insulin gene linked to it. Thus, insulin

chains were synthesized in the form of a fusion

product to beta-galactosidase. In other words, one

long protein chain was composed of a portion of

the beta-galactosidase protein and the entire insulin chain linked together end to end.

Ingeniously, the genetic code for the amino

acid, methionine, was attached ahead of the code

for the first amino acid of both the A and B insulin chains. Methionine can be destroyed by the

chemical, cyanogen bromide, and thus this construction enabled the insulin polypeptides to be

readily cleaved from beta-galactosidase. Since

neither the A nor B insulin chain contains a

methionine residue, the protein was not affected

by cyanogen bromide cleavage.

The scheme to produce biologically active insulin was to isolate the A and B chains from the

recombinant strains harboring the respective genes

and then mix the polypeptides together. In the

presence of mild chemical treatment, the chains

were found to associate together correctly and the

net result was pure, biologically active insulin

(227). Subsequent clinical trials of recombinant

insulin have shown the recombinant hormone to

be as safe and effective as natural insulin in its

physiological effects (303). However, the cost of

the recombinant product is about twice the price

of the hormone extracted from bovine/porcine

pancreas, from which it has conventionally been

derived.

Another recombinant product currently undergoing clinical trials is the antiviral agent, interferon. Interferon actually refers to a collection of

three small proteins (known as alpha, beta and

gamma) that apparently affords protection to cells

from viral infection and some forms of cancer.

Before it was produced by recombinant methods,

interferon was isolated from lymphocytes, but the

yield and purity was poor. Using recombinant

methods, however, strains of E. coli harboring the

alpha interferon gene have been developed that

synthesize large amounts of interferon (153,228,

237,398). Preliminary results suggest comparable

efficacy and side effects for the synthetic molecules

as compared with the natural material isolated

from lymphocytes (579). In addition to alpha interferon, the successful cloning of beta and gamma

interferon has also been reported (153,154,237).

Although it should be clear from the foregoing discussion that pharmaceutically useful proteins can be produced in recombinant organisms,

it should be noted that in each case a certain

amount of serendipity was involved. For example, the techniques used to produce recombinantmade insulin can be used in only a limited number of cases. Since neither the A nor B chains of

insulin contain the amino acid methionine, the

cyanogen bromide treatment had no effect. However, if the protein did contain methionine, it would

be cleaved by the treatment at each methionine

site, resulting in a fragmented product that would

probably be inactive.

Another potential problem that fortuitously

was irrelevant for insulin or alpha interferon production is that neither protein needs modification

after its synthesis before it can function. One common modification of proteins after their initial

synthesis is the attachment of carbohydrate,

termed glycosylation. Should glycosylation be a

requirement for normal function, the product of

recombinant bacteria will have to be glycosylated

in some way in order to produce an active product.

One of the obstacles facing the biotechnology

industry is the production scale-up of a recombinant product and its subsequent large-scale purification. To this end, strains of bacteria are continually being sought that synthesize a desired

protein efficiently and in large amounts. The current maximum yield of product appears to be

about one gram of protein per liter of ferment.

With regard to the isolation of the desired protein from the bacteria, current methods generally

involve treatment of the bacteria to release the

protein. Treatment can include complete lysis of

the bacterial cell or a milder procedure that makes

the cell wall leaky. In either approach, a crude

preparation of the protein is initially recovered.

Impurities of the preparation may not be very

important, as in the case of industrial enzymes.

Alternatively, one common contaminant of the

lysed bacteria is cell wall fragments, which are

pyrogenic (fever-causing) in humans. Other contaminants may be antigenic in humans and thus
Ch. 6—Alternative Technologies Ž 159

elicit an antibody response upon repeated therapy with the product. Any product to be infused

into a human will have to meet FDA standards

for purity and safety. Thus, novel procedures capable of substantial scale-up may have to be

devised.

Because it is easier to purify a protein from

culture medium than it is from a bacterial lysate,

it would be advantageous if a recombinant-made

protein were secreted into the medium. One of

the shortcomings of E. coli as a host for cloning

is that this bacterium does not normally secrete

anything into its environment. This precludes

harvesting the product from spent culture medium.

Currently, a great deal of research is being done

to modify E. coli so that it will secrete recombinant products.

Alternatively, other bacterial species such as

Bacillus subtilis maybe suited for scale-up, since

this bacterial species already secretes a large

amount of its own proteins into the external environment. Thus, the secretory machinery already

operational in B. subtilis may be more easily exploited for more efficient production of plasma

proteins. The fact that this feature of Bacillus

strains has been exploited in the manufacture of

industrially used proteins provides encouragement

that the organism can be made to secrete recombinant plasma proteins.

Purification of protein products from recombinant organisms may be accomplished in a variety of ways. In many cases the purification

scheme will depend in large part upon the biochemical properties of the protein to be isolated.

One of the more specialized and successful methods available makes use of monoclinal antibodies

(see subsequent discussion of “immunoglobulins”

for an explanation of this new technology). If a

monoclinal antibody produced against the recombinant protein is coupled to a solid matrix, it is

possible to pass a crude mixture of proteins containing the protein of interest over the matrix, and

only the protein recognized by the antibody will

be retained. The desired protein can then be

recovered by a variety of methods (72,587). This

approach has proven successful for the large-scale,

one-step purification of interferon from recombinant bacteria (428).

Application of Recombinant DNA

Technology to Large-Scale Production

of Plasma Proteins

The proteins currently recovered from the fractionation process are albumin, factor VIII, prothrombin complex and immunoglobulins. Other

proteins with potential clinical application cannot be recovered in high yield from plasma or can

be recovered only at the expense of another product. In addition, transfusion of many plasma fractionation products carries the risk of infectious

disease, such as viral hepatitis and AIDS. It is for

these reasons that recombinant DNA technology

is believed to hold much promise. The gene sequences coding for a number of plasma proteins

have been cloned, but numerous problems must

be resolved before this new industry can effectively compete with conventional plasma fractionation.

The recombinant DNA industry will also likely

attempt to clone genes coding for newly identified,

clinically useful plasma proteins. This will probably be the easiest task facing genetic engineering technology, however, since the techniques discussed in the previous sections have proven so

successful in the isolation of virtually any desired

gene.

A major challenge facing gene cloning technology is scaling up production sufficiently to meet

demand. It is likely, therefore, that large-scale

production/purification capabilities must be available before genetic engineering can meet even the

U.S. demand for plasma products. For some

plasma products such as albumin, thousands of

kilograms will have to be synthesized and purified.

For products such as Factor VIII, such large

amounts will not be required, but purification

methods that will not inactivate this highly unstable

molecule will have to be developed. Thus, scaleup will involve challenges in both the production

of a recombinant plasma protein and its subsequent purification.

An additional problem to resolve will be to design biological systems for modifications after

genetic expression for those plasma proteins that

need such modifications to be functional. If the

gene coding for a plasma protein that needs to
160 ● Blood Policy and Technology

have a carbohydrate molecule attached (i.e.,

glycosylation) is cloned in a bacterial cell which

is incapable of doing so, a means of properly

glycosylating the protein once it is purified from

the recombinant bacteria must be devised. Alternatively, the gene may be cloned into yeast or

mammalian cells which, under proper circumstances, may correctly glycosylate the protein.

While glycosylation is perhaps the major form of

post-translational modification, other modifications are sometimes necessary for protein activity.

Each plasma protein will, therefore, have its

own specific problems. In the discussion that follows, the general status of cloning the genes that

code for the plasma proteins of demonstrated or

potential clinical value is reviewed.

Albumin. -Albumin is the major single protein

species in plasma, with a normal concentration

of approximately 70 mg/ml (371). It performs

many functions, including maintaining the oncotic

pressure of blood and serving as the carrier molecule for fatty acids and other small molecules in

plasma (467). Albumin is synthesized in the liver

and is the major protein product of that organ.

The large amount of albumin synthesized by the

liver is reflected in that tissue’s abundance of

albumin-specific mRNA, averaging 5 to 10 percent of the total mRNA in liver (474). With such

a high concentration, it has been a fairly straightforward task to clone the cDNA that codes for

albumin.

The gene for human albumin is probably the

first plasma protein gene to be cloned, and numerous recombinant DNA companies have publicly claimed to have both recombinant yeast and

bacterial strains carrying the human albumin gene

(table 43). In addition to the companies listed,

there are likely to be others that have all or part

of the albumin gene cloned.

One company, Genentech, Inc., has also published the detailed construction of a recombinant

E. coli that produces albumin (336). In these experiments, the albumin gene was linked to the

DNA that regulates the utilization of the amino

acid, tryptophan, in E. coli. In other words, the

human gene was under the control of a segment

of bacterial DNA that responded to the concentration of tryptophan in the medium. Under conTable 43.-rDNA Companies That Are Working on

Cloning the Gene for Serum Albumin

ditions of tryptophan starvation, the tryptophan

genes as well as the albumin gene would be activated.

The majority of the albumin synthesized by the

recombinant bacteria was found to be biochemically and immunochemically identical to native

human albumin (336). However, the complex

molecular configuration proposed for natural

albumin (96,168) was not evaluated in the recombinant protein. Thus, the degree to which the natural and recombinant albumin molecules are identical in any way other than amino acid sequence

and immunologic similarity remains unclear at

this time. Interestingly, the recombinant E. coli

of Lawn et al. (336) appeared to synthesize a small

amount of albumin that was smaller in size than

the native product, and may have represented incompletely synthesized albumin. Thus, not all the

protein synthesized by this particular strain is

comparable to native albumin.

The authors of the Genentech report do not give

specific numbers for the rate with which albumin

is synthesized by their bacterial strain(s). Rather,

they state that the strain(s) make albumin at a

“modest” rate (336). Other biotechnology companies claiming to have the cloned albumin gene

have not published the biochemical properties of

their product, its rate of synthesis by the host cell,

or other technical information—all of which is

regarded as proprietary.

In brief, it appears that the biotechnology industry has conducted the necessary initial research

and development for production of recombinant

albumin, and recombinant albumin production

appears to be at the scale-up phase of production.

But most companies appear to have this project
Ch. 6—Alternative Technologies. Ž 161

on a back burner for the present, given the considerations discussed below.

The first obstacle to be faced in producing

albumin by rDNA technology is whether the technology can produce enough protein to meet present needs, and in a cost-effective manner. Currently, most developed countries use between 100

and 400 kg of serum albumin per million population per year (62). In the United States in 1982,

approximately 87,500 kg of serum albumin was

used (356), or a rate of use of approximately 387

kg/million population/year. To address the feasibility of producing sufficient albumin to meet

U.S. demand (as well as the additional 57,5oo kg

of albumin that was exported in 1982), an estimate of how much albumin could be synthesized

by “state of the art” recombinant strains of bacteria or yeast is needed.

Although no rDNA company will divulge synthetic rates for individual proteins due to the proprietary nature of such information, it is general

knowledge that in current expression systems the

synthesis of a cloned gene product can constitute

10 to 50 percent of the total protein synthesized

by the cell. The maximum achievable rate may

vary significantly, however, for individual proteins (186,305,569). In general, the larger the protein the less efficiently it is synthesized by E. coli.

To determine how much fermentation will be

necessary to meet the U.S. consumption of

albumin, two important assumptions must be

made: 1) that 50 percent of the cellular protein

synthesized by an optimized strain of bacteria will

be albumin (in the optimized strains of E. coli producing human insulin, 50 percent of the cellular

protein was insulin); and 2) that it will be possible to obtain 10 wet weight grams of bacterial

paste from a liter of fermented culture (which, in

fact, can readily be done). Of the 10 grams harvested, about 15 percent (1s grams) will be protein (34o). Thus, 0.75 grams of albumin could be

obtained per liter of fermented bacteria (i. e., 1.5

g protein/liter of fermented culture x 50 percent

of total protein being albumin).

Extending the calculation further: 87,500 kg of

albumin equals 87.5 x 106 grams of protein.

Dividing 87.5 x 106 grams by 0.75 per liter of

culture obtains 116.7 x 106 liters (or about 31 x

106 gallons) of fermented culture per year that will

be necessary to produce sufficient albumin to meet

U.S. demand. In order to supply the worldwide

market, 193 x 106 liters (or about 51 x 106 gallons)

of fermented culture will have to be produced.

Production capabilities already in place in this

country could ferment this volume easily. For example, a typical bakers’ yeast production facility may have 6 to 1230,000 to 40,000 gallon fermenters in operation (286). These fermenters are

capable (using yeast) of producing about 1-2 x 106

liters of ferment every day. Thus, if a recombinant strain of E. coli producing albumin at 0.75

g/liter of ferment and growing at a rate comparable to a yeast cell were given to such a production facility for albumin production, U.S. needs

for albumin could be met within about 80 to 100

days of routine production. Worldwide albumin

supply could be produced within a year.

The ease with which the albumin supply may

be produced will, of course, depend upon the

validity of the assumptions made. Once again, the

assumptions were that a strain of E. coli is available that produces albumin at a rate comparable

to the current rate of recombinant insulin production, and that this strain will multiply efficiently

in a fermenter to yield 10 grams of cells per liter.

In addition, it is assumed that the time necessary

tore-seed a fermenter (i.e., the turnaround time)

is comparable for yeast and bacteria. The first

assumption regarding the albumin production rate

is dependent upon the efficiency of the expression

vector. But even if the maximum biosynthetic rate

for recombinant albumin production were onetenth that observed for insulin, the world market for albumin could be satisfied within a year

by several companies with fermentation facilities

comparable to those of Anheuser Busch in St.

Louis.

Others, using more conservative numbers for

the rate of recombinant albumin synthesis, arrived

at a quite different conclusion; namely, that the

current rDNA industry is not equipped to produce and process sufficient albumin to keep pace

with worldwide, or even nationwide, demand

(167). They estimated that 12.5 grams of albumin

fractionated from plasma that currently sells for

$25 will cost anywhere from $40 to $80 if pro-
162 ● Blood Policy and Technology

duced by recombinant DNA technology. In their

calculations, the rate of albumin production is

assumed to be 10 percent of the bacterial protein,

or a yield of about 100 mg/liter of ferment, compared to the previous calculation of sO percent

and 750 mg/liter.

Their conclusion, however, is based primarily

upon processing considerations. For example, they

assume that 50 gallons of water will be needed

to process each liter of plasma by standard fractionation techniques. Based on the yield of recombinant albumin per gallon of water used, and

extending water usage to an annual rate, they conclude that 10 billion gallons of water would be

needed to produce the albumin that is currently

fractionated from plasma with only 50 million

gallons of water. They estimate that the cost of

the additional water and disposing the effluent

from the processing would greatly increase the

cost of the product.

However, the entire contents of the fermenter

will not have to be processed. Processing recombinant E. coli is not the same as plasma fractionation. First, the bacteria need to be separated from

the media in which they are growing. Separation

is achieved by continuous-flow centrifugation.

This technique is commonly used in the fermentation industry and has the capacity to centrifuge

cells from 30,000 gallons of ferment in about 2

to 4 hours (286). Thus, only the cell paste which

is obtained from the fermenter is processed. The

amount of water used, therefore, will be much

less than in conventional plasma fractionation.

Since it costs only about $400 to produce a ton

of bacteria or yeast in a fermenter (169) and 2,100

tons of cells will be needed to produce the world

market of albumin, the costs incurred in the scaleup of albumin (or any other plasma protein) are

likely to come from purifying the protein rather

than from producing it.

Initial scale-up for recombinant products, however, is likely to be quite expensive. Although Eli

Lilly will not divulge the scale-up costs for recombinant insulin, it has been reported that their costs

were $7o million over expectations (584). This has

resulted in an average of 50 to 55 cents per dose

for recombinant insulin, whereas the price for

mixed bovine and porcine insulin averages 28 to

35 cents and for highly purified porcine insulin

44 to 52 cents.

Perhaps the greatest difficulty in producing clinically acceptable recombinant albumin is the

purification of the protein of bacterial contaminant. Several biochemical techniques to fractionate protein on the basis of size maybe useful.

Ultrafiltration is one such technique, in which a

filter of controlled pore size retains molecules

above a certain size while allowing smaller molecules to flow through. Thus, if albumin is significantly larger or smaller than the contaminants,

it can be easily separated from them on a large

scale by filtration. However, for a membrane filter to effectively separate two molecules, their

respective molecular weights must differ by tenfold. Thus, in practice, ultrafiltration may prove

incapable of purifying recombinant albumin.

Alternatively, purification of albumin on a column containing a resin that separates molecules

by size is a further refinement of the size-separation technique, although not so easily scaled-up.

Recombinant albumin may also be purified

using techniques that exploit its affinity for specific molecules. For example, albumin is known

to bind fatty acids, so chromatographic resins that

are “fat-like” in their chemistry may prove useful.

Likewise, electrostatic attractions between albumin

and oppositely charged molecules (i.e., ion exchange chromatography) may prove effective for

purification. In fact, this technique is currently

being used by some plasma fractionates in the

purification of albumin (119). All of these methods can be scaled-up for industrial production,

and should any one prove ineffective, a combination of two or more may purify recombinant

albumin to an extent sufficient to meet safety requirements.

Scale-up in other countries maybe more costeffective. Japan, for example, has considerable experience in bioprocessing technology (549). In addition, there are extensive fermentation facilities

in Japan, and many such corporations have ties

with U.S. rDNA companies. Furthermore, the

Japanese government has targeted biotechnology

as a key industry and has provided tax incentives

and other subsidies to bioprocessing. Thus, it may

be cost-effective to produce high-volume prod-
Ch. 6—Alternative Technologies ● 163

ucts like albumin in Japan, and import the product to the United States.

Finally, the cost considerations discussed above

were based on the rate with which the protein

product is synthesized and how the product is

recovered from the recombinant organism. It is

very likely that further R&D will result in more

efficient protein production, thus reducing the cost

of the final product.

One possible method to increase the efficiency

of production involves use of other strains of bacteria, such as Bacillus subtilis, or yeast. B. subtilis is a common, non-pathogenic, soil bacterium

that has been used industrially for large-scale production of proteins used in detergents and in the

processing of corn starch. The annual production

of these proteins by B. subtilis ranges in the

thousands of tons. B. subtilis has attracted the interest of the rDNA industry because of its great

biosynthetic capability. When grown under suitable conditions, it can produce up to 10 to 15g/liter v. 1.5 gram/liter for E. coli (186,265). In addition, products made by B. subtilis are excreted

into the medium rather than accumulated intracellularly, as is the case with E. coli.

Thus, if the gene coding for albumin were expressed in B. subtilis, the yield would be far

greater than with E. coli, and the product would

accumulate in the medium rather than in the cells.

This would facilitate subsequent purification and

processing and possibly continuous fermentation

without re-seeding. To date, however, the use of

B. subtilis for production of recombinant proteins

is still several years behind the E. coli system.

Expression of recombinant albumin in yeast

also lags behind the E. coli system, yet offers certain advantages for scale-up. Yeast, like B. subtilis, have been grown industrially for years, and

considerable experience exists in large-scale bioprocessing techniques. In addition, the wet weight

yield of yeast in a fermenter is about 2.5 times

the wet weight yield of E. coli. Since current

strains of recombinant yeast can accumulate protein to a level comparable to E. coli (569), the yield

of recombinant protein should be increased 2.5

times per liter of ferment.

Also, yeasts have the capacity to secrete certain recombinant proteins into the medium. For

example, a group from Chiron Corp. (543) synthesized the gene coding for the hormone urogastrone, and were able to get the gene expressed

in a yeast system. In their report, the protein accumulated intracellularly to a level of approximately

30 mg per liter of non-fermented yeast culture.

The Chiron group has now extended its early

work and has linked the urogastrone gene to a

gene coding for a yeast protein that is secreted

into the medium (214). Thus, there is successful

exploitation of a natural process in yeast, resulting

in secretion of the recombinant protein.

Success of the secretion process also depends

upon the individual properties of the recombinant

protein, with small proteins being more efficiently

secreted than larger ones. The secretion rate for

the small hormone urogastrone, for example, is

in the range of 20 mg per liter of ferment. But

according to industry spokemen, a protein as large

as albumin would not be secreted by this mechanism. Thus, different methods will have to be developed for successful secretion of albumin and

other larger proteins by yeast cells. But even if

the protein is not secreted, yeast offers an attractive approach to producing albumin in a very

cost-effective manner.

One potential disadvantage to use of the yeast

system in which the recombinant product accumulates intracellularly is the difficulty encountered in breaking yeast cells open to recover

the recombinant protein. The yeast cell wall is

very resistant to treatments such as detergent,

osmotic shock and even sonic disruption, thus

complicating initial processing procedures. Furthermore, the harsh procedures employed to

break open the cells can have a denaturing effect

on the biologic activity of the protein to be

isolated.

In summary, current technology employing E.

coli is capable of producing recombinant albumin

to meet worldwide demand. Attention is now

focused on the purification of recombinant albumin and whether this can be accomplished in a

cost-effective manner. It is possible that sophis-
164 • Blood Policy and Technolog y

ticated purification techniques will be efficacious

but not cost-effective. Alternatively, albumin may

be produced in a more cost-effective manner in

other cloning systems (e.g., B. subtilis) where

removal of hazardous contaminants may be less

of a problem. However, these systems are not as

well developed as is E. coli, and more research

and development will be required. However, the

ability to produce albumin by recombinant technology in a cost-effective manner will probably

be achieved; exactly when this will happen is

uncertain.

Coagulation Proteins. —Blood coagulation involves a large number of plasma proteins, at least

one tissue protein, phospholipid membrane surfaces, calcium, and platelets (148,287). Coagulation of blood can occur via one of two mechanisms, known as the intrinsic and extrinsic

pathways. The end result of both pathways is the

conversion (activation) of the plasma protein prothrombin to thrombin, which then converts the

soluble plasma protein fibrinogen to an insoluble fibrin clot.

Factor VIII.—Currently, most Factor VIII is

obtained by fractionating fresh-frozen plasma.

Factor VIII is generally quantitated in “units of

activity” and in the United States in 1982, approximately 500 million units of Factor VIII were prepared by plasma fractionation (356). The 500 million units of Factor VIII have been estimated

to constitute only about 280 grams of purified

protein.

The Factor VIII molecule itself appears to consist of at least two proteins (63,178,339,378). One

of these is known as Factor VIII:von Willebrand’s

factor (VIII: vWF). Deficiency of this protein is the

underlying cause of the bleeding disorder known

as von Willebrand’s disease. The other component of the Factor VIII complex (VIII:C) appears

to be a glycoprotein with an apparent molecular

weight of around 200,000 (178,287). It is VIII:C

that is lacking in hemophilia A patients and the

molecule that the rDNA industry hopes to produce using gene splicing techniques. The world

market for recombinant Factor VIII:C has been

estimated to be as high as $2 billion (255).

The site of synthesis of factor VIII:C is not conclusively known, but recent evidence points to the

cells lining the hepatic sinusoids (516a). The normal circulating concentration of factor VIII:C is

approximately 100 nanograms per milliliter of

plasma, and the protein is very unstable. Information regarding the molecular nature of factor

VIII:C has been slow to accumulate. Consequently,

the approach that has been taken to obtain recombinant-made Factor VIII:C has been to synthesize an oligonucleotide probe based on the

amino acid sequence of the molecule, which was

then used to screen bacteria containing human

DNA (535). Using this technique, segments of

human chromosomal DNA that code for portions

of factor VIII:C have been identified, and the approach has been to splice these segments together

to construct the complete factor VIII:C gene. A

list of the companies claiming to have cloned at

least a portion of the factor VIII:C gene is shown

in table 44.

The clones identified in this manner were constructed with chromosomal DNA, and, therefore,

the factor VIII:C gene exhibits the exon/intron

gene structure characteristics of mammalian chromosomal DNA, which are not present in bacterial

DNA. Recall that bacteria are incapable of properly expressing genes that consist of exons and introns. Thus, investigators will have to splice together the regions of the factor VIII:C gene that

actually code for the protein in a bacterial expression vector in much the same way as were the

cDNAs for albumin and interferon discussed

earlier.

While a factor VIII:C gene spliced together from

the separate gene segments may be necessary for

expression of the gene by bacteria or yeast cells,

Table 44.-Companies Working on Cioning the Gene

Coding for Factor Viii
Ch. 6—Altrernative Technologies ● 165

an intact chromosomal gene with its exon/intron

organization may be suitable for expression by

mammalian cells. In fact, techniques exist for the

efficient introduction of foreign DNA into a variety of cultured mammalian cell lines (585), and

results from several studies have shown that the

genetic information coded in a clone of human

chromosomal DNA can be properly expressed by

a mouse cell line. Because this approach may

prove feasible, virtually all the rDNA companies

working on cloning factor VIII:C are considering

mammalian expression systems.

Several problems will be encountered in synthesizing factor VIII:C by rDNA methods. First,

the molecule is fairly large in size (i.e., molecular

weight of approximately 200,000). To date, the

largest human protein efficiently made by bacteria has been albumin, which has a molecular

weight about a third that of factor VIII:C (i. e.,

68,000 vs. 200,000). But in the E. coli strain used

to synthesize albumin as described by Lawn et al.

(336), a significant proportion of the albumin

made was smaller in size than the native molecule. These results suggest that when large recombinant proteins are produced by E. coli, incompletely synthesized proteins may also appear.

Cloning the factor VIII:C gene in yeast or mouse

cells may overcome this problem. In addition, it

is possible that only a portion of the factor VIII:C

molecule is required for the activity of the entire

molecule, so DNA coding for the smaller fragment

alone might be cloned and efficiently expressed

in a bacterial system.

Another potential problem is that factor VIII:C

is a glycoprotein, and it is still unclear whether

or not the associated carbohydrate is important

for procoagulant activity (600). If carbohydrate

is important for coagulant activity, the factor

VIII:C molecule synthesized by recombinant bacteria somehow has to be glycosylated before it is

clinically effective. Alternatively, the factor VIII:C

gene could be cloned and expressed using hosts

capable of glycosylating proteins (e.g., yeast or

mammalian cells).

One final problem to be faced by the rDNA industry in producing factor VIII:C will be the inherent instability of the molecule. Factor VIII:C

is extremely sensitive to proteases (enzymes that

degrade protein), and recombinant organisms synthesizing factor VIII:C will have to be engineered

to have low levels of protease. Furthermore, since

disrupting virtually any cell results in the release

of proteases, it would be desirable for the recombinant organism to secrete the molecule into the

medium.

Because of our lack of knowledge regarding the

precise molecular biology of factor VIII:C, it is

unclear how difficult or cumbersome it will be to

produce the recombinant-made product. Thus, it

is impossible to estimate its potential costs. But

availability of the product and its safety with regard to infectious diseases are also important, and

recombinant factor VIII:C should be a far better

product than the plasma derivative. Since the

worldwide market for factor VIII:C has been estimated at only 280 grams, recombinant organisms

synthesizing factor VIII:C, even inefficiently,

should have little problem producing this amount.

Several rDNA companies have publicly announced that recombinant factor VIII:C will soon

be available. Genetics Institute, for example, has

claimed that it hopes to begin testing recombinant

factor VIII:C in about 2 years (216). Genentech

has announced that it had cloned the entire Factor VIII:C gene and inserted it into mammalian

cells, which then made and secreted Factor VIII:C

into the culture medium. The gene was found to

consist of 26 exons separated by introns and consisted of about 200,000 nucleotides, of which

about 9,000 comprised the exon segments. Laboratory experiments showed that the product,

about 4 times larger than albumin, was biologically active (484). These findings were published

in November 1984 (226,536,570,592). The next

steps to be undertaken include increasing the

amount of Factor VIII:C produced by the cell line,

scale-up, purification and producing a homogeneous product, and pre-clinical and clinical testing.

Factor IX.—Factor IX is another plasma coagulation factor whose congenital deficiency

results in the bleeding disorder known as hemophilia B (148,287). Although less common than

hemophilia A, hemophilia B can be equally

severe, and treatment is by infusion of Factor IX

complex (404). Factor IX complex actually consists of several procoagulant proteins, including

Factors II, VII, IX and X. Thus, it can be used for
166 • Blood Policy and Technology

treatment of the congenital deficiency for each of

these factors as well as for other hemorrhagic conditions (404). Like plasma-derived Factor VIII,

however, treatment with Factor IX complex

presents an increased risk of infectious disease.

The market for Factor IX is fairly limited because of the relative rarity of hemophilia B and

an ample supply of Factor IX from plasma fractionation (78). A recent survey showed the Factor IX market to be only approximately $13 million in 1982, and that reflected a 15 percent gain

over 1981 (356). The Factor IX market is not as

great as for Factor VIII ($13 million v. $51 million

in the United States), and some analysts believe

the synthesis of recombinant Factor IX is not

financially practical at this time (78). Nonetheless,

several rDNA companies as well as academic laboratories have actually cloned the gene coding for

Factor IX (115,290,323).

Factor IX consists of a single polypeptide chain

of approximately 55,000 molecular weight (148,

287), containing 26 percent carbohydrate (148).

It is synthesized in the liver in an inactive form

and subsequently modified by glycosylation and

by conversion of 12 molecules of glutamic acid

to gamma-carboxyglutamic acid, a vitamin Kdependent process (571).

Upon activation in the coagulation process, Factor IX is cleaved into three polypeptide chains of

29,000, 16,000 and 9,000 molecular weight (MW)

(287). The 9,000-MW fragment contains most of

the carbohydrate associated with the entire Factor IX molecule, while the 16,000-MW chain appears necessary for its activation. The site for Factor IX coagulation activity is located on the

29,000-MW species (287). Circulating concentration of Factor IX is approximately 2 to 4 mg/ml

(115).

The Factor IX gene clone was identified from

a cDNA library generated by using mRNA extracted from human liver. An oligonucleotide

probe was chemically synthesized based upon the

known amino acid sequence of Factor IX. These

oligonucleotides were subsequently radioactively

labeled and used as specific hybridization probes

against the liver cDNA library (115,290,323). The

cDNA clone isolated by Kurachi and Davie (323)

contained the entire coding sequence for Factor

IX. In addition to the identification of cDNA

clones, Choo et al. (115) have cloned the actual

chromosomal DNA coding for Factor IX.

Production of recombinant Factor IX protein

should be less difficult than making Factor VIII:C.

The size of the polypeptide (i.e., 55,000 MW) is

within the current limits of commonly used expression vectors. Furthermore, a report detailing

the cloning of the Factor IX gene has already been

published (323) and other clones have been constructed by some rDNA companies (535). Finally,

an organism producing even a moderate amount

of Factor IX should be capable of yielding sufficient amounts to meet market demands. However, the limited market and the availability of

an ample supply of Factor IX fractionated from

plasma, have together slowed the impetus to develop a recombinant Factor IX in favor of the

more profitable Factor VIII:C molecule.

Production of recombinant Factor IX will not,

however, be an altogether easy task. In the first

place, the molecule is a glycoprotein, and it is not

yet known how the activity of Factor IX is influenced by the associated carbohydrate. As with

Factor VIII:C, it may be necessary to clone the

Factor IX gene in a yeast or mammalian host capable of correctly glycosylating the protein. However, a large part of the carbohydrate associated

with Factor IX is attached to the 9,000-MW fragment, which is cleaved from the molecule as it

is activated (323). Thus, the carbohydrate portion of Factor IX may not function in coagulation. If this is the case, glycosylation of recombinant Factor IX may not be necessary to obtain

a useful molecule.

A second, more challenging, obstacle to the

production of functional recombinant Factor IX

will involve the other major post-translational

modification of the protein that normally occurs

in the liver, the conversion of several N-terminal

glutamic acid molecules of Factor IX to gammacarboxyglutamate residues by a vitamin K-dependent enzyme system (416). This enzyme system is lacking in bacterial and yeast hosts (571).

It may therefore be necessary to modify these

glutamic acids by chemical means in order to produce a functional Factor IX molecule.
Ch. 6—Alternative Technologies . 167

In summary, it does not appear that a great deal

of industrial interest has been generated toward

production of recombinant Factor IX. The lack

of interest appears to result from the smaller market for the product as well as an abundant supply

of Factor IX concentrate from plasma fractionation. Thus, development of recombinant Factor

IX is likely to occur after the development of

recombinant Factor VIII:C. Although the production of recombinant Factor IX will probably require some post-expression modification, chemical rather than enzymatic reactions may be used

to accomplish that goal.

Other Coagulation Factors .—There is currently

a great deal of scientific and medical interest in

all of the other protein factors that participate in

coagulation. As a result, virtually all of the coagulation factors have attracted the attention of

rDNA companies. Should a market for these proteins develop, the genes for these additional factors will probably be identified using oligonucleotide probes synthesized from known stretches

of the amino acid sequence of these proteins. Industrial development of these products is likely

to occur after development of Factor VIII:C and

Factor IX.

Plasma Enzyme Inhibitors. —There are numerous proteins in plasma whose physiological role

is to inhibit proteases. Although these inhibitors

are not currently fractionated from plasma on a

commercial basis, they have gained widespread

attention for their potential as therapeutic agents.

The plasma proteins of interest are alpha 1-antitrypsin, anti-thrombin III, and C1-esterase inhibitor (496).

Alpha 1-antitrypsin. Alpha 1-antitrypsin inhibits the enzyme, neutrophil elastase, a potent

protease that degrades structural proteins (335).

In addition to inhibiting elastase, alpha 1-antitrypsin is capable of inhibiting a number of other

proteases, including trypsin, chymotrypsin, collagenase, thrombin, kallikrein and plasmin (335).

The inhibitor appears to act by combining with

the protease to form a stable, inactive complex

consisting of equal amounts of protease and inhibitor.

Alpha l-antitrypsin is a glycoprotein and is synthesized in the liver. The protein consists of a

single polypeptide chain of approximately 50,000

MW (139) with three carbohydrate side chains

(370). Its normal plasma concentration is about

2 mg/ml, and a low circulating level of the protein is often associated with chronic obstructive

pulmonary emphysema and infantile cirrhosis of

the liver (335). In essence, the continuous action

of proteases on structural tissues, particularly in

the lung and liver, results in autodigestion of the

tissue. Alpha 1-antitrypsin inhibits this self-destructive process. At present more than 30 genetic

variants of alpha 1-antitrypsin have been identified (138).

Preparations of alpha 1-antitrypsin are not currently available for routine use but are being

evaluated in certain experimental protocols. The

protein can be prepared from plasma using one

of several methods. Polyethylene glycol precipitation has been used to prepare a crude concentrate

of alpha 1-antitrypsin which retains some biological activity (210). Alpha 1-antitrypsin concentrates have also been made by further processing

of the remaining plasma after the usual plasma

fractions have been extracted (102). The product

can be pasteurized to inactivate potential infectious contaminants.

The potential market for alpha 1-antitrypsin is

uncertain. As of 1982, only 2.5 percent of the

plasma fractionated in the United States was

devoted to preparation of all inhibitor products

(i.e., alpha 1-antitrypsin, anti-thrombin III, Clesterase inhibitor, etc. ) (356). Patients suffering

from a deficiency of the inhibitor require maintenance therapy, but the deficient condition is

fairly uncommon. It is possible, however, that

alpha 1-antitrypsin may play a role in the pathophysiology of other diseases, such as acute respiratory distress syndrome. Alpha l-antitrypsin

therapy is currently being evaluated for its effect

on such patients. Should the inhibitor be of benefit for this disease, its use could become quite

common (496).

The gene coding for alpha l-antitrypsin has

been cloned by at least one laboratory (323). This

group synthesized an oligonucleotide probe based

upon the known amino acid sequence of the molecule and used the oligonucleotide probe to screen

a cDNA library prepared from liver mRNA. A
168 ● Blood Policy and Technology

cDNA clone was identified that coded for the Cterminal region of the molecule (323). Given that

Kurachi and co-workers reported on their work

in 1981, a full length cDNA clone has most likely

been isolated, and one company, Chiron Corp.,

reportedly has the entire gene coding for alpha

1-antitrypsin cloned in both yeast and E. coli

(569).

In the yeast system, 20 percent of the total protein inside the cell during fermentation is alpha

1-antitrypsin. By performing a simple calculation,

one can deduce that every liter of ferment of this

yeast strain would yield almost 1 gram of alpha

1-antitrypsin, which is the concentration of the

molecule in approximately one unit of whole

blood. While the Chiron Corp. claims to have a

strain of yeast synthesizing the protein, the company would not provide information regarding

the efficacy of the recombinant product. Alpha1-antitrypsin has been given “orphan drug status”

by the FDA (193), and this designation will hasten the FDA review process and provide manufacturers with tax credits to offset development

costs.

Since alpha 1-antitrypsin is a glycoprotein, it

is possible that the associated carbohydrate is necessary for activity. The yeast host should be capable of glycosylation, but Chiron Corp. would

not divulge whether or not its yeast expression

system glycosylated the molecule correctly, if at

all. Therefore, many of the glycosylation problems discussed earlier for the coagulation proteins

may also be relevant to the synthesis of functional

alpha 1-antitrypsin.

Antithrombin III. Among members of a family

of plasma proteins with antithrombin activity,

anti-thrombin III (ATIII) is the most potent and

physiologically relevant inhibitor of the procoagulant protease, thrombin. In addition to inhibiting thrombin, ATIII significantly inhibits

many other proteases involved in coagulation

(496). The mechanism of ATIII inhibition, like

that of alpha 1-antitrypsin, involves the binding

of protease to inhibitor to form an inactive complex (114,448). The rate of inactive complex

formation is greatly enhanced by heparin. This

finding has led to successful use of ATIII in conjunction with low doses of heparin to prevent

post-operative thrombosis (304).

Increasing awareness of the clinical importance

of ATIII has also come from descriptions of

hereditary deficiencies of the molecule. The frequency of congenital ATIII deficiency is approximately 1:3500 (410). Most cases of the inherited

disorder are characterized by ATIII levels at approximately 50 percent of normal; levels less than

25 percent of normal are rare. Yet, families with

even 50 percent of normal ATIII levels have a

hyperactive clotting system.

A transient deficiency in ATIII levels can also

be acquired, especially in patients with venous

thrombosis from a number of causes, including

chronic liver or kidney disease. ATIII depression

also occurs in women taking oral contraceptives

(496). Such women have an increased propensity

for thrombosis, and the ATIII deficiency is felt

by many to be the underlying cause. However,

this theory is not firmly established.

Several varieties of ATIII concentrates are

available commercially, but as was mentioned in

the discussion for alpha 1-antitrypsin, 1982 plasma

fractionation statistics indicate that production of

inhibitor concentrates constituted only about 2.5

percent of the total plasma fractionated (356). But

in reviewing the literature concerning ATIII, it becomes apparent that a much more significant market may exist for the product.

ATIII is a glycoprotein and member of the

alpha-globulin family of plasma proteins. It has

a molecular weight of 55,000 to 60,000 (1,114,

512). Much of the amino acid sequence of the protein is known (426). As a result, an oligonucleotide

probe to identify the ATIII gene has now been

prepared in several laboratories, with both the

cDNA coding for the entire protein sequence and

the entire chromosomal gene having been cloned

in E. coli (114,448,512). The ATIII gene has not

yet been cloned in any host other than E. coli.

Although there has been no report of a recombinant cell that synthesizes ATIII, it should not

be difficult to engineer such a cell, and several

rDNA companies including Genex and Genentech

have expressed interest (119,280). ATIII activity

is present in stored blood (279), which suggests

that the ATIII protein is a relatively stable molecule. Problems associated with production of

recombinant ATIII should not present any unique
Ch. 6—Alternative Technologies • 169

challenge, other than the potential need for glycosylation of the protein.

C1 Esterase Inhibitor. C1 esterase inhibitor is

a protein that inhibits the enzyme of the same

name. Deficiency of the inhibitor results in prolonged esterase activity, with swelling of the

surrounding tissue (496). The most serious consequences of C1 esterase deficiency can be angioedema of the upper respiratory tract, with the

potential for suffocation.

The inhibitor can be extracted from fresh-frozen

plasma and is effective in treating acute episodes

of angioedema (496). Androgen (male hormone)

analogs are also successful in stimulation Cl

esterase levels in deficient patients, and therefore

the widespread use of C1 esterase inhibitor concentrates will probably never be realized. The gene

coding for C1-esterase inhibitor has not yet attracted the attention of the rDNA industry and

has probably not been cloned.

Plasminogen Activators.—Plasma contains an

enzyme system capable of digesting the fibrin in

blood clots, thus leading to clot dissolution. One

component of the system consists of a family of

proteins collectively known as plasminogen activators (116). Plasminogen activator (PA) converts plasminogen to plasmin, which then degrades the fibrin network of the clot to form

soluble products (130). The system is elegantly

specific in that the activating effect of PA on conversion of plasminogen to plasmin is dependent

upon the presence of fibrin. Thus, the anticoagulant effect of the system is limited to the immediate site of a clot. This is in contrast to the

more widespread effects of other clot dissolution

agents such as streptokinase and urokinase, which

are widely used clinically. In some cases the nonspecificity of these drugs can cause serious bleeding problems due to the digestion of fibrinogen

as well as fibrin (7).

Because of the site specificity of PA, production of the protein by recombinant methods has

received considerable attention. Recent commercial interest in PA has come as a result of advances

in two areas of research. First, it was shown that

the infusion of 7.5 mg of a purified PA induced

the dissolution of a 6-week-old thrombus without concomitant bleeding problems (580). Second,

the PA used in this study was harvested from a

melanoma cell line that overproduces PA and

secretes it into the medium (461). This PA was

found to be identical to the PA isolated from normal tissue (461). The 7.5 mg of PA used to treat

this patient (at a cost of about $2,000) was harvested from about 75 liters of spent culture medium from the melanoma cell line (7).

PA is composed of a single polypeptide chain

(578), and has a molecular weight of 70,000

(170,422). It is presumed that PA is the normal

vascular regulator of clot dissolution and is synthesized and released into the circulation by

vascular endothelial cells in response to the proper

stimuli. The amino acid sequence of much of the

molecule has been determined (578). Research on

PA has been hampered by its extremely low concentration in blood, tissue extracts, and cell

culture medium. However, since the amino acid

sequence of the protein was known, it was relatively easy to synthesize an oligonucleotide probe

for screening a cDNA library prepared from

mRNA extracted from the melanoma cell line that

overproduces PA (170,422).

Furthermore, Pennica et al. (1983) of Genentech, Inc. have cloned the entire coding sequence

for PA and have engineered an E. coli cell to produce recombinant PA. In addition to Genentech,

Inc., Integrated Genetics, Abbott Laboratories,

Biogen, Collaborative Research and HEM Research have all been involved in PA research and

gene cloning (119). Currently, Collaborative Research and Abbott Labs market PA synthesized

by the melanoma cell culture method (582). It is

likely that both companies have the gene sequences for PA cloned as well. It has been estimated that recombinant PA can be synthesized

at l/200 to 1/500 the cost of the product secreted

by the melanoma cell line (7).

The future market for PA in the United States

is estimated to be 400 million to 2 billion dollars

(215). Because of the clinical potential of PA, and

the difficulty incurred in purifying it from natural sources, recombinant PA is likely to have little competition for a potentially expanding clinical market. Initial results of Pennica et al. (422)

suggest that a biologically active recombinant

product can be produced by E. coli and optimiz38-647 0 - 85 - 12
170 ● Blood Policy and Technology

ing the level of expression in the recombinant

strain should be straightforward.

Immunoglobulin.The plasma fractionation industry currently isolates immunoglobulin fractions from plasma of donors hyperimmunized

against known antigens. In 1970, production of

immunoglobulins was significant, accounting for

some 10,000 kg of total production (404). Of this,

approximately 900 kg was immune globulin of

known titer and specificity. As of 1982, the market for immune globulin had not expanded and,

in fact, may have decreased slightly. Immunoglobulins are used for therapy and prophylaxis

of tetanus, poliomyelitis, and other viral agents,

including hepatitis (356,404).

Production of immunoglobulin using methods

other than plasma fractionation will probably not

utilize recombinant DNA technology. Instead, cell

fusion techniques, originally described by Kohler

and Milstein (318), will enable hybrid cell lines

to be constructed that secrete antibodies of known

specificity. A clonal population of such hybrid

cells is known as a hybridoma, and the antibody

product of the cell is said to be “monoclinal”

because the antibodies are identical in structure

and reactivity. Antibody-secreting cell lines (hybridomas) are routinely prepared in numerous

academic and industrial laboratories. In fact, the

number of new companies founded to produce

and market hybridoma technology is almost equal

to the number specializing in gene cloning. However, the major focus of the industry to date has

been in the development of monoclinal antibodies

as diagnostic reagents.

Construction of a hybridoma that secretes a

useful antibody essentially involves the physical

fusion of an antibody secreting lymphocyte isolated from an immunized host with a myeloma

tumor cell line that multiplies rapidly in cell

culture. The fusion process can occur simply by

mixing the cell types, but is greatly facilitated in

the presence of the chemical, polyethylene glycol.

The resulting hybrid cells exhibit the properties

of the two parents; namely, secretion of a specific antibody from the lymphocyte and capacity for unlimited growth from the myeloma. A

mixture of hybridomas resulting from a fusion can

be screened to select the hybrid that secretes the

desired antibody. Once identified, the hybridoma

is capable of providing an inexhaustible amount

of the antibody.

To date, essentially all hybridomas are constructed using mouse or rat lymphocytes and

mouse myeloma cells. The limited application of

hybridoma technology to development of diagnostic reagents has resulted from this fact, since

administration of a rodent antibody to humans

would result in potent immunization against that

antibody. The use of hybridomas employing

human lymphocytes and human myeloma cells

has been slow to develop. However, several

reports have appeared claiming to have produced

human hybridomas (321,414a,431), and human

monoclinal antibodies reacting with tetanus toxoid have been produced using the cell fusion technique (223,332,414a). Unfortunately, a human

myeloma cell line capable of producing stable

hybridomas has not yet emerged. Therefore,

human hybridoma technology has not yet developed sufficiently for the isolation of a wide variety of clinically suitable monoclinal antibodies.

Human hybridomas have also been produced

through viral transformation of peripheral blood

lymphocytes with Epstein-Barr virus (EBV) (515).

The antibody-secreting lymphocytes are converted to leukemia cells with EBV, and therefore

grow in culture yet still secrete their antibody

product. Although viral transformation has been

used to construct hybridomas, those produced

using this technique reportedly do not secrete large

amounts of antibody, and production is unstable

(98,414a).

Replacement of plasma fractionation by hybridoma technology as a source of immunoglobulin is not likely to occur in the next few years.

Although some useful human hybridomas have

been developed, the industrial scale-up of antibody production is still in its infancy. One company, Celltech in Great Britain, has pioneered the

scale-up of monoclinal antibody production, but

their experience is primarily with diagnostic antibodies used for tissue typing or imaging of

tumors.

Although most hybridoma companies are concentrating on the mass production of mouse an-
7

Future Direction;
Contents

Page

Part 1: Voluntary v. Commercial Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Voluntary Efforts in the Plasma Sector . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

Prospects for Further Voluntary Sector Involvement in Plasma Operations. . 179

Part 2: Organ and Tissue Banking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

The Current Scene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

The Procurement System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Supply and Demand... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

Compatibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

The American Council on Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

TABLE

Table No. Page

45. A Comparison of U.S. and Canadian Plasma Management . . . . . . . . . . . . . . 180
PART 1: VOLUNTARY V. COMMERCIAL APPROACHES

Introduction

Federal policy attention in the past has concentrated on the whole blood collection process,

spurred by differences in the safety of whole blood

from voluntary v. paid donors. Currently, the distinction between voluntary and paid whole blood

or blood component collections has been maintained through their labeling as being derived from

a “paid donor” or “voluntary donor. ” This labeling is applicable to whole blood, red cells, platelets, single-donor plasma, and cryoprecipitate (21

CFR pt. 640), but does not apply to source plasma

or plasma derivatives (21 CFR pt. 606.120).

Assurances of the safety of plasma and plasma

derivatives have been pursued through regulatory

policies of the Food and Drug Administration

(FDA), which has spelled out donor screening and

laboratory testing requirements (21 CFR, pts.

640.60-640.76). pooling of large amounts of

plasma from individual donors is necessary for

the efficient processing of plasma into plasma

derivatives. Together with the donor and laboratory screening tests that have been applied, these

technologies have resulted in the situation where

there are no substantial differences in the safety

of plasma derivatives whether they are derived

from voluntary or commercial sources of blood/

plasma.

But the availability of products derived from

human tissues may also be influenced by criteria

other than whether the market has resulted in a

safe, readily available product, as witnessed in

current legislative efforts to prohibit profit-making

in systems for collecting and distributing organs

(e.g., kidneys, livers and hearts) and other tissues

(e.g., bone, skin and corneas). Thus, another

viewpoint on the issue of voluntary v. commercial sources is, regardless of how well the present

dual system is working, whether or not public policy should steer blood resources to an all-volunteer supply.

An additional consideration in analyzing the

adoption of this type of public policy is whether

or not the United States and other countries

should be self-sufficient in resources that depend

on human sources. Much of the self-sufficiency

argument has been made in the context of exploitation of donors in developing nations, whose

plasma was then used by fractionation companies

for products used in the developed nations (250).

In 1975, at the Twenty-Eighth World Health

Assembly, the World Health Organization issued

a resolution urging its member States “to promote

the development of national blood services based

on voluntary nonremunerated donation of blood, ”

and “to further study the practice of commercial

plasmapheresis including the health hazards and

ethical implications, especially in developing

countries” (595).

Currently, however, at least as far as U.S.

plasma fractionation and use of plasma derivatives are concerned, the situation is such that U.S.

plasma sources constitute the world’s single largest

source of raw plasma and plasma derivatives, and

the primary issue among nations that use U.S.

fractionated derivatives seems to be self-sufficiency per se, regardless of the source of the

plasma derivatives. In addition, these importing

nations seem more concerned now with the safety

of U.S. plasma derivatives (because of AIDS, see

below) than with the ethical implications of importing these blood products.

A strict self-sufficiency policy would also mean

that international trade in voluntary blood products, as well as in commercially obtained products, would be discouraged. Thus, for example,

the sale of excess red cells accumulated by some

European countries in collecting whole blood for

plasma-derivative production to the New York

Blood Center (and commonly referred to as “Euroblood”) would also be discouraged.

175
176 ● Blood Policy and Technology

On the issue of self-sufficiency, one possible

outcome of the AIDS controversy is that it is forcing nations currently dependent on U.S. plasma

to look into the question of whether or not they

should and could be self-sufficient. Currently,

only the United Kingdom officially prohibits the

import of U.S. plasma, but several western European countries have recently investigated their imports of U.S. plasma and have urged their own

fractionators to show cause why they must continue such importation. Since an immediate ban

on U.S. imports would seriously curtail the availability of Factor VIII concentrates, these countries

have not taken any official action (466).

Voluntary Efforts in the Plasma Sector

There have been some forays into plasma collection and fractionation by the voluntary sector.

In the mid-1970s, at least one voluntary blood

bank conducted a small-scale plasmapheresis program for over 4 years, and although it was not

economically feasible to continue, it was found

that people would donate plasma voluntarily on

a regular basis (402).

Some plasma fractionation activities also exist

in the voluntary sector, and a few years ago the

Red Cross attempted to build a fractionation plant

with one of the commercial fractionators. The

States of Michigan and Massachusetts maintain

plants with capacities to fractionate 50,000 liters

of plasma a year, and the Massachusetts plant is

currently the sole source of herpes zoster immune

globulin in the United States (see ch. 3, pt. 2). The

New York Blood Center also maintains its own

350,000 liter/year plasma fractionation plant to

fractionate its own and some Red Cross plasma,

which required an investment of approximately

$12.5 million (306).

In 1978, the American Red Cross negotiated an

agreement with Baxter-Travenol to jointly fund

the construction of a fractionation plant for

plasma products. The cost of the plant was estimated at $45 million (406). Under the agreement,

each organization would have been entitled to half

the production capacity of the plant, but each

organization would have handled its own acquisition of plasma and distribution of the plasma

products. The plant was to have an annual fractionation capacity of 1 million liters, and industry sources estimated that the joint venture would

have resulted in control of 30 to 44 percent of the

U.S. plasma fractionation business (103,134).

The American Red Cross had requested a business review in April 1978 by the antitrust division of the Justice Department in regard to the

legality of the joint venture’s effect on substantially lessening competition in the plasma fractionation industry. In May 1978, the American

Blood Resources Association submitted comments

arguing that the joint venture would violate the

antitrust laws by eliminating actual and future

competition between the Red Cross and BaxterTravenol (328), but the Justice Department announced in October 1978 that it would not challenge the proposed venture.

The Justice Department discounted the lessening of potential competition on the grounds that

the Red Cross lacked the requisite technological

ability to enter the fractionation business alone.

It also dismissed the notion of a lessening of actual competition because: 1) Red Cross and BaxterTravenol were clearly not actual competitors in

fractionation at the time the venture was being

considered, and 2) although the market shares of

the Red Cross and Baxter-Travenol would have

been significant enough to violate the Court’s

interpretation of “reasonable,” the structure of the

joint venture clearly delineated plasma collection

and product marketing as separate responsibilities

of each organization (328,391). Thus, the department concluded that competition in the plasma

industry would continue and that the joint venture should be allowed to proceed.

In March 1979, the Red Cross and BaxterTravenol announced the agreement (406).

During June-December 1979, West Germany

began a procedure to remove the German Red

Cross’s tax-exempt status on income from manufacture and sale of plasma derivatives through

its blood donor service (317,329). In June 1981,

the German Minister of Finance concluded that

such income should be taxed and treated as a profitable business activity because of the competitive nature of the industry, distinguishing between

blood collection and the “secondary step of fractionation” (438). The decision was made retroactive to January 1, 1981 (320).
Ch. 7—Future Directions • 177

Although no official statement to the effect was

made, the joint venture may have raised similar

issues for the American Red Cross. The issue

would have been “whether plasma collection,

fractionation, sale and other distribution constitute a trade or business which is sufficiently

related to the Red Cross’s exempt purposes that

that business does not generate unrelated business

income” (329). Traditionally, the provision of

blood to health care facilities at the lowest possible price has been regarded as a charitable service to the public, and plasma has been included.

The joint venture may have provided a new

answer to one of the Internal Revenue Service’s

standard tests for taxable activities; i.e., whether

or not the activities in question were “of a kind

regularly carried on for profit” (Rev. Rul. 66-323).

In late 1979, the Red Cross and Baxter-Travenol

terminated their agreement, citing general economic conditions as the cause. The Red Cross’

public relations office gave increases in construction costs of one-third over the budgeted amounts,

inflation, and the increase in interest rates, as the

relevant factors in the decision to shelve the project. Today, the Red Cross continues to contract

with independent fractionators for the necessary

service. Recently, the Red Cross entered into an

agreement with Travenol Laboratories for the

fractionation of Red Cross-provided plasma by

Travenol’s Hyland Therapeutics Division. Under

the agreement, Hyland will increase its fractionation for the Red Cross on a fee-for-service basis

to four times the volume of plasma fractionated

for the Red Cross under current agreements, and

Hyland will provide the Red Cross with a pilot

plant facility for research on new orphan products, to be developed by the Red Cross under

Travenol’s FDA license.

In Canada, all blood and most plasma, with

the exception of a small amount of plasma collected for production of plasma products, are collected by the Canadian Red Cross (CRC) from

volunteer donors. Although the Canadian national blood policy is still under development, all

activities related to the blood program are guided

by principles which have been followed since the

early 1970s. The current version of the principles

was adopted by the Ministers of Health (one

Federal, ten provincial, and two territorial) in

November 1980. As health services are the constitutional responsibility of the Provinces, their

endorsement has considerable authority. The policy, however, is not incorporated in either Federal or Provincial law.

Further, the Ministers of Health have conferred

on the Canadian Blood Committee (CBC) the

responsibility to “direct the Canadian blood system on their behalf” in accordance with the four

guiding principles. The members of the CBC are

representatives of 13 governments (Federal, Provincial, and Territorial), and are funded equally

by the Federal government and the Provincial and

Territorial governments (337).

The “Four Principles” approved by the Provincial Ministers of Health are (106):

1.

2.

3.

4.

to protect the voluntary donor system by

enhancing the opportunities of Canadians to

voluntarily donate a gift for society’s general benefit and by responsibly managing

that resource;

to ensure self-sufficiency of blood products

by reducing Canada’s dependence on foreign

sources of blood products supply, particularly those that rely on purchased plasma for

raw material;

to ensure gratuity of blood products by reinforcing the Canadian tradition whereby no

payment is made for a donation of blood

and/or plasma and no specific charge is

made to recipients of blood and blood products; and

that a Canadian nonprofit policy be maintained and that any charge to recover more

than the real cost of producing a blood fractionation product for Canadians in Canada

should be considered profit.

The first three principles were articulated in

1973, and the fourth was added in 1980 after Connaught Laboratories, one of the two fractionators

serving the CRC, changed its status from nonprofit to commercial. The reason given for adding the fourth principle was that “it was consid-
178 • Blood Policy and Technology

ered that the Canadian public would not accept

the ‘exploitation’ of plasma donated voluntarily

to the CRC” (147).

The second principle was based on a national

goal of self-sufficiency, especially with respect to

plasma fractions. The third principle, which

denies any specific charge for blood, means that

patients or their insurers are not billed by CRC

for any cost of providing blood products. They

may, however, be billed for the service of crosshatching if provided by an institution (hospital

or private laboratory) other than the CRC. (The

Canadian Blood Committee sets the prices of

blood fractions. ) The CRC views the blood program as an expenditure. The Blood Transfusion

Service recovers the costs of recruitment, processing, etc., through direct grants from the Provinces and funding from the Canadian Red Cross

Society. (See subsequent discussion on finances

of the Blood Programmed.)

The nonprofit/no-charge principles apply to

human products for therapeutic use, not to diagnostics. However, CRC itself produces diagnostic reagents for its own use and distributes some

histocompatibility trays to other Canadian laboratories free of charge. (The human leukocyte

antigen (HLA) trays distributed in 1982 at no

charge had an estimated market value of $556,140

at average U.S. prices. )

Currently, there are two Canadian firms which

pay donors for plasma. Their products are commercially marketed. The first is The Winnipeg RH

Institute, Inc., which is associated with the University of Manitoba. It is a nonprofit organization which primarily produces immune globulins

and is also licensed by the U.S. FDA as a source

plasma location. The second is BioResources,

Ltd., of Halifax, Nova Scotia, which collects

plasma principally for manufacture of diagnostic reagents, some immune globulin products, etc.

Plasma is fractionated for the CRC by Connaught Laboratories Ltd., of Toronto, Ontario,

and Cutter Laboratories, of Clayton, NC. Each

receives 70,000 to 75,000 liters per year. New facilities in Winnipeg (RH Institute) and Montreal

(Institute Armand Frappier) will allow fractionation of all CRC plasma in Canada; each will process 50,000 to 60,000 liters annually.

The blood collection system in Canada is administered by the Blood Transfusion Service

(BTS) of the Canadian National Red Cross and

is coordinated from a national (blood transfusion

service) office in Toronto. The BTS includes 17

regional transfusion centers within 10 provincial

divisions. The technical operations are directed

nationally, but blood donor recruitment is the

responsibility of each division. There is a national

Blood Donor Recruitment Program which provides information, resources, etc., but the national

division is not responsible for regional recruitment. The regional transfusion centers collect and

distribute blood and blood products.

In addition, the BTS operates the National

Reference Laboratory (NRL), which also functions

as the World Health Organization’s National

Blood Group Reference Laboratory. The NRL’s

activities include reagent production and quality

control, hepatitis testing, HLA typing tray production and distribution, and a variety of reference and investigational testing.

In 1982, there were 8,928 clinics throughout

Canada. In the Canadian system, “blood donor

clinics” (bloodmobiles, blood drives, blood collection sites, etc. ) are divided into three types:

● Region 1: clinics are permanent sites at or

close to a regional transfusion center. These

represent 48 percent of the total number of

clinics.

● Region 2: clinics are mobile clinics close

enough for blood to be collected, delivered

to a center, and processed within 12 hours

of collection. These constitute 42 percent of

all clinics.

● Region 3: clinics are mobile clinics beyond

12 hours of a regional center, and make up

the remaining 10 percent of clinics. Blood collected from Region 3 clinics is used for the

extraction of those components whose shelf

life before processing exceeds 12 hours.

In 1982, the Blood Transfusion Service of the

CRC collected 1,129,159 units of blood. Of these,

855,765 units were transfused as whole blood or

red cell concentrates (There was a 24.2 percent

national outdate rate for collected whole blood

and red cells in 1982. ) Ninety percent of the whole

blood collected was processed into components.
Ch. 7—Future Directions ● 179

Plasma recovered from whole blood equaled

797,922 units, or approximately 160,000 liters. In

addition, 7,831 voluntary plasmapheresis donations yielded over 3,900 liters of plasma. About

51,600 liters of plasma were transfused, and

153,650 liters (including 113,267 liters of freshfrozen plasma) were available for fractionation

(107).

The CRC meets all Canadian requirements for

blood and blood components, other than plasma

fractions. The only major import is Factor VIII

concentrate, which is imported at the rate of 20

million to 22 million activity units per year at a

value of approximately $2 million in Canadian

dollars. Other products imported in relatively

small amounts are specific immunoglobulins to

varicella zoster, hepatitis B, tetanus and rabies,

and the activated Factor IX Complex. CRC plasma

sources supply all albumin, normal Factor IX

Complex and pooled immune serum globins, and

about 20 million units of Factor VIII (147).

Both Canada and the United States collect approximately the same amount of whole blood

from voluntary donations per capita. Both countries separate the majority of whole blood into

components, although Canada processes a higher

percentage (90 v. 77 percent) of the blood available after whole blood transfusions. Perhaps the

most significant difference is the percentage of

plasma which is prepared as fresh-frozen plasma

(FFP). Plasma must be in the fresh-frozen state

to be useful for Factor VIII preparation. Of the

plasma prepared from whole blood donations, the

United States prepared only 33 percent in the

fresh-frozen state (in 1980, the last year for which

national statistics are available), while Canada

prepared 72 percent as fresh-frozen plasma (for

1982). A comparison of U.S. and Canadian plasma

management by the voluntary sector is summarized in table 45.

The Blood Transfusion Service of the Canadian

Red Cross Society is supported in part by the government and in part by CRC fundraising efforts.

The Provinces fund the blood program directly

by grants for operating budgets and also by payment per item for fractionation products supplied

to hospitals. In addition, the Canadian Red Cross

funds the blood program along with its other charitable activities, such as international disaster relief, veterans’ services, and safety services. The

Canadian Red Cross Society programs and budget are subject to the review and approval of the

Canadian Blood Committee.

About 60 percent, or $80,959,000, of the Canadian Red Cross’s total expenditures ($135,249,000)

for 1982 was spent on the blood program. These

expenditures include all aspects of the blood program; i.e., all 10 regions, the National Reference

Laboratory, national BTS offices, and the Blood

Donor Recruitment Program. There was a deficit of $451,000 in 1982 (108).

In 1983, the Canadian Red Cross instituted a

revised system of accounting in order to provide

for the large amount of working capital needed

for operating the blood program. The new system provides for separate financial reporting for

the activities of the BTS, the national BTS office

and fractionation operations. Each dollar is budgeted in the following proportions:

Prospects for Further Voluntary Sector

Involvement in Plasma Operations

Voluntary sources for all products made from

human blood and plasma remain as the ideal goal

for many, and volunteers are relatively untapped

sources of plasma, perhaps even on the sustained

basis that is the norm for the commercial source

plasma industry. Furthermore, volunteers need

not be the exclusive source of plasma for national

policies that stress the voluntary approach, as

witnessed by Canada’s experience. However,

other factors make it unlikely that a policy will

be pursued to make the voluntary sector the exclusive or even dominant collector of plasma as

well as whole blood in the United States.
180 . Blood Policy and Technology

Table 45.—A Comparison of U.S. and Canadian Plasma Management

United States—1980 Canada—1982

Voluntary whole blood donation per 1,000

population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Whole blood collected . . . . . . . . . . . . . . . . . . . . . . . .

Paid donations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Voluntarily donated blood . . . . . . . . . . . . . . . . . . . . .

Whole blood transfused . . . . . . . . . . . . . . . . . . . . . . .

Units available whole blood . . . . . . . . . . . . . . . . . . . .

Percent whole blood processed into

components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Percent whole blood transfused . . . . . . . . . . . . . . .

Maximum recoverable plasma from volunteer

donor blood left after whole blood

transfusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Estimated plasma available from separated whole

bloodf 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fresh-frozen plasma producedg

. . . . . . . . . . . . . . . . .

Other plasma produced . . . . . . . . . . . . . . . . . . . . . . .

Total plasma produced . . . . . . . . . . . . . . . . . . . . . . . .

Percent plasma prepared as FFPi 

. . . . . . . . . . . . . . .

Donated source plasmai 

. . . . . . . . . . . . . . . . . . . . . . .

Voluntarily donated source plasma per 1,000

population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47 units

10,863,442 units b

233,127

10,630,315

1,930,081

8,700,234 units

77%

180/0

1,740,047 liters

1,631,780 liters

440,377 liters

878,536

1,320,510 liters

33 ”/0

21,722 liters

96 ml.

46 units

1,129,159 units

o

1,129,159

77,517

1,051,642 units

9 0 %

7%

210,328 liters

202,585 liters

143,433 liters

56,151

199,584 liters

72°10

3,900 liters

160 ml.

sion Service, 7982 Statistic/ Report,

One consideration is whether the voluntary sector could meet the U.S. demand for plasma derivatives. Drees has estimated that an additional 20

million whole blood donations would have to be

made to replace the 5 million liters of plasma collected by commercial collectors (at the time of his

estimate), assuming a 250 ml plasma yield per

volunteer donation of 500 ml of whole blood

(165). This would have required tripling the approximately 10 million units of whole blood collected at the time of his estimates. An equivalent

amount of plasma collected by plasmapheresis

would need approximately 8.34 million collections, based on a yield of 600 ml of plasma per

procedure.

U.S. plasma sources, however, also supply a

large part of the world market, and not as much

plasma would be needed for the U.S. market

alone. However, it has been argued that U.S. sales

abroad at prices as high as three times the U.S.

price for Factor VIII help keep domestic prices

down (7), and a self-sufficiency policy that would

discourage international sales of U.S.-derived

plasma products might reduce this beneficial impact on U.S. prices. It could be argued that this

salutary effect on U.S. prices is due to “price gouging” abroad, but the other side of the coin is that

these other users are paying the “market price”

for products they do not produce in sufficient

quantities themselves.
Ch. 7—Future Directions • 181

There obviously is no resolution of these conflicting opinions on the “morality” of selling

plasma products at prices which can be obtained

in the market. Of interest to this essentially unresolvable debate is that, once plasma is processed

into derivatives, they are treated as commodities,

or perhaps more accurately, are treated in much

the same way as prescription drugs by both manufacturers and purchasers. This is true especially

for albumin (whose marketing is similar to that

for generic drugs) and increasingly true even for

Factor VIII concentrates, and nonprofit organizations are commonly involved in marketing both

nationally and internationally (see ch. 3 on the

plasma sector).

Marketing of plasma derivatives by both profit

and nonprofit organizations in direct competition

with each other also points to the fact that, once

past the stage of plasma or whole blood collections, the profit and nonprofit sectors have become more intertwined over the past decade. This

is largely due to the increasing use of component

therapy and the excess plasma that has become

available from the voluntary sector. So any fundamental changes that occur in the plasma derivatives industry will cause problems for the voluntary sector as well.

Voluntary organizations may also be unwilling to become the major suppliers of plasma and

plasma derivatives. Aside from the problems of

establishing and maintaining an adequate donor

supply, costs for starting up or retooling plants

for plasma fractionation are substantial, as witnessed by the abandoned Red Cross/BaxterTravenol proposed joint venture.

Even if present commercial fractionators continued to fractionate plasma that would come primarily from voluntary sources, there is still the

question of the medium- and long-range health

of the plasma derivatives industry. Albumin is no

longer the driving force in the derivatives market and sales are very competitive. As noted

earlier (see ch. 3), the market is not large compared to other industrial sectors, and major companies have left the industry in recent years.

The major factor, however, in determining the

future of the plasma derivatives industry is the

real chance that, by the end of the century, plasma

as a source of current biological proteins will be

(largely) replaced by recombinant DNA and

hybridoma technologies (see ch. 6). These developments would affect not only the source plasma

industry, but also plasma fractionators, some of

whom are sponsoring biotechnology R&D in anticipation of these events. Thus, biotechnology

currently has two major impacts on the issue of

voluntary v. commercial supplies of source plasma

and plasma derivatives. First, it makes the future

prospects of this sector of the blood services complex sufficiently doubtful so that no planned

movement toward a voluntary system can be expected. Second, however, biotechnology shows

sufficient promise that, for the first time, there

are real prospects that the longstanding controversy over commercial plasma donors may be

solved, not through implementation of a deliberate, contested public policy, but through advances in technology which could make the voluntary v. commercial policy debate moot.

PART 2: ORGAN AND TISSUE BANKING

Introduction

In a recent volume on the role of blood bankers The idea that blood bankers are particularly

in tissue and organ preservation, one conclusion well-suited to have a central role in preservation

was that: “Within a decade after the end of this and distribution of organs and tissues other than

century, it is unlikely that there will remain more blood is not entirely novel. In its first paragraph,

than a few vestiges of conventional blood bank- the decade-old National Blood Policy speaks not

ing as it exists today. There area number of health only of “improvement in the quality of blood and

service areas into which blood centers can diver- blood products, ” but also of “development of an

sify, but one of the most obvious is tissue bank- appropriate ethical climate for the increasing use

ing” (376). of human tissues for therapeutic medical pur-
182 ● Blood Policy and Technology

poses” ((179); emphasis added). A year later, in

1975, an editorial in Transfusion (299) asked: “Are

blood banks to become tissue banks?”

Advances in surgical techniques and development of more sophisticated immunological agents

to combat rejection problems have made it possible to transplant a host of solid organs and

tissues, including the heart, lungs, kidney, liver

and pancreas. Some transplantable substances,

like bone marrow, are akin to blood and its components because they are renewable substances

which can be provided by living donors. Organs

such as hearts, livers, and lungs are procured from

the bodies of people who have been declared dead

on the basis of total and irreversible loss of all

brain functions, but whose heart and lungs continue to be supported by artificial means, allowing the organs to be perfused. For tissues, including corneas, skin, and bone, potential donors

include almost any dead body. Clinically, tissue

donors are unlike organ donors in that tissues can

be taken after the donor’s heart has stopped

beating and the actual retrieval is technically less

rigorous.

Although the nature of the donor and the techniques and methods used to arrange for collection, storage, and distribution vary among the different types of organs and tissues, many features

of the process have much in common with the

blood banking enterprise. Finding donors, storing and inventorying products, assuring safety

through a variety of screening tests, distributing

the product, and recovering costs are all features

common to blood banking and tissue and organ

banking.

The blood bank’s traditional role is also a key

element in many transplant procedures. One dramatic example of the need for blood is in the area

of liver transplants. At the University of Pittsburgh, where this procedure was pioneered by Dr.

Thomas Starzl, liver transplants require about

3,OOO to 4,OOO units of blood from the hospital

blood bank’s annual dispersal of about 130,000

units (229). The strain on the blood bank is not

so much the volume of blood needed (open heart

procedures at the same center account for five

times as much blood usage) but rather the unpredictable nature of the need. When a liver from

a brain-dead donor is found, blood must be available within 4 to 6 hours—on occasion as much

as 100 units.

While the need for this much blood is the exception, routine requirements for a range of blood

products are nevertheless rather substantial. One

study of 60 adult first-time liver transplant recipients revealed the following mean intraoperative

and postoperative requirements per patient: red

blood cells, 42 units; fresh-frozen plasma, 39

units; platelets, 19 units; cryoprecipitate, 8 units

(283). According to Richard Crout, the director

of the Office of Medical Applications of Research

of the National Institutes of Health: “The amount

of blood required is much greater than most people realize. It is an important limitation on expansion of this new technology—a major reason why

local hospitals aren’t about to get into transplanting livers” (229).

The Current Scene

The modem era of transplantation began in the

1950S with the first attempts at kidney transplantation. These initial procedures were limited to

identical twins, whose common genotype obviated the problem of rejection. With the development of immunosuppressive drugs to combat

such problems, surgeons were soon able to utilize less closely related living donors and eventually, cadaver donors. In 1963 the first liver

transplant was performed, and in 1967, the first

heart transplant (389). To date, there have been

approximately 500 heart transplants performed

in the United States and about 600 liver transplants worldwide, most of them in this country

(278). In 1983 alone there were 6,138 kidneys, 163

livers, 172 hearts, 37 heart-lung combinations,

and 150 pancreatic transplants performed in the

United States.

With burgeoning interest in transplantation in

the late 1960s, it became apparent that the law

was lagging behind medical advances. Law reform

bodies and professional associations drafted a

model statute to clarify the legal status of organ

donation and transplantation, codifying the common-law powers of an individual to donate body

parts for use after death. By 1971, all State juris-
Ch. 7—Future Directions . 183

dictions save one had adopted the Uniform Anatomical Gifts Act (UAGA) as recommended by the

National Conference of Commissioners on State

Laws (Kentucky joined the rest in 1977) (362).

The UAGA allows people to make known their

intention to become organ donors by signing

wallet-sized documents they can carry with them.

In addition a number of States have made similar provisions to provide evidence of such intent

on drivers’ licenses. The UAGA also allows family

members, in the absence of any contrary intent,

to consent to organ removal on behalf of their

relatives who have been declared brain-dead. The

act, in addition to specifying who may give thirdparty consent for organ donation, also spells out

an important division of labor: in order to avoid

any conflict of interest, physicians responsible for

declaring that the donor is dead may not be the

same ones involved in the transplant procedure.

The Procurement System

A network of approximately 110 independent

and hospital-based procurement agencies exists to

coordinate distribution of organs. There are about

360 people in the country whose full-time work

involves coordinating organ donation (278). The

procurement centers have also been grouped into

regional networks and have established computer

and phone links. For example, the Southeast

Organ Procurement Foundation is one such network, consisting of 30 centers. In addition to

transplant coordinators, surgical transplant teams,

intensive care unit personnel, patients, and the

families of donors are also involved. To date this

patchwork system has worked remarkably well,

but many predict that without further refinements

it will be unable to meet the increasing demand

for organs suitable for transplantation (152).

One key actor in the transplant process is the

transplant coordinator. This person, often a nurse

or social worker, is responsible for maintaining

a liaison between the transplant team and the

family and caregivers of the potential donor. Most

often the potential donor is identified by a neurosurgeon or neurologist upon declaration of brain

death or by a nurse in the intensive care unit. The

coordinator is often the person who must broach

the sensitive issue of organ donation to a grieving family, explaining the ofttimes disconcerting

concept of “brain death. ” It has been estimated

that only 1.6 to 3.5 percent of people dying in

acute care settings are potential organ donors;

most often these are people who have sustained

traumatic injury (64). Since many fewer actually

become donors, it is difficult to build ongoing relationships among the professionals involved. The

situation can be further complicated when there

are a number of teams involved seeking multiple

organs from the same body (243).

The transplant coordinator’s role in motivating

the families of potential organ donors is critical.

Studies have shown that when the situation presents

itself, between 70 and 80 percent of families will

consent to donation on behalf of their deceased

relatives. But, as in the blood donation context,

misunderstandings can confound the situation. A

Gallup poll showed that willingness to donate

one’s own organs after death is linked to perceptions about the success of the procedure. Of the

49 percent who agreed that kidney transplantation

would “extend a person’s life substantially, ” 60

percent were willing to donate; but of the 42 percent who were uncertain and believed that a

transplant “might or might not extend that person’s life, ” only 36 percent were willing to donate

(460). And in a further parallel to blood donor

motivation, there are apparent cultural barriers

to donation; for example, blacks are substantially

less likely than whites to agree to donation.

Another group in need of education about

transplantation possibilities are the physicians and

nurses on the “front lines” in community hospitals or trauma centers. As one student of the procurement system put it: “The ‘keys to the kingdom’ are held, in organ procurement, by the

nurses and neurosurgeons (sometimes neurologists) in nontransplant hospitals” (451). It is often

complained that this is the weakest link in the system. Physicians and nurses are often understandably reticent about broaching the possibilities of

organ donation with grief-stricken and vulnerable

families.

There has been criticism of the current system’s

overreliance on single individuals as transplant

coordinators. Critics of the practice describe the

coordinator’s role as inherently stressful because
184 ● Blood Policy and Technology

of the simultaneous dual allegiance to the donor’s

family and to the recipient and transplant team.

These stressful and conflicting functions are often

undertaken on a 24-hour-a-day, on-call basis. Red

Cross spokespersons have argued that their cadre

of volunteer and professional staff, experienced

in motivating blood donors, would be well suited

to the task of coordinating procurement and

counseling the families of prospective donors

(376).

The Red Cross first embarked on pilot programs in St. Louis, MO, and St. Paul, MN. In

Minnesota, the opportunity for some Red Cross

blood bankers long interested in tissue preservation and storage to get involved in organ and

tissue procurement came about when the transplant coordinator at the University of Minnesota

left and the Red Cross agreed to fill the gap. A

March 1984 survey conducted by the Red Cross

of its 57 regions revealed 6 with at least one active program in organ or tissue banking (or definite plans to begin within 6 months).

Thirteen regions are actively planning or investigating the need for a number of specific services: seven in the area of public and professional

education, seven in bone banking, three in cornea retrieval, and one in skin banking. Thirtytwo regions expressed some interest but were still

in the investigatory stages of contacting other

agencies, hospitals, and professional groups to

assess possible roles for the Red Cross. Finally,

representatives of six regions stated they were not

planning to become involved in organ or tissue

banking in the foreseeable future (51).

Upon reviewing the pilot programs in the Midwest and the survey of its regional centers, the

Red Cross Board of Governors in 1984 adopted

a policy statement, pledging to:

1.

2.

Participate in a national effort to increase the

supply of tissues and organs for transplantation through a program of public and professional education and counseling.

Develop and coordinate systems for tissue

donor identification, retrieval, distribution,

and use that are equitable and meet high professional standards.

3.

4.

In

Provide tissue services to meet community

needs as is feasible and appropriate.

Assess the need for, and when appropriate,

develop programs in support of organ donation services.

April 1984, the American Association of

Blood Banks (AABB) also adopted policies relating to organ transplantation. It was agreed that

the “AABB will promote, among its members, histocompatibility testing, organ procurement, tissue

banking and organ exchange among members and

non-members. ” The AABB also opposes the buying and selling of organs. In its policy statement,

it also argued against any “operational” role for

the Federal Government, instead urging it to increase public awareness about organ donation and

encourage development of private sector organ

procurement agencies. According to the AABB,

the Federal Government should also explore

mechanisms to pay the medical bills of transplant

patients (27).

Supply and Demand

The number of brain-dead bodies available and

suitable for the procurement of organs for transplantation is estimated by the Centers for Disease

Control to be approximately 20,000 annually; yet

only 2,OOO are actually used as donors. In a recent 2-year period at the University of Pittsburgh,

71 candidates for liver transplantation died while

awaiting transplants. Of the 58,000 patients who

are maintained on dialysis under the federally

funded End-Stage Renal Disease Program, there

are 8,000 listed on formal recipient registries,

awaiting compatible donors (52). The AMA’s

Council on Scientific Affairs estimates that up to

half of those on dialysis maybe eligible for transplant (37).

An additional supply issue involves organ preservation. Organs, once removed, must be transplanted quickly; hearts within 8 hours, kidneys

within 30 to 50 hours (depending on the method

of preservation), and livers within 4 hours. The

“wastage” rate is quite high for a number of

organs; e.g., about 20 to 25 percent of kidneys

procured annually are wasted (460). (This con-
Ch. 7—Future Directions ● 185

trasts with a wastage rate for kidneys of about

5 percent in Western Europe, which some have

attributed to better typing and crosshatching capabilities. )

Recently, attention has been focused on the propriety of buying and selling human organs as a

way to alleviate shortages. Much of this controversy can be traced to a proposal by a Virginia

physician to open a brokerage service which

would pay living kidney donors in the United

States and the Third World (463). The hue and

cry that greeted this proposal was considerable.

The experience with the risk of blood from paid,

“skid row” donors in the late 1960s and early

1970s has been frequently cited as a reason to be

wary of embarking on commercial ventures in

transplantation (231). Others have expressed concerns, often raised in the blood donation context,

that the impact of payment will be to make it less

likely for people to donate voluntarily.

The Uniform Anatomical Gifts Act and related

Federal and State laws and regulations have not

addressed the question of whether financial reimbursement could be provided to an organ donor

or the donor’s estate for the organ itself (as opposed to compensation for lost wages or medical

expenses associated with the donation procedure).

A number of groups, including the National Association of Patients on Hemodialysis and Transplantation and the International Transplantation

Society, have issued statements opposing commercialism in organ transplantation. The Executive Council of the American Society of Transplant Surgeons (which includes virtually all of the

organ transplant surgeons in the country) went

so far as to agree to expel any member participating in a transplant “under proprietary conditions. ” A number of States have considered or

adopted legislation to ban the buying and selling

of organs. All of these statutes have explicitly excepted blood and blood components, because they

are “self-replicating fluids” (374).

Increasing attention has been given to making

the most use of each individual donor by procuring multiple organs from each body. Yet the 110

aforementioned procurement agencies are ostensibly funded by the Federal Government for the

sole purpose of kidney procurement. As one commentator has observed (450):

Legally speaking, however, they are “kidney”

procurement agencies. With trivial exceptions,

each is totally funded by the End-Stage Renal Disease Program, a program that only pays for

kidney acquisition. In practice, however, they

have already exceeded that limitation. Almost all

organ procurement agencies routinely attempt to

retrieve corneas and, frequently, skin and bone

as well. The added costs of such efforts are minimal as the tissue-specific banks usually do the actual excision themselves. All the agency does is

ask the permission of the family, make arrangements in the hospital, and contact the eye, skin,

or bone bank. Government ignorance or benign

neglect has simply allowed these organ procurement efforts to “piggy-back” on kidney procurement without cost.

As the number of liver and heart transplants

has increased in the last few years, “kidney” procurement agencies have taken responsibility for

locating these organs as well. The transplant

centers needing such organs have reimbursed the

agencies for the additional costs. So long as the

number of non-renal transplants is 2 or 3 percent

of the number of kidney transplants, there is little problem with this informal, ad hoc approach.

But what will occur when the percent is 10 percent, or 30 percent, or even 60 percent!

Thus, one of the reasons why blood bankers have

been interested in organ banking is the need to

develop “full-service” organ banks.

There are also a number of tissues of use in

transplantation which do not have to be maintained in a “living” state and which carry no risk

of rejection because of immunological barriers.

Some of these, such as nerves, arteries, dura, and

fascia, have been collected and stored (either

freeze-dried or frozen) by individual surgeons for

later use. Other tissues such as bone and corneas

have been collected and distributed by banks

established for these specific purposes (491).

One commentator has suggested that blood

banks aggressively explore possibilities in bone

transplantation, by undertaking the initial step of

38-647 0 - 85 - 13
186 ● Blood Policy and Technology

contacting medical and dental schools and societies (especially departments of neurosurgery and

orthopedics) to find potential clients. Because of

recent breakthroughs and new uses, there may be

needs going unmet in the absence of an adequate

SUPPlY (296).

Bone harvesting must take place within 24

hours of the time of death. It is recommended that

procurement take place in a sterile environment,

such as an operating suite or under a laminar-flow

hood, so that there is no need to sterilize the material prior to transplantation. Although there are

obvious logistical and cost considerations in the

use of such facilities, it may also be preferable to

retrieval in a funeral home or blood collection center because of “psychological concerns” (296).

Bones can be stored in a variety of forms and

used in many ways. They can be freeze-dried and

kept in a vacuum; stored in this way they have

been kept for up to 15 years without any diminution in clinical quality. Bones can also be deep

frozen below –80° C for future use. Transplants

of freeze-dried bone can be used to treat fractures,

to reconstruct limbs after surgical removal of

tumors, and to fill in bone cysts after cervical

spinal fusions. Freeze-dried, crushed cortical bone

has been especially useful in periodontal therapy

and in maxilofacial surgery (473).

There are a number of uses for human skin,

which can be procured from dead bodies and

stored in a frozen state. Transplanted skin is especially critical in the treatment of severely burned

patients and can be used to cover open wounds

to ward off infection and guard against loss of

water, electrolytes, protein, and heat—usually as

an interim measure until the patient’s own skin

can be transplanted in an autograft procedure.

As with the establishment of bone banks, it has

been suggested that blood banks interested in

diversifying into skin banking first contact local

trauma centers, plastic and reconstructive surgeons, burn treatment centers, and geriatricians

to gauge the need for banked skin. The donor pool

and economies of scale are such that it has been

suggested that large metropolitan or regional

blood banks are best suited for this enterprise. It

has been estimated that investment in the equipment necessary for cryopreservation and microbiological screening and staffing costs make it inefficient to operate a skin bank using less than 50

donors per year (which would involve screening

approximately 2,500 potential donors) (151).

Compatibility

Many in the blood banking field have considerable experience in doing the kinds of tests necessary to ensure immunologic compatibility. The

use of donor-specific blood components for therapeutic procedures has led to the establishment

of registries of donors, organized not only by

ABO/Rh blood groups, but also by HLA types.

The Red Cross markets an HLA tissue typing

tray, and also maintains files of donors with rare

blood characteristics or needs. The AABB maintains a similar file, and there also is a similar file

on an international basis. Since 1.970, the American Association of Blood Banks has had a Committee on Organ Transplantation and Tissue Typing. Upon the recommendation of this Committee,

the AABB recently established a Bone Marrow

Transplantation Information Service, “designed

to speed the flow of information between the

various centers while insuring individual rights

to privacy and avoiding the expense and encumbrance of maintaining a registry” (249). The

AABB collects information about potential recipients provided by transplant centers, including the

name of a staff contact person, a coded identifier

for the recipient and the recipient’s HLA type,

ABO/Rh type, and relevant diagnostic information. This information is compiled and distributed

at regular intervals.

According to the former chair of the AABB

Committee on Organ Transplantation and Tissue

Typing: “The ‘matching’ and subsequent considerations are carried on directly between the

centers involved; the AABB is not a party to these,

nor indeed, will it even know when such negotiations are going on.” The AABB does, however,

anticipate conducting retrospective evaluations to

judge the success of the procedures (249).

Use of such registries has not only raised hopes

about increased ease of matching, but also has occasioned concerns about confidentiality of donor

records and the integrity of the consent process

Appendix A - The Blood Resources Program,

Division of Blood Diseases and Resources,

National Heart, Lung, and Blood lnstitutel

The National Heart, Lung, and Blood Institute through its Division of Blood

Diseases and Resources (DBDR) supports research to improve the quality,

safety and availability of blood and blood products for therapeutic uses.

The DBDR in collaboration with members of the scientific community recently

completed a planning study in which research needs and opportunities in the

field of blood resources were delineated . A summary of the recommendations

that emerged from this study are underscored below. Immediately following each

recommendation are brief descriptions of related research projects currently

supported by the DBDR.

BLOOD BANK MANAGEMENT

Better methods of collecting, separating, transferring, and preserving the

cellular and liquid Portions of blood are needed. Th ese achievements de~end

upon developments in’ Instrumentation, techniques, and automation.

0 A platelet harvesting device is being developed to separate platelet-rich

plasma from blood, based upon a centrifugal elutriation technique. This

device should improve the amount of platelets recovered and reduce the

contamination of platelet-rich plasma by erythrocytes and leukocytes.

(R43 HL-31873)

0 Investigators are employing counter-current distribution techniques to

separate cells and membranes in a two-polymer aqueous phase systems. This

technique has been shown to be a sensitive, versatile method for characterizing

and fractionating cell subpopulations based upon their surface or membrane

properties.

(RO1 HL-24374)

0 Studies are being performed to test the feasibility of using pressure,

generated by ultrasonic waves, to separate cellular elements of blood

from plasma.

(R43 HL-31890)

0 A regional blood

all products, is

center. Results

at all hospitals

(PO1 HL-09011 )

1

distribution system, using computer bar codes to identify

being developed and tested at a large metropolitan blood

indicate that a uniform supply of blood could be maintained

while reducing regional outdating.

‘Provided by George Nemo, Ph.D., Chief, Blood Resources Branch, DBDR, NHLBI

191
192 ● Blood Policy and Technology

More effective data COllection on blood and blood resource usage would help

guide the development of predoctoral and postdoctoral education programs and

provide a b asis for exploring the need for autotransfusion, bl ood substitutes,

and related Issues of bl ood management.

0 In June, 1984, the NHLBI will initiate a study to determine future blood

data collection, analysis, and reporting activities. The study will be

conducted over a period of nine months. Technical support will be provided

by a contractor experienced with medical records, medical abstracts, and

standard coding and reporting systems. The study will involve a number of

Federal agencies includinq the National Center for Health Statistics, the

Food and Drug Administration, and the Department of Defense as well as

major blood banking organizations.

CELLULAR ELEMENTS

An improved ability to reduce damage to the cellular elements from storage

Will depend on a better understanding of the factors responsible for the

loss of viability and function of these cells. Basic research to understand

the metabolic processes involved , the function of the cellular membrane in

these activities. and how external forces interact with th ese features is

critical to progress in this area.

0 Biochemical and ultrastructural studies are being performed to characterize

the structure of the platelet cytoskeleton. These studies are expected to

provide basic information relevant to the practical aspects of separating,

storing and preserving platelets for transfusion.

(PO1 HL-29583)

0 Studies of the relationship between surface saccharides and senescence in

normal red blood cells have shown that the glycoconjugates of the cell membrane play a significant role in aging and sequestration of old erythrocytes.

(RO1 HL-17881 )

0 A blood bag is being developed of semipermeable membrane material that will

permit glycerolization and deglycerolization of blood cells without entry

into the blood bag and thus insure sterility.

(RO1 HL-24466)

0 Studies are being performed to define the morphologic, metabolic, and

functional changes that occur during storage of platelets in the liquid

state. Information gained from these studies will be used to develop

techniques to permit storage of platelets for one week or more with minimal

loss of viability and function.

(RO1 HL-20818)

0 Baseline studies of changes in lipids and proteins of red cell membranes

have demonstrated that improved methods of erythrocyte preservation result
App. A—The Blood Resources Program, Division of Blood Diseases and Resources ● 193

in a significant reduction of lipid loss. These studies have al so shown

that red blood cells lose pieces of membranes in vivo, supporting the

finding that the membranes of older cells contain less lipid than membranes

of younger cells.

(RO1 HL-25867)

Frozen preservation of blood cells, including bone marrow and stem cells,

would expand the range of herapeutic modalities available to th e clinician

in many conditions for which there is limited therapy at present. In addition,

culture techniques for growing bone marrow, stem cells, and other cellular -

elements should be developed th at permit the exploration of new therapeutic

approaches.

0 Research is being performed on the cryopreservation of human platelets and

granulocytes. Studies are focusing on the use of varying concentrations

of cryoprotectants to achieve good recovery of functioning cells.

(RO1 HL-27537)

Immunologic characteristics of the cellular elements have long been recognized

as important aspects of their viability and function. Better methods to identify

important immunologic features of cells and a better understanding of the clinical

function of specific antigenic determinants will aid greatly in providing matched

cells for therapeutic use. HLA registries, particularly for platelet and for

bone marrow donors, are already required, and this need will undoubtedly extend

to the other cellular elements as well.

0 Efforts are underway to determine the role of the HLA complex in the

control of immune responses. Initial studies are focusing on the in

vitro association of HLA phenotypes with cellular responses to artificial

antigens.

(POl HL-09011)

0 A study of the membrane biochemistry of Rh antigens is providing information

suggesting that the Rh antigen is associated with the main glycoprotein,

band 3, of the red cell membrane.

(R01 HL-23108)

0 Investigators are developing and applying immunochemical methods to detect

and characterize structural variations on HLA Class I and Class 11 cell-surface

glycoproteins. Specific HLA gene products will be isolated and defined on

the basis of molecular weight. Attempts will be made to relate the newly

identified structural components to specific HLA-D region genes.

(POl HI--29583)

0 Investigators are determining molecular weights of Rh antigens, as well as

other antigens in the red cell membrane. These studies have shown that

the molecular weight of solubilized Rh antigen is over 500,000 daltons.

(RO1 HL-24009)

38-647 0 - 85 - 14
194 . Blood Policy and Technology

o

0

0

A

Investigators are attempting to produce human monoclinal antiplatelet

antibodies using spleen cells obtained from patients with immune platelet

disorders. If monoclinal antibodies can be produced, useful reagents

will be obtained that will enable investigators to identify antigen expression during the clinical course of immune platelet disorders.

(ROl HL-29513)

Using allospecific hybridoma antibodies, investigators

spondyloarthropathy is associated with the presense of

cells of patients. These data are significant because

that the use of allospecific monoclinal antibodies may

of susceptibility markers of inherited diseases.

(RO1 HL-29572)

have shown that

HLA B27 antigens in the

they demonstrate

improve identification

An International Bone Marrow Transplant Registry has been established for

the purpose of collecting, analyzinq and disseminating data on bone marrow

transplantation performed at medical centers throughout the world. This

registry is concerned with the identification of factors that affect graft

and patient survival . These factors include pre-transplant transfusion,

donor compatibility, granulocyte transfusion, and infection.

(Intra-agency Agreement with NIAID)

larqe number of substances are actively transported on. or secreted bv.

cellular elements.

.

Some are recognized to be of siqnificant physiological=

importance. Th e myriad of potentially useful agent; found in’ asociation

with these cells, including the lymphokines, mediators of several varieties,

enzymes, and other biologically active chemicals, must be isolated, identified,

and studied. Wh en Important functions are identified, isolation and purification usinq monospecific antibodies and other techniques.

o

0

A research project is focusing on the physiological functions of plateletderived factors in the regulation of cellular growth, migration, and metabolism of specific target cells in culture. This project involves studies

of platelet-derived growth factor, platelet factor 4, beta-thromboglobulin,

serotonin and thrombin.

(PO1 HL-29583)

In an ongoing project, platelet-activating factor (PAF), a low molecular

weight substance released by white blood cells, is being studied along with

an inhibitor of PAF. Studies are focusing on the role of these molecules

in several diseases, notably asthma and immunologically mediated lung

diseases.

(RO1 HL-25220)
App. A—The Blood Resources Program, Division of Blood Diseases and Resources ● 195

PLASMA AND PLASMA DERIVATIVES

Perhaps the greatest immediate challenge in the area of plasma derivatives is

related to the development of techniques that utilize existing or new methods

of separation to isolate, purify, and prepare safe products for research and

therapeutic use. Such advances in technology will not only lead to better,

more abundant, and less costly products, but Will also provide opportunities

to isolate and study trace agents of the plasma that have important functions

in relation to coagulation, inflammation, the complement system, and other

important response mechanisms of the body.

0 In an ongoing study, arginal peptides are being synthesized for use in the

affinity chromatographic purification of serine proteases. Arginal peptides

attached to agarose resins will serve as a general affinity chromatography

procedure in plasma protease purification, and the procedure may have

therapeutic importance in the isolation of proteases for the treatment of

hemophilia and thrombolytic disorders.

(RO1 HL-2491OO)

0 Work is continuing on the combined use of polyethylene glycol precipitation

and Cibacron B1ue Sepharose in the purification of several plasma proteins.

(RO1 HL-26887)

0 A study is being conducted to determine the feasibility of purifying alphal-antitrypsin from the plasma of normal donors for supplementation in infants

with alpha-1-antitrypsin deficiency who have early symptoms of liver disease.

(RO1 HL-29731 )

Specifically needed in this area (plasma and plasma derivatives) is the development of disease-f ree products, particularly reagents free of hepatitis virus,

that can be used safely in clinical situations. There is also a need to

identify th e etiology of other adverse reactions caused by transfusion of

plasma d erivatives, such as th ose th at occur with some clotting fractions

and immune qlobulins.

0 A variety of chemical and physical inactivation methods are being employed

to reduce the infectivity of non-A,non-B hepatitis viruses (NANB) in labile

blood derivatives. The efficacy of the inactivation process is being eval

by inoculating treated material into chimpanzees.

(NO1-HB-37009)

0 Research is continuing on the development of new plasma derivatives which

uated

have existing or potential clinical use. A factor IX concentrate preparation

has been developed that is non-thrombogenic. Methods are also being developed

to reduce viral infectivity in factor VIII concentrates and similar methods

are being applied to the production of factor X and Protein C concentrates.

(RO1 HL-24944)
196. Blood Policy and Technology

SAFETY

0 Investigators are attempting to identify and to characterize NANB hepatitis

agents or antigens in the sera, liver extracts and tissues of infected

humans and chimpanzees. If successful, new tests for NANB agents would

be developed; immunization with purified NANB antigens would be evaluated

in chimpanzees; in vitro cultivation of the agents would be attempted; and

the epidemiology and natural history of NAHB hepatitis would be studied.

(PO1-HL-09011-18A1)

0 Attempts are being made to modify hepatitis B surface antigen (HBsAg) by

chemical means in order to induce or amplify an immune response in nonresponder mice. If successful, these studies will be extended to humans and

include HBsAg carriers and vaccinated individuals. In addition, interferon,

which decreases the concentration of Dane particles and HBsAg in human

carriers, will be encapsulated in polysomes or covalently linked to polysaccharides in an effort to direct the lymphokine to liver tissue. A separate

project entails introduction of the HBV genome into eukaryotic cells in

order to study viral expression.

(POl HL-09011)

0 A computerized serum and data bank, established in 1969, is projected to

contain approximately 300,000 samples by 1985. Long-tern surveillance

studies continue to be performed with these serum samples to explore

epidemiological patterns of NANB hepatitis.

(POl HL-09011)

0 Studies are focusing on the relationship of HLA-linked genes to immune

responses that include vaccination with HBsAg or natural infection with

HBV.

(POl HL-09011)

0 A repository of coded, frozen serum samples from the Transfusion-Transmitted

Viruses Study is being maintained. These samples are available to investigators for hepatitis research, with approval of the National Heart, Lung,

and Blood Institute.

(N01 W-27000)
App. A—The Blood Resources Program, Division of Blood Diseases and Resources • 197

0 A breeding colony of chimpanzee, presently consisting of 43 animals, is

being maintained for hepatitis research ●

(NO1 HB-27004)

0 A prospective investigation is being conducted to identify the agent(S) of

NANB hepatitis. A rapid screening procedure, initially developed to detect

anti -HBsAg, is being applied to the detection of the agent( s) of NANB

hepatitis. Serum samples from NANB patients and 1iver homogenates from

infected chimpanzees are being evaluated with this method.

(NO1 HB-37010 )

0 A blood donor survey and serun sample analysis is being performed to

correlate clinical manifestations of hepatitis with concentrations of

1iver enzymes in the blood. Studies also include the development of methods

for detecting and isolating DNA in serum with elevated concentrations of

alanine aminotransferase (ALT), and of methods for molecular cloning of

the nucleic acid isolates.

(NOl HB-370ll)

0 The transmission of Epstein-Barr virus (EBV) by blood transfusion is beinq

studied. Investigations are concerned with the frequency of EBV transmission,

the frequency of clinical illness in infected individuals, antibody responses

to parenterally derived infections, and the role of passive immunity and

transfusion volume in the development of infection.

(ROI HL-30311)

0 A prospective study is being performed to determine the incidence of transfusion-associated cytomegalovirus (CMV) infections, including primary,

reinfection, and reactivated latent infection in immunocompetant and immunodeficient blood recipients. Investigators will determine the clinical

significance of CMV infection in these patients and will attempt to develop

tests for determining which blood donors are capable of transmitting CMV.

(RO1 HL-30329)

0 A longitudinal study is being performed to determine the prevalence of immunologic abnormalities in patients with hemophilia. These abnormalities may be

induced by factor VIII treatment and are similar to the severe dysfunction

of the immune system observed in patients with acquired immunodefici

syndrome (AIDS).

(RO1 HL-31015)

0 A study is underway to investigate the possible causative and contri

ency

buting

factors and their interactions in the pathogenesis of AIDS. A large population

of healthy, but at-risk, homosexual men will be followed prospectively, using a

variety of serologic and immunologic markers to define the sequence of events

leading from good health, to altered immunity, to AIDS.

(PO1 HL-09011)
198 . Blood Policy and Technology

0 A study has been initiated to demonstrate whether an AIDS-inducing infectious

agent is present in the plasma of patients with this syndrome. Plasma

samples have been inoculated into chimpanzees that are being monitored for a

variety of immune functions as well as clinical manifestations of the

disease.

(YO2-HB-30006)

0 Investigators are attempting to determine whether patients with hemophilia A

display immune function changes similar to those observed in patients with

AIDS. In addition to hemophilia patients, the immunological status of patients

with sickle cell anemia and thalassemia major will be evaluated, since both

groups repeatedly receive substantial quantities of cellular blood products.

(YOl-HB-30034)

0 An outbreak of an acquired immunodeficiency disorder, which resembles human

AIDS, has been observed in rhesus monkeys at the University of California

Davis Primate Center. The disorder is referred to as Simian Acquired

Immunodeficiency Syndrome or SAIDS. Recently, it was found that SAIDS

could be experimentally transmitted to monkeys. A project is currently in

progress to determine the role of blood and blood components in the transmission

of this disease in monkeys.

(Y02-HB-30018)

0 Methods are being developed to detect circulating antigen-antibody complexes

containing the putative agent of AIDS. A variety of laboratory procedures

will be used to detect and characterize specific antigens and antibodies

found in the sera of patients with AIDS.

(RO1-HL-32434)

0 A study is beinq performed to quantitate specific breakdown products of

nucleic acid metabolism, including purine and pyrimidine bases, in the serum

and urine of several study groups including patients with AIDS. It is hoped

that this study will lead to the development of a laboratory test to detect

asymptomatic carriers of AIDS.

(RO1 HL-32432)

0 A study is being performed to determine the functional role and significance

of human CMV, human T-cell leukemia virus (HTLV), and other agents associated

with AIDS. Several experimental approaches, including transmission experiments

in non-human primates, will be tried.

(RO1 HL-32505)

0 A research program is underway to assess the value of a battery of assays to

detect the carrier state of AIDS. These include tests for T-cell subsets

using 10 diverse monoclinal antibodies, measurement of antibodies to the
App. A—The Blood Resources Program, Division of Blood Diseases and Resources ● 199

three known types of HTLV, and measurement

will be followed prospectively for a three

(RO1 HL-32453)

0 A number of tests are being conducted that

of immune complexes. Study groups

year period.

include serological assays (thymosin,

microglobulin, alpha interferon, anti-HTLV, anti-HB core antigen and anti-CMV)

and cell marker assays (helper T cells, suppressor T cells, B cells, natural

killer cells, monocytes, DR-antigen-positive cells, and surface imnunoglobulin

positive cells) in an attempt to discriminate between healthy individuals

and those who are asymptomatic carriers of AIDS.

(ROl HL-32477)

0 Methods are being developed that would make biological assays of human alpha

interferon feasible for mass screening procedures. Studies will specifically

focus on the ability of these assays to detect asymptomatic carriers of AIDS.

(ROl HL-32473)

0 DNA hybridization procedures are being applied to the detection of viral

nucleic acid in lymphocytes of patients with AIDS, AIDS-related complex, homosexuals with immune abnormalities, and controls. Viruses to be studied

include CMV, EBV, and HTLV.

(RO1 HL-32471)

Donor safety is only now being viewed with any deqree of interest. Because of

th e proliferation of apheresls techniques and th e increasing use of single

donors to provide large quantities of a reagent, more information must be

developed on the threat that accompanies the loss of cellular or plasma

constituents and the hazards posed by th e repeated introduction of steroids

and colloids into the circulation of the donor.

0 A project concerned with the effects of cytapheresis on the lymphoid system

of donors is underway. This study deals with the short and long-tern effects

of repeated cytapheresis, particularly on the number, distribution, and

function of lymphocyte subpopulations.

(POl HL-09011)

APHERESIS

The technique of apheresis is being applied to many diverse clinical conditions.

Research in th e immediate future must deal with the development of new instrumentation, new immunoabsorbents, hazards to th e donor, th e clinical eff lcacy

of newly emerging treatment strategies, and cost-benefit ratios of its largescale use.
200 . Blood Policy and Technology

0 In a study of methods to reverse platelet alloimmunization, therapeutic

apheresis and immunoabsorbant columns are being used to remove platelet

alloantibodies.

(RO1 HL-28880)

IMMUNOLOGY

Although immunologic investigation is important in many of the topics already

mentioned, new concepts are being associated with transfusions and specific

lood cell antigens in organ transplantation. In addition, further work is

needed on the use of extracorporeal systems to treat bl ood and bone marrow

BLOOD SUBSTITUTES

The clinical evaluation of existinq and newly formulated perfluorochemicals

represents an immediate chall enge for the lood transfusion specialist. Although

add itional perfluorochemical reagents are being developed and new surfactants

are being devised, research with other oxygen-carrying solutions should be

pursued.

0 In an ongoing study, investigators are testing hemosomes, which are stroma-free

hemoglobin solutions encapsulated in artificial phospholipid membranes, as

red cell substitutes. Sterile hemosomes are being produced in sufficient

quantities for safety and efficacy tests in laboratory animals.

(RO1 HL-28595)

0 New red cell substitutes, utilizing hemoglobin bound to polymeric compounds,

are being synthesized and tested for safety and efficacy in laboratory

animals. The polymeric compounds such as hydroxyethyl starch or dextran

are coupled to hemoglobin to increase the circulatory dwell time of the

oxygen-carrier in the circulation.

(RO1 HL-25955)

0 Investigators are determining oxidation-reduction equilibria of hemoglobin

covalently modified with various organic phosphates. These studies will

provide new information on modifiedimportance as red cell substitutes.

(ROl HL-30850)

0 Investigators are exploring the use

solutions and perfluorochemical red

moderate and severe anemia.

(RO1 HL 30113)

hemoglobins which are of potential

of tetrameric and Polymerized hemoglobin

cell substitutes in the treatment of

0 .A perfluorochemical emulsion is being used to obtain hemoglobin-free rat

neural tissue preparations that will permit characterization of cerebral
App. A—The Blood Resources Program, Division of Blood Diseases and Resources • 201

intramitochondrial respiratory chain function in situ. The 1ong-term

objective of this project is to evaluate the potential therapeutic effectiveness of perfluorochemicals to prevent or reduce central nervous system

metabolic damage caused by cerebrovascular pathology.

(RO1 HL 301OO)

0 Investigators are using perfluorochemical emulsions of defined particle size

as models of platelets and chylomicra in order to determine their distribution

near the wall of microcirculatory vessels. This work combines methods of

rheology, transport phenomena, and circulatory physiology. Its aim is to

obtain a comprehensive rheologic picture of blood cell effects in flowing

blood.

0 Investigators are studying the nuclear magnetic resonance (NMR) spectral

characteristics of new and promising perfluorochemicals. It is hypothesized

that perfluorochemical emulsions can accelerate the restoration of myocardial

function following coronary flow reduction and that imaging could be used

to monitor this process.

( The efficacy of a number of selected perfluorochemical s in the in vitro

perfusion of mammalian testis is being explored to determine the effect of

on these artificial oxygen carriers testosterone secretion.

(RO1~~ HL 30083)

CLINICAL TRIALS

Throughout the entire range of subjects in the blood resources area, the

need for controlled, statistically significant clinical trials repeatedly

surfaces. Clin ical indications for th e use of th e various blood fractions

must be better delineated, and the appropriate use of the resource must be

ascertained. Timely development of indications for the use of a product

will not only assure th e rapid application of techniques but also limit the

use of costly, ineffective treatment modalities popularized by anecdotal

reports and inadequate trials.

0 A multi-institutional clinical study is underway to evaluate the capacity

of intravenously administered CMV imnune globulin to protect high risk

prelature infants against CMV infection acquired by blood transfusion.

EDUCATION

The authors of this report make frequent reference to the need to develop

appropriate educational opportunities for users of blood fractions. In
202 ● Blood Policy and Technology

this summary, the importance of this plea to provide proper training for

hose who administer b lood is reemphasized, since both t ne success of

clinical care and the control of health care costs are intimately related

to t he appropriate use of this vital resource. In addition, t he factors

th at motivate or inhibit blood donors should be investigated, inasmuch as

an understanding and sympathetic public is necessary for an adequate supply

of blood.

0 In September, 1984, the NHLBI and the FDA will cosponsor an NIH Consensus

Develo ment Conference entitled, “Fresh Frozen Plasma: P

Indications and

Risks.’

0 In 1983, the NHLBI implemented the Transfusion Medicine Academic Award.

This program provides for the integration of educational programs in transfusion medicine into the medical school curriculum. The program will be

announced each year until needs in transfusion medicine are fulfilled.

“Transfusion Medicine” is defined as a multidisciplinary area concerned with

the proper use or removal of blood and its components in the treatment or

prevention of disease states (other than in renal hemodialysis).

KO7 HL-01252

K07 HL-01253

K07 HL-01258

K07 HL-01270

K07 HL-01274
Appendix B.—Glossary of Acronyms and Terms

Glossary of Acronyms

AABB

ABC

ABRA

ACT

ADP

AHF

AIDS

ALT

AMA

AMS

ARC

ASCP

ATIII

ATP

BTS

CBC

CCBC

cDNA

CDC

CFR

CMV

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

CPDA-1 –

CRC

DBDR

DHEW

DHHS

DNA

DRG

EBV

EIA

ELISA

FDA

FFP

GAO

HBIG

HBcAg

HBsAg

HCFA

HLA

HTLV

IATC

IRB

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

American Association of Blood

Banks

American Blood Commission

American Blood Resources

Association

American Council on

Transplantation

Adenosine Triphosphate

Antihemophilic Factor

Acquired Immunodeficiency

Syndrome

Alanine Aminotransferase

American Medical Association

Automated Microplate Systems

American Red Cross

American Society of Clinical

Pathologists

Antithrombin III

Adenosine Triphosphate

Blood Transfusion Service

Canadian Blood Committee

Council of Community Blood

Centers

Complementary DNA

Centers for Disease Control

Code of Federal Regulations

Cytomegalovirus

Citrate Phosphate Dextrose

Adenine-1

Canadian Red Cross

Division of Blood Diseases and

Resources (Division of NHLBI)

(See USDHEW)

(See USDHHS)

Deoxyribonucleic Acid

Diagnosis-Related Group

Epstein-Barr Virus

Enzyme Immunoassay

Enzyme-linked Immunosorbent Assay

Food and Drug Administration

Fresh-Frozen Plasma

General Accounting Office

Hepatitis B Immune Globulin

Hepatitis B Core Antigen

Hepatitis B Surface Antigen

Health Care Financing

Administration

Human Leukocyte Antigen

Human T-cell Lymphotropic Virus

Interagency Technical Committee

Institutional Review Board

ISBT

ISG

IVGG

JCAH

KS

mRNA

MWBB

MW

NANB

NBP

NCI

NHF

NHLBI

NIAID

NIH

NRDC

NSA

NTIS

NYBC

OoB

OTA

PA

PAF

PCP

PFC

PPF

PTC

RBC

RES

RHo(D)

RIA

RNA

RSA

SBB

SFBS

STS

T&S

UAGA

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

.

—

—

—

—

USDHEW –

USDHHS –

VZIG –

WHO –

International Society of Blood

Transfusion

Immune Serum Globulin

intravenous Gamma Globulin

Joint Commission on the

Accreditation of Hospitals

Kaposi’s Sarcoma

Messenger RNA

Metropolitan Washington Blood

Bank

Molecular Weight

Non-A, Non-B Hepatitis

National Blood Policy

National Cancer Institute

National Hemophilia Foundation

National Heart, Lung, and Blood

Institute

National Institute of Allergies and

Infectious Diseases

National Institutes of Health

National Research and

Demonstration Center

Normal Serum Albumin

National Technical Information

Service

New York Blood Center

Office of Biologics Research and

Review

Office of Technology Assessment

Plasminogen Activator

Platelet Activating Factor

Pneumocystis Carinii Pneumonia

Perfluorochemicals

Plasma Protein Fraction

Prothrombin Complex

Red Blood Cells

Reticuloendothelial System

Anti-Rh Antigen Immune Globulin

Radioimmunoassays

Ribonucleic Acid

Resource Sharing Agreement

Specialist in Blood Banking

South Florida Blood Service

Serological Test for Syphilis

Type-and-Screen

Uniform Anatomical Gifts Act

U.S. Department of Health,

Education and Welfare

U.S. Department of Health and

Human Services

Varicella Zoster Immune Globulin

World Health Organization

203
204 ● Blood Policy and Technology

Glossary of Terms

ABO blood group: The major human blood type

determined by the presence or absence of two antigenic structures, A and B, on red blood cells, consisting of four blood types (A, B, AB, and O).

Acquired immunodeficiency syndrome (AIDS): A disease believed to be of viral origin (human T-cell

lymphotropic virus, type III) and characterized by

a deficiency of the immune system, that is complicated by infections caused by organisms that usually do not produce infections in individuals with

normal immunity and/or by the development of a

rare type of cancer (Kaposi’s sarcoma) usually seen

in the elderly or in individuals who are severely immunocompromised from other causes.

Agglutination: A reaction in which particles (e.g., red

blood cells or bacteria) suspended in a liquid collect into clumps and which occurs especially as a

serologic response to a specific antibody.

Albumin: A small protein, synthesized in the liver,

which is the principal protein in plasma and is important in maintaining plasma volume through

maintenance of an osmotic gradient between plasma

in the blood vessels and fluids in the surrounding

tissues. Albumin also serves as the carrier molecule

for fatty acids and other small molecules in plasma.

Allogeneic: Refers to individuals of the same species

who are sufficiently unlike genetically to interact

antigenically.

Alloimmunity: Development of immunity by one individual against the antigens of another individual

of the same species; for example, development of

anti-Rh antibodies in a Rh negative individual upon

infusion of R(h) positive blood.

Antibiotic: A chemical substance used against bacterial

infections which is produced by a micro-organism

and has the capacity to inhibit the growth of or to

kill other micro-organisms.

Antibody: A protein component of the immune system in mammals found in blood.

Antigen: A large molecule, usually a protein or carbohydrate, which when introduced into the body

stimulates the production of an antibody that will

react specifically with the antigen.

Antihemophilic factor (AHF) (or Factor VIII): A

plasma coagulation factor whose congenital deficiency results in the bleeding disorder known as hemophilia A.

Anti-inhibitor complex: An “activated” form of Factor IX concentrate, which is used in the treatment

of hemophilia A patients with inhibitors to Factor

VIII. (See also “Factor IX concentrate” and “concentrate.”)

Apheresis: A method of collecting individual components of blood instead of whole blood from the

donor; e.g., plasmapheresis, plateletapheresis.

Autologous donation: A blood donation that is stored

and reserved for return to the donor as needed, usually in elective surgery.

Bacillus subtilis: A common nonpathogenic, anaerobic soil bacterium that has been used industrially

for the large-scale production of proteins used in

detergents and in the processing of corn starch and

has attracted the attention of the recombinant DNA

industry because of its great biosynthetic capability.

Bacteria: Any of a group of microscopic organisms

having round, rodlike, spiral, or filamentous single

cell or noncellular bodies that are often aggregated

into colonies or motile by means of flagella, living

in soil, water, organic matter, or in the bodies of

plants and animals.

Bacteriophage: Any of various viruses that multiply

in bacteria. The bacteriophage, lambda, is commonly used as a vector in recombinant DNA

processes.

Biologics: Vaccines, therapeutic serums, toxoids, antitoxins, and analogous biological products used

against the agents of infectious diseases or their

harmful byproducts.

Biotechnology: Techniques that use living organisms,

or substances from such organisms, to make or

modify a product.

Blood: A complex liquid mixture of specialized cells

(white cells, red cells, and platelets), proteins and

other molecules, among whose functions are the

transport of oxygen and nutrients to body tissues,

removal of carbon dioxide and other wastes, transfer of hormonal messages between organs, prevention of bleeding, and transport of antibodies and

infection fighting cells to sites of infection.

Blood bank: General name for a facility or part of a

facility (e.g., a hospital) that stores blood and blood

components and which also may collect and process blood.

Blood cells: Erythrocytes (red blood cells), leukocytes

(white blood cells), or thrombocytes (platelets).

Blood center: A facility that provides a full range of

blood services, including the collection, testing,

processing, and distribution of blood and blood

products, to a particular geographic area (e.g., community or regional).

Blood components: Products separated from whole

blood; i.e., red cells, white cells, platelets and

plasma. Compare with “plasma derivatives.”

Bone marrow: A highly vascular, modified connective

tissue found in the long bones and certain flat bones

of vertebrates that is the origin of blood cells.
App. B—Glossary of Acronyms and Terms . 205

Cell line: Living cells obtained from humans and other

animals and which are cultured under special conditions so that they can multiply indefinitely in

vitro.

Centrifugation: The rapid whirling of fluids in a machine known as a centrifuge to separate substances

of different densities by centrifugal force.

Clone: A group of genetically identical cells or organisms produced asexually from a common ancestor.

(See also “recombinant DNA techniques.”)

Coagulation: The process of blood clotting, in which

the plasma protein prothrombin (Factor II) is converted to thrombin, which in turn converts the soluble plasma fibrinogen (Factor I) to insoluble fibrin.

Coagulation concentrates or complexes: Products obtained through selective precipitation of the proteins

in plasma, resulting in concentrated forms of the

plasma proteins that are needed for blood to coagulate (clot). Immune globulins and albumin are also

obtained in this manner. See also “cold ethanol

precipitation technique. ”

Coagulation factors or proteins: Naturally occurring

proteins in plasma (e.g., Factor VIII, Factor IX) that

aid in the coagulation of blood. See also “Factors

I-XII.”

Cold ethanol precipitation technique: The principal

method used to separate plasma into its major protein groups. A three-variable system (temperature,

ionic strength, and ethanol concentration (pH)) is

used to precipitate different proteins in the following order: Fraction I (chiefly Factor VIII and fibrinogen); Fraction II (the immune globulins); Fractions

III and IV (other coagulation proteins and trace

components); Fraction V (the albumins); and Fraction VI (the remaining residue).

Complementary DNA (cDNA): DNA that is complementary to messenger RNA; used for cloning or

as a probe in DNA hybridization studies.

Components: See “blood components. ”

Concentrates: In general, refers to blood cells or proteins that have been separated from the rest of blood

or plasma in concentrated form. For example, preparations of platelets that are separated from whole

blood after donation are called “platelet concentrates” (see also “coagulation concentrates”).

Cosmids: Genetic hybrids constructed from plasmids

and the bacteriophage, lambda, and used as vectors in DNA cloning.

Crosshatching: Testing to determine compatibility of

blood types between donor and recipient.

Cryoprecipitate: A precipitate that remains after blood

plasma has been frozen and then thawed. This

precipitate is rich in Factor VIII (antihemophilic factor), fibrinogen, and fibronectin.

Cytomegalovirus (CMV): One of a group of highly

host-specific herpes virus that infect man, monkeys,

or rodents, with the production of unique large cells

bearing intranuclear inclusions.

Diagnosis-related groups (DRGs): A classification system that groups patients according to principal diagnosis, presence or absence of a surgical procedure,

presence or absence of significant comorbidities or

complications, age, and other criteria; used as the

basis for Medicare’s current hospital payment

system.

DNA: Deoxyribonucleic acid.

Directed donations: Donations from identified individuals, such as family and friends, intended to

be used as the sole source of blood for the patient

for whom the donations were made.

Enzyme: Any of a group of catalytic proteins that are

produced by living cells and that mediate and promote the chemical processes of life without themselves being altered or destroyed.

Erythrocytes: Red blood cells.

Escherichia coli (E. coli): A species of bacteria that inhabits the intestinal tract of most vertebrates. Some

strains are pathogenic to humans and animals.

Many nonpathogenic strains are used as hosts in

recombinant DNA technologies.

Eukaryote: A cell or organism with membrane-bound,

structurally discrete nuclei and well-developed cell

organelles. Eukaryotes include all organisms except

viruses, bacteria, and blue-green algae. (Compare

with “prokaryote.”)

Exons: Fragments of eukaryotic genes which contain

the coding regions of DNA for gene expression. (See

also “introns. ”)

Factors I-XII: Refers to a classification of the multiple

factors involved in coagulation. For example, hemophilia A is a result of a deficiency in Factor VIII,

while hemophilia B is a deficiency in Factor IX.

Fibrinogen: Factor I; a plasma protein, synthesized in

the liver, which is involved in coagulation as the

precursor of fibrin,

Fibronectin: A plasma protein, synthesized in the liver,

which plays a variety of roles ranging from cell

adhesion to enhancing the phagocytic clearance of

particulate contaminants from the body.

Fractionation: See “plasma fractionation.”

Fresh frozen plasma (FFP): Plasma that has been frozen soon after collection to preserve the activity of

the coagulation proteins.

Gene: The basic unit of heredity; an ordered sequence

of nucleotide bases, comprising a segment of DNA.

A gene contains the sequence of DNA that encodes

one polypeptide chain (via RNA).

Gene expression: The mechanisms through which
206 • Blood Policy and Technology

directions contained within the genes that code for

the cell’s products are transferred and used to direct the production process.

Genome: The genetic material of an organism.

Glycosylation: The attachment of a carbohydrate molecule (glycogen) to another molecule such as a

protein.

Granulocytes: White blood cells (leukocytes) containing neutrophilic, basophilic, or eosinophilic granules in their cytoplasm; a term used to identify a

particular subset of white blood cells in one of several methods of classification.

Hemagglutination: Visual clumping of red blood cells;

refers to compatibility testing between donor and

recipient and observation of clumping from antibodies against the red blood cells. (See also “agglutination.”)

Hematocrit: The volume occupied by the cellular elements of blood in relation to the total volume.

Hematology: The science of blood, its nature, function, and diseases.

Hematopoiesis: The process by which the cellular elements of blood are formed.

Hemoglobin: The iron-containing, oxygen-carrying

proteins within red blood cells.

Hemolysis: The lysis, or destruction, of erythrocytes.

Hemolytic transfusion reaction: An antigen-antibody

reaction in the recipient of a blood transfusion that

results in the destruction of red blood cells.

Hemophilia: A rare, hereditary bleeding disorder

caused by a deficiency in the ability to synthesize

one or more of the coagulation proteins; e.g., Factor VIII (hemophilia A) or Factor IX (hemophilia B).

Hemorrhage: The escape of blood from the vascular

system.

Hemostasis: The arrest of a flow of blood or hemorrhage; stopping or slowing of blood circulation.

Hepatitis: Inflammation of the liver; may be due to

many causes, including viruses, several of which are

transmissible through blood transfusions.

Histocompatibility: The extent to which individuals

(or their tissues) are immunologically similar.

Hybridoma: Product of fusion between a myeloma cell

(which divides continuously in culture and is “immortal”) and a lymphocyte (antibody-producing

cell). Such cells are used to produce monoclinal antibodies.

Hyperimmune globulins: Immune globulin products,

derived from the plasma of donors hyperimmunized

against known antigens. An example is hyperimmune anti-Rh globulin for the prevention of hemolytic disease of newborns.

Immune globulins (immunoglobulins): A type of

plasma protein that comprises the antibodies.

Interferon: A class of glycoproteins (proteins with carbohydrate groups attached at specific locations) important in immune function and thought to inhibit

viral infections.

Introns: Fragments of eukaryotic genes that contain

the noncoding regions of DNA for gene expression.

In prokaryotes such as bacteria, genes do not consist of exons and introns but rather consist of a

single coding sequence of DNA.

In vitro: Literally, in glass; pertaining to a biological

reaction taking place in an artificial apparatus;

sometimes used to include the growth of cells from

multicellular organisms under cell culture conditions.

In vivo: Literally, in life; pertaining to a biological reaction taking place in a living cell or organism.

Lambda: A bacterial virus that infects E. coli; used as

a vector in gene cloning.

Leukocytes: White blood cells. Lymphocytes and

granulocytes are particular types of leukocytes.

Liposomes: Closed spheroidal vesicles composed of

lipid molecules arranged in a bilayer structure as

in a normal cell membrane and enclosing an aqueous

internal compartment.

Lymphocytes: Specialized white blood cells involved

in the immune response.

Lymphokines: Proteins that mediate interactions

among lymphocytes and are vital to proper immune

function.

Lyophilized: Freeze-dried.

Megakaryocytes: Precursors of platelets.

Messenger RNA (mRNA): RNA (ribonucleic acid) that

serves as the template for protein synthesis in living organisms; it carries the transcribed genetic code

from the DNA to the protein synthesizing complex

to direct protein synthesis.

Monoclinal antibodies: Homogeneous antibodies

derived from clones of a single cell, Monoclinal antibodies recognize only one chemical structure and

thus have remarkable specificity. They are easily

produced in large quantities and have a variety of

industrial and medical uses.

Nonreplacement fee: An additional fee that may be

charged to users of whole blood or red cells if no

replacement donations are made.

Normal serum albumin: Concentrates of albumin obtained through plasma fractionation and used to

maintain or restore plasma volume. The appropriateness of using albumin preparations instead of

other fluids is under examination. (See also “plasma

protein fraction.”)

Oligonucleotides: Short segments of DNA or RNA.

Oncotic (osmotic) pressure: The maximum pressure

that develops in a solution separated from a solvent

by a membrane permeable only to the solvent.

Perfluorochemicals (PFCs): Organic compounds in
App. B—Glossary of Acronyms and Terms ● 207

which all the hydrogen atoms have been replaced

by fluorine atoms and which are chemically inert

and not metabolized by the body.

Plasma: The liquid portion of blood, excluding the

cellular elements but including the proteins. (See

also “serum.”)

Plasma derivatives: Products derived from the fractionation of plasma to concentrate selected proteins.

Compare with “blood components. ”

Plasma fractionation: The separation of plasma into

its major proteins. (See also “cold ethanol precipitation techniques.”)

Plasma protein fraction (PPF): A product of plasma

fractionation that is at least 85 percent albumin and

used interchangeably with albumin preparations.

(See also “normal serum albumin.”)

Plasmapheresis: Collection of plasma. (See also

“apheresis. ”)

Plasmid: An extrachromosomal, self-replicating, circular segment of DNA found in the cytoplasm of

various strains of E. coli and other bacteria; used

as a vector in gene cloning in bacterial “host” cells.

Plasminogen activator: A substance that converts

plasminogen to plasmin, a proteolytic enzyme in

plasma which degrades the fibrin network in a

blood clot, leading to clot dissolution.

Platelets (thrombocytes): Cells (minute protoplasmic

disks) in blood which are involved in blood clotting.

Prokaryote: A cell or organism lacking membranebound, structurally discrete nuclei and organelles,

such as bacteria. (Compare with “eukaryote. ”)

Proteins: Polypeptides consisting of amino acids. In

their biologically active states, they function as

catalysts in metabolism and as structural elements

of cells and tissues.

Prothrombin: Factor II; an inactive plasma protein

precursor of thrombin.

Prothrombin complex (PTC): A product of plasma

fractionation consisting of Factors 11, VII, IX, and

X, but mostly Factor IX; also known as Factor IX

complex (concentrate). Used in the treatment of hemophilia B. An “activated” form of this concentrate

is used in the treatment of hemophilia A patients

with inhibitor to Factor VIII. (See also “anti-inhibitor complex.”)

Recombinant DNA (rDNA): The hybrid DNA produced by joining pieces of DNA from different

organisms.

Recombinant DNA techniques: Techniques that allow

specific segments of DNA to be isolated and inserted

into a bacterium or other host (e. g., yeast, mammalian cells) in a form that will allow the DNA segment to be replicated and expressed as the cellular

host multiplies. The DNA segment is said to be

“cloned” because it exists free of the rest of the DNA

of the organism from which it was derived. (See also

“cloned.”)

Recovered plasma: Plasma removed from outdated

blood or remaining after the cells have been removed but not frozen in time to preserve the

coagulation proteins; it is fractionated for the remaining proteins.

Red blood cells: The oxygen-carbon dioxide transporting cells of blood; erythrocytes.

Restriction enzymes (endonucleases): Enzymes that cut

DNA at specific nucleotide sequences.

Reticuloendothelial system (RES): A diffuse system of

cells arising from mesenchyme and comprising all

the phagocytic cells of the body except the circulating leukocytes.

Rh blood group: A major blood group consisting of

genetically determined substances present on the red

blood cells of most persons and of higher animals

and capable of inducing intense antigenic reactions.

(See also “ABO blood group.”)

Serum: The liquid portion of blood that remains when

blood clots, removing the cells and coagulation

proteins.

Source plasma: Plasma collected directly by plasmapheresis for fractionation into plasma derivatives.

Stem cells: Undifferentiated cells in the bone marrow

with the ability both to replicate and to differentiate into specific hematopoietic cell lines.

Thrombin: An enzyme which induces clotting by converting fibrinogen to fibrin; precursor form in blood

is prothrombin.

Thrombocytes: Platelets.

Typing and screening (T&S): Determining ABO and

Rh blood groups and screening of blood for unexpected antibodies prior to transfusion.

Vector: In recombinant DNA technology, refers to the

DNA molecule used to introduce foreign DNA into

host cells. Vectors include plasmids, bacteriophages

(viruses), and other forms of DNA. A vector must

be capable of replicating autonomously and must

have cloning sites for the introduction of foreign

DNA.

Viruses: A large group of submicroscopic agents capable of infecting plants, animals, and bacteria, and

characterized by a total dependence on living cells

for reproduction and by a lack of independent metabolism.

White blood cells: General description of specialized

cells involved in defending the body against invasion by organisms and chemical substances and including the circulating white blood cells and the cells

of the reticuloendothelial system; defenses mediated

through phagocytosis and immune responses;

leukocytes.
Appendix C.—Acknowledgments and

Health Program Advisory Committee

The staff would like to express its appreciation to

assistance.

Amoz Chernoff

National Institutes of Health

Bethesda, MD

Gilbert Clark

American Association of Blood Banks

Arlington, VA

Paul Cumming

American Red Cross

Washington, DC

Martin Davey

Canadian Red Cross

Toronto, Canada

Dennis Donohue

U.S. Food and Drug Administration

Bethesda, MD

Bernice Hemphill

Irwin Memorial Blood Bank

San Francisco, CA

Nancy Holland

American Blood Commission

Arlington, VA

the following people for providing information and

Robert Huitt

Council of Community Blood Centers

Falls Church, VA

Joan Maher

American Association of Blood Banks

Arlington, VA

Stephen Paik

Claremont College

Claremont, CA

Robert Reilly

American Blood Resources Association

Annapolis, MD

Joel Solomon

National Institutes of Health

Bethesda, MD

Chester Somerville

American Red Cross

Washington, DC

Jane Starkey

Council of Community Blood Centers

Falls Church, VA

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Index
—

Index

Alpha Therapeutics, 21

AIDS, 10-17, 37, 44, 99-107

directed donations, 17

evaluation of donor screening criteria, 14

identification of suspected AIDS-carrying

donors, 16

laboratory tests for AIDS, 16

alternatives and substitutes for blood products, 20

impact on consumers, 22

impact on the plasma derivatives industry, 21

impact on the voluntary whole blood sector, 22

alternative technologies, 133-172

alternative sources of blood products, 133-151

platelet substitutes, 150

liposomes as platelets, 151

red blood cell substitutes, 136

stem cell culturing, 134

hemoglobin solutions, 141

liposomes, 146

perfluorochemicals, 138

alternative source for plasma products—use of

recombinant DNA technology, 152-172

application of recombinant DNA technology

to large-scale production of plasmaproteins, 159

American Association of Blood Banks, 4, 9, 23,

35, 52, 54, 112

American Blood Commission (ABC), 3, 9, 24, 34,

55, 108

American Blood Resources Association (ABRA), 6

American Council on Transplantation, 187

American Red Cross (ARC), 4, 8, 9, 19, 23, 24,

35, 52, 53, 60, 61, 65, 114

appropriate use of blood products, 22

direct attempts to improve use, 23

indirect effects on improved use, 23

blood and blood products, 36-38

risks for donors, 39

blood services complex, 4, 51-75

commercial plasma and plasma derivatives

sector, 63-73

sources of raw plasma, 65

finished products licensed for use in the United

States, 67

coagulation factors, 69

costs of major plasma derivatives, 72

immune globulins, 70

normal serum albumin and plasma protein

fraction, 67

reagent products, 72

voluntary, whole blood, and blood components

sector, 51-62

blood collecting organizations, 52

blood collections in the voluntary sector, 57

costs of blood and blood components, 59

costs and charges for blood products, 59

blood technologies, 79-95

plasma fractionation technologies, 91

fractionation methods and products, 93

new and emerging technologies, 95

plasma collection, 91

technologies for blood collection and processing,

79-91

blood collection, 80

blood component preparation, 84

pre-transfusion testing techniques, 90

testing and labeling of blood from doctors, 85

containment of health care costs, 18

DRG method of payment, 19

financing of blood center operations, 19

supply and distribution systems, 20

coordination of blood resources, 23

American Blood Commission, 24

regionalization, 24

sharing and the blood credit system, 24

costs of blood products, 7, 17

Council of Community Blood Centers (CCBC), 4,

52, 54

current issues, 99-129

appropriate use of blood products, 121-129

albumin and plasma protein fraction, 126

cryoprecipitate, 125

Factor VIII, 127

fresh-frozen and single-donor plasma, 126

granulocytes, 125

methods to change usage patterns, 127

platelets, 124

red cell concentrates, 122

whole blood, 121

coordination of blood resources, 107-117

American Association of Blood Banks, 112

American Red Cross, 114

regionalization, 108

resource sharing, 111

volume of sharing, 115

impact of AIDS on blood collection and use,

99-107

impact of health care cost containment, 117-121

239
240 ● Blood Policy and Technology

Clearinghouse Lifeline Program, 111, 112, 113

Congress:

House Committee on Energy and Commerce, 4

Canadian Red Cross, 25

Centers for Disease Control (CDC), 13, 41, 100

Department of the Army, 44

Department of Health and Human Services

(DHHS), 3, 14, 15, 33, 43, 103

Department of Justice, 9, 111

diagnosis-related groups (DRGs), 118

Factor VIII, 64, 72, 92, 93, 95, 101, 126, 127, 164,

165

Factor IX Complex, 95, 101

Federal activities, 41-48

Food and Drug Administration (FDA), 45-47

National Institutes of Health (NIH), 43

payment for blood products and services, 42

Health Care Financing Administration, 42

payment for hemophilia care, 43

Food and Drug Administration (FDA), 5, 10, 12,

13, 15, 33, 34, 41, 45, 100, 103

future directions, 175-188

organ and tissue banking, 181

American Council on Transportation, 187

compatibility, 186

current scene, 182

procurement system, 183

supply and demand, 184

voluntary v. commercial approaches, 175-181

prospects for further voluntary sector

involvement in plasma operations, 179

voluntary efforts in the plasma sector, 176

Genentech, 20

General Accounting Office (GAO), 35, 36, 59

Genetics Institute, 20

Green Cross of Japan, 21

Gulf Coast Regional Blood Center, 62, 107

Hastings Center, 16

Health Care Financing Administration (HCFA), 36,

41, 42, 59, 120

history of’ Federal interest, 33-36

Irwin Memorial Blood Bank, 14, 104

issues, 12

League of Red Cross Societies, 40

legislation:

National Heart Act, 43

National Heart, Blood Vessel, Lung, and Blood

Act of 1972, 43

Public Health Service Act of 1975 (Public Law

9443), 34, 43

Senate Bill, S. 140, 35

Senate Bill, S. 1610, 35

Social Security Amendments of 1983, 41

Massachusetts Biologics Laboratory, 9

Mississippi Blood Services (MBS), 62

National Blood Policy (NBP), 3, 12, 33

National Cancer Institute, 43

National Gay Task Force, 13, 100

National Heart, Lung, and Blood Institute, 16, 33,

34, 36, 43, 44

National Hemophilia Foundation, 13, 101

National Institutes of Health (NIH), 13, 41, 43,

100

Netherlands Red Cross, 38

New York Blood Center, 5, 6, 9, 14, 52, 65, 109

Nixon, President Richard M., 33

Puget Sound Blood Center, 23

Rite-Aid Corp., 5

safety, 10

Stanford Medical Center, 11

Stanford University Blood Bank, 14

Titmuss, Prof. Richard, 33

Truman, President Harry S., 33

voluntary v. commercial blood sources, 25

World Health Organization (WHO), 40, 175