TH E MA N A G E M E N T

O F SI C K L E

CE L L DI S E A S E

N A T I O N A L I N S T I T U T E S O F H E A L T H

N A T IONAL HEART, LUNG, AND BLOOD INSTITUTE

Division of B l o o d D i s e a s e s a n d R e s o u r c e s

THE MANAGEMENT

OF SICKLE

CELL DISEASE

NATIONAL INSTITUTES

OF HEALTH

National Heart, Lung, 

and Blood Institute

Division of Blood Diseases 

and Resources

NIH PUBLICATION

NO. 02-2117

ORIGINALLY PRINTED 1984

PREVIOUSLY REVISED 1989, 1995

REPRINTED JUNE 1999

REVISED JUNE 2002

(FOURTH EDITION)
II
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

DIAGNOSIS AND COUNSELING

1. World Wide Web Resources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2. Neonatal Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

3. Sickle Cell Trait. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4. Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

HEALTH MAINTENANCE

5. Child Health Care Maintenance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

6. Adolescent Health Care and Transitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

7. Adult Health Care Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

8. Coordination of Care: Role of Mid-Level Practitioners . . . . . . . . . . . . . . . . . 47

9. Psychosocial Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

TREATMENT OF ACUTE AND CHRONIC COMPLICATIONS

10. Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

11. Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

12. Transient Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

13. Stroke and Central Nervous System Disease . . . . . . . . . . . . . . . . . . . . . . . . . 83

14. Sickle Cell Eye Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

15. Cardiovascular Manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

16. Acute Chest Syndrome and Other Pulmonary Complications . . . . . . . . . . . 103

17. Gall Bladder and Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

III

CONTENTS
IV

18. Splenic Sequestration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

19. Renal Abnormalities in Sickle Cell Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 123

20. Priapism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

21. Bones and Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

22. Leg Ulcers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

SPECIAL TOPICS

23. Contraception and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

24. Anesthesia and Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

25. Transfusion, Iron Overload, and Chelation . . . . . . . . . . . . . . . . . . . . . . . . . 153

26. Fetal Hemoglobin Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

27. Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

28. Genetic Modulation of Phenotype by Epistatic Genes . . . . . . . . . . . . . . . . 173

29. Highlights from Federally Funded Studies. . . . . . . . . . . . . . . . . . . . . . . . . . 181
iduals with sickle cell disease and provides 

relevant online resources at the end of the

chapters, is to serve as an adjunct to recent

textbooks that delve more deeply into all

aspects of the disorder.

The authors hope that this book will be used

by medical students, house staff, general practitioners, specialists, nurses, social workers, psychologists, and other professionals as well as

the families and patients who are coping with

the complexities of sickle cell disease on a daily

basis. The book, any part of which can be

copied freely, will be placed on the National

Heart, Lung, and Blood Institute (NHLBI)

Web site and will be updated as needed.

Research is essential to provide the knowledge

required to improve the care of individuals

with sickle cell disease, but it is the physicians

and other health care personnel who must

ensure that the very best care is actually 

delivered to each child and adult who has 

this disorder. We hope that this book will 

help to achieve this goal.

Claude Lenfant, M.D.

Director, NHLBI

Enclosed is the fourth edition of a book that 

is dedicated to the medical and social issues of

individuals with sickle cell disease. This publication, which was developed by physicians,

nurses, psychologists, and social workers who

specialize in the care of children and adults

with sickle cell disease, describes the current

approach to counseling and also to management of many of the medical complications 

of sickle cell disease.

Each chapter was prepared by one or more

experts and then reviewed by several others 

in the field. Additional experts reviewed the

entire volume. This book is not the result of a

formalized consensus process but rather represents the efforts of those who have dedicated

their professional careers to the care of individuals with sickle cell disease. The names of

the authors, their affiliations, and their e-mail

addresses are listed in the front of the book. 

Multiple new therapies are now available for

children and adults with sickle cell disease,

and often the options to be chosen present 

a dilemma for both patients and physicians.

This book does not provide answers to many

of these newer questions but rather explains

the choices available. The book, which focuses

primarily on the basic management of indivV

PREFACE
VI
Henny Billett, M.D.

Director, Clinical Hematology

Albert Einstein College of Medicine

Comprehensive Sickle Cell Center

Montefiore Hospital Medical Center

111 East 210th Street

Bronx, NY 10467

Tel: (718) 920-7373

Fax: (718) 920-5095

E-mail: billett@aecom.yu.edu

E-mail: hbillett@montefiore.org

Carine Boehme, M.S.

Associate Professor

The Johns Hopkins University School of Medicine

CMSC Room 1004

600 North Wolfe Street

Baltimore, MD 21287-9278

Tel: (410) 955-0483

Fax: (410) 955-0484

E-mail: CBOEHM@jhmi.edu

Kenneth Bridges, M.D.

Associate Professor of Medicine

Director, Joint Center for Sickle Cell 

and Thrombosis and Hemostasis Disorders

Brigham and Women’s Hospital

Harvard Medical School

75 Francis Street

Boston, MA 02115

Tel: (617) 732-5842

Fax: (617) 975-0876

E-mail: kbridges@rics.bwh.harvard.edu

Robert Adams, M.D.

Associate Professor, Department of Neurology

Room HB-2060

Medical College of Georgia

Augusta, GA 30912

Tel: (706) 721-4670

Fax: (706) 721-6757

E-mail: rjadams@neuro.mcg.edu

Kenneth I. Ataga, M.D.

Division of Hematology/Oncology

CB# 7305, 3009 Old Clinic Building

University of North Carolina at Chapel Hill

Chapel Hill, NC 27599-7305

Tel: (919) 843-7708

E-mail: kataga@med.unc.edu

Harold Ballard, M.D.

Assistant Chief, Hematology Division

New York Veterans Administration

Medical Services, 12th Floor

New York, NY 10010

Tel: (212) 951-3484

Fax: (212) 951-5981

Lennette Benjamin, M.D.

Associate Professor of Medicine

Montefiore Hospital Medical Center

Comprehensive Sickle Cell Center

111 East 210th Street

Bronx, NY 10467-2490

Tel: (718) 920-7375

Fax: (718) 798-5095

E-mail: lbenja2725@aol.com

VII

CONTRIBUTORS
VIII

Joseph DeSimone, Ph.D.

Geneticist

VA West Side Medical Center

Hematology Research (151C)

820 South Damen Avenue

Chicago, IL 60612

Tel: (312) 666-6500 x2683

Fax: (312) 455-5877

E-mail: Jdesimon@UIC.edu

Ann Earles, R.N., P.N.P.

Research Nurse

Children’s Hospital of Oakland

747 52nd Street

Oakland, CA 94609-1809

Tel: (510) 428-3453

Fax: (510) 450-5635

E-mail: aearles@mail.cho.org

James Eckman, M.D.

Professor of Medicine

Emory University School of Medicine

69 Butler Street

Atlanta, GA 30303

Tel: (404) 616-5982

Fax: (404) 577-9107

E-mail: jeckman@emory.edu

Morton Goldberg, M.D.

Director, Department of Ophthalmology

The Johns Hopkins Hospital

The Wilmer Ophthamological Institute

Maumanee Building, Room 729

600 North Wolfe Street

Baltimore, MD 21287-9278

Tel: (410) 955-6846

Fax: (410) 955-0675

E-mail: mgoldbrg@jhmi.edu

Harry E. Jergesen, M.D.

Department of Orthopaedic Surgery

University of California, San Francisco

500 Parnassus Avenue, MU-320W

San Francisco, CA 94143

Tel: (415) 476-8938

Fax: (415) 476-1301

E-mail: jergesen@orthosurg.ucsf.edu

Oswaldo Castro, M.D.

Professor of Medicine/Pediatrics

Howard University School of Medicine

Comprehensive Sickle Cell Center

2121 Georgia Avenue, NW

Washington DC 20059

Tel: (202) 806-7930

Fax: (202) 806-4517

E-mail: olcastro@aol.com

Samuel Charache, M.D.

2006 South Road

Baltimore, MD 21209-4510

Tel: (410) 466-6405

Fax: (410) 466-4330

E-mail: scharach@erols.com

Wesley Covitz, M.D.

Professor of Pediatrics

Wake Forest School of Medicine

Medical Center Boulevard

Winston-Salem, NC 27157-1081

Tel: (336) 716-4267

Fax: (336) 716-0533

E-mail: wcovitz@wfubmc.edu

Gary R. Cutter, Ph.D.

Professor of Medicine

Director, Center for Research Design 

and Statistical Methods

UNR School of Medicine, Mail Stop 199

Reno, Nevada 89557

Tel: (775) 784-1565 

Fax: (775) 784-1142

E-mail: cutterg@prodigy.net

Carlton Dampier, M.D.

Director, Marian Anderson SCC

Hematology/Oncology

St. Christopher’s Hospital for Children

Erie Avenue at Front Street

Philadelphia, PA 19134

Tel: (215) 427-5096

Fax: (215) 427-6684

E-mail: carlton.dampier@tenethealthcare.com
IX

Cage Johnson, M.D.

Professor of Medicine

University of Southern California

2025 Zonal Avenue

Los Angeles, CA 90033

Tel: (323) 442-1259

Fax: (323) 442-1255

E-mail: cagejohn@hsc.usc.edu

Adrena Johnson-Telfair, P.A.C.

Associate Director for Clinical Services

University of Alabama at Birmingham

Comprehensive Sickle Cell Center

1900 University Boulevard 

513 Tinsley Harrison

Birmingham, AL 35294-0006

Tel: (205) 975-2281

Fax: (205) 975-5264

E-mail: ajtelfair@hotmail.com

Clinton Joiner, M.D., Ph.D.

Associate Professor of Pediatrics

Director, Comprehensive Sickle Cell Center

Children’s Hospital Medical Center

3333 Burnett Avenue, OSB 4

Cincinnati, OH 45229-3039

Tel: (513) 636-4541

Fax: (513) 636-5562

E-mail: clinton.joiner@chmcc.org

John Kark, M.D.

Professor, Hematology/Oncology

Howard University Hospital

5145 Tower Building

2041 Georgia Avenue, NW

Washington, DC 20060

Tel: (202) 865-1511

Fax: (202) 865-4607

E-mail: vkark@adventisthealthcare.com

Mabel Koshy, M.D.

University of Illinois

840 South Wood Street

MSC 787, Room 833

Chicago, IL 60612

Tel: (312) 996-5680

Fax: (312) 996-5984

Peter Lane, M.D.

Director, Colorado Sickle Cell Treatment 

and Research Center

Campus Box C-222

University of Colorado Health Sciences Center

4200 East Ninth Avenue

Denver, CO 80262

Tel: (303) 372-9070

Fax: (303) 372-9161

E-mail: Peter.Lane@uchsc.edu

Dimitris Loukopoulos, M.D., D.Sci.

First Department of Medicine

University of Athens School of Medicine

Laikon Hospital

Athens 11527 GREECE

Tel: +30 1 7771 161

Fax: +30 1 7295 065

E-mail: dloukop@otenet.gr

Bertram Lubin, M.D.

Director of Medical Research

Children’s Hospital Oakland Research Institute

5700 Martin Luther King Junior Way

Oakland, CA 94609

Tel: (510) 450-7601

Fax: (510) 450-7910

E-mail: blubin@chori.org

Elysse Mandell, M.S.N.

Division of Hematology

Brigham and Women’s Hospital

75 Francis Street

Boston, MA 02115

Tel: (617) 732-8485

Fax: (617) 975-0876

E-mail: emandell@partners.org

Vipul Mankad, M.D. 

Professor and Chairman

Kentucky Clinic, Room J406

University of Kentucky

Chandler Medical Center

Lexington, KY 40536-0284

Tel: (859) 323-5481

Fax: (859) 257-7706

E-mail: vnmank1@pop.uky.edu
X

Orah Platt, M.D.

Director, Department of Laboratory Medicine

Enders Research Building, Room 761

Children’s Hospital Medical Center

320 Longwood Avenue

Boston, MA 02146

Tel: (617) 355-6347

Fax: (617) 713-4347

E-mail: platt@tch.harvard.edu

Sonya Ross, B.S.

Director of Program Development

Sickle Cell Disease Association of America

P.O. Box 1956

Baltimore, MD 21203

Tel: (410) 363-7711

Fax: (410) 363-4052

E-mail: siross@sicklecelldisease.org

Frank Shafer, M.D.

St. Christopher’s Hospital for Children

Hematology/Oncology

Erie Avenue at Front Street

Philadelphia, PA 19134

Tel: (215) 427-4399

Fax: (215) 427-6684

E-mail: Frank.shafer@drexel.edu

Jeanne Smith, M.D.

Associate Professor of Clinical Research

Columbia University Comprehensive

Sickle Cell Center

Suite 6164

506 Lenox Avenue at 135th Street

New York, NY 10037

Tel: (212) 939-1701

Fax: (212) 939-1692

E-mail: mdjasmith@aol.com

Kim Smith-Whitley, M.D.

Associate Director for Clinic Sickle Cell Program

Children’s Hospital of Philadelphia

324 South 34th Street

Philadelphia, PA 19104

Tel: (215) 590-1662

Fax: (215) 590-5992

E-mail: whitleyk@e-mail.chop.edu

Marie Mann, M.D., M.P.H.

Deputy Chief, Genetic Services Branch

Maternal and Child Health Bureau

Health Resources and Services Administration

5600 Fishers Lane

Rockville, MD 20857

Tel: (301) 443-4925

Fax: (301) 443-8604

E-mail: Mmann@hrsa.gov

Ronald Nagel, M.D.

Head, Division of Hematology

Albert Einstein College of Medicine

1300 Morris Park Avenue

Bronx, NY 10461

Tel: (718) 430-2186

Fax: (718) 824-3153

E-mail: nagel@aecom.yu.edu

Ms. Kathy Norcott

Sickle Cell Disease Association of the Piedmont

P.O. Box 20964

Greensboro, NC 27420

Tel: (336) 274-1507 or (800) 733-8299

E-mail: knorcott@scdap.org

Kwaku Ohene-Frempong, M.D.

Director, Comprehensive Sickle Cell Center

Children’s Hospital of Philadelphia

324 South 34th Street and Civic Center Boulevard

Philadelphia, PA 19104

Tel: (215) 590-3423

Fax: (215) 590-3992

E-mail: ohene-frempong@email.chop.edu

Eugene Orringer, M.D.

Professor of Medicine

Director, Comprehensive Sickle Cell Program

University of North Carolina

125 MacNider Building

Chapel Hill, NC 27599-7000

Tel: (919) 843-9485

Fax: (919) 216-3602

E-mail: epo@med.unc.edu
XI

Martin Steinberg, M.D.

Director, Center for Excellence in Sickle Cell Disease

Boston Medical Center

88 East Newton Street

Boston, MA 02118

Tel: (617) 414-1020

Fax: (617) 414-1021

E-mail: msteinberg@medicine.bu.edu

Marie Stuart, M.D.

Professor of Pediatrics

Division of Pediatric Hematology

Thomas Jefferson University

1025 Walnut Street, Suite 727

Philadelphia, PA 19107

Tel: (215) 955-9820

Fax: (215) 955-8011

E-mail: Marie.Stuart@mail.tju.edu

Paul Swerdlow, M.D.

Director of Red Cell Disorders

Associate Professor, Wayne State University

Harper Hospital, 4 Brush South

Barbara Ann Karmanos Cancer Institute

3990 John R St.

Detroit, MI 48201

Tel: (313) 745-9669

Fax: (313) 993-0307

E-mail: swerdlow@Karmanos.org

Joseph Telfair, Dr.P.H., M.S.W., M.P.H.

Department of Maternal and Child Health

School of Public Health

University of Alabama at Birmingham

320 Royals Building

1665 University Boulevard

Birmingham, AL 35294-0022

Tel: (205) 934-1371

Fax: (205) 934-8248

E-mail: jtelfair@uab.edu

Tim Townes, Ph.D.

Professor, Department of Biochemistry 

and Molecular Genetics

Schools of Medicine and Dentistry

University of Alabama at Birmingham

BBRB 260

1530 3rd Avenue South

Birmingham, AL 35294-0022

Tel: (205) 934-5294

Fax: (205) 934-2889

E-mail: ttownes@bmg.bhs.uab.edu

Marsha Treadwell, Ph.D.

Hematology Behavioral Services Coordinator

Children’s Hospital Oakland

747 52nd Street

Oakland, CA 94609-1809

Tel: (510) 428-3356

Fax: (510) 428-3973

E-mail: MTreadwell@mail.cho.org

Elliott Vichinsky, M.D.

Division Head, Hematology/Oncology

Director, Comprehensive Sickle Cell Center

Children’s Hospital of Oakland

747 52nd Street

Oakland, CA 94609-1809

Tel: (510) 420-3651

Fax: (510) 450-5647

E-mail: evichinsky@mail.cho.org

Mark Walters, M.D.

Fred Hutchinson Cancer Research Center

100 Fairview Avenue North, C1-169

P.O. Box 10924

Seattle, WA 98109-1024

Tel: (206) 667-4103

Fax: (206) 667-6084

E-mail: mwalters@mail.cho.org

Winfred Wang, M.D.

Department of Hematology/Oncology

St. Jude’s Children’s Research Center

P.O. Box 318

32 North Lauderdale

Memphis, TN 38101

Tel: (901) 495-3497

Fax: (901) 521-9005

E-mail: winfred.wang@stjude.org
XII

Robert Yamashita, Ph.D.

Interdisciplinary Studies in Science and Society 

Liberal Studies Department

California State University

San Marcos, CA 92096-0001

Tel: (760) 750-4204

E-mail: yamashta@csusm.edu

NATIONAL INSTITUTES OF HEALTH

Barbara Alving, M.D.

Deputy Director

National Heart, Lung, and Blood Institute

Building 31, Room 5A47, MSC 2490

31 Center Drive

Bethesda, MD 20892-2490 

Tel: (301) 594-5171

Fax: (301) 402-0818

E-mail: alvingb@nih.gov

Griffin Rodgers, M.D.

Deputy Director

National Institute of Diabetes and Digestive 

Kidney Diseases

Building 31, Room 9A52, MSC 1822

31 Center Drive

Bethesda, MD 20892-1822

Tel: (301) 496-5741

Fax: (301) 402-2125

E-mail: rodgersg@extra.niddk.nih.gov

Henry Chang, M.D.

Health Scientist Administrator

Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950

Bethesda, MD 20892-7950

Tel: (301) 435-0065

Fax (301) 480-0867

E-mail: changh@nih.gov

Charles Peterson, M.D.

Director, Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950

Bethesda, MD 20892-7950

Tel: (301) 435-0080

Fax: (301) 480-0867

E-mail: petersoc@nih.gov

Russell Ware, M.D., Ph.D.

Professor of Pediatrics

Duke University Medical Center

Box 2916 DUMC

R-133 MSRB, Research Drive

Durham, NC 27710

Tel: (919) 684-5665

Fax: (919) 684-5752

E-mail: ware0005@mc.duke.edu

Doris Wethers, M.D.

1201 Cabrini Boulevard

Apartment #57

New York, NY 10033

Tel: (212) 928-2600

E-mail: dlwethers@earthlink.net

Charles Whitten, M.D.

President Emeritus, Sickle Cell Disease Association 

of America

Distinguished Professor of Pediatrics and Associate Dean

Wayne State University School of Medicine

Scott Hall, Room 1201

540 East Canfield Street

Detroit, MI 48201

Tel: (313) 577-1546

Fax: (313) 577-1330

E-mail: cwhitten@med.wayne.edu

Wanda Whitten-Shurney, M.D.

Attending Pediatrician

Children’s Hospital of Michigan

3901 Beaubien Boulevard

Detroit, MI 48201

Tel: (313) 745-5613

Fax: (313) 745-5237

E-mail: wshurney@dmc.org

Nevada Winrow, Ph.D.

Postdoctoral Fellow

9624 Devedente Drive

Owings Mills, MD 21117

Tel: (240) 601-8683

Fax: (410) 902-3457

E-mail: nwinrow@jhmi.edu
Petronella Barrow

Office Manager

Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950

Bethesda, MD 20892-7950

Tel: (301) 435-0080

Fax: (301) 480-0867

E-mail: barrowp@nih.gov

Kathy Brasier

Secretary

National Heart, Lung, and Blood Institute

Building 31, Room 5A47, MSC 2490

Bethesda, MD 20892-2490

Tel: (301) 496-1078

Fax: (301) 402-0818

E-mail: brasierk@nih.gov

Duane Bonds, M.D.

Health Scientist Administrator

Sickle Cell Disease Scientific Research Group

Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950

Bethesda, MD 20892-7950

Tel: (301) 435-0055

Fax: (301) 480-0868

E-mail: bondsd@nih.gov

Greg Evans, Ph.D.

Health Scientist Administrator

Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950

Bethesda, MD 20892-7950

Tel: (301) 435-0055

Fax: (301) 480-0868

E-mail: evansg@nih.gov

David Bodine, Ph.D.

Chief, Hematopoiesis Section

Genetics and Molecular Biology Branch

National Human Genome Research Institute, 

Building 49, Room 3W16, MSC 4442

Bethesda, MD 20892-4442

Tel: (301) 402-0902

Fax: (301) 402-4929

E-mail: tedyaz@nhgri.nih.gov

Jonelle Drugan, Ph.D.

Program Analyst

Office of Science and Technology

National Heart, Lung, and Blood Institute

Building 31, Room 5A06, MSC 2482

Bethesda, MD 20892-2482

Tel: (301) 402-3423

Fax: (301) 402-1056

E-mail: druganj@nih.gov

XIII
XIV
1

INTRODUCTION

pneumococcal vaccine developed after the

trial, which has not been tested formally in 

a sickle cell population. Earlier trial results

may be accepted, based on the assumption

that the change is small. 

In some cases, RCTs cannot be done satisfactorily (e.g., for ethical reasons, an insufficient

number of patients, or a lack of objective 

measures for sickle cell “crises”). Thus the 

bulk of clinical experience in SCD still

remains in the moderately strong and weaker

categories of evidence.

Not everyone has an efficacious outcome in 

a clinical trial, and the frequency of adverse

events, such as with long-term transfusion 

programs or hematopoietic transplants, might

not be considered. Thus, an assessment of 

benefit-to-risk ratio should enter into translation of evidence levels into practice recommendations. A final issue is that there may be two

alternative approaches that are competitive

(e.g., transfusions and hydroxyurea). In this

case the pros and cons of each course of treatment should be discussed with the patient.

This edition of The Management of Sickle 

Cell Disease (SCD) is organized into four

parts: Diagnosis and Counseling, Health

Maintenance, Treatment of Acute and Chronic

Complications, and Special Topics. The original intent was to incorporate evidence-based

medicine into each chapter, but there was 

variation among evidence-level scales, and

some authors felt recommendations could 

be made, based on accepted practice, without

formal trials in this rare disorder. 

The best evidence still is represented by randomized, controlled trials (RCTs), but variations exist in their design, conduct, endpoints,

and analyses. It should be emphasized that

selected people enter a trial, and results should

apply in practice specifically to populations

with the same characteristics as those in 

the trial. Randomization is used to reduce

imbalances between groups, but unexpected

factors sometimes may confound analysis or

interpretation. In addition, a trial may last

only a short period of time, but long-term

clinical implications may exist. Another issue

is treatment variation, for example, a new
Introduction

2

The practice guidelines best supported 

by scientific evidence are:

■ Penicillin prophylaxis prevents pneumococcal sepsis in children [evidence from

Prophylactic Penicillin Studies I and II

(PROPS I & II)].

■ Pneumococcal vaccine prevents 

pneumococcal infection in children.

■ In surgical settings, simple transfusions 

to increase hemoglobin (Hb) levels to 10

g/dL are as good as or safer than aggressive

transfusions to reduce sickle hemoglobin

(Hb S) levels to below 30 percent.

The following nomenclature, derived from the Council of Regional Networks for Genetic Services

(CORN) guidelines for the U.S. newborn screening system [Pass KA, Lane PA, Fernhoff PM, et al.

U.S. newborn screening system guidelines II: Follow-up of children, diagnosis, management, and 

evaluation. Statement of the Council of Regional Networks for Genetic Services (CORN). J Pediatr

2000;(4 Suppl):S1-46], is used throughout this book:

Genotype Full Name Abbreviation

βs / βs Sickle cell disease-SS SCD-SS

βs / βc Sickle cell disease-SC SCD-SC

βs / βo thalassemia Sickle cell disease-S βo thalassemia SCD-S βo thal

βs / β+ thalassemia Sickle cell disease-S β+ thalassemia SCD-S β+ thal

■ Transfusions to maintain a hematocrit 

of more than 36 percent do not reduce

complications of pregnancy.

■ Transfusions to reduce Hb S levels to

below 30 percent prevent strokes in children with high central nervous system

blood flow [evidence from the Stroke

Prevention Trial in Sickle Cell Anemia

(STOP I)].

■ Hydroxyurea decreases crises in patients

with severe sickle cell disease [evidence

from the Multicenter Study of Hydroxyurea

in Sickle Cell Anemia (MSH) trial].
3

DIAGNOSIS AND COUNSELING
4
SICKLE CELL AND GENETIC WEB SITES

Sickle Cell Disease Association of America (SCDAA)

http://www.sicklecelldisease.org 

A patient advocacy site with information for the public.

Center for Disease Control and Prevention: Hemoglobin S Allele and Sickle Cell Disease

http://www.cdc.gov/genomics/hugenet/reviews/sickle.htm

An excellent article about sickle cell genetics and epidemiology.

The Comprehensive Sickle Cell Centers

http://www.rhofed.com/sickle

A description of a major clinical research program supported by the NHLBI.

Harvard Sickle Cell Program

http://sickle.bwh.harvard.edu

A comprehensive source for information for patients and health care providers.

The Sickle Cell Information Center

http://www.emory.edu/PEDS/SICKLE 

A broad range of information for the public and professionals.

National Organization for Rare Disorders, Inc.

http://www.rarediseases.org 

A portal for all rare diseases.

ClinicalTrials.gov—Linking Patients to Medical Research 

http://www.clinicaltrials.gov

A search engine for clinical trials in different diseases. 

The National Newborn Screening and Genetics Resource Center (NNSGRC)

http://genes-r-us.uthscsa.edu

Information and resources for health professionals, the public health community, consumers 

and government officials.

Genetic Alliance

http://www.geneticalliance.org

A support organization for different genetic problems.

WORLD WIDE WEB RESOURCES 1

5
Chapter 1: World Wide Web Resources

6

REGIONAL GENETIC NETWORKS

Mid-Atlantic Regional Human Genetics Network (MARHGN)

http://www.pitt.edu/~marhgn/

Genetic services for Delaware, Maryland, New Jersey, Pennsylvania, Virginia, West Virginia, 

and the District of Columbia.

Mountain States Genetics Network

http://www.mostgene.org 

Genetic services for Arizona, Colorado, Montana, New Mexico, Utah, and Wyoming.

Pacific Northwest Regional Genetics Group (PacNoRGG)

http://mchneighborhood.ichp.edu/pacnorgg/

Genetic services for Alaska, Idaho, Oregon, and Washington. 

Southeastern Regional Genetics Group (SERGG)

http://www.emory.edu/PEDIATRICS/sergg/index.html

Genetic services for the Southeastern region: Alabama, Florida, Georgia, Kentucky, Louisiana,

Mississippi, North Carolina, South Carolina, and Tennessee.

Texas Genetics Network (TEXGENE)

http://www.tdh.state.tx.us/genetics/home.htm

Genetic services for Texas.
NEONATAL SCREENING 2

7

The sensitivity and specificity of current

screening methodology are excellent (11), but

neonatal screening systems are not foolproof.

A few infants, even in states with universal

screening, may not be screened. Other infants

with SCD may go undiscovered because of

extreme prematurity, blood transfusion prior

to screening, mislabeled specimens, clerical

errors in the laboratory, or the inability to

locate affected infants after discharge from 

the nursery (5,14,16-20). It is imperative that

all infants, including those born at home, be

screened and that the initial screening test

always be obtained prior to any blood transfusion, regardless of gestational or postnatal age.

Information requested on screening forms

should be recorded accurately and completely

to facilitate the followup of positive screening

tests and interpretation of results. In states

that have not yet implemented universal

screening, neonatal screening for SCD should

be requested for all high-risk infants (those 

of African, Mediterranean, Middle Eastern,

Indian, Caribbean, and South and Central

American ancestry). Any high-risk infant 

not screened at birth, or for whom neonatal

screening results cannot be documented,

should be screened for hemoglobinopathies

prior to 2 months of age.

Hemoglobins (Hb) identified by neonatal

screening are generally reported in order of

quantity. Because more fetal hemoglobin (Hb

F) than normal adult hemoglobin (Hb A) is

present at birth, most normal infants show 

Hb FA. Infants with hemoglobinopathies also

The demonstration in 1986 that prophylactic

penicillin markedly reduces the incidence of

pneumococcal sepsis (1) provided a powerful

incentive for the widespread implementation

of neonatal screening for sickle cell disease

(SCD) (2). Neonatal screening, when linked

to timely diagnostic testing, parental education, and comprehensive care, markedly

reduces morbidity and mortality from 

SCD in infancy and early childhood (2-11).

Approximately 2,000 infants with SCD are

identified annually by U.S. neonatal screening programs (12,13). Screening also identifies infants with other hemoglobinopathies,

hemoglobinopathy carriers, and in some

states, infants with α-thalassemia syndromes.

METHODS 

Forty-four states, the District of Columbia,

Puerto Rico, and the Virgin Islands currently

provide universal screening for SCD.

Screening is available by request in the other

six states. The majority of screening programs

use isoelectric focusing (IEF) of an eluate from

the dried blood spots that also are used to

screen for hypothyroidism, phenylketonuria,

and other disorders (13-15). A few programs

use high-performance liquid chromatography

(HPLC) or cellulose acetate electrophoresis as

the initial screening method. Most programs

retest abnormal screening specimens using 

a second, complementary electrophoretic 

technique, HPLC, immunologic tests, or

DNA-based assays (13-15).
Chapter 2: Neonatal Screening

8

show a predominance of Hb F at birth. Those

with SCD show Hb S in absence of Hb A

(FS), Hb S with another hemoglobin variant

(e.g., FSC, FSDPunjab), or a quantity of Hb S

greater then Hb A (FSA). Hundreds of other

Hb variants may also be identified. Most of

these variants are associated with few or no

clinical consequences, but some are associated

with significant anemia or other problems.

Many screening programs also detect and

report Hb Bart’s, indicative of α-thalassemia.

SICKLE CELL DISEASE 

As shown in table 1, a number of different

neonatal screening results may be indicative 

of sickle cell disease (14,21). Hb FS in infancy

is associated with a variety of genotypes with 

a wide range of clinical severity. Most infants

with screening results that show Hb FS have

SCD-SS, but other possible conditions include

sickle βo-thalassemia, sickle δβ-thalassemia,

and sickle HPFH. Some infants with sickle

β+-thalassemia also show FS screening results

when the quantity of Hb A at birth is insufficient for detection (22). The coinheritance of

α-thalassemia may complicate differentiation

of genotypes in some infants (23). For infants

with positive screening tests, confirmatory

testing of a second blood sample should be

accomplished by 2 months of age so that

parental education, prophylactic penicillin,

and comprehensive care can be promptly

implemented (11,14). In many states, confirmatory testing is provided by the screening

program using hemoglobin electrophoresis

(cellulose acetate and citrate agar), IEF,

HPLC, and/or DNA-based methods.

Solubility tests to detect Hb S are inappropriate screening or confirmatory tests, in part

because high levels of fetal hemoglobin (i.e.,

low concentrations of Hb S) give false-negative results in infants with SCD.

Hemolytic anemia and clinical signs and

symptoms of SCD are rare before 2 months 

of age and develop variably thereafter as Hb F

levels decline (table 1). Thus for infants with

an FS phenotype, serial complete blood counts

(CBCs) and reticulocyte counts may not clarify the diagnosis during early infancy, and testing of parents or DNA analysis may be helpful

in selected cases (14). In all cases, infants with

Hb FS should be started on prophylactic penicillin by 2 months of age, and parents should

be educated about the importance of urgent

medical evaluation and treatment for febrile

illness and for signs and symptoms indicative

of splenic sequestration (11,14).

Achieving an optimal outcome for each

affected infant is a significant public health

challenge. State public health agencies should

have a responsibility to ensure the availability,

quality, and integration of all five components

of the neonatal screening system: screening,

follow-up, diagnostic testing, disease management and treatment, and evaluation of the

entire system (12-15). To be beneficial,

screening, follow-up, and diagnosis of sickle

cell disease must be followed by prompt referral to knowledgeable providers of comprehensive care (2,11). Comprehensive care includes

ongoing patient and family education about

disease complications and treatment, diseasespecific health maintenance services including

pneumococcal immunizations and prophylactic penicillin, access to timely and appropriate

treatment of acute illness, nondirective genetic counseling, and psychosocial support (14).

The extent to which these services are provided directly by public health agencies or by

other clinics and providers will vary among

states and communities. However, all states

should have the responsibility to ensure 

that each infant and family with SCD 

receive appropriate services and to conduct 
9

Table 1. Sickle Hemoglobinopathies: Neonatal Screening and Diagnostic Test Results

Approx. Neonatal Hb separation

% of U.S. screening by 2 months Serial CBC, 

Disorder patients results1 of age1 reticulocytes Hematologic studies by 2 years 

MCV2 Hb A23 Hb F Hb F

(%) (%) distribution

SCD-SS 65 FS FS Hemolysis and anemia N or ↑4 <3.64 <25 Heterocellu

by 6-12 months

SCD-SC 25 FSC FSC Mild or no anemia N or ↓ NA5 <15 Not applica

by 2 years

SCD-S 8 FSA or FS7 FSA Mild or no anemia N or ↓ >3.6 <25 Not applica

β+ thal by 2 years

SCD-S 2 FS FS Hemolysis and anemia ↓ >3.6 <25 Heterocellul

βo thal by 6-12 months

SCD-S <1 FS FS Mild anemia by ↓ <2.5 <25 Heterocellul

δβ thal 2 yearsS HPFH <1 FS FS No hemolysis N or ↓ <2.5 <25 Pancellular 

or anemia

Hb = hemoglobin, MCV = mean cell volume, thal = thalassemia, N = normal, ↑ = increased, ↓ = decreased, HPFH = hereditary persistance of Hb F.

Table shows typical results—exceptions occur. Some rare genotypes (eg. SDPunjab, SO Arab, SC Harlem, S Lepore, SE) not included. 1. Hemoglobins reported in order of quantity (e.g. FSA = F>S>A).

2. Normal MCV: >70 at 6-12 months, >72 at 1-2 years.3. Hb A2 results vary somewhat depending on laboratory methodology.

4. Hb SS with co-existent α-thalassemia may show ↓MCV and Hb A2 >3.6 percent; however, neonatal screening results from such infants usually show H

5. Quantity of Hb A2 can not be measured by hemoglobin electrophoresis or column chromatography in presence of Hb C.6. Test not indicated.7. Quantity of Hb A at birth sometimes insufficient for detection. 
10

Chapter 2: Neonatal Screening

a continuing program of long-term followup

(12,14,15). Providers may be asked to supply

public health agencies with the followup data

needed for tracking and outcomes evaluation. 

OTHER HEMOGLOBINOPATHIES

As shown in table 2, neonatal screening identifies some infants with non-sickle hemoglobinopathies (14,25-30). Infants with Hb F

only may be normal infants who do not yet

show Hb A because of prematurity or may

have β-thalassemia major or another thalassemia syndrome. Infants without Hb A

need repeat testing to identify those with SCD

and other hemoglobinopathies. Homozygous

β-thalassemia may cause severe transfusiondependent anemia. Infants with FE [Hb F +

hemoglobin E (Hb E)] require family studies,

DNA analysis, or repeated hematologic evaluation during the first 1 to 2 years of life to differentiate homozygous Hb E, which is asymptomatic, from Hb E βo-thalassemia, which 

is variably severe (26-29). It is important 

to note that most infants with β-thalassemia 

syndromes (i.e., β-thalassemia minor and βthalassemia intermediate) are not identified 

by neonatal screening. 

ALPHA-THALASSEMIA 

SYNDROMES

The red cells of newborns with α-thalassemia

contain Hb Bart’s, a tetramer of γ-globin.

Many, but not all, neonatal screening programs

detect and report Hb Bart’s (14,25,31,32).

As shown in table 3, infants with Hb Bart’s 

at birth may be silent carriers or have α-thalassemia minor, Hb H disease, or Hb H

Constant Spring disease. Silent carriers, the

largest group with Hb Bart’s at birth, have 

a normal CBC. Persons with α-thalassemia

minor generally show a decreased mean cell

volume (MCV) with mild or no anemia.

Newborns with more than 10 percent hemoglobin Bart’s by IEF or more than 30 percent

hemoglobin Bart’s by HPLC or those who

develop more severe anemia need extensive

diagnostic testing and consultation with a

pediatric hematologist to accurately diagnose

and appropriately treat more serious forms 

of α-thalassemia such as Hb H disease or Hb

H Constant Spring disease (33). The identification of Hb Bart’s in Asian infants may have

important genetic implications because subsequent family testing may identify couples at

risk for pregnancies complicated by hydrops

fetalis (14,25,34).

CARRIERS OF 

HEMOGLOBIN VARIANTS

Approximately fifty infants who are carriers 

of hemoglobin variants (i.e., hemoglobin traits)

are identified for every one with SCD (14).

The screening laboratory can usually confirm

the carrier state by using a complementary

methodology. Some programs recommend

confirmation of carriers by testing a second

specimen from the infant.

Carriers are generally asymptomatic (table 4),

and thus identification is of no immediate

benefit to the infant. However, parents are

entitled to the information and can benefit

from knowing the child’s carrier status, in part

because the information may influence their

reproductive decision-making. Therefore, parents of infants who are detected to be carriers

through neonatal screening should be offered

education and testing for themselves and their

extended family (2,11,14). Such testing may

raise concerns about mistaken paternity and

should not be performed without prior discussion with the mother. Testing of potential carriers requires a CBC and hemoglobin separation by hemoglobin electrophoresis, IEF, or

HPLC. To identify those with β-thalassemia,
11

Table 2. Non-Sickle Hemoglobinopathies Identified by Neonatal Screening*

Screening Results Possible Condition Clinical Manifestations

F only Premature Infant Repeat screening necessary

Homozygous βο-thalassemia Severe thalassemia

FE EE Microcytosis with mild or no anemia

E βο-thalassemia Mild to severe anemia

FC CC Mild microcytic hemolytic anemia

C βο-thalassemia Mild microcytic hemolytic anemia

FCA C β+-thalassemia Mild microcytic hemolytic anemia

*Other, less common hemoglobins, also may be identified.

Table 3. Alpha-Thalassemia Syndromes Identified by Neonatal Screening

Screening Results Possible Condition Clinical Manifestations

FA+Bart’s α-thalassemia silent carrier Normal CBC

α-thalassemia minor Microcytosis with mild or no anemia

Hb H disease Mild to moderately severe 

microcytic hemolytic anemia

Hb H Constant Spring Moderately severe hemolytic anemia

FAS+Bart’s, α-thalassemia with Clinical manifestations, if any, depend on 

FAC+Bart’s, structural Hb variant the structural variant (e.g., Hb E) and severity

FAE+Bart’s, of α-thalassemia

FE+Bart’s
Table 4. Hemoglobinopathy Carriers Identified by Neonatal Screening 

Screening Results Possible Condition Clinical Manifestations

FAS Sickle cell trait Normal CBC

Generally asymptomatic (see chapter 3)

FAC Hb C carrier No anemia

Asymptomatic

FAE Hb E carrier Normal or slightly ↓ MCV without anemia

Asymptomatic

FA Other Other Hb variant carrier Depends on variant; most without clinical 

or hematologic manifestations

12

Chapter 2: Neonatal Screening

accurate quantitation of Hb A2 by column

chromatography or HPLC and of Hb F by

alkali denaturation, radial immune diffusion,

or HPLC is also needed if the MCV is borderline or decreased.

UNIDENTIFIED HEMOGLOBIN

VARIANTS

Many of the more than 600 known hemoglobin variants are detected by current neonatal

screening methods. Many are rare, and most

are not identifiable by neonatal screening or

clinical laboratories. Each year more than

10,000 infants with unidentified hemoglobin

variants are detected by U.S. neonatal screening

programs (13,35). The definitive identification

of these variants is accomplished for fewer

than 500 of these infants, in part because of

limited reference laboratory capacity. Most

infants are heterozygotes, and most will have

no clinical or hematologic manifestations.

However, some variants, particularly unstable

hemoglobins or those with altered oxygen

affinity, may be associated with clinical 

manifestations even in heterozygotes. Other

variants have no clinical consequences in 

heterozygous or homozygous individuals, but

may cause SCD when coinherited with Hb S,

and thus have potential clinical and genetic

implications (21).

Followup of these infants is problematic, 

in part because uncertainty may cause frustration and anxiety for parents and health care

providers. No national consensus has yet been

produced to guide neonatal screening programs and clinicians in the followup of infants

with unidentified hemoglobin variants. The

following approaches may be considered. If

the infant is a heterozygote (i.e., the quantity

of Hb A is equal to or greater than the quantity of the unidentified hemoglobin), the infant

is well (without anemia or neonatal jaundice),

and the family history is negative for anemia

or hemolysis, then no further hematologic

evaluation may be necessary. 

Alternatively, some recommend repeat IEF,

HPLC or hemoglobin electrophoresis and/or

obtaining a CBC, reticulocyte count, and

peripheral smear for red cell morphology

between 6 and 12 months of age. Fetal hemoglobin (γ−globin) variants disappear by 1 year

of age, and the absence of anemia or hemolysis
13

may be reassuring for parents of infants with

hemoglobin variants that persist (α- or β-globin variants). For some families, it may be

appropriate to offer hemoglobin electrophoresis,

IEF, or HPLC and/or CBC, blood smear, and

reticulocyte counts on parents. Infants with

clinical or laboratory evidence of hemolysis 

or abnormal oxygen affinity and those without

Hb A, especially compound heterozygotes

with Hb S, require definitive hemoglobin

identification (21,36,37). This may require

protein sequencing, DNA analysis, or HPLC

combined with electrospray mass spectrometry

in a specialized reference laboratory (38).

Identification of the hemoglobin variant to

clarify genetic risks should also be considered

for families in which another hemoglobin 

variant (e.g., Hb S) is present.

REFERENCES

1. Gaston MH, Verter JI, Woods G, et al. 

Prophylaxis with oral penicillin in children with

sickle cell anemia. A randomized trial. N Engl J

Med 1986;314:1593-9.

2. Consensus Development Panel, National 

Institutes of Health. Newborn screening for 

sickle cell disease and other hemoglobinopathies.

JAMA 1987;258:1205-9.

3. Powars D, Overturf G, Weiss J, et al.

Pneumococcal septicemia in children with 

sickle cell anemia. Changing trend of survival.

JAMA 1981;245:1839-42.

4. Vichinsky E, Hurst D, Earles A, et al. Newborn

screening for sickle cell disease: effect on mortality.

Pediatrics 1988;81:749-55.

5. Githens JH, Lane PA, McCurdy RS, et al.

Newborn screening for hemoglobinopathies in

Colorado. The first 10 years. Am J Dis Child 

1990;144:466-70.

6. Wong WY, Powars DR, Chan L, et al.

Polysaccharide encapsulated bacterial infection 

in sickle cell anemia: a thirty-year epidemiologic

experience. Am J Hematol 1992;39:176-82.

7. Lee A, Thomas P, Cupidore L, et al. Improved survival in homozygous sickle cell disease: lessons

from a cohort study. Br Med J 1995;311:1600-2.

8. Davis H, Schoendorf KC, Gergen PJ, et al.

National trends in the mortality of children with

sickle cell disease, 1968 through 1992. Am J Public

Health 1997;87:1317-22.

9. Mortality among children with sickle cell disease

identified by newborn screening during 1990-94

—California, Illinois, and New York. MMWR

1998;47:169-72.

10. Eckman JR, Dent D, Bender D, et al. Follow-up of

infants detected by newborn screening in Georgia,

Louisiana, and Mississippi (abstr). Proceedings of

the 14th National Neonatal Screening Symposium.

Association of Public Health Laboratories,

Washington DC, 1999.

11. Sickle Cell Disease Guideline Panel. Sickle Cell

Disease: Screening, Diagnosis, Management, and

Counseling in Newborns and Infants. Clinical

Practice Guideline No. 6. AHCRP Pub. No 93-0562.

Rockville, MD: Agency for Health Care Policy and

Research, Public Health Service, U.S. Department

of Health and Human Services. April 1993. 

12. AAP Newborn Screening Taskforce. Serving the

family from birth to the medical home. Newborn

screening: a blueprint for the future. Pediatrics

2000;106(Suppl):383-427.

13. The Council of Regional Networks for Genetics

Services (CORN). National Newborn Screening

Report—1992, CORN, Atlanta, December 1995.

14. Pass KA, Lane PA, Fernhoff PM, et al. U.S. newborn screening system guidelines II: follow-up of

children, diagnosis, management, and evaluation.

Statement of the Council of Regional Networks for

Genetic Services. J Pediatr 2000;137(Suppl):S1-46.

15. Eckman JR. Neonatal screening. In: Embury SH,

Hebbel RP, Mohandas N, et al., eds. Sickle Cell

Disease: Basic Principles and Clinical Practice. New

York: Raven Press, 1994:509-15.

16. Papadea C, Eckman JR, Kuehner RS, et al.

Comparison of liquid cord blood and filter 

paper spots for newborn hemoglobin screening:

laboratory and programmatic issues. Pediatrics

1994;93:427-32.

17. Lobel JS, Cameron BF, Johnson E, et al. Value of

screening umbilical cord blood for hemoglobinopathy. Pediatrics 1989;83:823-6.

18. Pass KA, Gauvreau AC, Schedlbauer L, et al.

Newborn screening for sickle cell disease in 

New York State: the first decade. In: Carter TP,

Willey AM, eds. Genetic Disease: Screening and

Management. New York: Alan R. Liss, 1986:359-72.
Chapter 2: Neonatal Screening

14

19. Miller ST, Stilerman TV, Rao SP, et al. Newborn

screening for sickle cell disease. When is

an infant “lost to follow-up?” Am J Dis Child

1990;144:1343-5.

20. Reed W, Lane PA, Lorey F, et al. Sickle-cell 

disease not identified by newborn screening

because of prior transfusion. J Pediatr

2000;136:248-50.

21. Shafer FE, Lorey F, Cunningham GC, et al.

Newborn screening for sickle cell disease: 4 

years of experience from California’s newborn

screening program. J Pediatr Hematol Oncol

1996;18:36-41.

22. Strickland DK, Ware RE, Kinney TR. Pitfalls 

in newborn hemoglobinopathy screening: 

failure to detect β+-thalassemia. J Pediatr

1995;127:304-8.

23. Adams JG. Clinical laboratory diagnosis. 

In: Embury SH, Hebbel RP, Mohandas N,

et al., eds. Sickle Cell Disease: Basic Principles 

and Clinical Practice. New York: Raven Press,

1994:457-68.

24. Update: Newborn screening for sickle cell disease

—California, Illinois, and New York, 1998.

MMWR 2000;49:729-31.

25. Dumars KW, Boehm C, Eckman JR, et al.

Practical guide to the diagnosis of thalassemia. 

Am J Med Genet 1996;62:29-37.

26. Lorey F. California newborn screening and the

impact of Asian immigration on thalassemia.

J Pediatr Hematol Oncol 1997;4:11-6.

27. Johnson JP, Vichinsky E, Hurst D, et al.

Differentiation of homozygous hemoglobin 

E from compound heterozygous hemoglobin 

Eβo-thalassemia by hemoglobin E mutation 

analysis. J Pediatr 1992;120:775-9.

28. Krishnamurti L, Chui DHK, Dallaire M, et al.

Coinheritance of α-thalassemia-1 and hemoglobin

E/βo-thalassemia: practical implications for neonatal screening and genetic conseling. J Pediatr 1998;

132:863-5.

29. Weatherall DJ. Hemoglobin E β-thalassemia: 

an increasingly common disease wih some 

diagnostic pit falls. J Pediatr 1998;132:765-7.

30. Olson JF, Ware RE, Schultz WH, et al.

Hemoglobin C disease in infancy and 

childhood. J Pediatr 1994;125:745-7.

31. Zwerdling T, Powell CD, Rucknagel D.

Correlation of α-thalassemia haplotype with 

detection of hemoglobin Bart’s in cord blood 

by cellulose acetate or isoelectric focusing.

Screening 1994;3:131-9.

32. Miller ST, Desai N, Pass KA, et al. A fast hemoglobin variant in newborn screening is associated with

α-thalassemia trait. Clin Pediatr 1997;36:75-8.

33. Styles LA, Foote DH, Kleman KM, et al.

Hemoglobin H-Constant Spring Disease: an 

under recognized, severe form of α-thalassemia.

Internat J Pediatr Hematol/Oncol 1997;4:69-74.

34. Chui DHK, Waye JS. Hydrops fetalis caused by 

α-thalassemia: an emerging health care problem.

Blood 1998;91:2213-22.

35. Council of Regional Networks for Genetic

Services, (CORN). Unknown hemoglobin variants

identified by newborn screening: CORN statement. CORN, Atlanta, 1999.

36. Lane PA, Witkowska HE, Falick AM, et al.

Hemoglobin D Ibadan-βo thalassemia: detection

by neonatal screening and confirmation by electrospray-ionization mass spectrometry. Am J Hemotol

1993;44:153-61.

37. Witkowska HE, Lubin BH, Beuzard Y, et al. Sickle

cell disease in a patient with sickle cell trait and

compound heterozygosity for hemoglobin S and

hemoglobin Quebec-Chori. N Engl J Med 1991;

325:1150-4.

38. Witkowska HE, Bitsch F, Shackleton CH.

Expediting rare variant hemoglobin characterization by combined HPLC/electrospray mass spectrometry. Hemoglobin 1993;17:227-42.
SICKLE CELL TRAIT 3

15

deprivation or intranasal DDAVP may be 

as low as 400 to 500 mOsm/kg. Coexistent 

α-thalassemia provides partial protection

against this urine-concentrating defect (2).

HEMATURIA

(ALSO SEE CHAPTER 19, RENAL ABNORMALITIES

IN SICKLE CELL DISEASE)

Necrosis of the renal papillae can result in

hematuria, which is usually microscopic. Gross

hematuria is occasionally provoked by heavy

exercise or occurs spontaneously. Individuals

with hematuria should be evaluated by a urologist, who will perform imaging studies as

needed to exclude neoplasms (3-5) or renal

stones or any related problems with flow of

urine from the calyces to the urethra. 

Individuals with acute episodes of gross hematuria are cautioned to avoid exercise but are

encouraged to continue to perform sedentary

work. They are encouraged to take fluids

(equivalent to half-normal saline) and may

also receive sodium bicarbonate 650 to 1,200

mg per day. If bleeding persists, an antifibrinolytic agent such as epsilon aminocaproic

acid (EACA) can be prescribed (6). In a controlled trial of individuals with SCT who had

hematuria, administration of EACA at an oral

dose of 6 to 8 grams daily in four to six divided doses caused resolution of hematuria at a

mean of 2.2±0.3 days, compared with 4.5±1.9

days for those individuals not receiving the

Individuals who have sickle cell trait (SCT) 

do not have vaso-occlusive symptoms under

physiologic conditions and have a normal life

expectancy. The inheritance of SCT should

have no impact on career choices or lifestyle.

SCT is found in 8 percent of African

Americans and is also prevalent in persons 

of Mediterranean, Middle Eastern, Indian,

Caribbean, and Central and South American

descent. Neonatal screening (chapter 2) will

provide early detection of SCT. This chapter

will discuss clinical syndromes associated with

SCT, some of which occur only under conditions of extreme physiologic stress.

EYE

TRAUMATIC HYPHEMA

The presence of SCT significantly alters the

management of traumatic hyphema, which is

discussed more fully in chapter 14, Sickle Cell

Eye Disease.

RENAL AND 

GENITOURINARY TRACT

HYPOSTHENURIA

Individuals with SCT can develop microscopic

infarction of the renal medulla, resulting in loss

of maximal urine concentrating ability; this

condition is present in most adults with SCT

(1). Maximum urine osmolality following fluid
Chapter 3: Sickle Cell Trait

16

drug (6). The authors reported a high incidence

of ureteral obstruction by clots accompanied

by flank pain (in 15 of 38 episodes with an

intravenous pyelogram [IVP]), which resolved

without specific therapy over 2 to 37 days.

However, ureteral obstruction by clot also

occurred at the same frequency in the absence

of EACA. Although the best dose and duration for use of EACA in treatment of hematuria related to SCT has not been adequately

investigated, one effective regimen is administration of 3 grams 3 or 4 times per day for 

1 week; in most patients, hematuria will

resolve after 2 to 3 days (7). In some individuals,

iron replacement and even transfusions may

be required.

Occasionally, bleeding is so brisk or persistent

that it is necessary to perform invasive surgery

to visualize bleeding sites, identify the pathology at those sites, and stop the bleeding by

local measures in order to save the kidney.

URINARY TRACT INFECTION

The frequency of urinary tract infection is

higher in women with SCT than in racially

matched controls, especially during pregnancy,

when the frequency is about double (8). The

presence of SCT in men was not associated

with increased frequency of urinary tract 

infection in a large study of patients in U.S.

Department of Veterans Affairs’ hospitals (9). 

AUTOSOMAL DOMINANT POLYCYSTIC

KIDNEY DISEASE

The incidence of end-stage renal failure from

this disorder is identical for Caucasians and

African Americans; however, the onset of 

end-stage renal failure occurs at an earlier 

age for individuals with SCT than for African

Americans without SCT (38 years versus 48

years [p<0.003]) (10).

COMPLICATIONS OF 

STRENUOUS EXERCISE

Risk factors for exercise-related death of young

adults with SCT include environmental heat

stress during the preceding 24 hours (11),

incomplete heat acclimation, wearing heatretaining clothing, dehydration, delay in

recognition or treatment of exertional heat 

illness, obesity with poor exercise fitness (12),

sustained heroic effort above customary activity, and inadequate sleep. Many of these factors

were present in military recruits under extreme

conditions of 8 weeks of physical training,

where the excess mortality rate for those with

SCT was 1 per 3300 in the late 1970’s (13).

The higher risk of exercise-related death is

attributed mainly to the intensity of new exercises or to sustained duration for which the

individual is unprepared. This higher risk is

eliminated by measures to prevent exertional

heat illness, which should be incorporated into

all intensive exercise programs and made available to all participants. 

SCT does not contraindicate participation in

competitive sports. In fact, many reports show

no increased morbidity or mortality for professional athletes with the trait (1) who stay fit

during the off-season. Prevention of exertional

heat illness requires hydration or similar measures for distance runners and military recruits

(1,14,15). Individuals should increase performance levels gradually, and training should

cease and restart slowly if myalgia occurs.

There is no requirement to screen for SCT

before participation in athletic programs.

SPLENIC INFARCTION

Splenic infarction usually presents as severe

abdominal pain localized within a few hours

to the left upper quadrant. It is best seen on 

a computerized tomography (CT) scan, which

may show a region of hemorrhage. An episode
17

of splenic infarction with SCT usually resolves

in 10 to 21 days and rarely requires surgical

intervention. Splenic infarction associated with

SCT may occur with hypoxemia from systemic

disease or from exercise at sea level or at high

altitude (1). Splenic infarction is associated

with flights in unpressurized aircraft at 15,000

feet or more but may occur rarely at mountain

altitudes higher than 6,000 feet above sea level.

The frequency seems to be disproportionately

greater in phenotypically non-African American

individuals (16), an observation that may be

due to reporting bias. Nevertheless, numerous

individuals with SCT have participated 

successfully in long-distance races in the

Cameroon and in high-altitude sports, including the Olympics in Mexico City. Thus, the

majority of people with SCT can travel safely

to mountain altitudes for recreational activities;

however, rare individuals who have had splenic

complications may risk recurrence. 

SURGERY AND OTHER 

MEDICAL CONDITIONS

Surgery is not likely to be complicated by 

the fact that an individual has SCT (17).

Individuals with SCT are not at increased 

risk for an adverse outcome from anesthesia,

and they are not limited in their choice of

anesthetic agents. There is no convincing 

evidence that SCT is associated with increased

frequency or severity of diabetic retinopathy,

stroke, myocardial infarction, leg ulcers, avascular necrosis and arthritis, or the bends due

to diving. Some case reports of possible associations of SCT with increased medical morbidity may represent situations in which other

variants of β- or α-globin chains produced

undiagnosed SCD (18). Rare cases may be

due to increased 2,3-DPG or altered oxygen

affinity, which might increase polymerization

of Hb S sufficiently to cause a phenotype of

SCT to behave like SCD (18,19).

EDUCATION AND 

GENETIC COUNSELING

All persons with SCT should be educated

about the inheritance of SCD and about the

availability of partner testing, genetic counseling, and prenatal diagnosis (see chapter 4).

REFERENCES

1. Kark JA, Ward FT. Exercise and hemoglobin S.

Semin Hematol 1994;31:181-225.

2. Gupta AK, Kirshner KA, Nicholson R, et al.

Effects of alpha-thalassemia and sickle

polymerization tendency on the urineconcentrating defect of individuals with SCT. 

J Clin Invest 1991;88:1963-8.

3. Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal

medullary carcinoma. The seventh sickle

cell nephropathy. Am J Surg Pathol 1995;19:1-11.

4. Avery RA, Harris JE, Davis CJ Jr, et al. Renal

medullary carcinoma: clinical and

therapeutic aspects of a newly described tumor.

Cancer 1996;78:128-32.

5. Baron BW, Mick R, Baron JM. Hematuria in 

sickle cell anemia—not always benign: evidence 

for excess frequency of sickle cell anemia in 

African Americans with renal cell carcinoma. 

Acta Haematol 1994;92:119-22.

6. Black WD, Hatch FE, Acchiardo S. Aminocaproic

acid in prolonged hematuria of patients with sicklemia. Arch Intern Med 1976;136:678-81.

7. McInnes BK III. The management of hematuria

associated with sickle hemoglobinopathies. J Urol

1980;124:171-4.

8. Pastore LM, Savitz DA, Thorp JM Jr. Predictors 

of urinary tract infection at the first prenatal visit.

Epidemiology 1999;10:282-7.

9. Heller P, Best WR, Nelson RB, et al. Clinical

implications of sickle-cell trait and glucose6-phosphate dehydrogenase deficiency in 

hospitalized black male patients. N Engl J Med

1979;300:1001-5.

10. Yium J, Gabow P, Johnson A, et al. Autosomal

dominant polycystic kidney disease in

blacks: clinical course and effects of sickle-cell

hemoglobin. J Am Soc Nephrol 1994;4:1670-4.

11. Kark JA, Burr PQ, Wenger CB, et al. Exertional

heat illness in Marine Corps recruit training. 

Aviat Space Environ Med 1996;67:354-60.
Chapter 3: Sickle Cell Trait

18

12. Gardner JW, Kark JA, Karnei K, et al. Risk factors

predicting exertional heat illness in male Marine

Corps recruits. Med Sci Sports Exerc 1996;28:939-44.

13. Kark JA, Posey DM, Schumacher HR, Ruehle CJ.

Sickle-cell trait as a risk factor for sudden death in

physical training. N Engl J Med 1987;317:781-7.

14. Armstrong LE, Epstein Y, Greenleaf JE, et al.

American College of Sports Medicine. Heat and

cold illnesses during distance running: American

College of Sports Medicine Position Stand. Med

Sci Sports Exerc 1996;28:(12):i-x.

15. Montain SJ, Latzka WA, Sawka MN. Fluid

replacement recommendations for training 

in hot weather. Mil Medicine 1999;164:502-8. 

16. Lane PA, Githens JH. Splenic syndrome at 

mountain altitudes and SCT. Its occurrence 

in non-black persons. JAMA 1985;253:2251-4.

17. Steinberg MH. Sickle Cell Trait. In: Steinberg

MH, Forget BG, Higgs DR, et al., eds. Disorders 

of Hemoglobin: Genetics, Pathophysiology and 

Clinical Management. Cambridge, UK: Cambridge

University Press, 2001:811-30.

18. Witkowska E, Lubin B, Beuzard Y, et al. Sickle cell

disease in a patient with SCT and compound

heterozygosity for hemoglobin S and hemoglobin

Quebec-Chori. N Engl J Med 1991;325:1150-4.

19. Cohen-Solal M, Prehu C, Wajcman H, et al. 

A new sickle cell disease phenotype associating 

Hb S trait, severe pyruvate kinase deficiency 

(PK Conakry), and an alpha2 globin gene variant

(Hb Conakry). Br J Haematol 1998;103:950-6.
GENETIC COUNSELING 4

19

CONTENT AND APPROACHES

Although there is basic information that all

counselees should receive, the goals are sufficiently different for the two groups, so that

there should be substantive differences in the

content and the approaches of the respective

counselors. An essential principle for each

counseling group is that advice, personal opinions, and societal positions must not be given

or implied. This admonition must be obeyed

strictly because, in each case, self-determination is the desired outcome. Counselors must

not influence decisions inappropriately—

overtly through statements or covertly 

through facial expressions, tone of voice, 

body language, etc.—particularly if asked, 

“What should I do?”

Since counseling goals are based entirely 

upon the principle of self-determination, and

are not intended to be preventive, the counselor’s success is not determined by a decline

in the incidence of sickle cell disease (SCD)

but the extent to which informed self-interest

decisions are made.

BASIC CONTENT FOR ALL SESSIONS

■ Purpose and goal of the session

■ How sickle cell conditions are acquired—

genetic basis

■ Difference between SCT and SCD

■ Health problems that can occur in SCD

Sickle cell trait (SCT) is not considered to 

be a health problem, but individuals who test

positive should be informed about the implications for their health and family planning.

Thus, the primary issues addressed in this

chapter are what information should individuals receive, and who should provide it (1-8).

Despite mandatory newborn screening programs implemented in most states by 1991,

children with SCT may not recall or understand the implications by the time they reach

childbearing age. Currently, there are two

major circumstances in which adults will 

learn that they have SCT, leading to two

groups of counselees:

1. Parents of a child with SCT. When a 

newborn with SCT is identified through

screening, at least one of the parents will

have SCT.

2. Pregnant women. During prenatal care,

women from racial groups with a high

prevalence of the sickle cell gene frequently are tested for the gene.

SCT counseling has two components—education and decision-making—but the emphasis

differs in the two cases above. For the first

group, the focus is on education, that is, to

enable individuals to make informed decisions,

in their own interest, about future family

planning. For the second group, the focus is

on education and informed decisions, in their

best interest, about the current pregnancy.
Chapter 4: Genetic Counseling

20

■ Variability of and inability to predict

occurrence and frequency of health 

problems in SCD

■ Potential outcome of each pregnancy 

if one or both partners has SCT

■ Family planning options

■ Racial groups who have SCD and the 

percent of individuals in the counselee’s

racial group who have SCT and SCD

■ Average life span of individuals with 

SCT and SCD

ADDITIONAL CONTENT

FOR PREGNANCY OUTCOME

DECISIONMAKING SESSIONS

There are several noncognitive factors that

pregnant women (and the fathers) may wish

to consider in order to reach a decision consistent with the goal. These factors include:

■ Coping skills relative to a child with 

a serious illness 

■ Personal and cultural values relative 

to childbearing

■ Religious beliefs 

■ The need and desire to have children

■ Feelings and attitudes about abortion

■ Belief about self-determination versus 

fate as determinants of adverse events

INSTRUCTIONAL/EDUCATIONAL

TECHNIQUES

■ Use lay language whenever possible.

■ Translate scientific terms into common

everyday usage whenever possible.

■ Use graphics to illustrate key points.

■ Establish a dialogue rather than using 

a strict lecture format or informationgiving format.

■ Implement a pre- and postassessment.

■ Use the postassessment as an opportunity

to clarify misinterpretation or uncertainties that the genetic test revealed.

■ Provide literature written in lay language

covering the essential facts.

■ Make available sources of more detailed

information for those who are interested.

■ Communicate the availability of the

provider for followup questions.

■ Follow a structured protocol to ensure that

the essential features are covered. This

should not prevent interaction.

WHO SHOULD COUNSEL

Ideally, the first group should be counseled 

by geneticists and genetic counselors with

master’s degrees who have been certified by

the American Board of Medical Genetics or

the American Board of Genetic Counselors.

However, the number to be counseled far

exceeds the supply and the availability of these

professionals. Thus, there has been a need to

train others to provide this service. This can

be achieved with laypersons and paraprofessionals (2,4). Individuals selected for this 

task must possess certain personal qualities,

including good communication skills, an

engaging personality, and the discipline to

limit information transmission to what has

been approved for them to provide. Several

training programs offer certification for all

comers; however, there is no statewide or

national requirement for certification. 

It is not sufficient to have trained and certified

counselors. Since certification simply means

that individuals are qualified, they should be

periodically monitored to see if they consistently follow the protocol. In one program 

this is achieved by audiotaping all sessions and
21

randomly selecting tapes for review and critique (4). Other procedures are to conduct

postsession interviews with counseled individuals, or to periodically schedule sessions with 

a trained, knowledgeable, simulated counselee

(preferably without the counselor’s awareness).

Ideally, individuals who are trained to provide

services for the first group should be titled

“sickle cell educators” rather than “sickle 

cell counselors” because the term counseling

implies assisting individuals to make decisions, which is not their role. The individuals

who are trained to provide services for the

second group are indeed counselors. The use

of the title counselors for the first group is 

so traditional that changing the title will not

occur, but the distinction is worth noting.

The second group should be counseled only

by individuals specifically trained to assist

individuals to make psychosocial decisions.

This includes geneticists, master’s degree

genetic counselors, social workers, and psychologists. The latter two, of course, would

have to be “sickle cell educated.”

MINIMAL ACCEPTABLE

ACHIEVEMENTS

For the first group, the interest in being counseled and the information of personal value is

so highly variable it is desirable to have a minimal acceptable achievement level in a basic

counseling session. For example, the counselee

should understand:

■ The family planning options open 

to persons with SCT.

■ SCT is not an illness, so no restrictions

need to be placed on his or her activities.

■ The variability in severity of SCD.

■ Both parents must have the trait for 

the child to have SCD. 

■ The 25 percent chance that each pregnancy will result in a child with SCD if both 

parents have the trait.

■ Some of the reasons couples might decide

to have or not have children if both have

the trait.

SCT COUNSELOR 

TRAINING PROGRAMS

University of South Alabama

1433 Springhill Avenue

Mobile, Alabama 36604

Contact Person: Linda Jones 

(334) 432-0301

Texas Department of Health

1100 West 49th

Austin, Texas 78756

Contact Person: Mae Wilborn 

(512) 458-7111 x2071

Cincinnati Comprehensive Sickle Cell Center

3333 Burnet Avenue

Cincinnati, Ohio 45229

Contact Person: Lisa McDonald 

(513) 636-4541

Genetic Disease Branch

State Department of Health Services Branch

Berkeley, California 94704

Contact Person: Kathleen Valesquez 

(510) 540-3035

Sickle Cell Disease Association of America,

Michigan Chapter 

18516 James Couzens Highway

Detroit, Michigan 48235

Contact Person: Jetohn Thomas 

(313) 864-4406
Chapter 4: Genetic Counseling

22

REFERENCES

1. Headings V, Fielding J. Guidelines for counseling

young adults with SCT. Am J Pub Health

1975;63:819-27.

2. Day SW, Brunson GE, Wang WC. Successful 

newborn SCT counseling using health department

nurses. Pediatr Nurs 1977;23:557-61.

3. St. Clair L, Rosner F, James G. The effectiveness 

of sickle cell counseling. Am Fam Phys

1978;17:127-30.

4. Whitten CF, Thomas JF, Nishiuria EN. SCT 

counseling—evaluation of counselors and 

counselees. Am J Hum Genet 1981;33:802-16.

5. Grossman L, Holtzman N, Charney E, et al.

Neonatal screening and genetic counseling 

for SCT. Am J Dis Child 1985;139:241-4.

6. Rowley PT, Loader S, Sutera CJ, et al. Prenatal

screening for hemoglobinopathies III. Applicability

of the health belief model. Am J Hum Genet

1991;48:452-9.

7. Sickle Cell Disease Guideline Panel. Sickle Cell

Disease: Screening, Diagnosis, Management and

Counseling in Newborns and Infants. Clinical Practice

Guideline No. 6. AHCPR Pub. No. 93 0562.

Rockville, MD: Agency for Health Care Policy and

Research, Public Health Service, U. S. Department

of Health and Human Services. April 1993.

8. Yang YM, Andrews S, Peterson R, Shah A. Prenatal

sickle cell screening education effect on the followup rates of infants with SCT. Patient Educa Couns

2000;39:185-9.
HEALTH MAINTENANCE
24
CHILD HEALTH CARE MAINTENANCE 5

25

useful because they give negative results when

the fetal hemoglobin (Hb F) level is high, and

do not distinguish between sickle trait (Hb

AS) and different forms of SCD. Tests on 

the parents may help to confirm the hemoglobin (Hb) genotype of the baby but can 

be incorrect in cases of single parenthood 

or nonpaternity. “Deductive” methods based 

on blood counts, red cell indices, and relative

levels of Hb F and A2 cannot distinguish

between conditions such as SCD-SS with 

α-thalassemia and SCD-S βo-thalassemia, 

nor are they useful in children younger than 

6 months of age where the relative levels of

hemoglobins have not stabilized (3). These

problems are avoided if DNA-based methods

are applied to detect specific mutations. The

determinations of βs haplotypes and α-thalassemia contribute to the definitive diagnosis

of SCD but play a minor role clinically. 

Once a definitive diagnosis is made, the parents should start an educational program with

practical information about the specific type

of SCD that affects their child (4-6). The initial counseling session sets the tone for how

the parents regard their child’s condition and

the new health care team. Parents often ask

about the expected course and capabilities of

the child with SCD. A person experienced in

the care of children with SCD should be available to answer these questions without medical jargon and should allow time for other

questions. It is important to tell parents not 

to raise children with SCD as sick children,

since they are not ill most of their lives. 

For decades, complications of sickle cell disease (SCD) produced the highest mortality

rate in the first 3 years of life (1). However,

public health programs and comprehensive

care for children who have SCD reduced early

childhood mortality in countries such as the

United States, United Kingdom, France,

Jamaica, and Saudi Arabia. Unfortunately,

childhood mortality is high in other parts of

the world, especially sub-Saharan Africa where

SCD is prevalent but organized SCD programs

are rare. These guidelines are directed to

health care workers mainly in the United

States, but the approaches may be modified 

as other conditions and situations permit.

PATHOLOGIC MECHANISMS

Sickle cells can obstruct blood flow to the

spleen, which results in functional asplenia

within the first few years of life. In addition 

to a filtration function, the spleen has B-cells

for antibody production, and when the organ

suffers infarcts and shrinks, this capacity is

lost. Asplenia causes susceptibility to bacterial

infections, particularly with pneumococcus.

CLINICAL FINDINGS

NEONATAL DIAGNOSIS

Newborn screening may be performed on

blood from the umbilical cord or a heel-prick.

Abnormal results should be confirmed with 

a second sample, using a different method (2).

Sickling and solubility tests generally are not
Chapter 5: Child Health Care Maintenance

26

Parental education about SCD cannot be

accomplished in one counseling session.

Providers who do not have the resources 

to provide this important service should 

refer the family to an appropriate facility.

Future sessions should be planned to provide

information appropriate for the child’s age,

diagnosis, and clinical course.

SPECIAL EVALUATIONS

Specific physical, laboratory, and other 

evaluations are needed to monitor children

with SCD (7).

Physical Examination

SCD in young children has a variable presentation. The earliest physical sign may be jaundice in the first few weeks of life. If hemolysis

is not significant clinically, parents and other

family members should be reassured about 

eye color changes so that they do not become

overly anxious. Hepatomegaly is a common

finding in children with SCD; the cause is

unknown, but it does not signify liver dysfunction. Spleen size should be measured, 

and parents should be made aware of it.

Organomegaly leads many children with SCD

to have a protuberant abdomen, often with an

umbilical hernia. Almost all SCD patients

with moderate-to-severe anemia have a cardiac

systolic flow murmur that does not require

further evaluation. Parents should be reassured

about the murmur so that they will not be

alarmed when other doctors and nurses notice

it. Bone marrow expansion often causes maxillary hypertrophy with overbite; orthodontics

are recommended to prevent or correct this

problem. Growth and development should be

followed closely in children with SCD, and

nutrition should be optimized. Children and

parents should be counseled about potential

social problems related to short stature and

delayed sexual development, which greatly

affects adolescents.

Laboratory Evaluation

It is useful to collect a series of baseline values

on each patient to compare with those at times

of acute illness. Table 1 shows a typical schedule of routine clinical laboratory evaluations.

Table 1. Suggested Routine Clinical Laboratory Evaluations

Tests Age Frequency

CBC with WBC differential, reticulocyte count 3 mo – 24 mo every 3 mo

>24 mo every 6 mo

Percent Hb F 6 mo – 24 mo every 6 mo

>24 mo annually*

Renal function (creatinine, BUN, urinalysis) ≥12 mo annually

Hepatobiliary function (ALT, fractionated bilirubin) ≥12 mo annually

Pulmonary function (transcutaneous O2 saturation) ≥12 mo every 6 mo*

* Frequency may vary based on patient’s clinical course.
27

Special Studies

The brain and lungs are among the organs

susceptible to serious damage in SCD. Early

detection of dysfunction may allow intervention to reduce risk of further damage.

Brain. Transcranial Doppler ultrasonography

(TCD), magnetic resonance imaging (MRI)

with or without angiography, and neuropsychometric (NPM) studies have been used extensively to evaluate children with SCD. An

abnormally high blood flow velocity by TCD

in the middle cerebral or internal carotid arteries is associated with an increased risk of stroke;

however, blood flow results should be interpreted cautiously because they are dependent on

the technique employed. TCD screening of

children with SCD-SS is recommended to start

at 2 years of age and continue annually if TCD

is normal and every 4 months if TCD is marginal. Children who have abnormal results

should be retested within 2 to 4 weeks. The

STOP trial (Stroke Prevention Trial in Sickle

Cell Anemia) in 1997 showed that a transfusion program reduces the risk of strokes in

patients with abnormal TCDs (see chapter 13,

Stroke and Central Nervous System Disease).

Children with SCD who have “silent” cerebral

infarcts detected by MRI have a higher rate 

of abnormal NPM studies and a higher risk

for overt strokes. Stroke prevention strategies

based on abnormal MRI results have not been

tested, but children with abnormal MRI or

NPM studies could be evaluated more frequently and carefully and considered for 

therapeutic measures.

Lungs. Children with SCD frequently have

abnormal pulmonary function tests (PFT).

PFT should be done regularly in those with

history of recurrent acute chest episodes or 

low oxygen saturation. Lung function declines

with age, so it is important to identify those

who need close monitoring and treatment.

MANAGEMENT

The major complications of SCD are discussed in other chapters, so only topics of 

special relevance to children and parents are

mentioned below.

PARENT EDUCATION

Home caregivers have a crucial role in the 

successful management of children with SCD,

and this should be emphasized at each counseling session. Parents should be taught physical

assessment skills (e.g., palpation of spleen), how

to avoid vaso-occlusive complications and treat

pain, and when to administer prophylactic

antibiotics. Educational materials and methods

should be matched to the literacy level of the

caregiver. Instruction should be provided on

how to navigate the medical system. Information about physical findings, laboratory values,

and medications should be retained by the

caregiver in case it is needed in an emergency.

FEVER

The constant danger of overwhelming infection is one of the most difficult concepts to

impart to caregivers (8). Fever is one of the

most common signs of illness in children, 

and most parents are unaware that their child

could die from infection. Pneumococcal vaccination and penicillin prophylaxis have reduced

the risk of mortality for SCD children, and

because of vigilance of parents and health care

providers, death from pneumococcal infection

is rare at major sickle cell centers in the United

States. Current recommendations for vaccinating children, providing prophylactic therapies,

and educating parents about the signs and

dangers of infection should not be relaxed. 

Parents should be discouraged from giving

antipyretics at home at the first sign of fever.

Advice that the febrile child deserves further

evaluation only after recurrence or persistence
Chapter 5: Child Health Care Maintenance

28

of fever (following antipyretic therapy) is

wrong and potentially dangerous. A history 

of fever should be taken seriously, and health

care workers, particularly those in emergency

rooms, should not challenge parents whose

children may have no or only low-grade fever

on presentation. At a minimum, the welllooking, nonfebrile child should be observed

in the emergency room for a few hours to

determine whether fever or other signs of

infection develop. 

All children with SCD who have fever

(>38.5o

C or 101oF) and other signs of infection

(chills, lethargy, irritability, poor feeding, 

vomiting) should be evaluated promptly. The

younger the child, the higher should be the

index of suspicion. In a child with no obvious

source of infection, a minimum evaluation

should include blood culture, complete blood

count, reticulocyte count, and chest x rays (for

those younger than 3 years of age). Immediately

after the blood is taken, the child should be

given broad-spectrum antibiotics, preferably

intravenously. Broad-spectrum antibiotics

should be given even if these tests cannot be

performed. In areas of the world where malaria

is endemic, antimalarial treatment should 

be added to the antibiotic coverage. Further

management protocols vary by locality. 

While bacterial infection is the major reason

for concern about the febrile child with SCD,

other complications should not be overlooked

(9). Both acute splenic sequestration and erythroid aplasia (“aplastic crisis”) are commonly

associated with fever. Early acute chest syndrome in young children may show no pulmonary signs.

PAIN EPISODES

Painful events are common in children with

SCD. The earliest complication observed 

clinically is often dactylitis (“hand-foot syndrome”), which starts at less than 1 year of

age. Typical vaso-occlusive pain may involve

limbs, abdominal viscera, ribs, sternum, 

vertebrae, and sometimes skull bones. Pain

episodes can start suddenly, or they may 

follow an illness along with decreased activity,

loss of appetite, and increased jaundice.

Parents should be assured that most pain

episodes have no identifiable precipitating 

factors, so that they do not blame themselves

or their children. Likewise, health care

providers should not assume that the pain 

is due to the fault of the parent. 

Children with pain should be evaluated.

Parents should be taught to localize the exact

site of pain, to ensure that a limp is due to

pain and not weakness, and to assess the

degree of pain for appropriate treatment. 

The object of pain management is relief, even

in the youngest children. Parents should be

taught proper analgesic use in order to manage

most pain episodes at home. Medications

given for mild and moderate pain include

acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen,

and mild opioids, such as codeine, for young

children. Stronger NSAIDs and opioids are

reserved for older children with severe pain.

Parents should be educated about the side

effects of these drugs and reassured about 

the risk of drug addiction when they are used

properly. If home management fails, parents

are encouraged to call for consultation or 

a hospital visit.
29

CLINICAL SEVERITY

A report from the Cooperative Study of

Sickle Cell Disease (CSSCD) identified early

predictors of clinical severity such as dactylitis

before 12 months of age, average Hb level 

of less than 7 g/dL in the second year of life, 

and elevated leukocyte count (>13,700/μL)

before 10 years of age (10). Further studies

will be required to identify those at high 

risk in order to consider therapies such 

as hydroxyurea, chronic transfusions, or 

bone marrow transplants.

COMPREHENSIVE MANAGEMENT

Comprehensive management of SCD often

requires a team that comprises doctors, nurses, 

health educators, and medical social workers.

Often emergency room physicians, radiologists, anesthesiologists, surgeons, and critical

care specialists also become involved. Facilities

generally should have medical consultants,

hematology and microbiology laboratories, 

a radiology service, and blood bank available

24 hours a day. On occasion, patients may

need TCD, computerized axial tomography,

MRI, and MRI with angiography, which are

available at major medical centers.

After the diagnosis of SCD, the comprehensive care team must initiate and coordinate

medical and psychosocial care for the child

and family. These activities should include

education, genetic counseling, and preparation

for independent living.

SUMMARY

Survival of children with SCD has been

improved largely through prevention of overwhelming bacterial infections. Preventive 

measures include newborn screening, protective

vaccinations, teaching caregivers to recognize

early signs of illness, and prompt treatment 

of suspected infections.

RECOMMENDATIONS

GENERAL HEALTH MAINTENANCE

FOR CHILDREN

Frequent Visits

Children with SCD should receive the same

general health care as children without the disease. Well-child visits for growth monitoring,

immunizations, and counseling on preventive

health measures should be supplemented with

specific information about SCD. The schedule

of visits in the first 2 years of life should be

every 2 to 3 months, planned to coincide with

the immunization schedule. After the age of 

2, the frequency of visits depends on patient/

family needs and access to medical consultation, but it should be at least every 6 months.

Immunizations

In addition to routine immunizations against

hepatitis B, polio, diphtheria, pertussis,

tetanus, Haemophilus influenzae type b,

measles, mumps, and rubella, children with

SCD require additional immunizations. The

recent introduction of the pneumococcalconjugated vaccine (PCV) for children in 

the United States is important for those with

SCD. Prevnar (Wyeth-Lederle), the 7-valent

PCV (PCV7) licensed in the United States,

covers pneumococcal serotypes 4, 9V, 14, 

19F, 23F, 18C, and 6B, and has possible 

cross-reactivity with serotypes 6A, 9A, 9L,

18B, and 18F. Together these serotypes

account for 87 percent of bacteremia and 83

percent of meningitis due to pneumococcus 

in the United States. The American Academy

of Pediatrics (AAP) recommends Prevnar for 

children with SCD up to 59 months of age.

However, there is no reason why older SCD

patients should not receive the vaccine. The

23-valent pneumococcal polysaccharide vaccine (PPV23, also known as 23PS), previously

recommended at 2 years of age with a booster

at age 5, still should be used in addition to the
30

Chapter 5: Child Health Care Maintenance

conjugated vaccine. The recommended schedules of vaccination for the prevention of pneumococcal infection in U.S. children with SCD

are shown in tables 2 and 3 [modified from

(11,12)].

Meningococcal vaccination has not been recommended routinely for children at most U.S.

sickle cell centers, probably due to infrequent

meningococcal infections reported. If children

live in or travel to areas with a high prevalence

of meningococcal infection, this vaccine

should be given. In addition, influenza vaccination is recommended seasonally for patients

with SCD.

Penicillin Prophylaxis

The most important intervention in the routine management of children with SCD is

penicillin prophylaxis to prevent pneumococcal infection (13), which justifies newborn

screening. Penicillin is given twice daily from

as early as 2 months of age, a treatment supported by the hallmark Penicillin Prophylaxis

Studies of the 1980s. It was recommended

that children with SCD-SS be given penicillin

VK: 125 mg by mouth twice daily for those

under 3 years of age, and 250 mg twice daily

for those 3 and older. Penicillin may be given

as a liquid or tablet; finely crushed pills may

be given to young children. Pills have an

important advantage because they are stable

for years, compared to liquid forms of penicillin that must be discarded after 2 weeks. 

An alternative to oral penicillin is an injection

of 1.2 million units of long-acting BicillinTM

every 3 weeks.

A study in children older than 5 years of age,

found no clinical benefit of penicillin prophylaxis compared with placebo, indicating that treatment may be stopped at that age (14). Patients

on penicillin had no increased infections with

penicillin-resistant organisms or other adverse

effects. Since splenic function is still absent in

patients with SCD older than 5 years of age,

parents should be given the option to continue penicillin if desired. For patients allergic 

to penicillin, erythromycin ethyl succinate 

(20 mg/kg) divided into 2 daily doses can provide adequate prophylaxis. The importance of

prophylactic antibiotics should be emphasized 

at all visits because parents may become noncompliant with this essential treatment.

Although the data that support these recommendations were generated in SCD-SS

patients, they are assumed to be valid for

SCD-S βo-thalassemia. The CSSCD showed 

a higher-than-expected incidence of bacteremia

in children younger than 3 years of age with

SCD-SC. Pneumococcal infection has been

reported in SCD-SC in the first two decades of

life, although less frequently than in SCD-SS.

Protection of SCD-SC patients with prophylactic penicillin and antipneumococcal vaccine

is probably wise even without experimental

data. It is difficult to recommend prophylaxis

for children with SCD-S β+-thalassemia.

Nutrition

Nutrition counseling is an important part 

of routine health care. Mothers should be

encouraged to breastfeed their infants; ironfortified formulas are an alternative. However,

additional iron should not be given unless the

patient is proved iron-deficient, since people

with SCD accumulate iron faster than normal.

Microcytosis in children with SCD could be

due to α- or β-thalassemia trait rather than

iron deficiency. Folic acid (1 mg orally) is

given daily to patients with chronic hemolysis,

such as those with SCD, to reduce the risk of

bone marrow aplasia.
31

Table 2. Recommended Schedule of Pneumococcal Immunization in 

Previously Unvaccinated Children with Sickle Cell Disease

Product Type Age at 1st dose Primary series Additional doses

PCV7 (Prevnar) 2-6 mo 3 doses 6-8 wk apart 1 dose at 12 to <16 mo

7-11 mo 2 doses 6-8 wk apart 1 dose at 12 to <16 mo

≥12 mo 2 doses 6-8 wk apart —

PPV23 (Pneumovax) ≥24 mo 1 dose at least 6-8 wk 1 dose, 3-5 yr after 

after last PCV7 dose 1st PPV23 dose

Table 3. Recommended Schedule for Catch-up Pneumococcal Immunization 

for Previously Vaccinated Children with Sickle Cell Disease

Age Previous doses Recommended

12-23 mo Incomplete primary PCV7 2 doses PCV7, 6-8 wk apart

≥24 mo 4 doses PCV7 1st dose PPV23, 6-8 wk after PCV7;

2nd PPV23 dose, 3-5 yr after 1st PPV23

1-3 doses PPV7 1 dose PCV7;

(before 24 mo of age) 1st dose PPV23, 6-8 wk after PCV7;

2nd PPV23 dose, 3-5 yr after 1st PPV23

1 dose PPV23 2 doses PCV7, 6-8 wk apart, 1st dose given 

at least 8 wk after PPV23 dose; 2nd PPV23

dose, 3-5 yr after 1st PPV23

Current U.S. Food and Drug Administration indications are for administration of PCV7 only to children younger than 24 months of age.
Chapter 5: Child Health Care Maintenance

32

Deficiencies in nutrients (e.g., zinc) should 

be corrected if they occur. Fluoride, given in

vitamins or in drinking water, will prevent

dental caries. Standard antibiotic prophylaxis

should be used to cover dental procedures

such as extractions and root canal therapy. 

COUNSELING

In addition to genetic counseling, children

and teens with SCD and their families may

need academic and vocational guidance, as

well as advice on recreational activities and

travel. The basic premise is that parents should

treat their affected child as normally as possible,

and they should encourage activities that 

foster self-esteem and self-reliance. These 

feelings will help children and adolescents 

to cope more effectively with their illness.

Academic and Vocational Counseling

Educational materials should be provided to

teachers and other school officials who interact

regularly with children with SCD. School 

personnel should meet with the parents to 

set realistic educational goals. Illness often

interrupts schooling and extracurricular 

activities, so tutoring or other assistance may 

be needed. Unless impaired by cerebrovascular

disease, children with SCD have normal intelligence and should be encouraged to reach their

full potential. 

Vocational counseling is important for adolescents and adults with SCD. The long-term

goal is to prepare the child with SCD for

independent living. Introducing children and

adolescents to adults with SCD who have

coped successfully with their illness has a 

positive effect. 

Recreation and Travel

Patients should be encouraged to exercise regularly on a self-limited basis. School-age children should participate in physical education,

but they should be allowed to rest if they tire

and encouraged to drink fluids after exercise.

The potential risks of strenuous exertion

should be discussed with the patient. Children

and adolescents may engage in competitive

athletics with caution because signs of fatigue

may be overlooked in the heat of competition.

Coaches are advised against blanket exclusion

from participation or excessive demands for

athletic excellence. Patients with SCD should

dress warmly in cold weather and avoid swimming in cold water. 

Children with SCD may benefit from attendance at a summer camp, either an appropriate regular camp or a special one for children

with SCD. If the staff members are knowledgeable about the disease and comfortable

with the care of these children, the campers

can learn self-reliance and share experiences

about SCD while having fun. Health care

providers have found such camps to be a 

valuable experience for children with SCD.

Patients or families often seek advice on the

best modes of travel. Flying in pressurized aircraft usually poses no problems for sickle cell

patients; however, they should dress warmly 

to adjust for the cool temperature inside, drink

plenty of fluids, and move about frequently

when possible. On the other hand, travel

above 15,000 feet in nonpressurized vehicles

can induce vaso-occlusive complications.

Ordinary travel by car, bus, or train is not

associated with an increased risk of complications, although frequent rest and refreshment
33

stops should be taken. Patients are encouraged

to consult their physicians before travel, and

they are advised to carry with them specific

medical information about their diagnosis,

baseline hematologic values, a list of current

medications, and the name and telephone

number of their physicians. Providers should

give patients the names of physicians or health

care facilities to contact in case of emergencies.

TRANSITION TO ADOLESCENCE

Adolescence is a difficult time of life for

youngsters with chronic diseases. While their

peers become independent, teenagers with

SCD may need frequent help due to illness.

They can become frustrated and have trouble

expressing their feelings. Concern about issues

such as body size, sexual function, pain management, and death often is expressed as rebellion, depression, or refusal to heed treatment

plans and medical advice.

Adolescents should be advised not to use

tobacco, alcohol, and illegal drugs. Postpubertal

adolescents should be educated about sexuality, safe sex practices, and the use of condoms

to prevent sexually transmitted diseases. Girls

should be counseled about the risks of pregnancy in women with SCD, safe birth control

practices, and the merits of pregnancy at the

right age and social circumstances.

Adolescents may view their long-time pediatric

health care providers as too close to their parents and not speak frankly to them. In this

case, families could be referred to adolescent

medicine specialists to discuss sensitive issues

and preparation for adulthood. Alternatively,

adolescents may be able to express their concerns through “teen support groups.” 

The change from a pediatric to an adult 

care setting is often difficult, and adolescents

should be given help to access adult care 

facilities. In some centers, this transition is

eased by concurrent pediatric/adolescent/adult

sickle cell clinic sessions. Chapter 6 provides

more information about how to facilitate 

the patient’s transfer from pediatric to adult

health care specialists.

REFERENCES

1. Leiken SL, Gallagher D, Kinney TR, et al.

Mortality in children and adolescents with sickle

cell disease. Pediatrics 1989;84:500-8.

2. Sickle Cell Disease Guideline Panel. Sickle Cell

Disease: Screening, Diagnosis, Management,

Counseling in Newborns and Infants. Clinical

Practice Guideline No. 6. Rockville, Maryland:

Agency for Health Care Policy and Research, Public

Health Service, U.S. Department of Health and

Human Services. 1993. AHCPR Pub. No. 93-0562.

3. Brown AK, Sleeper LA, Miller ST, et al. Reference

values and hematological changes from birth to 

five years in patients with sickle cell disease. Arch

Pediatr Adolesc Med 1994;48:796-804.

4. Lessing S, Vichinsky E, eds. A Parents’ Handbook 

for Sickle Cell Disease. Part I, Birth to Six Years 

of Age. Children’s Hospital, Oakland Sickle Cell

Center. Copyright 1990. State of California,

Department of Health Services Genetic Disease

Branch, Revised 1991.

5. Sickle Cell Disease Guideline Panel. Sickle Cell

Disease in Newborns and Infants. A Guide for

Parents. Consumer Version, Clinical Practice

Guideline No. 6. Rockville, Maryland: Agency for

Health Care Policy and Research, Public Health

Service, U.S. Department of Health and Human

Services. 1993. AHCPR Pub. No. 93-0562.

6. Day, S. Your Child and Sickle Cell Disease.

Biomedical Communications Department, St. 

Jude Children’s Research Hospital, Memphis,

Tennessee. Mid-South Sickle Cell Center. P.O. 

Box Suite 235, 1 Children Plaza, Memphis,

Tennessee 38103.

7. Gill F, Sleeper L, Weiner S, et al. Clinical events 

in the first decade in a cohort of infants with sickle

cell disease. Blood 1995;86:776-83.
34

Chapter 5: Child Health Care Maintenance

8. Zarkowsky HS, Gallagher D, Gill FM, et al.

Bacteremia in sickle hemoglobinopathies. 

J Pediatr 1986;109:579-85.

9. Pearson HA, Gallagher D, Chilcote R, et al.

Developmental pattern of splenic dysfunction in

sickle cell disorders. Pediatrics 1985;76:392-7.

10. Miller ST, Sleeper LA, Pegelow CH, et al.

Prediction of adverse outcomes in children with

sickle cell disease. N Engl J Med 2000;342:83-9

11. Committee on Infectious Diseases. American

Academy of Pediatricts. Policy statement: recommendations for the prevention of pneumococcal

infections, including the use of pneumococcal 

conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis.

Pediatrics 2000;106:362-6.

12. Overturf GD, the American Academy of Pediatrics

Committee on Infectious Disease. Technical report:

prevention of pneumococcal infections, including

the use of pneumococcal conjugate and polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics

2000;106(2 Pt 1):367-76.

13. Gaston MH, Verter JI, Woods G, et al. Prophylaxis

with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593-9.

14. Falletta JM, Woods RM, Verter JI, et al. Discontinuing penicillin prophylaxis in children with 

sickle cell anemia. J Pediatr 1995;127:685-90.
ADOLESCENT HEALTH CARE AND TRANSITIONS 6

35

Moreover, the current health care environment

tends to neglect the needs of patients with

chronic disorders. Insurers seek groups of

young and healthy people to reduce costs.

Patients with chronic illnesses such as SCD

frequently lose medical coverage when they

become legally independent of their parents.

To reduce expensive hospitalizations, integrated transition programs can provide age-appropriate treatment and continuity of care from

pediatric to adult facilities.

CLINICAL FINDINGS

Studies from the Duke Comprehensive Sickle

Cell Center show that a patient’s coping style

significantly predicts the extent of health care

contact, activity, and psychological distress 

(3). Patients with active coping styles (use of

multiple cognitive and behavioral strategies)

had fewer emergency room visits. Those 

using passive adherence coping styles (reliance

on concrete, passive approaches to pain, such

as resting, without resourcefulness when 

initial efforts fail) had more emergency room

visits and participated in fewer activities at

home and in school. Another study found 

that negative thinking (expression of fear 

and anger) correlates with psychological 

distress (4). Nine months after the initial

assessment, these studies showed that the

coping strategies of younger children and

adults are relatively stable, but those of adolescents are in flux. For individuals who rely 

on less adaptive strategies (passive adherence

or negative thinking), adolescence may be 

Adolescents with sickle cell disease (SCD) 

face the same challenges as their healthy counterparts. They desire acceptance by their peers

but, at the same time, wish to become more

independent. Additional help is needed to

transition to new health care providers and

facilities (1). In a prospective study of over

3,500 patients (2), the course of SCD varied

as patients matured, but the frequency of 

pain episodes correlated with disease severity.

Patients older than age 20 with frequent

painful events had the greatest risk of early

death, indicating that continuity of care is

important to minimize morbidity and mortality. Communication with the patient, family,

and multiple providers is needed, but coordination may be difficult between different

departments, such as pediatric and adult clinics.

ISSUES

Several factors conspire to make transition 

difficult. Young people with SCD become

familiar with the pediatric environment and

providers to whom they may literally owe their

lives. Adolescent bravado may result in a tendency to deny illness and a reluctance to go 

to a strange adult care facility. Adolescents

desire independence as adults but may not be

ready to face new responsibilities for appointments and medications. For example, although

young patients with SCD feel healthy, they

must have routine ophthalmology exams to

forestall blindness. They also need support to

deal with issues such as contraception, sexually

transmitted diseases, and family planning.
Chapter 6: Adolescent Health Care and Transitions

36

a period when these maladaptive styles predominate. This stress complicates transition.

The unpredictability and stress of SCD pain

episodes affects the entire family, but the

extent of the psychological impact varies

among studies. Some show little psychological

variation between adjustment in siblings and

patients, and little difference from population

norms (5), while others show significant stress

on siblings (6). Parents’ coping styles also

affect children’s activity levels, distress, and

coping strategies. Kramer (7) found 49 percent of the parents of SCD patients in their

sample to be clinically depressed according 

to the Center for Epidemiological Studies

Depression scale (CES-D). Programs exist to

improve the education and coping of family

members, reduce daily strain, and teach stress

management techniques (8,9).

IMPLEMENTATION 

OF TRANSITION

ASSESSMENT

The members of a transition team include

physicians, mid-level practitioners (e.g., nurses

or physician assistants), and social service

workers—from both pediatric and adult facilities. Each of these providers views patients

from a different perspective, so they must meet

together often to assess readiness of patients

and their families for transition. Written medical records may not contain enough details 

of a patient’s history, so verbal discussion of

“group” knowledge helps. New providers can

miss problems when presented with just a discharge summary and list of medications. The

meetings also give providers who treat adults 

a chance to ask questions and to assure pediatricians that patient needs will be met.

Physicians and nurses are the primary health

care providers for most people with SCD, but

pediatric and adult teams are organized differently, which creates problems with transition.

General pediatricians often are the focus of

care for children with SCD, and hematologists

are usually consultants. This structure was

established because all children need to see

pediatricians for development checks and 

routine immunizations. Since many children

with SCD have few other problems, general

pediatricians are the main contacts, and pediatric hematologists advise about additional

interventions such as pneumococcal vaccination and penicillin prophylaxis.

By contrast, most adolescents and young

adults ages 18–30 are healthy, so few see

health care providers for preventive measures.

The result is that hematologists become the

primary providers for young people with

SCD. Because patients must take the initiative

for health maintenance, their readiness to

accept this responsibility should be assessed.

A patient’s chronologic age should not automatically trigger transition. Some 18-year-old

youths are not ready to go from pediatric to

adult care, so developmental age is a more

appropriate guide. For instance, delayed neurocognitive development from cerebrovascular

injury may hamper a patient’s ability to adjust

to adult health care until age 20 or 21.

Similarly, a patient who has just experienced 

a serious complication, such as acute chest

syndrome, is unprepared psychologically for

transition to new providers.

Social service workers play a major role in

assessment, since they have more contact with

patients and parents than any other members of

the team and can judge how families deal with

psychosocial problems of chronic illness, such

as anxiety and depression. If they concur that

the patient and family are ready for transition,

the subject should be broached to the parents

and child well ahead of time to prepare them.
37

PREPARATION AND SUPPORT

All parties—patients, providers, and facilities—

must agree beforehand on a plan for transition,

which is an orderly movement of the patient’s

medical care from one set of places and

providers to another. This is a process that

occurs gradually, in contrast to an abrupt transfer of locale. The idea of transition is mentioned a year or so before the process begins, 

to prepare families mentally; reading material

can reinforce the concept between clinic visits.

Patients and providers should make plans

together to ensure they are clear to all. Providers

can gauge success at each point, and patients

may ask questions and voice concerns.

For parents, transition to adulthood entails

loss of responsibility for, and control over,

their child’s medical care. They often have 

difficulty relinquishing the central role, and

this can produce resistance to the transition

effort. Reassurance that the pediatric and adult

providers will remain in contact is important

to alleviate the fear that the pediatricians are

abandoning them. Patients, parents, and

providers should view transition as a positive

milestone. Together, they have achieved a 

significant step and should be congratulated.

Adult providers then become positive additions to an already successful team. 

One of the most effective ways to dispel fears

of transition is to make contact with people

who have gone through the process. Support

groups with older adolescents and young

adults are particularly helpful. Community

events, such as picnics or holiday celebrations,

often work better than meetings because they

focus on activity rather than disability, and

discussion is easier without health providers.

Institutional administrators are also important

to support transition programs, which require

personnel allocated by the administration. 

A single provider without nursing or social

service support cannot deliver care or transition patients adequately. Some pediatric facilities have an upper age limit for inpatient care,

and transition may be suboptimal if patients

with delayed development are transferred to

adult facilities just because of age.

TRANSFER PROCESS

The pediatric providers should introduce the

adult team to the patient and parents in the

pediatric setting first, if possible. In this familiar environment, the family will have a chance

to clarify details of the transition before a last

pediatric visit. Pediatric providers should not

simply give patients the phone number and

instruct them to call. At the last pediatric visit,

providers should schedule the next appointment as they normally do, but it will be with

the adult team. The first transferred clinic

appointment is a crucial test of transition. 

A member of the adult team should escort the

family to the new facility, and introduce them

to the staff there. Patients with SCD may find

it hard to locate a new clinic, especially if they

are symptomatic. For example, a pain episode

is not the best time to meet new providers in 

a strange place.

If the patient misses the next appointment, 

a pediatric team member (e.g., social worker)

should call and work with the patient, parents,

and adult providers to resolve any issues. 

A “no show” at the adult facility may be an

indirect way to ask for more help with the

transition process. Often, patients are reluctant because the adult clinic is unfamiliar, 

yet they will not return to the pediatric clinic,

which they perceive to have discharged them.

Continuity is lost, and patients may suffer 

a medical catastrophe.
Chapter 6: Adolescent Health Care and Transitions

38

Young adults with mild SCD tend to skip 

followup with specialists who can prevent

complications of SCD. For example, asymptomatic retinal blood vessel proliferation may

result in ocular hemorrhage unless treated by

an ophthalmologist before visual loss occurs.

Prevention is a key step in the management 

of SCD, but young people may be lost during

the transition from pediatric to adult care and

suffer unnecessarily. Intervention, coaching,

and continued support can avert this potential disaster.

Other obstacles may exist, due to the infrastructure of the medical system. The best situation is where good programs for children and

adults with SCD coexist, and efforts are coordinated easily. However, when health care

delivery is unbalanced (e.g., a strong pediatric

program but a weak adult one), transition is

more difficult. 

Most children with SCD are the offspring of

heterozygous parents who have health insurance. They have fewer chronic complications

than adults, and hospitalizations occur mainly

for self-limited painful events. In contrast,

adults with SCD have difficulty keeping steady

jobs because their organ damage progresses.

Thus they often require government assistance,

but these programs lack full coverage, such as

for transition programs. The combination of

chronic illness and poor reimbursement deters

some adult providers from the care of patients

with SCD. Adult providers sometimes feel 

they are given only problem patients, while

pediatricians keep those who are easiest to

treat. Frequent transition team meetings where

adult and pediatric providers discuss the

patients can dispel such misconceptions. In

fact, institutional commitment to transition

programs should be bolstered by data indicating that a well-organized adult care program

for SCD is financially beneficial (10). Both

professional and lay patient advocates should

make this point known.

If no local adult care program exists, pediatricians may hold on to their patients and treat

problems outside their area of expertise (e.g.,

ischemic heart disease). Nevertheless, they also

should empower the patients to deal with an

unfamiliar system. They should give parents a

summary of the child’s medical course for use

in emergencies. This should include copies of

basic records, such as immunizations, blood

type, complications, and current medications,

especially those that work during an acute

pain episode.

SUMMARY

Transition programs prepare an adolescent 

to assume responsibility for his or her health

care. The primary charge lies with the pediatric providers, whose first step is to assess the

readiness of the patient and family. The transition process encourages the gradual maturation of relationships with adult providers via

steps that are designed individually, due to 

differences among institutions, providers, and

patients. Such development does not occur

automatically, and a comprehensive transition

program is not always possible. Nevertheless,

adult providers and administrators should be

enlisted to deliver continuous care, which can

avert medical disasters.
39

REFERENCES

1. Telfair J, Myers J, Drezner S. Transfer as a component of the transition of adolescents with sickle cell

disease to adult care: adolescent, adult, and parent

perspectives. J Adolesc Health 1994;15:558-65.

2. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. 

N Engl J Med 1991;325:11-6.

3. Gil KM, Williams DA, Thompson RK Jr, Kinney

TR. Sickle cell disease in children and adolescents:

the relation of child and parent pain coping strategies to adjustment. J Psychol 1991;16:643-63.

4. Gil KM, Thompson RK Jr, Keith BR, et al. Sickle

cell disease pain in children and adolescents:

change in pain frequency and coping strategies 

over time. J Pediatr Psychol 1993;18:621-37.

5. Gold J, Treadwell M, Barnes M, et al.

Psychological and social effects of sickle cell disease

on live-in siblings. Annual Meeting of the National Sickle Cell Disease Program, Boston, MA, 1995. 

6. Treiber F, Mabe A, et al. Psychological adjustment

of sickle cell children and their siblings. Child Heath Care 1987;16:82-8.

7. Kramer K, Nash K. The prevalence of depression

among a sample of parents of children with sickle

cell disease. Annual Meeting of the National Sickle

Cell Disease Program, Boston, MA, 1995.

8. Kaslow N, Rowland S, Dreelin B, et al.

Psychosocial interventions for children and adolescents with sickle cell syndromes. Annual Meeting, National Sickle Cell Disease Program, Boston,

MA, 1995. 

9. Shearer J. Reducing hospital admissions for

uncomplicated pain episodes through intensive

case management and family therapy techniques.

Annual Meeting, National Sickle Cell Disease

Program, Boston, MA, 1995.

10. Benjamin LJ, Swinson GI, Nagel RL. Sickle 

cell anemia day hospital: an approach for the

management of uncomplicated painful crises. Blood 95;2000:1130-6.
40
ADULT HEALTH CARE MAINTENANCE 7

41

episodes increases in early adulthood (3).

Hydroxyurea provides the first pharmacologic

intervention that reduces the frequency of

pain episodes in adults (4). Proliferative

retinopathy is a life-long risk that increases 

in prevalence with age (5). Vision may be

compromised by these vascular changes that

predispose to retinal hemorrhages, retinal

detachments, and increased intraocular pressure (5). Renal glomerular disease is prevalent

in adults and may cause increasing anemia,

renal failure, and premature death (6-8).

Prevalence of chronic pulmonary disease and

pulmonary hypertension also increases as

patients age, and may contribute to morbidity

and mortality (9). Complications such as leg

ulcers and osteonecrosis of the hips and shoulders cause chronic pain and disability, which

require social and vocational adjustments

(10,11). Essentially unstudied are the pain

episodes that many women experience in association with menstruation and the increased

frequency and severity of pain episodes near

menopause. Geriatric challenges in patients

with SCD are not well studied.

Health maintenance activities must also

address interactions between SCD and other

common health problems of the adult population. Individuals with relative hypertension

and SCD have an increased risk of strokes 

and increased mortality, and therefore treatment for hypertension is an important aspect

of health care (12) (see chapter 15, Cardiovascular Manifestations). Patients with SCD

are not protected from developing cancer 

There have been significant improvements 

in the outlook for adults with sickle cell 

disease (SCD). The Cooperative Study of

Sickle Cell Disease (CSSCD) and other observational studies have helped to define the

prognosis and common complications that

occur as the patients age. Improved management of infections and central nervous system

(CNS) complications in childhood, active

health maintenance for adults, new interventions, and improved psychosocial support have

all contributed to a reduction in morbidity

and mortality.

The prognosis in SCD has dramatically

improved over the past 30 years. Estimates

based on the mortality in the CSSCD indicate

a median survival of 42 years for males and 

48 years for females with SCD-SS disease and 

60 years and 68 years, respectively, for SCDSC disease (1). Patients are now living into 

the seventh and eighth decades. More than 

90 percent of patients of all phenotypes will

survive past age 20, and significant numbers

are older than age 50 (1). Risk of early death

in adults with SCD is associated with acute

complications such as pain episodes, anemic

events, acute chest syndrome, chronic renal

failure, and pulmonary disease (2).

CHALLENGES

Improved survival provides opportunities 

to improve the quality of life for patients with

SCD; however, it also provides unique challenges

in health maintenance. The frequency of pain
Chapter 7: Adult Health Care Maintenance

42

as they age (13). Diabetes, asthma, arthritis, 

atherosclerotic vascular disease, and other

chronic illnesses may occur concurrently 

and provide unique challenges in managing

patients with SCD.

Many adults are well adjusted socially and 

psychologically. Others, however, experience

problems including anxiety and depression,

and have difficulty forming and maintaining

relationships, finding and keeping employment, and participating in usual daily activities (14-16). There is an increased need for

social and psychological support services to

maximize adjustment and productivity in

adults with SCD (14-16).

RECOMMENDATIONS

Ongoing care of the adult patient includes

preventive health maintenance, early recognition and treatment of complications, continuous assessment of social status, psychological

assessment and support, and continuing

patient education. Such services can be effectively accomplished only during regularly

scheduled well-patient visits where effective

doctor-patient relationships are established

and medical, social, and psychological issues 

are addressed.

INITIAL HEALTH MAINTENANCE VISIT

The initial visit provides an opportunity to

establish rapport with the patient and his or

her family and to determine the patient’s medical and social needs, as well as psychological

strengths and challenges. A complete database

should be developed that includes the information outlined in table 1.

ONGOING HEALTH CARE VISITS

Initially, a number of visits every 1 to 2 weeks

will facilitate developing rapport, discussing

laboratory and other test results, completing

the initial database, developing a problem list

and care plan, and exploring active social or

psychological issues. Routine medical evaluations are scheduled approximately every 

2 to 6 months, depending on the patient’s

phenotype and active problems. The database

is updated at every visit. Blood counts, reticulocyte counts, and urinalysis are repeated at

each visit to establish a baseline and detect

problems. Pulse oximetry at each visit is also

helpful. Routine chemistry tests should be

repeated at least annually. Complications such

as chronic organ failure, other medical problems, or complex psychosocial problems often

require more frequent visits and more extensive evaluations.

Patients with hypertension, proteinuria,

increased creatinine, renal tubular acidosis, 

or hyperuricemia should have more extensive

and regular evaluation of renal function (see

chapter 19, Renal Abnormalities in Sickle Cell

Disease). Individuals, especially those with

sleep apnea or chronic hypoxia requiring oxygen therapy with pulmonary disease or symptoms, should have regular pulmonary function

studies and evaluation of pulmonary hypertension. Patients should have an annual ophthalmology examination for retinopathy, increased

ocular pressure, and refraction errors. Followup

examinations of patients with significant 

proliferative retinopathy is scheduled by the

ophthamalogist at more frequent intervals 

(see chapter 14, Sickle Cell Eye Disease).

In many populations, tuberculosis screening

should be done annually. Tetanus immunizations are kept up to date, hepatitis vaccine is

given, and influenza vaccines are administered

annually based on recommendations of the
43

Centers for Disease Control and Prevention

(CDC). Pneumococcal vaccine is repeated every

5 years. Annual testing for HIV and hepatitis 

C may be indicated for patients who are sexually promiscuous. Women should be taught 

to practice breast self-examination, have an

annual breast examination by a physician, and

have mammograms with a frequency based 

on family history and age as recommended 

by the American Cancer Society (ACS). Males

should be screened for prostatic specific antigen after age 50. Screening for colon cancer 

is based on family history and age as recommended by the ACS.

PATIENT EDUCATION

Initial evaluation should include assessment 

of the patient’s and family’s understanding of

SCD. Educational activities should focus on

correcting deficits in knowledge about more

common complications such as infection, gallstones, aseptic necrosis, acute chest syndrome,

leg ulcers, and priapism. Patients should be

taught to seek medical care for persistent fevers

greater than 38 ̊C (100 ̊F); chest pain, cough,

and shortness of breath; symptoms of acute

anemia including weakness, dyspnea, or dizziness; abdominal pain with nausea and vomiting; respiratory infection with a productive

Demographic Information

• Name, address, phone number, family 

contacts, social security number, birth date

• Insurance status

Historical Information

• Names, addresses, and phone numbers 

of past physicians

• History of SCD related complications and 

other medical problems since birth

• Characteristics of pain episodes:

– frequency 

– duration

– usual home treatment

– usual emergency department treatment

– average number and duration 

of hospitalizations

• Past medical treatment:

– surgery

– transfusions—number, reactions, 

alloantibodies

– major complications, e.g., cerebrovascular event (CVA), liver, renal, or eye 

diseases

• Immunization history

• Medications and allergies

• Family history, including sickle cell, 

hypertension, diabetes, cancer, others

• Complete review of symptoms by system

Objective Data

• Complete physical examination

• Complete blood counts, reticulocyte count, 

hemoglobin phenotype, liver profile, 

electrolytes, BUN, creatinine

• If transfused, consider ferritin, hepatitis 

serologies, and red cell phenotype

• Urinalysis including testing for 

microalbuminuria

• Chest x ray and other x rays depending 

on historical and physical findings

• Electrocardiogram in older patients or 

those with cardiac symptoms or findings

• Ophthalmology evaluation for retinopathy

Social and Psychological Profile

• Level of education and school success

• Occupational history, hobbies, and 

leisure activities

• Financial resources

• Compliance with treatment and 

appointments

• Coping strategies, mental health, depressive 

symptoms, and stressors

• Family support, family participation in 

health care, past compliance

• Habits, including smoking history, alcohol 

use, and use of recreational drugs

• Sexual history, including birth control and 

safe-sex techniques

Table 1. Patient Database
Chapter 7: Adult Health Care Maintenance

44

cough; symptoms of urinary infection; or

unusually severe headaches. Preventive care

includes learning physical limits and regularly

participating in health maintenance, which

includes following medication and immunization recommendations, protecting lower legs,

and practicing safe sex. It is extremely important to discuss the specific risks to individuals

with SCD associated with use of alcohol,

cocaine, marijuana, and cigarettes.

All patients require education about appropriate management of pain. They must be taught

to recognize the sources and intensity of their

pain and to use appropriate therapeutic interventions. Headaches, menstrual cramps, strain,

and muscle pains are best managed with

aspirin, nonsteriodal anti-inflammatory drugs

(NSAIDs), and acetaminophen. Treatment 

of SCD-associated pain is initiated with these

agents. Physical therapy interventions—such

as use of rest and heat, drinking fluids, and

using relaxation or distraction—are taught. If

the pain is not controlled by these measures,

the patient is taught to seek medical care.

Patients and families should be reassured that

appropriate use of narcotics to adequately 

control pain does not lead to addiction. They

should be encouraged to use only the required

dosages of medication, follow medical directions, and not use the medication for stress,

anxiety, or other purposes.

The occurrence of chronic pain from avascular

necrosis, leg ulcers, and other complications

requires intense education so that patients

understand that the goals of therapy for

chronic pain are different from those for pain

control during acute episodes. These goals are

to minimize pain, increase pain coping skills,

and maintain maximum social and physical

functioning. In addition to pain medications,

treatment may require nonpharmacologic

interventions such as occupational and physical therapy, behavior modification, and other

neurocognitive interventions.

Nutritional counseling is also important, with

the goal of maintaining ideal body weight.

Underweight individuals may require nutritional support. A number of patients need

weight reduction, especially if they are overweight and develop complications such as avascular necrosis and diabetes. Folic acid supplementation is recommended for patients with

sickle cell anemia, although the optimum dose

to normalize homocysteine levels has not been

determined. Many patients take other vitamins

and nutritional supplements, but there is no

strong scientific evidence for their use.

Young adults with SCD must be taught to

approach activities in a way that minimizes

excessive stress, exhaustion, dehydration, and

extremes in temperature. Moderation and selfmonitoring of exertion level is the rule. Thus

individual, rather than team, sports generally

are preferred. Exercise is encouraged, but

activities should be regular and slowly progressive. Hydration with water is important

before, during, and after physical activities.

Cold exposure is minimized by adequate

dressing and avoidance of swimming in cold

water. Patients with avascular necrosis should

maintain ideal body weight, avoid vocations

that require prolonged standing or heavy lifting, and refrain from power weight lifting and

exercise that involves running or jumping.

With proper hydration, most patients can tolerate air travel in planes pressurized to 2,200

meters (17). Patients going above this altitude

in the mountains or in unpressurized aircraft

may experience pain episodes and other complications (17). With advance arrangements,

most airlines will provide supplemental oxygen

for patients who have experienced problems in

the past or who have other medical problems
45

that may contribute to risk of complications.

There is anecdotal evidence that persons with

splenic function may be at higher risk during

air travel.

Childbearing and birth control should be 

discussed with patients and their partners 

(see chapter 23, Contraception and Pregnancy).

Discussions should include the risks during

pregnancy, the potential for spontaneous 

abortion, and the physical and emotional 

challenges of raising an infant. Resources for

patient support during and after the pregnancy should be explored. Preconception education should include genetic counseling and

testing of the partner. Pre- or postconception

genetic counseling should include discussion

of prenatal diagnosis.

VOCATIONAL GOALS

Individuals with SCD should be encouraged 

to complete their education and pursue vocations. Jobs requiring strenuous physical exertion, long work hours, exposure to hypoxia, or

extremes in temperature may not be tolerated

and should be discouraged, especially if the

patient has increased symptoms when engaged

in the vocation.

Higher education and advanced vocational

training can provide vocations and professions

that are ideal for individuals with SCD. Many

young adults seem to have more frequent and

severe pain episodes during the first years of

college. This may be related to the rigors of

academic pursuits, excesses because of

increased independence, or perhaps, directly

related to the natural history of the disease (3).

Carefully teaching the individual to establish

excellent study habits and to practice moderation in social activities usually will reduce the

frequency of complications. These changes,

along with discussions with faculty and advisors, almost always allow motivated students

with SCD to complete their studies; however,

more time may be required than is usual for

students without medical problems.

Patients must also be encouraged to discuss

their disease with their employers. Maintaining employment may require intervention by

the health care provider to explain limitations

to the employer, provide excuses for absences

from work, and complete forms for the

employer. Health care providers also should be

familiar with legal protection against discrimination in the workplace, as provided by the

Americans with Disabilities Act. Individuals

with severe disease, cerebral vascular accidents,

and avascular necrosis may truly be disabled.

In these situations, the health care provider

should actively assist in obtaining benefits 

for the patient.

COUNSELING

Social services and psychologic support activities are a critical component of comprehensive

health maintenance in sickle cell patients (18).

These activities are best accomplished if social

workers and mental health professionals are

integrated into the sickle cell care team. Social

workers are invaluable in solving a myriad 

of social and family problems. Mental health

workers can assist in managing psychiatric

problems such as depression, teaching coping

skills, and giving instruction in cognitive and

behavioral management of pain. Nurses are an

essential part of the support team because they

have ongoing interactions with the patients

and their families that facilitate identification

of special patient and family needs. Nurses

coordinate health care efforts and education

about preventive health care, and provide

ongoing psychosocial counseling. 

Vocational rehabilitation services are also

important in adult health maintenance. Patients

with inadequate education can receive training
Chapter 7: Adult Health Care Maintenance

46

in order to acquire satisfying employment 

that supports independent and productive life

styles. This greatly improves their self-image

and often has a positive impact on their health

and utilization of health care resources. For

example, occurrence of avascular necrosis or

leg ulcers in patients with jobs that require

prolonged standing often requires training 

to allow them to qualify for desk jobs.

DENTAL CARE

Routine dental care is important to prevent

loss of teeth and infections that may lead to

other SCD complications. Dental procedures

that require local anesthesia can be performed

in the dentist’s office as with any other patient.

Procedures requiring general anesthesia necessitate hospitalization and may require the usual

perioperative care recommended for sickle cell

patients (see chapter 24, Anesthesia and

Surgery). Patients with a history of rheumatic

heart disease, mitral valve proplapse, heart

murmurs, or those with implanted venous

access catheters and orthopedic prothesis

should receive antibodics for subacute bacterial

endocarditis (SBE) prophylaxis with tooth

extractions, aggressive dental hygiene activities,

gum surgery, or root canal therapy.

REFERENCES

1. Platt OS, Brambilla DJ, Rosse WF, et al. 

Mortality in sickle cell disease. Life expectancy 

and risk factors for early death. N Engl J Med

1994;3430:1639-44.

2. Thomas AN, Pattison C, Serjeant GR. Causes of

death in sickle cell diseases in Jamaica. Br Med J

1982;285:633-5.

3. Platt OS, Thorington BD, Brambilla DJ, et al.

Pain in sickle cell disease. Rates and risk factors. N

Engl J Med 1991;325:11-16. 

4. Charache S, Barton FB, Moore RD, et al.

Hydroxyurea and sickle cell anemia. Medicine

1996;75:300-26.

5. Charache S. Eye disease in sickling disorders.

Hematol/Oncol Clin N Am 1996;10:1357-62.

6. Powars DR, Eliott-Mills DD, Chan L, et al.

Chronic renal failure in sickle cell disease: risk 

factors, clinical course, and mortality. Ann Intern

Med 1991;115:614-20.

7. Falk J, Sheinmen J, Phillips GM, et al. Prevalence

and pathologic features of sickle cell nephropathy

and response to inhibition of angiotensin converting enzyme. N Engl J Med 1992;326:910-15.

8. Gausch A, Cua M, Mitch WE. Early detection and

the course of glomerular injury in patients with

sickle cell anemia. Kidney Int 1996;49:786-91.

9. Powars D, Weidman JA, Odom-Maryon T, et al.

Sickle cell chronic lung disease: prior morbidity

and the risk of pulmonary failure. Medicine

1988;67:66-7.

10. Embury SH, Hebbel RB, Mohandas N, et al.

Sickle Cell Disease. Basic Principles and Clinical

Practice. New York: Raven Press, 1994.

11. Serjeant GR. Sickle Cell Disease. 2nd ed. Oxford:

Oxford University Press, 1992.

12. Pegelow CH, Colangelo L, Steinberg M, et al.

Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med

1997;103:171-7.

13. Dawkins FW, Him KS, Squires RS, et al. Cancer

incidence rate and mortality rate in sickle cell 

disease patients at Howard University Hospital.

1986-1996. Am J Hematol 1997;55:188-92.

14. Thompson RJ, Gil KM, Abrams MR, et al. Stress,

coping, and psychologic adjustment of adults with

sickle cell disease. J Consult Psychol 1992;60:433-40.

15. Faber MD, Koshy M, Kinney TR. Cooperative

study of sickle cell disease: demographic of 

adults with sickle cell disease. J Chronic Dis

1985;48:495-505.

16. Abrams MR, Philips G, Whitworth E. Adaption

and coping: a look at a sickle cell patient population over age 30-an integral phase of the life long

development process. J Health Soc Policy

1994;5:141-60.

17. Mahony BS, Githens JH. Sickle crisis and altitude:

occurrence in the Colorado patient population.

Clin Pediatr 1979;18:431-8.

18. Koshy M, Dorn L. Continuing care for adult

patients with sickle cell disease. Hematol Clin 

N Am 1996;10:1265-73.

ONLINE RESOURCES

http://www.emory.edu/PEDS/SICKLE
COORDINATION OF CARE: 8

ROLE OF MID-LEVEL PRACTITIONERS

47

PREVENTIVE CARE

Each patient encounter is a chance to stress

the importance of preventive health care.

Physical exams, eye exams, and PAP smears

should be done yearly. Immunizations, EKGs,

and pulmonary function tests are also important but, unfortunately, may get overlooked in

busy practices. Ways to help patients remember their annual preventive care needs include

timing appointments with their birthdays 

and reminder letters. Providers can review 

and track their patients’ needs with the use of

computerized databases and calendar functions.

Young patients and their families should be

trained to recognize the signs of infection and

other life-threatening complications of SCD.

They also should learn how to use a thermometer and palpate the spleen. The MLP

must stress constantly the importance of 

prophylactic penicillin and check that parents

give it properly. Parents should be taught

when to call their child’s health care provider

or seek care at a medical facility.

Discussions about sexuality start when patients

are teenagers, since they are more likely to 

ask for help if the subject already has been

raised. Because pregnancy poses a risk for

women with SCD, they often are advised 

to use birth control, especially those taking

hydroxyurea or deferoxamine mesylate

(Desferal) (1,2). If no history of thromboembolism exists, they can safely use any method,

including oral contraceptives, Depo Provera,

Patients with sickle cell disease (SCD) require

multidisciplinary care. They often need assistance to navigate the subspecialties of required

providers. Nurses, nurse practitioners, and

physician assistants, often referred to collectively as mid-level practitioners (MLPs), are wellqualified to coordinate patient care because

they are familiar with holistic approaches.

Patients and their families also need help 

to manage the daily problems of living with 

a chronic disease. Issues for MLPs include preventive and primary care, pain management,

transfusion and chelation therapy compliance,

and education of patients and other health

care providers.

MULTIDISCIPLINARY AND 

SUBSPECIALTY COORDINATION

The MLP is a liaison between the patient, 

primary care provider (often the patient’s

hematologist), and specialists. The MLP’s

important functions are to make appointments, encourage patients to keep them, and

implement the recommendations. Patients may

require a number of specialists—surgeons for

indwelling intravenous access devices; obstetricians/gynocologists for birth control counseling,

PAP smears, and later, menopause management; nephrologists for renal evaluations; cardiologists for cardiac function tests (especially

as patients age); psychologists for counseling;

and social workers for help with welfare, social

security, housing, or disability benefits.
Chapter 8: Coordination of Care: Role of Mid-Level Practitioners

48

or Norplant. The MLP should ensure that 

patients use birth control properly and 

obtain annual PAP smears and STD checks 

as required.

Over time, as patients learn about their medical history and the importance of regular

health care visits, they are encouraged to 

be proactive. They should be empowered 

to choose their own primary care providers 

and make their own appointments.

MANAGEMENT 

OF PAIN EPISODES

(SEE CHAPTER 10, PAIN)

HOME MANAGEMENT

Painful events are the most common manifestation of SCD. Oral analgesics can be used to

manage most mild-to-moderate pain episodes

at home. Nonmedical therapies, such as hot

baths and showers, massage, distraction, and

relaxation techniques, also can relieve pain.

Patients should contact their health care

providers for any symptoms such as fevers,

chest pain, difficulty breathing, or pain that

occurs in atypical locations or is more severe

than usual. Providers must educate patients

and their families about basic pain management principles, use of nonopioid medications

[such as nonsteriodal anti-inflammatory drugs

(NSAIDs) and antidepressants], use of opioid

drugs, and the signs of overuse or abuse.

Adults with SCD often experience chronic pain,

managed by daily use of prescription opioids.

The MLP must be vigilant in checking the

patient’s intake of opioids at home, and should

intervene if there is any suggestion of misuse.

A computerized pharmacy database can help

track usage over time. As few providers as possible should write prescriptions for a patient.

When patients know they can only receive

pain medication from one or two providers,

they are less likely to try “shopping around” 

for multiple prescriptions. A team approach,

which includes the primary care providers,

pain management experts, and a social worker,

is ideal to help patients manage chronic pain.

DAY TREATMENT CENTER

MANAGEMENT

When a painful event no longer can be treated

with oral analgesics, patients are encouraged 

to go to a day treatment center or emergency

room (3,4). Hospitals with many sickle cell

patients have dedicated day treatment clinics,

but in locations without such facilities, sickle

cell patients can be treated in chemotherapy

infusion suites that have been developed for

oncology patients. Outpatient day treatment

has advantages over the use of emergency

rooms, including the usually more prompt

administration of intravenous or intramuscular

pain medications. The MLP, who is familiar

with the patient, acts as a resource for the day

treatment staff and provides key information

and recommendations about each patient’s

needs. The MLP also assesses the patient for

any complications that require referral to a

physician or admission. Again, the patient’s

need for preventive services, prescription

refills, or any other general health issues should

be reviewed. Aggressive outpatient treatment

of moderate-to-severe pain, coupled with consistent, supportive care from familiar staff,

often can prevent hospitalization. 

INPATIENT MANAGEMENT

When hospitalization is needed for a pain

episode or any other SCD complication,

patients should be admitted consistently to the

same unit if possible. They should be treated

with intravenous opioids, by patient-controlled analgesia pumps, or even by patientcontrolled epidural analgesia pumps if available and required (see chapter 10, Pain).
49

The MLP follows the patient and offers 

background about the usual course of illness,

including the patient’s behavior and response

to treatment. This information makes patient

care a better experience for the in-house staff.

The MLP’s input can help the patient receive

appropriate and effective treatment, rather

than being undertreated or viewed as “difficult”

or “drug seeking.” Regular phone contact or

rounds with house staff provide education on

disease management. MLPs also should schedule in-service training for nurses to improve

care for sickle cell patients.

EMERGENCY DEPARTMENT CARE

By adulthood, all SCD patients have had many

emergency room visits. The most common

complaint about emergency care is inappropriate treatment of their disease (5,6). MLPs can

educate emergency department staff about the

course and complications of SCD and proper

pain management. Emergency physicians often

undertreat or overtreat painful episodes, not

because of lack of knowledge about SCD but

because of their unfamiliarity with certain

patients. Given the rapid pace in most emergency rooms, quick access to individual patient

care plans is essential. Computerized records,

patient “identification” cards, or a phone call

to the patient’s health care provider are all ways

to transmit information rapidly to emergency

department personnel. 

A two-sided identification card (7), about the

size of a business card, can contain enough

information to ensure prompt initial treatment for most sickle cell patients. The card

contains pertinent medical history, baseline

labs, allergies, outpatient medications, the

usual treatment plan for the patient’s pain

episodes, and the name and telephone number

of the patient’s primary health care provider.

The latter also signs the card to give it the

authority of a medical record. The card is laminated to be carried at all times by the patient.

TRANSFUSIONS AND 

CHELATION THERAPY

(SEE CHAPTER 25, TRANSFUSION, IRON-OVERLOAD,

AND CHELATION)

For patients being transfused regularly, MLPs

coordinate the schedules and tests for iron

overload. Persons on transfusion regimens usually have few painful events, so they can go to

school or work full time. Ideally, transfusions

should not interfere with these activities, and

they are given on evenings or weekends at

many sickle cell centers. If transfusions can 

be arranged only during regular business

hours, some patients will need help to discuss

this issue with school staff or their employer.

SCD patients should be transfused with

leukocyte-poor, antigen-matched blood to

reduce the frequency of transfusion reactions

and the development of antibodies (8).

Finding antigen-matched blood is often difficult in areas where blood donors are primarily

Caucasian. Providers should encourage blood

donations by African Americans as part of

their community education efforts.

When iron overload is documented, patients

are started on iron chelation therapy. MLPs

should teach children and their families about

the serious complications of iron overload, and

to understand that iron chelation is an integral

part of transfusion therapy, not something to

be ignored because of its inconvenience.

Desferal, the only iron chelator available at

this time, is given by slow, daily, subcutaneous

infusion. MLPs need to monitor compliance

with chelation therapy. If children are begun

on Desferal soon after chronic transfusions

start, compliance during the difficult teen

years may be greater. 
Chapter 8: Coordination of Care: Role of Mid-Level Practitioners

50

PREGNANCY MANAGEMENT 

(SEE CHAPTER 23, CONTRACEPTION

AND PREGNANCY)

Women with SCD can successfully carry pregnancy to term or near term. If a patient on

hydroxyurea is planning or trying to conceive,

the drug should be stopped immediately. The

MLP informs the patient and her family that

the frequency and severity of pain episodes

may increase during pregnancy, but treatment

is the same as that for nonpregnant patients,

with hydration, oxygen, and analgesics,

although doses of the last may be higher.

Reassurance should be given that narcotic 

use during pregnancy does not jeopardize the

baby’s health, but if large doses of opioids are

needed late in pregnancy, the newborn may

require opioid weaning.

The pregnancy should be comanaged by highrisk obstetrics and primary and mid-level SCD

health care providers. Patients are seen every

few weeks to reinforce healthy behaviors. The

MLP educates obstetric staff about current

standards of treatment for SCD during pregnancy and advocates for patients to ensure

proper treatment of painful events.

Prophylactic transfusions during pregnancy are

not warranted unless there are complications

such as acute chest syndrome that ordinarily

would be treated with transfusions. There is no

overall decrease in pain frequency, premature

labor, or deliveries for women who are transfused prophylactically during pregnancy (9).

EDUCATING FAMILIES 

AND THEIR COMMUNITIES

Family education is an integral part of care 

for patients with SCD. Family members gradually should reduce their involvement in their

child’s health care so that the patient can

become more independent. This process is 

not easy, and supportive assistance and counseling are important. 

SCD health care providers can inform their

patients’ communities about SCD by speaking

at meetings. Communities can become

involved through providing social support, 

job opportunities, and blood donations. As

patients go through different life stages, more

of their contacts will have to be educated.

SUMMARY

MLPs want patients to be independent, wellinformed, and active participants in their own

health care. Therefore, coordination must 

balance fostering independence and ensuring

optimal health care. Patient advocacy is a

rewarding aspect of the MLP’s experience 

of working with SCD patients.
51

REFERENCES

1. Castro O. Management of sickle cell disease;recent

advances and controversies. Br J Haematol

1999;107:2-11.

2. Shilalukey K, Kaufman M, Bradley S, et al.

Counseling sexually active teenagers treated with

potential human teratogens. J Adol Health

1997;21:143-6.

3. Benjamin LJ, Swinson GI, Nagel RL. Sickle cell

anemia day hospital: an approach for the management of uncomplicated painful crises. Blood

2000;95:1130-7.

4. Ware MA, Hambleton I, Ochaya I, et al. 

Day-care management of sickle cell painful crisis 

in Jamaica: a model applicable elsewhere? Br J

Haematol 1999;104:93-6.

5. Maxwell K, Streetly A, Bevan D. Experiences 

of hospital care and treatment seeking for pain

from sickle cell disease: qualitative study. BMJ

1999;318:1585-90.

6. Shapiro BS, Benjamin LJ, Payne R, Heidrich G.

Sickle cell-related pain: perceptions of medical practitioners. J Pain Symptom Manage 1997;14:168-74.

7. Mandell E. Medical identification cards facilitate

emergency care for people with sickle-cell disease.

Oncol Nurs Forum (letter) 1997;24:1500-1. 

8. Steinberg MH. Management of sickle cell disease.

N Engl J Med 1999;340:1021-30.

9. Koshy M, Burd L, Wallace D, et al. Prophylactic

red-cell transfusions in pregnant patients with 

sickle cell disease. A randomized cooperative study.

N Engl J Med 1988;319:1447-52.
52
9

53

of the health care team. However, psychosocial

interventions should be woven across the spectrum of medical care. 

Historically, psychosocial interventions were

reserved for emergency situations. Psychologists

or social workers were called for acting-out

behaviors, housing emergencies, noncompliance issues, and other crises. Crisis situations

may be minimized by identifying specific

points at which psychosocial interventions

may be necessary and planning for them, thus

eliminating the frustration and ineffectiveness

often experienced by patients and caregivers.

Pain, the most well-known symptom of SCD,

is the reason for most hospitalizations and 

precipitates many psychosocial crises. Skills 

for coping with pain and other complications 

of SCD must be taught early and reinforced

often (8,9). Which patients will have mild diseases and which will have a more severe course

is not predictable; however, stress is known 

to play an important role in the severity of

chronic illness and pain. Absence of the physical appearance of trauma in severe SCD pain

episodes can confound a patient’s ability to

cope. In addition, many health care providers

are not knowledgeable about sickle cell pain,

its causes, and the best management options.

This can lead to poorly controlled pain, continued treatment failure, and frustration of

patients and providers. 

Sickle cell disease (SCD) is a complex condition that affects the patient, the family, and

the patient’s and family’s relationship with

health care providers and the community. It 

is imperative that teaching the skills necessary

for coping with this illness begin at the time

of diagnosis and continue throughout the life

of the patient, and that providers recognize

that including the extended family and the

community in the education process will

ensure the most positive outcome. 

SUMMARY OF THE 

STATE OF THE ART

No interventions are proven to work with all

patients in all situations (1-15). While a team

knowledgeable about chronic illness and existing intervention models is ideal, available staff

sensitive to the special needs of these patients

can provide effective interventions even in 

primary care settings. Providers must recognize

that the complexities of SCD necessitate 

a team approach to management. Clinical 

management, pain control, coping skills,

genetic counseling, and community interactions, including school and work intervention,

require different expertise. The establishment

of Comprehensive Sickle Cell Centers introduced the concept of comprehensive care for

SCD and refined the multidisciplinary team

approach to health care. Psychosocial support

was recognized as a necessary, integral function

PSYCHOSOCIAL MANAGEMENT
Chapter 9: Psychosocial Management

54

RECOMMENDATIONS

PRENATAL

The availability of prenatal diagnosis offers 

the family choices regarding the continuation

of the pregnancy. When the decision is made

to continue, the practitioner has time to assist

the family in preparing for the arrival of a

child with SCD. This time must be spent educating the parents and family about the disease

and the need for family and community support. The better educated the family and the

community, the better care the patient will

receive. Many communities have SCD support

groups that provide an avenue for sharing 

anxieties, as well as helpful information (5).

Whenever possible, satisfactory housing, 

accessible optimal medical care, and reliable

transportation must be planned before the

baby arrives. 

INFANCY

Health insurance, emergency transportation,

housing, and anxiety about recognizing symptoms are some of the issues new parents may

need help acknowledging and addressing.

Frequent clinic visits and home visits will

allow the opportunity for parents and

providers to establish a comfortable relationship to address these issues and help establish

an ongoing pattern of compliance. 

Although advances in medical research have

increased the chances for longevity, lack of

understanding on the part of providers may

result in inappropriate treatment plans that defy

adherence. The establishment of clinical practice

guidelines in SCD has decreased—but not eliminated—preventable deaths. In addition, noncompliance may undermine the best care plans.

In many cases, a concerted effort to understand

the causes underlying noncompliant behaviors 

is necessary. Skepticism of the health care 

system, as well as barriers to access—such as

location of clinics, laboratories, and pharmacies—can all contribute to noncompliance (11).

CHILDHOOD

The most important task of childhood is

obtaining an education. Teachers must understand that children with SCD should be

expected to perform as well as their peers,

although special education is often needed.

Although undetectable micro-infarcts may

cause brain injury, many of the learning 

difficulties these cause can be overcome with

appropriate assistance. Failure to perform in

school could be a function of neurological

complications of SCD, but the lack of school

success could also be confounded by socioeconomic factors. Disabilities and limitations

must be acknowledged but, more important,

strengths must be identified and inspired.

Pediatric health care professionals, in their

desire to protect children with chronic illness,

often inadvertently erect barriers to normal

childhood behaviors and accomplishments.

While addressing special needs and routine

childhood health care, allowances must be

made for regular school attendance (by flexible

scheduling of appointments), for activity (by

offering alternatives to inappropriate sports),

and for learning (by providing support and

education to school staff).

ADOLESCENT HEALTH CARE

AND TRANSITION

For a discussion of the transition from 

pediatric to adult health care, see chapter 6,

Adolescent Health Care and Transitions.
55

ADULT

As longevity of SCD patients increased, 

the need for continued comprehensive care

became evident; however, while pediatric centers thrive, adult providers are scarce. Longterm management needs to focus not only on

health care needs but on the other goals of

psychosocial well-being—education, independence, and (eventually) marriage and family. 

In adulthood, reproductive issues are of major

concern and often are not addressed in a positive manner. Most individuals, including those

with disabilities, hope to achieve normalcy,

(e.g., independence, a meaningful job, and 

a family) (13). One barrier to care may be

providers’ lack of understanding of the multiple layers of learning needed to live with SCD

and the realities of trying to be “normal” and

fitting in. The pain experienced by many

patients with SCD can be demoralizing and

overwhelming. In addition to the psychological effects of inadequately treated pain,

patients have the added stress of continually

searching for effective pain relief, resulting in

frequent emergency room visits and episodic

care. This cycle can lead to depression, which

is highest among the chronically ill and in 

the 20-40 age group, and is often not recognized or addressed. Continued comprehensive

care—including a strong psychosocial 

component—for adults with SCD is most

important, since prevention of complications

is the key to longevity.

CONCLUSIONS

Psychosocial issues confronting patients, families, providers, and the community, though

multiple and multifactorial, can be addressed

and result in positive patient outcomes.

REFERENCES

1. Vichinsky EP. Comprehensive care in sickle cell

disease: its impact on morbidity and mortality.

Semin Hematol 1991;28:220-6.

2. Vichinsky EP, Johnson R, Lubin BH.

Multidisciplinary approach to pain management 

in sickle cell disease. Am J Pediatr Hematol Oncol

1982;4:328-33.

3. Adams RJ. Lessons from the Stroke Prevention

Trial in Sickle Cell Anemia (STOP) study. J Child

Neurol 2000;15:344-9.

4. Britto MT, Garrett JM, Dugliss MA, et al. Risky

behavior in teens with cystic fibrosis or sickle cell

disease: a multi-center study. Pediatrics

1998;101:250-6.

5. Campbell MK, Motsinger BM, Ingram A, et al.

The North Carolina Black Churches United for

Better Health Project: intervention and process

evaluation. Health Educ Behav 2000;27:241-53.

6. Maunder R, Esplen MJ. Facilitating adjustment to

inflammatory bowel disease: a model of psychosocial intervention in non-psychiatric patients.

Psychother Psychosom 1999;68:230-40.

7. Schultz A, Liptak G. Helping adolescents who have

disabilities negotiate transitions to adulthood. Issues

Compr Nurs 1998;21:187-201.

8. Gallagher RM. Treatment planning in pain medicine. Integrating medical, physical, and behavioral

therapies. Med Clin North Am 1999;83:823-49, viii. 

9. Benjamin LJ, Dampier CD, Jacox AK, et al.

Guideline for the Management of Acute and Chronic

Pain in Sickle-Cell Disease. APS Clinical Practice

Guidelines Series, No. 1. Glenview, IL, 1999.

10. Ross-Lee B, Kiss LE, Weiser MA. Should health

care reform be “color-blind”? Addressing the barriers to improving minority health. J Am Osteopath

Assoc 1994;94:664-71.

11. Lillie-Blanton M, Hoffman SC. Conducting 

an assessment of health needs and resources in 

a racial/ethnic minority community. Health Serv

Res 1995;30:225-36.

12. Bussing R, Aro H. Youth with chronic conditions

and their transition to adulthood. Findings from 

a Finnish cohort study. Arch Pediatr Adolesc Med

1996;150:181-6.

13. Gatchel RJ, Gardea MA. Psychosocial issues: their

importance in predicting disability, response to

treatment, and search for compensation. Neurol

Clin 1999;17:149-66.
Chapter 9: Psychosocial Management

56

14. Telfair J, Myers J, Drezner S. Transfer as a component of the transition of adolescents with sickle cell

disease to adult care: adolescent, adult, and parent

perspectives. J Adolesc Health 1994;15:558-65.

15. Betz CL. Adolescent transitions: a nursing concern.

Pediatr Nurs 1998;24:23-8.

SICKLE CELL DISEASE BOOKS 

(FOR ADDITIONAL REFERENCE)

■ Shapiro BS, Schechter NL, Ohene-Frempong K.

Sickle Cell Disease Related Pain: Quick Reference

Guide for Clinicians. New England Regional

Genetics Group (NERGG), 1994.

■ Hill SA. Managing Sickle Cell Disease in LowIncome Families. Temple University Press, 1994.

■ Brandon WE. Disabled: My Life, the First Fifty

Years with Sickle Cell Disease. Philadelphia: VACS

Books, 1997.

■ Nash, KB. Psychosocial Aspects of Sickle Cell Disease:

Past, Present, and Future Directions of Research. New

York: Haworth Press, 1994. 

■ Mindice K, Elander J. Sickle Cell Disease: A

Psychosocial Approach. Oxford, UK: Radcliffe

Medical Press, Ltd, 1994.

■ Franklin I. Sickle Cell Disease: A Guide for Patients,

Caregivers and Health Workers. London: Faber &

Faber, 1990.

■ Bloom M. Understanding Sickle Cell Disease: 

For General Readers a Guide to Understanding 

a Debilitating Genetic Disease That Affects Tens of

Thousands Who Are of African Ancestry. University

of Mississippi Press, 1995. 

■ Ballas SK. Sickle Cell Pain, Progress in Pain 

Research and Management, volume 11. International Association for the Study of Pain, 1998.
57

TREATMENT OF ACUTE AND 

CHRONIC COMPLICATIONS
58
PAIN 10

59

and use patients’ reports as the primary source

for assessment, except in infants where behavioral observations are the main basis for evaluation. Most SCD pain can be managed well 

if the barriers to assessment and treatment are

overcome; a comprehensive psychosocial clinical assessment should be performed yearly

(more often for patients with frequent pain). 

TYPES AND CHARACTERISTICS

OF PAIN ASSOCIATED WITH

SICKLE CELL DISEASE

The most common pain states associated with

SCD are summarized in table 1. When classified according to temporal characteristics,

sickle cell pain can be described as acute,

chronic, or mixed.

ACUTE PAIN

The acute painful event is the most common

type of pain, characterized by an unpredictably

abrupt onset without any other explanation.

Intensity varies from a mild ache to severe and

debilitating pain. Uncomplicated acute pain 

is self-limited and generally lasts hours to a

few days, but it can persist or recur and may

migrate from one site to another. With comorbid conditions or inadequate treatment, some

painful events can last for weeks.

CHRONIC PAIN

Chronic pain often is defined as pain that 

lasts 3 to 6 months or more and that no

longer serves a warning function. The time

Editors’ Note: The information in this chapter

has been abstracted with permission from the

1999 Guideline for the Management of Acute

and Chronic Pain in Sickle Cell Disease, published by the American Pain Society (1). This

guideline is based on scientific evidence and the

clinical judgment of experts in the management

of acute and chronic pain in sickle cell disease

(SCD). The information is provided in an

abbreviated form with several references in the

guideline, and additional comments in italics.

The hallmark clinical manifestation of SCD 

is the acute vaso-occlusive event, or painful

episode. This unique type of pain can start as

early as 6 months of age, recur unpredictably

over a lifetime, and require treatment with

opioids. Painful events are the top cause of

emergency room visits and hospitalizations,

and are a major focus of home management

(2). Management of pain in childhood affects

a person’s ability to cope as an adolescent and

adult. Past, present, and anticipated experiences affect pain management, so pain must

be assessed and treated in a developmental and

psychosocial context.

Major barriers to effective management of

pain are clinicians’ limited knowledge of SCD,

inadequate assessment of pain, and biases

against opioid use. Biases are based on ignorance about opioid tolerance and physical

dependence, and confusion with addiction.

Unwarranted fear of addiction is common

among patients and families, as well as health

care workers. Clinicians should ask about pain
Table 1. Major Pain Syndromes in Patients with Sickle Cell Disease (3)

Acute Pain Syndrome Chronic Pain Syndrome

Acute chest syndrome Arthritis

Cholecystitis Arthropathy

Hand-foot syndrome Aseptic (avascular) necrosis

Painful episodes Leg ulcers

Priapism Vertebral body collapse

Right upper quadrant syndrome

Splenic sequestration

Chapter 10: Pain

60

distinction is arbitrary, and the condition may

be difficult to distinguish from frequently

recurring acute pain, as in SCD. Chronic pain

(e.g., from bone changes) can be debilitating,

both physically and psychologically. The

involvement of sensation, emotion, cognition,

memory, and context can pose difficult management problems (4).

MIXED PAIN

Pain frequently is mixed as to type and mechanism due to confounding factors. Acute pain 

can be superimposed on chronic pain, and 

frequent episodes of acute pain can resemble

chronic pain. Neuropathic pain is insufficiently diagnosed in SCD but can result from

nerve infarction, compression from bony

structures, nociceptive substances, and/or 

iron overload neuropathy.

RECOMMENDATIONS 

FOR ASSESSMENT AND 

TREATMENT OF PAIN

A dedicated facility, such as a day hospital, which

includes experts to manage SCD pain, can

reduce overnight admissions and provide timely

relief (5). Should this resource be unavailable,

the following approach is recommended 

for patients with painful episodes due to SCD.

Patients should undergo a thorough history and

physical examination to determine whether an

illness might have precipitated the pain, so that

the cause and symptom can be treated simultaneously. Patients should be seen immediately by 

a physician if they experience severe abdominal

pain, recurrent vomiting, respiratory symptoms,

neurologic signs of paresis or paralysis, acute joint

swelling, priapism, or abrupt fall in hemoglobin.

Superimposition of acute pain on chronic pain

may confound assessment and treatment.

Clinicians should understand the pain in detail

to tailor therapy to the needs of the patient.

Assessment depends on chronologic age, developmental stage, functional status, cognitive

ability, and emotional state, so these factors

should be considered in the choice of measurement tools. Pain management should be aggressive to relieve pain and achieve maximum 

function. Physicians should reassess pain frequently and adjust treatment to provide relief.

ASSESSMENT OF PAIN IN SCD

The goals for assessment of acute and chronic

pain are to characterize a patient’s pain and

related experiences, provide a basis for therapeutic decisions, and document the efficacy 
61

of pain control. Because pain is subjective,

assessment requires patients’ self-reports, valid

tools, and measurements repeated over time.

Clinically, self-reports are supplemented by

physical findings, laboratory data, and diagnostic procedures. Figure 1 is a flowchart to

guide clinicians in pain assessment.

There are two major kinds of assessment:

■ Rapid assessment of an acute painful

episode. This type of assessment deals with

an isolated pain event and focuses on pain

intensity, prompt treatment, and relief.

■ Comprehensive assessment for chronic 

pain or followup of persons who have acute

pain. This type of assessment usually

occurs at the end of a painful episode, 

at office/clinic visits for chronic pain, or

between episodes. The objective is treatment planning (4), which involves the

patient, family (6), and health care team.

Assessment is multidimensional and

should include physiologic, sensory, 

affective, cognitive, behavioral, and 

sociocultural factors.

Figures 2 to 4 are examples of assessment

instruments. Figure 2 is a unidimensional

“Faces’ Pain” intensity scale (7,8), and figures 

3 and 4 show a visual analog scale (VAS) (9)

and multidimensional scales for either chronic

or acute pain assessment. Diaries are also 

useful for assessment of pain at home (10).

Rapid Assessment of Acute Pain Episodes

Severe pain should be considered a medical

emergency that prompts timely and aggressive

management (figure 5) until the pain is tolerable. The following recommendations are for

treatment in the emergency room, day treatment center, or hospital if the patient is

admitted directly.

■ Begin hydration. Total fluids should not

exceed 1.5 times maintenance (including

volume for drug infusions). Initial fluid

should be 5 percent dextrose + half-normal saline + 20 mEq KCl/L, adjusted for

serum chemistry results.

■ Assess the patient for the cause of pain 

and complications.

■ Rapidly assess pain intensity using 

a simple measurement tool. 

EMERGENCY TREATMENT

OF ACUTE PAIN EPISODES

Initial Treatment

The patient in acute pain at an emergency

room or clinician’s office usually has exhausted

all homecare options. Failure of home or outpatient therapy signals the need for parenteral

medications, which include strong opioids like

morphine. If a patient is on long-term opioids

at home, tolerance may have developed, so the

new episode can be treated with a different

opioid or with a higher dose of the same drug

if it is the only one the patient tolerates.

In general, medications and loading doses

should be selected after assessment of the

patient’s current condition and consideration

of the patient’s history, including 

■ usual drugs, dosages, and side effects 

during acute pain. 

■ effective treatments at home. 

■ medications taken since the onset 

of present pain. 

For patients with recurrent pain, the best initial dose of opioids for severe sickle cell pain 

is that which provided adequate analgesia at 

a previous time. Some patients and clinicians

may prefer a loading dose of parenteral morphine, usually equivalent to 5-10 mg (0.1-

0.15 mg/kg for children), depending on pain
62

Chapter 10: Pain

Determine type of pain

(onset, duration, frequency)

Acute or Chronic?

Acute Chronic

Brief

No

Yes

Persistent

(Frequently 

occurring acute or 

mixed acute superimposed 

on chronic)

Identify appropriate 

interventions based on 

comprehensive assessment

Conduct 

comprehensive 

assessment

Summarize, 

assimilate, and 

prioritize profile

Determine 

related 

symptoms

Determine 

probable cause(s) 

and precipitating 

factors

Related to SCD?

Treatment 

history

Brief or Persistent?

Conduct complete 

workup to determine 

etiology of pain

Treat based on 

characteristics of episode

Physical factors

• Blood pressure

• Respiration

• Oxygen saturation level 

• Chest/abdomen 

• Mobility of joints

• Lab/x-ray data 

• Comorbidities/complications

• Pain sites 

• Tenderness

• Warmth

• Swelling 

• Heart rate 

Determine 

characteristics, 

location, and 

intensity based 

on self-report

Determine 

characteristics, 

location, 

intensity, and 

impact on 

activities and 

mood based on 

self-report and 

observation

Demographic and 

Psychosocial Factors

• Age

• Gender

• Developmental level

• Family factors

• Cultural factors

• Adaptation to SCD

• Coping styles

• Cognitive abilities

• Mood

• Level of distress

Impact of Pain 

on Functioning

• Self-care

• School

• Work

• Social activities

• Relationships

• Parenting ability 

(adults)

• Frequency of painful episodes 

in previous year

• Number of emergency department 

visits in past year

• Frequency and duration 

of hospitalizations

• Other types of pain

• Pain medication history

• Current medication regime

Figure 1. Assessment Overview
63

intensity, patients’ size, and prior opioid experience. Smaller doses of 2.5-5 mg (0.05-0.1

mg/kg for children) can be added later.

■ Intramuscular administration of medication

should be avoided, if possible, because

absorption is unpredictable and children

may find this method frightening and

painful.

■ For severe pain, intravenous (IV) administration is the route of choice. For patients

with poor venous access, many opioids 

can be administered via the subcutaneous

route by bolus dosing, continuous 

infusion, or patient-controlled analgesia

pumps (PCA).

Patients who receive opioid agonists should

not be given mixed opioid agonist-antagonists

(e.g., pentazocine, nalbuphine, butorphanol),

because they can precipitate withdrawal 

syndromes.

Frequent Reassessment

Assess the pain before pharmacological intervention, at the peak effect of the medication,

and at frequent intervals, until the adequacy

and duration of the medication’s effects have

been determined. Define the measure to be

used in determining response to therapy. For

example, on a scale of 0 to 4 (0 = none, 1 =

little, 2 = moderate, 3 = good, and 4 = complete), relief could be defined as a score of 2 

or greater and a pain intensity reduction of at

least 50 or 60 percent from the upper end of

the pain scale. Evaluate the response to therapy

15 to 30 minutes after each dose by assessing

pain intensity, relief, mood, and sedation level.

Frequency of reassessment should take into

account the route of administration. Record

the pain assessment and reassessments, along

with the patient’s other vital signs, in the

patient’s chart and/or on a bedside flowsheet,

so that the effectiveness of treatment can be

evaluated in a timely manner.

Titration to Relief

The recurrent, lifelong nature of the pain

must be considered for consistent management of acute pain episodes, so the pain is

made tolerable and side effects are minimized.

Figure 6 presents three titration methods used

in different situations. Scheme 1 is an aggressive approach when close observation is possible. After the loading dose, one reassesses the

patient at 30-minute intervals and, based on

the results, treats with one-quarter to one-half

of the loading dose until the patient experiences relief. Scheme 2 is for more gradual

titration. The patient is started immediately

on “by the clock” (BTC) doses based on prior

history (e.g., morphine, 8 mg every 2 hours).

“Rescue” doses are used for titration between

BTC doses until relief is achieved. Scheme 3 

is for titration using PCA. 

Medications may be combined to enhance 

the efficacy/safety ratio. Anti-inflammatory

agents, acetaminophen, antihistamines, and

other adjuvant medications can be used with

opioids. Side effects, such as respiratory

depression, should be monitored and treated.

If a patient has pain between doses, the intervals could be decreased or the dose increased.

For patients on large doses of opioids, an alternative approach is to change to one-half the

equianalgesic dose of another opioid and

repeat titration to relief.

0 No Hurt1

Hurts 

Little Bit

2 Hurts Little 

More

3 Hurts Even 

More

4

Hurts 

Whole Lot

5

Hurts 

Worst

Figure 2. Wong-Baker Faces Pain Rating 

 Scale (7,8)
For adolescents and adults, the card is folded along the broken line so that each measure is presented separately in the numbered order.

Figure 3. Memorial Pain Assessment Card (9)

Best 

mood

Worst

mood

Worst 

possible 

pain

Least 

possible 

pain

Just noticeable

No pain

Moderate

Strong

Mild

Weak

Excruciating Severe

4

Mood Scale

1

Pain Scale

2

Complete 

relief 

of pain

No relief 

of pain

Relief Scale

3

64

Chapter 10: Pain

DATE ____/____/______ TIME ____:_____

Figure 4. Multidimensional Assessment of Acute Pain

No pain Worst possible pain

0 123456789 10

1. Circle the number that describes your pain right now.

No relief Complete relief

0 123456789 10

2. Circle the number that describes your pain relief.

Worst mood Best mood

0 123456789 10

3. Circle the number that best describes your mood.

Not drowsy Asleep

FRONT

RIGHT LEFT

LEFT RIGHT

BACK

0 123456789 10

4. Circle the number that describes how drowsy you feel.

5. Shade the figure

where you feel pain.

6. Mark an X where

you hurt most.
65

Change the medication delivery route or 

regimen if the pain is poorly controlled with

boluses, or if doses are required too frequently

for relief. Intraspinal analgesics, which require

anesthesiology consultation, should not be

considered before an adequate trial of maximal

doses of systemic opioids and adjuvant medications; however, case studies suggest that

epidural anesthetics alone or with fentanyl can

be effective in acute refractory pain of SCD (11). 

Disposition

After treatment in an emergency room,

patients may be sent home or admitted 

as inpatients. Prescriptions for equianalgesic

doses of oral opioids should be written for

home use if needed to maintain pain relief. 

If pain does not diminish significantly after

rigorous therapy, the patient should be 

admitted as an inpatient. 

PHARMACOLOGICAL MANAGEMENT

OF SICKLE PAIN

Analgesics are the foundation for the management of sickle cell pain, and their use should

be tailored to the individual patient. Sedatives

and anxiolytics alone should not be used to

manage pain, because they can mask the

behavioral response to pain without providing

analgesia. 

Management of pain associated with SCD

consists of the use of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and

adjuvant medications (12,13). Management of

mild-to-moderate pain should include NSAIDs

or acetaminophen, unless there is a contraindication; these are nonsedating, so patient activities can continue. If mild-to-moderate pain

persists, an opioid can be added. 

Treatment of persistent or moderate-to-severe

pain relies on repeated assessments and appropriate increases in opioid strength or dose. The

type of oral preparation used depends on the

characteristics and expected duration of the

pain. If the patient’s pain typically is of short

duration (less than 24 hours), opioids or formulations with a short duration of action are

appropriate, with the advantage of quicker

onset of action. For patients whose pain

requires several days to resolve, a sustainedrelease opioid preparation is more convenient to

take and provides a more consistent analgesia. 

The combination of nonopioid analgesics 

with opioids can permit lower doses of the 

latter. If an opioid like codeine is used, pain

relief is accompanied by mild sedation that

can facilitate rest. 

NSAIDs and Acetaminophen

Mild-to-moderate pain in children with a fever

or viral syndrome generally is managed with

NSAIDs or acetaminophen; aspirin is avoided

due to a risk of Reye’s syndrome. Acetaminophen

is an analgesic but not an anti-inflammatory

drug, and both NSAIDs and acetaminophen

have ceiling doses above which escalation does

not result in increased relief. Most NSAIDs

are given only orally, except for ketorolac,

which can be used orally or parenterally. 

NSAIDs and acetaminophen are not benign.

Many patients with SCD have varying degrees

of hepatic impairment, and acetaminophen

may be toxic when liver disease is present.

NSAIDs also are contraindicated in patients

with gastritis, peptic ulcers, coagulopathies,

and renal failure. All NSAIDs are associated

with renal failure when used on a long-term

basis, and patients must be told not to exceed

safe doses of these medications.

Clinicians should monitor doses and frequency of treatment, and order urinalyses and

renal function tests every 3 to 6 months in

chronic users. Current trials have been inconclusive regarding use of the parenteral NSAID
66

Severe acute pain

Assess pain, treat, 

and conduct complete 

workup to determine 

etiology

Typical pain?

Related to SCD?

Currently on chronic 

opioid therapy?

Yes

No

Assess for common acute pain 

states associated with SCD

Determine type of pain

(onset, duration, frequency)

Determine pain characteristics

(intensity, location, and quality 

based on self-report)

Determine cause

Determine related symptoms 

(look for infections, 

complications, other 

comorbidities, and 

precipitating factors)

Obtain treatment history: 

home meds, acute pain, hospital Rx, 

meds past 24 hrs, out-of-home meds?

Examine pertinent 

physical factors

Summarize assessment profile and select 

treatment (based on characteristics 

of episode, prior treatment 

history, and physical findings) Start IV loading dose of short-acting opiod

Adults/children < 50 kg of body weight

• Morphine 0.1-0.15 mg/kg

• Hydromorphone 0.015-0.020 mg/kg

Adults/children > 50 kg of body weight

• Morphine 5-10 mg

• Hydromorphone 1.5 mg

Administer by IV (if sufficient 

venous access) or subcutaneous route 

(if insufficient venous access)

Figure 5a. 

Arrival at 

emergency 

department

Assess

the pain

Time elapsed 

from admission 

to emergency 

department

15-20 

minutes

Select medication and loading dose 

based on overall assessment and prior 

treatment history.

Note: Patient/family often know what 

medication and dosage have been 

effective in the past.

Yes No

Yes

No

Chapter 10: Pain

(continued)
Provide rescue dosing

Monitor effectiveness

Admit to hospital

Refer back to 

clinician managing SCD

Moderate

pain relief?

Side effects

tolerable?

Breakthrough 

pain?

Treatment 

effective?

Complications

Can be 

maintained at 

home with oral 

medication?

Yes

Yes

No

Yes

No

Yes

No

No

No

No

Yes

Yes

Assess degree of relief

q 15-30 minutes

Continue to titrate with 

1/4-1/2 loading dose to relief 

plus coanalgesic

Use adjuvant medications 

in combination to enhance 

the efficacy: side effect ratio

Add combination therapy as indicated

(anti-inflammatory and/or antihistamine) 

to improve response to therapy

Send home with prescribed level 

of medication (PO) to maintain 

adequate pain relief

Begin around-the-clock dosing

Figure 5b. 

Reassess 

frequently

Titrate 

to relief

Maintain 

relief

Make 

disposition

Time elapsed from admission 

to emergency department

2-8 

hours

30 

minutes

67
Chapter 10: Pain

68

ketorolac as a single agent. It may be added to

opioids in situations in which opioids provide

inadequate analgesia after optimal titration, 

or when the side effects of opioids are problematic. Due to the need for more safety data,

the current recommendation is that ketorolac

should not be used by any route or combination of routes for longer than 5 days in a

given month because of the increased risk 

of toxicity (14).

Opioids

Moderate-to-severe pain is treated with opioids (figure 6, tables 2-3), with or without

NSAIDs and adjuvant medications. Codeineequivalent opioids, such as oxycodone and

hydrocodone, are used for moderate pain.

When opioids are given for the first time for

severe pain, morphine sulfate or hydromorphone should be used. Other morphine-equivalent opioids include oxymorphone, levorphanol, meperidine, fentanyl, and methadone. 

Considerations in opioid selection include

type of pain, analgesic history, pain intensity,

route of administration, cost, local availability,

provider comfort with analgesic modalities,

and patient preference. Patient preference

should not be ignored, because it is likely 

that individual variations in drug metabolism

contribute to differences in adverse effects 

or dose-response to analgesia. The recurrent

nature of SCD pain often allows the patient 

to experience multiple treatment options and

learn which regimen provides predictable relief.

Meperidine is the most commonly used opioid

in hospitals for SCD patients with acute

painful episodes. Many patients prefer meperidine because of long-standing prescribing

practices of physicians, and they are apprehensive about changing to a different medication.

There is general agreement, however, that oral

meperidine should not be used for acute or

chronic pain, and the indication for parenteral

meperidine use for acute sickle pain is controversial. Ideally, parenteral meperidine should

no longer be used as first-line treatment of

acute pain in SCD because of CNS toxicity

related to its metabolite, normeperidine. It has 

a long half-life and is a cerebral irritant, so

accumulation can cause effects ranging from

dysphoria and irritable mood to clonus and

seizures. Thus, meperidine should be reserved

for brief treatments in patients who have 

benefited, who have allergies, or who are 

intolerant to other opioids such as morphine

and hydromorphone. 

Meperidine should not be used for more than

48 hours or at doses greater than 600 mg/24

hours (13). Because normeperidine is excreted

by the kidneys, meperidine is contraindicated

for patients with impaired renal function as well

as for patients who are taking monoamine oxidase inhibitor antidepressants.

Fentanyl is in the same chemical family as

meperidine and can be used parenterally. In

addition, a transdermal fentanyl preparation

can be an adjunct for managing chronic sickle

pain because it has a 48-72 hour duration 

and provides continuous analgesic effect by 

a noninvasive, nonoral route of administration.

Hypoventilation and respiratory depression can

occur with the use of fentanyl (14).

Chronic Opioid Therapy. For patients with 

several days of pain, or who require chronic

opioid therapy, sustained-release or long-halflife opioid preparations are more convenient

and provide more consistent analgesia. Shortacting opioids may be used for rescue dosing

early in the treatment regimen for breakthrough pain, or until the sustained-release

preparation reaches steady-state levels. In these

situations, the administration of adjuvant

medications may be needed to control predictable opioid side effects such as pruritus,

nausea, sedation, and constipation.
69

Relief?

Relief?

Relief?

Relief?

Relief?

No No

No

Yes Yes

Yes

No

No

Yes

Yes

Continue maintenance 

therapy and reassessment

Treat with 

1/4-1/2 bolus of 

loading dose

Reassess and 

treat q 15-30 

minutes Reassess before 

each titration

Titrate with 

rescue dosing 

of 1/4-1/2 of 

by-the-clock dose

Give 1/3 

of estimated 

24-hour dosing 

by continuous 

infusion

2/3 of 24-hour 

dosing in 

divided doses 

per hour 

on demand

Reassess in 

15-30 minutes

Start 

by-the-clock 

dosing

Calculate 

24-hour dosing

Loading dose

Set lockout intervals 

at q 5 minutes 

during first 2 hours 

to relief

(titrate phase)

Maintain relief with 

around-the-clock 

dosing

Reassess at 30 

minute intervals

Adjust demand 

interval to 

q 15 or 30 minutes

Maintain relief with 

around-the-clock 

dosing

Set rescue dose at 

approximately 1/2 of 

maintenance dose for 

breakthrough pain

Set limits for number 

of rescue doses 

over given period, 

after which the 

maintenance dose 

should be adjusted

Figure 6. Titration Schemes

Loading dose Loading dose

Scheme 1

Aggressive

Scheme 2

Modified

Traditional

Scheme 3

Patient-Controlled

Analgesia (PCA)
70

Chapter 10: Pain

Table 2. Usual Starting Doses of Opioid Analgesics in Opioid-Naive Adults and Children ≤ 50 kg Body Weight1

Usual Starting Dose for Moderate-to-Severe Pain

Medication Oral Parenteral

Short-acting opioid agonists2

Morphine3 (MSIR) 0.3 mg/kg every 3-4 h 0.1-0.15 mg/kg every 2-4 h

Hydromorphone3 (Dilaudid) 0.06-0.08 mg/kg every 3-4 h 0.015-0.020 mg/kg every 3-4 h

Meperidine4 (Demerol) not recommended (1.1-1.75 mg/kg not recommended (0.75-1.0 mg/kg,

every 3-4 h only if deemed to 1.1-1.75 mg/kg every 3-4 h 

be necessary after evaluation). only if deemed to be necessary 

after evaluation).

Combination opioid/NSAID preparations5

Codeine6 (with aspirin 0.5-1mg/kg every 3-4 h not recommended

or acetaminophen) 

Hydrocodone (in Lorcet, 0.15-0.20 mg/kg every 3-4 h not available

Lortab, Vicodin, others)

Oxycodone (Roxicodone, also in 0.15-0.20 mg/kg every 3-4 h not available

Percocet, Percodan, Tylox, others)

Long-Acting Opioid Agonists Because is not possible to determine the appropriate starting dose 

(e.g., morphine controlled-release, of controlled-release opioids without knowing the patients’s opioid

Levorphanol, methadone, and requirements as determined by immediate-release preparation,

oxycodone controlled-release) usual starting doses are not listed for these medications. 

1Caution: Doses listed for patients with body weight less than 50 kg cannot be used as initial starting doses for babies younger than 

6 months of age. 

2Caution: Recommended doses do not apply to patient with renal or hepatic insufficiency, or other conditions affecting drug 

metabolism and kinetics.

3Caution: For morphine, hydromorphone and oxymorphone, rectal administration is an alternate route for patients unable to take 

oral medications. Equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.

4Chronic administration of meperidine may result in central nervous system stimulation, including agitation, irritability, nervousness,

tremors, twitches myoclonus, or seizures, due to accumulation of the toxic metabolite normeperidine. The risk is much greater for

patients with renal or hepatic impairment.

5These products contain aspirin or acetaminophen. Total daily doses of acetaminophen that exceed 6 grams may be associated with

severe hepatic toxicity. Aspirin is contraindicated in children in the presence of fever or other viral disease because of its association 

with Reye’s syndrome.

6Caution: Codeine doses higher than 65 mg often are not appropriate because of diminishing incremental analgesia with increasing

doses but continually increasing nausea, constipation, and other side effects.

DO NOT REPRODUCE TABLES 2 AND 3 WITHOUT INCLUDING THIS WARNING.

NOTE: Published tables vary in the suggested doses that are equianalgesic to morphine. Clinical response is the criterion that

must be applied for each patient; titration to clinical responses is necessary. Because there is not complete cross-tolerance among

these drugs, it is usually necessary to use a lower than equianalgesic dose when changing drugs and to retitrate to response.
71

Table 3. Usual Starting Doses of Opioid Analgesics in Opioid-Naive Adults and Children ≥ 50 kg Body Weight1

Usual Starting Dose for Moderate-to-Severe Pain

Medication Oral Parenteral

Short-acting opioid agonists2

Morphine3 (MSIR) 10-30 mg every 3-4 h 5-10 mg every 2-4 h

Hydromorphone3 (Dilaudid) 7.5 mg every 3-4 h 1.5 mg every 3-4 h

Codeine4 15-60 mg every 3-6 h

Meperidine (Demerol)5 not recommended (50 -150 mg not recommended (50-150 mg 

every 3-4 h only if deemed to every 3 h only if deemed to 

be necessary after evaluation). be necessary after evaluation).

Oxymorphone3 (Numorphone) not available 1-1.5 mg every 6 h or 0.5 mg IV

and cautiously titrate upward

Oxycodone (Roxicodone, OXYIR) 10 mg every 4-6 h not available

Long-Acting Opioid Agonists Because is not possible to determine the appropriate starting dose 

(e.g., morphine controlled-release, of controlled-release opioids without knowing the patients’s opioid

Levorphanol, methadone, and requirements as determined by immediate-release preparation, usual

oxycodone controlled-release) starting doses are not listed for these medications. 

1Caution: Recommended doses do not apply to adult patients with body weight less than 50 kg. For recommended starting doses

for children and adults less than 50 kg body weight, see table 2.

2Caution: Recommended doses do not apply to patient with renal or hepatic insufficiency, or other conditions affecting drug 

metabolism and kinetics.

3Caution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to 

take oral medications. Equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.

4Caution: Codeine doses higher than 65 mg often are not appropriate because of diminishing incremental analgesia with increasing

doses but continually increasing nausea, constipation, and other side effects.

5Chronic administration of meperidine may result in central nervous system stimulation, including agitation, irritability, nervousness,

tremors, twitches, myoclonus, or seizures, due to accumulation of the toxic metabolite normeperidine. The risk is much greater for

patients with renal or hepatic impairment.

Equianalgesic doses of oral opioids are prescribed for home use if needed for the pain

relief achieved in the emergency room or 

day hospital, or for recurrence of severe pain.

Opioid tolerance and physical dependence 

are expected with long-term opioid use and

should not be confused with psychological

dependence (addiction). Opioids should be

tapered carefully in patients at risk for withdrawal syndromes.

Side Effects of Opioids. Sedation usually precedes one of the most feared side effects of 

opioids, respiratory depression. Fortunately,

tolerance to this side effect develops faster than

to the analgesic action; nevertheless, nurses

should monitor sedation levels when patients

are at risk. If sedation persists after prompt 

intervention, then pulse oximetry, apnea 

monitors, and blood gas levels may be needed.
72

Chapter 10: Pain

Nausea and vomiting can be treated with

antiemetics such as compazine, metochlorpropamide, or hydroxyzine. Pruritus can be

treated with hydroxyzine or with diphenhydramine; smaller doses given more frequently

may be more effective, causing less sedation

than larger doses administered less often.

Patients should not be considered allergic to

an opioid only on the basis of itching. If opioids are prescribed for home use, patients also

should take stool softeners daily to prevent

constipation.

Adjuvant Therapies

Adjuvant medications are used to increase 

the analgesic effect of opioids, reduce the side

effects of primary medications, or manage

associated symptoms such as anxiety. No 

controlled studies of adjuvant medications in

SCD have been done, and guidelines for their

use are derived from use in other pain states. 

Sedatives and anxiolytics can be given to

reduce anxiety associated with SCD if pain

also is being treated. When used alone, 

however, these drugs can mask the behavioral

response to pain without analgesic relief. 

If they are combined with potent opioids, 

care must be taken to avoid excessive sedation.

Although much distress and anxiety in patients

is related to unpredictable interruption of 

normal activities and the uncertain duration 

of pain, some symptoms may be reduced by 

a consistent treatment plan.

Antidepressants, anticonvulsants, and clonidine can be used for neuropathic pain, and

antihistamines may counteract histamine

release by mast cells due to opioids.

TRANSFUSIONS

(SEE CHAPTER 25, TRANSFUSION, 

IRON OVERLOAD, AND CHELATION)

A small percentage of patients have unusually

frequent and severe pain episodes. They have 

a poor quality of life and cannot perform daily

activities. There is empirical evidence that chronic transfusions may reduce debilitating pain

(15), but patients must be assessed periodically 

as part of a multidisciplinary pain program.

TOLERANCE, PHYSICAL 

DEPENDENCE, ADDICTION, 

AND PSEUDOADDICTION

A major barrier to effective management of

sickle cell pain is a lack of understanding of

opioid tolerance, physical dependence, and

addiction. Tolerance and physical dependence

are expected pharmacologic consequences of

long-term opioid use and should not be confused with addiction.

■ Tolerance is a physiologic response to the

exogenous administration of opioids, and

the first sign is decreased duration of medication action. When tolerance develops,

larger doses or shorter intervals between

doses may be needed to achieve the same

analgesic effect.

■ Physical dependence also is a physiologic

response to the exogenous administration

of opioids. It requires no treatment unless

withdrawal symptoms—such as dysphoria,

nasal congestion, diarrhea, nausea, vomiting, sweating, and seizures—occur or are

anticipated. The risk varies among individuals, but when opioids are given for more

than 5 to 7 days, doses definitely should

be tapered to avoid physiologic symptoms

of withdrawal. 
73

■ Addiction is a not physical dependence

but, rather, a psychologic dependence.

Addiction is a complex phenomenon with

genetic, psychologic, and social roots. The

use of opioids for acute pain relief is not

addiction, regardless of the dose or duration of time opioids are taken. Patients

with SCD do not appear to be more likely

than others to develop addiction. The

denial of opioids to patients with SCD

due to fear of addiction is unwarranted

and can lead to inadequate treatment.

■ Pseudoaddiction (16) applies to patients

who receive inadequate doses of opioids or

whose doses are not tapered, and therefore

they develop characteristics that resemble

opioid addiction. 

Understandably, some patients whose pain is

managed poorly will try to persuade medical

staff to give them more analgesic, engage in

clock-watching, and request specific medications or dosages. Staff often regard this as

manipulative or demanding behavior. Patients

with SCD often are quite knowledgeable

about the medications they take for their condition and the doses that have worked in the

past. Requests for these specific medications

and doses should not be interpreted as indications of drug-seeking behavior. In addition,

patients who have had frequent painful

episodes often behave in ways learned from

prior experiences. A patient, for example, who

believes that a medication will not be given

unless he or she appears to be in severe pain

may lie quietly when alone but begin to

writhe and moan when a nurse or physician

enters the room. Pseudoaddiction or clockwatching behavior usually can be resolved by

effective communication with the patient to

ensure accurate assessment and by adequate

opioid doses. 

As in the general population, some persons

with SCD will use illicit drugs, such as

cocaine. Patients who have problems with 

substance abuse require individual treatment

to provide competent and humane management of their pain. The treatment of patients

who have problems with substance abuse is 

complex and is beyond the scope of this chapter;

consultation with appropriate specialists should

be considered.

PATIENT EDUCATION

Education about pain management is the basis

for collaboration among patients, families, and

health care providers for optimal treatment.

SCD is incurable, except possibly by bone

marrow transplantation. Health care professionals should tell patients about hydroxyurea,

the drug that is used prophylactically to

reduce the frequency of acute painful events 

in severe cases. While no drug is approved 

for treatment of SCD itself during an acute

episode, patients must be assured that when

they do experience pain, it will be taken seriously and managed optimally with a plan.

Because patient needs change over time, 

the care plan must be assessed and modified

accordingly. Nurses and physicians who care

for inpatients with sickle cell pain should be

trained to assess and manage pain so they do

not unwittingly dismiss a patient’s pain or

cause an exacerbation of pain-related behaviors.

Education of clinicians who work in emergency rooms or day treatment centers is also

important because inconsistent or adversarial

care given in these settings can cause mistrust

or other problems that affect patients’ relationships with other health care professionals.
74

Chapter 10: Pain

REFERENCES

1. Benjamin LJ, Dampier CD, Jacox AK, et al.

Guideline for the Management of Acute and Chronic

Pain in Sickle-Cell Disease. APS Clinical Practice

Guidelines Series, No. 1. Glenview, IL, 1999.

2. Platt OS, Thorington BD, Brambilla DJ, et al.

Pain in sickle-cell disease. Rates and risk factors. 

N Engl J Med 1991;325:11-6.

3. Ballas SK, Carlos TM, Dampier C, et al. 

Guidelines for Standard of Care of Acute Painful

Episodes in Patients with Sickle Cell Disease.

Pennsylvania Department of Health, 2000.

4. Vichinsky EP, Johnson R, Lubin BH.

Multidisciplinary approach to pain management 

in sickle-cell disease. Amer J Pediatr Hematol Onc

1982;4:328-33.

5. Benjamin LJ, Swinson GI, Nagel RL. Sickle cell

anemia day hospital: an approach for the management of uncomplicated painful crises. Blood

2000;95:1130-7.

6. Walco GA, Dampier CD. Pain in children and

adolescents with sickle-cell disease: a descriptive

study. J Pediatr Psychol 1990;15:643-58.

7. Wong DL, Hackenberry-Eaton M, Wilson D, et

al. Whaley and Wong’s Nursing Care of Infants and

Children; 6th edition. St. Louis: Mosby-Year Book,

Inc., 1999:1153.

8. Wong DL, Baker CM. Pain in children: 

comparison of assessment scales. Pediatr Nurs

1998;14:9-17.

9. Fishman B, Pasternak S, Wallenstein SL, et al. 

The Memorial Pain Assessment Card. A valid

instrument for the evaluation of cancer pain.

Cancer 1987;60:1151-8.

10. Shapiro BS, Dinges DF, Orne EC, et al. Home

management of sickle cell-related pain in children

and adolescents: natural history and impact 

on school attendance. Pain 1995;61:139-44.

11. Yaster M, Tobin JR, Billette C, et al. Epidural analgesia in the management of severe vaso-occlusive

sickle cell crisis. Pediatrics 1994;93:310-5.

12. Jacox A, Carr DB, Payne R, et al. Management 

of Cancer Pain. Clinical Practice Guideline No. 9.

Rockville, MD: Agency for Health Care Policy and

Research, Public Health Service, U.S. Department

of Health and Human Services, 1994. AHCPR

Pub. No. 94-0592.

13. American Pain Society. Principles of Analgesic 

Use in the Treatment of Acute Pain and Cancer; 

4th edition. Glenview, IL 1999.

14. United States Pharmacopeial Convention, Inc.

USP Dispensing Information Volume I: Drug

Information for the Health Care Professional.

Rockville, MD, 1999:1810. 

15. Styles LA, Vichinsky E. Effects of a long-term

transfusion regimen on sickle cell-related illnesses.

J Pediatr 1994;125:909-11.

16. Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic syndrome. Pain 1989;36:363-6.
INFECTION 11

75

children, without evidence of a “booster” effect

(3). Unfortunately, the less-immunogenic 

antigens are probably responsible for vaccine

failures, but the vaccine still should be administered to all children at age 2. Although it has

not been shown formally to reduce Streptococcus

pneumoniae sepsis, the vaccine has potential

benefits that compare favorably to the risks.

The adverse effects are limited to local reactions in previously immunized individuals.

Fortunately, a new conjugated Streptococcus

pneumoniae vaccine has been developed, and 

it holds promise for being more immunogenic

than the previous one, even in infants.

Prophylactic Penicillin

The single most important clinical study in

SCD in the past 20 years was a randomized,

placebo-controlled trial that demonstrated 

that the administration of penicillin twice 

a day prevents 80 percent of life-threatening

episodes of childhood Streptococcus pneumoniae sepsis (4). This important milestone was the

impetus for the aggressive newborn screening

program enacted by most states. The goal is 

to identify all newborns with SCD and start

them on prophylactic penicillin as early as

possible. The recommended regimen is:

■ Newborn to 3 years: 

Penicillin VK, 125 mg orally twice daily

(PO BID)

■ 3 to 5 years: 

Penicillin VK, 250 mg PO BID

Infection is a major complication of sickle 

cell disease (SCD). Special preventive measures against infection exist in addition to 

routine immunizations; treatment regimens

are based on local formularies and antibiotic

sensitivity tests.

PREVENTION

STREPTOCOCCUS PNEUMONIAE SEPSIS

The single most common cause of death in

children with SCD is Streptococcus pneumoniae

sepsis (1,2). The unusual susceptibility results

from two problems: splenic malfunction, 

and failure to make specific IgG antibodies 

to polysaccharide antigens. Two prevention

strategies are recommended: vaccination and

prophylactic penicillin.

Vaccination

Standard practice is to give a 23-valent

Streptococcus pneumoniae polysaccharide vaccine (PPV23) to all children with SCD at 24

months of age (see chapter 5, Child Health

Care Maintenance). Children with SCD typically do not respond to the vaccine as well as 

normal children, but it causes a rise in IgG

antibody against the most immunogenic 

polysaccharides, and a lower response to less

immunogenic polysaccharides. For example,

previously immunized children with SCD at

age 5 have specific IgG antibody concentrations comparable to healthy nonimmunized
Chapter 11: Infection

76

To test the effectiveness of prophylaxis beyond

5 years of age, a followup study randomized

400 children (age 5 years) who had been on

prophylactic penicillin to receive placebo or

continue penicillin. After about 3 years of 

followup, there was no significant difference

between the groups in the incidence of

Streptococcus pneumoniae meningitis or sepsis

(table 1).

The study demonstrated that it was safe to

discontinue prophylactic penicillin at age 5

(5). Despite these results, some clinicians still

continue prophylaxis beyond age 5, but this

approach is less popular now that penicillinresistant organisms have emerged (6).

Prophylaxis does not eliminate nasopharyngeal

colonization with Streptococcus pneumoniae,

and it is associated with increased resistance 

to penicillin and other antibiotics in some

series (7) but not others (8). An alternate 

(but unproved) approach for children older

than age 5 is to prescribe penicillin for the

onset of fever. This theoretically provides some

treatment while the patient is on the way to

the doctor. This “just in time” approach sometimes is recommended as an alternative to 

prophylaxis for children with SCD-SC or

SCD-S β+-thalassemia, where the incidence 

of Streptococcus pneumoniae sepsis is lower 

than in sickle cell anemia (SCD-SS).

HEMOPHILUS INFLUENZAE

AND NEISSERIA MENINGITIDIS

Historically, Hemophilus influenzae was a 

significant pathogen in children with SCD as

well as normal children. Routine immunization

with conjugated Hemophilus influenzae vaccine

has reduced markedly the risk of infection.

Another encapsulated organism, Neisseria

meningitidis, classically infects individuals 

with poor or absent splenic function but is 

not a common pathogen in SCD. Routine

immunization against this organism is not 

recommended unless there is an exposure 

or outbreak.

INFLUENZA

Viral influenza infections can cause severe

morbidity in individuals with SCD. Yearly

vaccination recommendations should be 

followed.

HEPATITIS

Intrahepatic sickling, dietary and transfusional

iron overload, and transfusion-related hepatitis

contribute to liver dysfunction in SCD. To

minimize additional risk, some clinicians advise

hepatitis B immunization. This is now routine

for children and should be considered seriously for seronegative adults. Very little evidence

supports routine vaccination against hepatitis

A, although the rationale would be the same.

Table 1: Sepsis and Meningitis in Children after 5 Years of Penicillin Prophylaxis 

Who Were Randomized To Stop Prophylaxis at Age 5

Group Number with Infection, N=200 95% Confidence Interval

Placebo 4 (2%) 0.5-5.0

Penicillin 2 (1%) 0.1-3.6
77

PREVENTION IN ADULTS

Virtually all adults with sickle cell anemia 

are functionally asplenic, but their immune

systems have matured to allow type-specific

polysaccharide antibody production. Because

they are not as susceptible as children to overwhelming sepsis and the incidence of sepsis is

relatively low, there is only anecdotal evidence

about preventive strategies. Streptococcus pneumoniae vaccination is recommended for adults

with SCD. Some patients keep penicillin on

hand for fever, but most are not prescribed

penicillin prophylaxis routinely.

EMPIRIC THERAPY

Most antibiotic treatments are started empirically, before culture results are available. Table

2 summarizes the pathogens that should be

covered in different clinical situations (9-12).

Additional information on some specific situations follows.

FEVER WITHOUT A SOURCE

Febrile patients with SCD should be evaluated

and treated in the context of functional asplenia. In essence, this means more rapid and

intensive evaluation (exam, blood counts, 

cultures, x rays) and lower threshold for

empiric therapy than in a general population.

Because minor febrile illnesses are common 

in children, and the risk of death from overwhelming Streptococcus pneumoniae sepsis is 

so high, aggressive management is critical. 

The following represent key principles in 

the management of febrile children (13-15):

■ Parents and clinicians should be taught that

a temperature over 38.5 ̊C is an emergency.

■ Basic laboratory evaluation includes CBC,

U/A, chest x ray and/or oxygen saturation,

and cultures of blood, urine, and throat.

■ “Toxic-looking” children and those with

temperatures above 40 ̊C should be treated

promptly with parenteral antibiotics—

before obtaining x rays or laboratory

results. They should be admitted to the

hospital for treatment.

Table 2: Pathogens To Be Covered by Empiric Therapy

Empiric therapy for: Should include coverage for: Consider broadening to include:

Fever without source Streptococcus pneumoniae Salmonella

(rule out sepsis) Hemophilus influenzae Gram-negative enterics

Meningitis Streptococcus pneumoniae Neisseria meningitidis

Hemophilus influenzae

Chest syndrome Streptococcus pneumoniae Legionella

Mycoplasma pneumoniae Respiratory syncytial virus

Chlamydia pneumoniae

Osteomyelitis/septic arthritis Salmonella

Staphylococcus aureus

Streptococcus pneumoniae

Urinary tract infection Escherichia coli

Other gram-negative enterics
Chapter 11: Infection

78

■ Lumbar puncture should be performed 

on “toxic” children and those with signs 

of meningitis.

■ Nontoxic children with temperatures

below 40 ̊C but with any of the following

should receive prompt parenteral antibiotics and be admitted:

–Infiltrate on chest x ray or abnormal 

oxygen saturation (see chapter 16, Acute

Chest Syndrome and Other Pulmonary

Complications)

–White blood cell count greater than

30,000/μL or less than 5,000/μL

–Platelet count less than 100,000/μL

–Hemoglobin less than 5g/dL

–History of sepsis

■ Candidates for outpatient treatment may

include nontoxic children with temperatures

less than 40 ̊C who have never been septic

and have normal chest x ray or oxygen saturation, baseline white cell count, platelet

count, and hemoglobin. They can be

observed at home after parenteral administration of a long-acting antibiotic that covers

Streptococcus pneumoniae and Hemophilus

influenzae (e.g., ceftriaxone, 75 mg/kg) if:

–They have remained clinically stable for 

3 hours after the antibiotic dose.

–Endemic Streptococcus pneumoniae in 

the community are likely to be antibioticsensitive.

–The parents have been appropriately

trained, have a history of compliance with

prophylactic penicillin, keep appointments

reliably, and have emergency access to the

hospital.

–A followup program is in place to assure

assessment and retreatment within 24 hours.

■ Documented bacteremia should be treated

parenterally for 7 days, and children with

meningitis should have at least 14 days of

treatment.

ACUTE CHEST SYNDROME

The acute chest syndrome is covered in chapter 16. Please refer to table 2 above to guide

antibiotic choice.

BONE PAIN WITH FEVER

Acute bone pain is caused by marrow

ischemia. When necrosis and inflammation

are associated with ischemia, the painful event

resembles osteomyelitis or septic arthritis—

including fever, leukocytosis, local swelling

and tenderness, effusions, and abnormal imaging studies. Aspiration of some purely ischemic

bone and joint lesions may yield purulent

material. The overlap in physical, radiographic, and laboratory findings requires an unambiguous bacterial diagnosis to be established.

Blood, joint fluid, or subperiosteal fluid must

be cultured before antibiotics are started to

treat osteomyelitis or septic arthritis. Once

these cultures are obtained, empiric treatment

should cover the pathogens in table 2. 

MISCELLANEOUS INFECTIONS

See chapter 12, Transient Red Cell Aplasia, 

for discussion of Parvovirus B19, and 

chapter 25, Transfusion, Iron Overload, 

and Chelation, for discussion of transfusiontransmitted infections.
79

REFERENCES

1. Leikin SL, Gallagher D, Kinney TR, et al.

Mortality in children and adolescents with sickle

cell disease. Cooperative Study of Sickle Cell

Disease. Pediatrics 1989;84:500-8.

2. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical

events in the first decade in a cohort of infants

with sickle cell disease. Cooperative study of sickle

cell disease. Blood 1995;86:776-83.

3. Bjornson AB, Falletta JM, Verter JI, et al. Serotypespecific immunoglobulin G antibody responses to

pneumococcal polysaccharide vaccine in children

with sickle cell anemia: effects of continued penicillin prophylaxis. J Pediatr 1996;129:828-35.

4. Gaston MH, Verter JI, Woods G, et al. Prophylaxis

with oral penicillin in children with sickle cell 

anemia. A randomized trial. N Engl J Med

1986;314:1593-9.

5. Falletta JM, Woods GM, Verter JI, et al.

Discontinuing penicillin prophylaxis in children

with sickle cell anemia. Prophylactic Penicillin

Study II. J Pediatr 1995;27:685-90.

6. Chesney PJ, Wilimas JA, Presbury G, et al.

Penicillin- and cephalosporin-resistant strains 

of Streptococcus pneumoniae causing sepsis and

meningitis in children with sickle cell disease. 

J Pediatr 1995;127:526-32.

7. Steele RW, Warrier R, Unkel PJ, et al. Colonization

with antibiotic-resistant Streptococcus pneumoniae 

in children with sickle cell disease. J Pediatr

1996;128:531-5. 

8. Norris CF, Mahannah SR, Smith-Whitley K, et al.

Pneumococcal colonization in children with sickle

cell disease. J Pediatr 1996;29:821-7.

9. Wright J, Thomas P, Serjeant GR. Septicemia

caused by Salmonella infection: an overlooked

complication of sickle cell disease, J Pediatr

1997;130:394-.

10. Zarkowsky HS, Gallagher D, Gill FM, et al.

Bacteremia in sickle hemoglobinopathies. J Pediatr

1986;109:579-85.

11. Poncz M, Kane E, Gill FM. Acute chest syndrome

in sickle cell disease: etiology and clinical correlates. J Pediatr 1985;107:861-6.

12. Miller ST, Hammerschlag MR, Chirgwin K, et al.

Role of chlamydia pneumoniae in acute chest 

syndrome of sickle cell disease. J Pediatr

1991;118:30-3.

13. Williams LL, Wilimas JA, Harris SC, et al.

Outpatient therapy with ceftriaxone and oral

cefixime for selected febrile children with sickle cell

disease. J Pediatr Hematol Oncol 1996;18:257-13. 

14. Rogers ZR, Morrison RA, Vedro DA, et al.

Outpatient management of febrile illness in 

infants and young children with sickle cell anemia. 

J Pediatr 1990;117:736-9.

15. Platt OS. The febrile child with sickle cell disease:

a pediatrician’s quandary. J Pediatr 1997;130:693.
80
TRANSIENT RED CELL APLASIA

81

12

levels. However, the diagnosis of TRCA is 

supported by increased B19 parvovirus IgM

levels. In at least 20 percent of patients with

serologic evidence of past B19 parvovirus

infection, there was no acute severe anemia.

Following B19 infection, parvovirus-specific

IgG concentrations are increased in most

patients and protective immunity appears 

to be life-long; no cases of recurrent disease

have been reported in children with SCD

(1,3). Recovery is often heralded by a massive

outpouring of nucleated red blood cells

(>100/100 white blood cells). 

Although the majority of adults have acquired

immunity to B19 parvovirus, hospital workers

who are susceptible and are exposed to

patients with TRCA are at high risk of contracting nosocomial erythema infectiosum (4).

Because infection during the mid-trimester 

of pregnancy may result in hydrops fetalis and

stillbirth, isolation precautions for pregnant

staff are a necessity if a parvovirus problem 

is suspected (5). 

MANAGEMENT

No experimental trials have been reported

regarding the management of TRCA. Although

many patients recover spontaneously, red cell

transfusions should be considered for those

who become symptomatic (see chapter 25,

Transfusion, Iron Overload, and Chelation). 

If patients are beginning to show evidence for

red cell production, as determined by the reticulocyte count, they may not need transfusions.

Because the life span of red blood cells is

greatly shortened in sickle cell disease (SCD),

temporary suppression of erythropoiesis can

result in severe anemia. Transient red cell 

aplasia (TRCA) typically is preceded by or

associated with a febrile illness. The infectious

nature of TRCA is apparent from the fact that

several members of families with congenital

hemolytic anemia may be affected within 

a period of several days.

ROLE OF PARVOVIRUS B19 

Between 70 and 100 percent of episodes of

TRCA are due to infection by human parvovirus B19, also the cause of erythema infectiosum (“fifth disease”) (1). Aplasia is the result

of direct cytotoxicity of the parvovirus to erythroid precursors, although other progenitors

may be affected in some conditions. Patients

may present with increased headache, fatigue,

dyspnea, more severe anemia than usual, and 

a severe decrease in reticulocytes (usually <1

percent or 10,000/μL). Patients may have

fever, signs of upper respiratory infection,

and/or gastrointestinal symptoms. Skin rashes

are characteristically absent. Reticulocytopenia

begins about 5 days postexposure and continues for 7 to 10 days. Exacerbation of anemia

develops shortly after reticulocytopenia.

Hemoglobin levels reached a mean nadir of

3.9 g/dL in one series (2). Patients who present in the convalescent phase may be thought

mistakenly to have a hyperhemolytic process

because of severe anemia and high reticulocyte
Chapter 12: Transient Red Cell Aplasia

82

Transfusion was required in 87 percent of 

children with SCD-SS and TRCA in a large

Jamaican series (2), but it is much less commonly needed for SCD-SC. Because parvovirus is so contagious, siblings and close

contacts with SCD should be monitored for

the development of aplastic events.

A single case report describes an alternative 

to transfusion in a child with Hb SD whose

mother was a Jehovah’s Witness and refused

transfusion (6). This patient was treated with 

a single dose of intravenous immune globulin

(1 g/kg) and daily infusions of erythropoietin

(100 units/kg) and exhibited a reticulocytosis

beginning on day 4 after onset of this treatment. Intravenous immune globulin is now the

treatment of choice for parvovirus and aplasia

since it will clear the parvovirus infection (7).

In the past decade, it has become apparent

that a number of complications of B19 parvovirus infection besides TRCA can occur in

patients with SCD. Complications reported 

at single centers or in small series include 

bone marrow necrosis with pancytopenia (8),

glomerulonephritis (9), stroke (10), acute

chest syndrome (11), and splenic or hepatic

sequestration (12,13). Treatment must then 

be based on these manifestations.

REFERENCES

1. Serjeant GR, Serjeant BE, Thomas PW, et al.

Human parvovirus infection in homozygous sickle

cell disease. Lancet 1993;341:1237-40.

2. Goldstein AR, Anderson MJ, Serjeant GR.

Parvovirus associated aplastic crisis in homozygous

sickle cell disease. Arch Dis Child 1987;62:585-8.

3. Rao SP, Miller ST, Cohen BJ. Transient aplastic crisis in patients with sickle cell disease. Am J Dis

Child 1992;146:1328-30.

4. Bell LM. Human parvovirus B19 infection among

hospital staff members after contact with infected

patients. N Engl J Med 1989;321:485-91.

5. Anand A, Gray ES, Brown T, et al. Human parvovirus infection in pregnancy and hydrops fetalis.

N Engl J Med 1987;316:183-6.

6. Lascari AD, Pearce JM. Use of gamma globulin

and erythropoietin in a sickle cell aplastic crisis.

Clin Pediatr 1994;33:117-9.

7. Brown KE, Young NS, Barbosa LH. Parvovirus B19:

Implications for transfusion medicine. Summary of

a workshop. Transfusion 2001;41:130-5.

8. Eichhorn RF, Buurke EJ, Blok P, et al. Sickle celllike crisis and bone marrow necrosis associated

with parvovirus B19 infection and heterozygosity

for hemoglobins S and E. J Intern Med

1999;245:103-6.

9. Tolaymat A, Mousily FA, MacWilliam K, et al.

Parvovirus glomerulonephritis in a patient with

sickle cell disease. Pediatr Nephrol 1999;13:340-2.

10. Balkaran B, Char G, Morris JS, et al. Stroke in 

a cohort of patients with homozygous sickle cell

disease. J Pediatr 1992;120:360-6.

11. Lowenthal EA, Wells A, Emanuel PD, et al. Sickle

cell acute chest syndrome associated with parvovirus B19 infection: Case series and review. 

Am J Hematol 1996;51:207-13.

12. Mallouh AA, Qudah A. Acute splenic sequestration

together with aplastic crisis caused by human parvovirus B19 in patients with sickle cell disease. 

J Pediatr 1993;122:593-5.

13. Koduri PR, Patel AR, Pinar H. Acute hepatic

sequestration caused by parvovirus B19 infection 

in a patient with sickle cell anemia. Am J Hematol

1994;47:250-1.
STROKE AND CENTRAL NERVOUS SYSTEM DISEASE 13

83

STROKE AND CENTRAL 

NERVOUS SYSTEM 

DISEASE IN CHILDREN

TRANSIENT ISCHEMIC ATTACK (TIA)

AND BRAIN INFARCTION

Brain dysfunction occurs when oxygen supply

to the brain falls below a critical level based 

on need. Symptoms of brain ischemia include

hemiparesis; visual and language disturbances;

seizures (especially focal seizures); and altered

sensation, mentation, and alertness. There is

evidence that oxygen demands are higher in

children than in adults, making the child with

SCD who also has significant anemia at particular risk. 

As soon as brain ischemia is suspected, 

a prompt and thorough evaluation and consideration for therapy is recommended (figure

1). After initial stabilization and evaluation,

patients should receive urgent noncontrast

computed tomography (CT) scan of the brain

to rule out hemorrhage or other nonischemic

etiologies. Consideration should be given to the

possibility that the symptoms are due to CNS

infection, trauma (e.g., subdural hematoma),

or intoxication—particularly if focal signs are

not prominent.

In the acute stage of ischemic stroke for the

general non-SCD adult population, the only

approved therapy is recombinant tissue plasminogen activator (t-PA) if given within 3

hours (3), but there are no data establishing 

Stroke is one of the major complications of

sickle cell disease (SCD). The Cooperative

Study of Sickle Cell Disease (CSSCD) showed

that the prevalence and incidence of stroke in

patients with SCD-SS was four times that of

those with SCD-SC (1). Because of this difference in risk, and because most of the available

data are from patients with SCD-SS, screening

of neurologically asymptomatic patients and

primary stroke prevention recommendations

pertain to those with SCD-SS, not SCD-SC.

Recommendations for treatment of symptomatic patients and secondary prevention pertain to all SCD patients. 

Children with SCD may have a variety of

anatomic and physiologic abnormalities

involving the central nervous system (CNS)

even if they appear to be neurologically “normal” (2). The abnormalities may be associated

with deterioration in cognitive function with

effects on learning and behavior and may

increase the risk for clinical and subclinical

damage to the CNS in the future.

The approach to management depends on the

specific brain manifestation of interest and the

age of the patient. Therefore, this chapter is

divided into sections based on the major CNS

concerns of children and adults.
84

Figure 1. Child with SCD and Symptoms

Immediate CT—no contrast

Child with SCD 

with symptoms

Stroke

Hemorrhage Ischemia

Chronic 

transfusion

Exchange 

transfusion

Evaluate and treat 

based on source 

of bleeding

Consider chronic 

transfusion

MRI / MRA

Negative

MRA—Severe 

disease

MR tests 

negative

Observe vs. 

empiric therapy

PET / MRS

MRI / DWI 

positive

Chronic 

transfusion

Consider transfusion or other

empiric therapy

MRI / MRA / DWI

Other etiology— 

treat as 

appropriate

Chapter 13: Stroke and Central Nervous System Disease
85

its use in children with SCD where the pathophysiology may differ completely. Therefore, 

it is not recommended. 

The usual treatment for pediatric patients in

the acute stage of ischemic stroke is hydration

with transfusion, although there are no controlled treatment studies. Exchange transfusion

is preferred, as it avoids the theoretical risk of

increasing blood viscosity that may accompany

rapid elevations in hematocrit, but care must

be taken to avoid hypotension that may worsen cerebral ischemia (4). Because fever increases cerebral metabolism, any degree of hyperthermia should be treated. Hypothermia to

treat stroke is promising but not supported 

by data adequate to form a recommendation.

Acute treatment in an intensive care unit

(ICU) or stroke unit will facilitate close 

observation and treatment. Seizures should 

be treated, but prophylactic therapy or corticosteroids are not recommended. Hypoxemia

and hypotension should be treated and normoglycemia maintained. There are no proven

neuroprotective therapies as yet to lessen 

damage or promote recovery.

In early ischemia (less than 3 hours), the cranial

CT may be negative or show only subtle signs.

Magnetic resonance imaging (MRI) provides

better detail of the areas of ischemia, and diffusion weighted imaging (DWI) shows hyperintense areas of brain ischemia within minutes

after onset of severe ischemia. Unless the diagnosis is in doubt, MRI should be deferred until

treatment has been initiated. Evaluation within

the first hours to days with MRI is recommended, because MRI-based studies provide

significant additional information, such as the

ability to detect very early and sometimes clinically silent acute lesions with DWI and prior

infarction that may not be seen on CT. Imaging

of the arteries by magnetic resonance angiography

(MRA), may show large vessel occlusive disease (5) or aneurysms. EEG is recommended

only if there is a clinical suspicion of seizure. 

In the subacute phase, evaluations should be

undertaken to make a final determination of

the cause. In many cases, evaluation of the

intracranial vessels will show occlusive vasculopathy characteristic of SCD. Even though

intracranial arterial vasculopathy is the most

likely cause of stroke in this setting, consideration should be given to other etiologies that

cause stroke in young persons (6). If there is 

a history of head or neck trauma and arterial

dissection is suspected, the radiologist should 

be notified so that appropriate changes in the

magnetic resonance (MR) acquisition protocol

can be made prior to study.

Other causes of stroke in children—such as

infection, cardiac embolism, and clotting disorders including anticardiolipin antibodies—

should be considered (7). While hemiparesis

typically improves, cognitive deficits are often

significant and long lasting; formal testing

should be carried out to identify rehabilitation

and educational needs.

TIAs have been defined as ischemic events 

in which the symptoms resolve in less than 

24 hours. Because TIAs are a strong predictor

of stroke in other settings and in SCD as well,

there is a general recommendation that all

patients with TIA receive appropriate therapy

for stroke prevention. In this particular setting

there are few data. The diagnosis of TIA is 

difficult in children, especially those who are

very young, and painful episodes can mimic

hemiparesis or paraparesis. In cases where the

history is weak for the event actually being 

a TIA, caution is advised, especially if longterm transfusion is being considered. 

In the case of a child in which a TIA is observed

or strongly suspected, a prior recommendation

is reiterated as a reasonable approach (2): if
Chapter 13: Stroke and Central Nervous System Disease

86

the patient has significant large vessel disease

on imaging, transfusion should be undertaken.

If the patient has not been screened for stroke

risk by transcranial Doppler (TCD) ultrasound (8), this should be done and treatment

initiated according to the discussion under

“Prevention of Brain Infarction,” below, and

figure 2. Alternatively, other tests, if available,

such as positron emission tomography (PET)

(9) or MR spectroscopy, could be employed. 

If these indicate significant “brain at risk,”

prophylactic treatment with transfusion can 

be undertaken on the basis that the child’s

brain blood supply has already failed once,

even if transiently, and is at significant risk 

for subsequent deterioration.

Antiplatelet agents are usually recommended

for TIAs in cases without SCD, but there are

very few data on efficacy in SCD. Agents

such as aspirin, clopidogrel, and combination

dyprimadole/aspirin are used in adults and 

in cases where transfusion is not undertaken. 

INTRACRANIAL HEMORRHAGE

The clinical presentation of intracranial 

hemorrhage is dramatic and may include

severe headache, vomiting, stupor, or coma.

However, hemiparesis may be present, especially with intraparenchymal bleeding. A child

with such a presentation requires rapid but

careful evaluation to rule out meningitis, 

sepsis, hypoxemia, drug intoxication, or other

metabolic derangements. A noncontrast 

cranial CT should be performed as soon as

possible. Intracranial hemorrhage should be

approached based on the location of the blood

on the CT scan, as described below.

Subarachnoid hemorrhage (SAH) 

The usual cause of subarachnoid hemorrhage

(SAH) is rupture of a berry aneurysm. The

aneurysm may not be seen on CT, but can

sometimes be inferred by the location of blood.

Minor subarachnoid hemorrhages may have

no identifiable cause even when angiography

is performed, but an angiogram is recommended to identify aneurysms or arteriovenous malformations (AVM) if surgery is being

considered. This is clinically relevant because

aneurysms may rebleed, and SCD patients 

may have multiple aneurysms that require

management. Surgical clipping, as well as

AVM removal, has been successfully performed

in many patients with SCD. Although

aneurysms can be identified using MR, MRA

is not a definitive test for aneurysms unless

special techniques are used (20). However,

MRI/MRA can reliably detect AVM.

The initial treatment of subarachnoid hemorrhage is stabilization in a neurological intensive care unit or pediatric ICU, depending on

local expertise and the age of the child. Initial

care includes intravenous normotonic fluids 

to avoid dehydration. The effect of transfusion

on the course and outcome of hemorrhage 

is not known; however, reduction of sickle

hemoglobin (Hb S) to less than 30 percent 

of total hemoglobin is recommended.

Nimodopine, a calcium antagonist that

improves outcome after SAH by counteracting

delayed arterial vasospasm, is indicated in

adults with SAH (10). Use in this setting 

with young children is not approved but 

is reasonable on an empiric basis. The adult

dosage of 60 mg orally every 4 hours for 

21 days should be adjusted by weight.

Intraparenchymal Hemorrhage

If the CT shows blood primarily confined 

to the parenchyma, the cause may still be 

an AVM, but an aneurysm is not likely 

unless there is also subarachnoid bleeding.

Intraparenchymal bleeding may be associated

with large vessel vasculopathy, especially if 

a moyamoya formation is present. In some
87

* Optimal frequency of rescreening not established. Younger children with velocity 

closer to 200 cm/sec should be rescreened more frequently.

** Prior TIA, low steady state Hb, rate and recency of acute chest syndrome, elevated systolic blood pressure.

Figure 2. Child with Hb SS and No Symptoms

Child with Hb SS, age >2 

with no symptoms

Neuropsychological 

testing

Abnormal 

(≥ 200 cm/sec)

Not abnormal 

(< 200 cm/sec)

Chronic 

transfusion

Repeat TCD 

every 3-12 months*

Confirm 

abnormal

MRI / MRA Abnormal exam

TCD unavailable

Low risk High risk based on 

other information**

Protocol treatment 

or clinical trial

Observation

Or treatment options: 

 ■ Observation 

 for progression 

 ■ Hydroxyurea 

 ■ Transfusion 

 ■ Other (e.g., 

antiplatelet agents)

Transcranial Doppler (TCD) 

ultrasound

Evaluate 

educational needs 

based on results
Chapter 13: Stroke and Central Nervous System Disease

88

patients, no vessel pathology can be seen 

on angiography. Evaluation of these patients

with MRA may be sufficient if there is no 

subarachnoid blood, because an aneurysm 

is not likely as the source of bleeding. Better

definition of the vasculature can be obtained

with conventional angiography.

Initial management depends on the size and

location of the bleeding. A rapid search for

coagulopathy should be made with a determination of the activated partial thromboplastin

time (aPTT) and prothrombin time (PT) and

correction of any coagulopathy. Management

of the hematoma includes medical control of

intracranial pressure and consideration for surgical removal in selected cases, particularly if

there is a large (>3 cm) cerebellar hematoma.

Rebleeding in this setting in the short term 

is rare. Normotonic fluids and avoidance of

hypotension are important (11). 

Intraventricular Hemorrhage 

Intraventricular hemorrhage is unusual but

may be seen in the case where fragile moyamoya vessels near the ventricular wall rupture

into the ventricular space. In such cases the

pediatric patient is at risk for acute hydrocephalus and death if ventricular flow is

obstructed. The child should receive prompt

neurosurgical evaluation for intraventricular

catheter placement for drainage. After acute

stabilization, evaluation of the cerebral vessels

(best done by conventional angiography)

should be undertaken to try to identify the

underlying cause. 

PREVENTION OF 

BRAIN INFARCTION

SECONDARY PREVENTION

Several uncontrolled studies have documented 

a reduction in recurrent cerebral infarction

using chronic blood transfusion with the target

of reducing Hb S to less than 30 percent of

total hemoglobin (12,13). The reduction in

recurrent stroke risk is significant, but patients

may still have a stroke despite adequate transfusion and low Hb S levels. If a patient on

transfusion has a “breakthrough” cerebral

infarction or TIA, the Hb S level should be

checked to ensure that it is being maintained

at 30 percent or below, and the etiology of

ischemia should be evaluated. Consideration

should be given to risk factors beyond SCDrelated vasculopathy, including elevated homocysteine or a hypercoagulable state. Elevated

homocysteine can be reduced with folate, as 

is recommended for patients without SCD

(14). Data suggest that some SCD patients

have elevated antiphospholipid antibodies 

(15) and protein C and S deficiencies (16). 

If the abnormalities are severe enough, anticoagulation with warfarin should be considered.

Treatment of these conditions has not been

tested in randomized clinical trials but is 

reasonable based on pathophysiology. 

After several years of transfusion therapy, it

may be reasonable to allow Hb S levels to rise

up to 50 percent by reducing the intensity of

transfusions; this has not been formally tested,

however. Moreover, the duration of time after

which transfusion can be safely stopped has

not been defined. Some studies have reported

high rates of recurrent stroke (17), although

others have suggested that transfusion may 

be safely withdrawn in older patients who

have been extensively treated (18). Current

recommendations are that transfusion should

be continued for at least 5 years or at least

until the child reaches the age of 18. Chronic 

transfusion induces iron overload, which 

must be managed along with the transfusions

(see chapter 25, Transfusion, Iron Overload,

and Chelation).
89

Patients with stroke have received bone marrow

transplantation (19). The current indications,

efficacy, and outcome of this therapy are 

discussed in chapter 27, Hematopoietic Cell

Transplantation. Hydroxyurea is used for

reduction of painful episodes in adults with

SCD, but the trial establishing its use provides

no guidance on whether hydroxyurea is a suitable alternative to transfusion for prevention of

stroke. Clinical studies in children have reported short-term safety, but these studies have not

established hydroxyurea as an alternative to

transfusion for stroke prevention in this setting

(20). Anticoagulants and antiplatelet agents

have not been studied in this indication.

PRIMARY STROKE PREVENTION

The CSSCD established that patients with

SDC-SS have rates of stroke in childhood in

the range of 0.5-1 percent per year (1). In the

Stroke Prevention Trial in Sickle Cell Anemia

(STOP) study, children between 2 and 16

years of age who were at risk for first-time

stroke, as determined by having TCD velocity

greater than 200 cm/sec, were randomized to

receive either periodic transfusions to maintain

the Hb S level below 30 percent or standard

supportive care (21). An interim analysis

demonstrated that periodic transfusions were

efficacious in preventing first-time stroke, 

in the children randomized to the transfusion

arm. At the end of the trial, all participants

were offered periodic transfusion therapy. The

main side effects of the transfusion therapy

were iron accumulation and alloimmunization,

through the rate of occurrence was low. A 

new trial, known as STOP II, is now in place

to determine whether transfusions need to 

be continued indefinitely of if they can be

stopped after some period of time when risk 

of stroke has diminished.

TCD can be performed with either the 

dedicated 2-MHz pulsed Doppler device 

used in STOP or with TCD attachments to

ultrasound imaging machines (transcranial

Doppler imaging, or TCDI) that have also

been used in this setting (22). 

IDENTIFICATION OF PATIENTS AT RISK

In addition to TCD, a number of other

approaches have been used to identify children at risk for stroke (figure 2). The CSSCD

identified five significant risk factors in a

long-term prospective study: prior TIA, low

steady-state hemoglobin, rate and recency 

of acute chest syndrome (ACS), and elevated

systolic blood pressure. The newborn cohort

of the CSSCD identified three early life (first

2 years) predictors of severe outcomes such 

as stroke (23). These were dactylitis, severe

anemia, and leukocytosis.

Other clinical and laboratory indicators of

stroke risk that have been reported include

stroke in a sibling, subtle neurological abnormalities, severe anemia, high leukocyte count,

certain βs

-gene haplotypes, and no α-gene

deletion (2).

SUBCLINICAL BRAIN DISEASE

The CSSCD confirmed that about 13 percent

of children with SCD have “silent” brain

lesions on MRI, in predominantly frontal and

parietal cortical, subcortical, and border-zone

locations (24,25). These lesions are associated

with poor performance on neuropsychological

testing. Recent evidence from the CSSCD

confirms an earlier smaller study indicating

that the risk of clinical stroke is increased if

MRI is abnormal. The presence of these

lesions should prompt evaluation of the child

for learning and cognitive problems, and evaluation of cerebral vessels for primary stroke

prevention (see above). Silent lesions are evidence of brain injury and should also lead to

reevaluation of the patient’s history, which
Chapter 13: Stroke and Central Nervous System Disease

90

may reveal symptoms that were not previously

recognized, as well as reexamination of the

patient’s clinical and laboratory risks for stroke.

The rate of stroke in children with positive

MRI and with TCD that do not reach current

treatment guidelines is not clear, and the risks

and benefits of prophylactic transfusion based

on silent MRI lesions have not been determined. Intervention in patients with silent

lesions and additional indicators of cerebral

dysfunction or abnormality have been suggested, but no recommendation for treatment can

be made at this time.

STROKE AND BRAIN DISEASE 

IN ADULTS WITH SCD

INFARCTION

The CSSCD confirmed the relatively high

rates of stroke in adults with SCD and the 

predominance of hemorrhage compared with

infarction in adults with SCD. There is less

information on treatment and prevention in

adults with SCD. The clinician must decide

whether to approach a patient with TIA or

stroke who has SCD in a manner similar to

that used in children with SCD, or along

guidelines established for adults without SCD

(26,27). The interaction of SCD-specific risk

factors with risks factors for stroke seen in

adults without SCD has not been determined,

although high blood pressure was identified 

as a stroke risk in the CSSCD. Specifically, the

role of chronic transfusion is unclear. The recommendations that follow are based primarily

on current recommendations for treatment and

prevention in patients without SCD (figure 3).

Treatment of hyperacute ischemic stroke in

adults is accomplished using recombinant tissue plasminogen activator (t-PA). It is not

clear whether t-PA, which has a significant risk

of bleeding, is appropriate for patients with

SCD; no experience with its use has been

reported. However, there is no clear justification to exclude SCD patients from t-PA therapy, and it remains the only therapy approved

by the U.S. Food and Drug Administration

for treatment of ischemic stroke. 

According to established guidelines, 

use of t-PA is indicated when:

■ the patient is at least 18 years old.

■ the patient’s National Institutes of Health

Stroke Scale score is greater than 4

(ischemic stroke in any vessel with 

a clinically significant deficit). 

■ t-PA therapy can begin within 3 hours 

of symptom onset.

■ cranial CT shows no evidence 

of hemorrhage.

Thrombolytic therapy cannot be 

recommended if:

■ stroke duration is longer than 3 hours.

■ INR is greater than 1.7 or PT of 15 seconds.

■ patient received heparin in last 48 hours

and has a prolonged aPTT.

■ platelet count is less than 100,000/μL.

■ patient has had a stroke or serious head

injury in the past 3 months.

■ patient underwent major surgery within 

the preceding 14 days.

■ pretreatment blood pressure is greater 

than 185 mmHg systolic or 110 mmHg

diastolic.

■ patient has rapidly improving neurological

signs or isolated ataxia, sensory loss,

dysarthria or minimal weakness.

■ patient has a history of intracranial 

hemorrhage.

■ blood glucose is less than 50 mg/dL or

greater than 400 mg/dL.
91

Figure 3. Adult with SCD and Symptoms

Immediate CT—no contrast

Adult with SCD 

with symptoms

Hemorrhage

Evaluate/treat based 

on source of bleeding

Ischemic stroke 

or negative

ASA 325 mg if no TPA

MRI / MRA / DWI

Ischemic 

stroke Negative

Clinical 

suspicion of TIA

Chronic 

blood 

transfusion

Secondary 

prevention with 

antiplatelet 

agents, warfarin

High Low

Observe

Other etiology— 

treat as 

appropriate

Consider TPA 

if < 3 hours 

from onset

OR
92

Chapter 13: Stroke and Central Nervous System Disease

■ patient had seizure at onset of symptoms.

■ patient has experienced GI or GU bleeding within the preceding 21 days.

In addition, t-PA should not be given unless

emergent care and appropriate facilities are

available. Caution is advised before giving t-PA

to patients with severe stroke, and careful explanation of the risk of bleeding to patient and

family is advised. There is a 6.4 percent risk of

symptomatic brain hemorrhage, and about half

of these are fatal. If a hemorrhage occurs, the

guidelines suggest red cell transfusions as needed (for extracranial bleeds) and urgent administration of 4 to 6 units of cryoprecipitate or

fresh frozen plasma and 1 unit of single donor

platelets. Surgical drainage of intracranial hemorrhage should be considered. Although t-PA

can be given to patients on antiplatelet agents,

these drugs, as well as any dose of heparin,

should not be given for the first 24 hours after

using t-PA. There is evidence that aspirin (325

mg one-time dose) within the first 48 hours

after stroke onset has a small beneficial effect

and is recommended if t-PA is not used.

The acute evaluation of the patient requires 

a noncontrast CT scan to rule out hemorrhage.

After the decision is made regarding t-PA, an

MR study of the brain is recommended to

better delineate the area of ischemia/infarction. 

Prevention of stroke in patients with TIA or

stroke is accomplished with either antiplatelet

agents or warfarin, based on the likely cause 

of the symptoms.

The following workup is recommended for

adults presenting with TIA or ischemic stroke:

CBC with differential and platelet count;

EKG; transthoracic echocardiogram with consideration given to transesophageal echocardiogram, especially in younger patients; aPTT;

PT; and a brain study to include MRI, DWI,

and MRA, and/or TCD and carotid duplex

ultrasound or CT angiography to determine

the status of the intracranial and extracranial

vessels. Blood tests for protein C and S deficiency, homocysteine elevation, and anticardiolipin antibodies may be appropriate. Health

care providers also should consider etiologies

seen in young patients with stroke without

SCD, including CNS infection, illicit drug

use, and arterial dissection.

Table 1. Use of Antithrombotic Agents in Patients With TIAs 

Event Recommended Therapy Therapeutic Options

TIA (atherothrombotic) acetylsalic acid (aspirin, ASA) extended-release dipyridamole (ER-DP) 

50–325 mg/d 200 mg + ASA 25 mg

Clopidogrel 75 mg/d

ASA 50–1300 mg/d

TIA (atherothrombotic) and ER-DP 200 mg + ASA 25 Warfarin (INR 2–3)

aspirin-intolerant1, or if TIA mg BID ASA 50–1300 mg/d

occurs during ASA therapy2 Clopidogrel 75 mg/d

TIA (cardioembolic) Warfarin, target INR 2.5 ASA 50–325 mg/d 

(range 2–3) (if warfarin is contraindicated)

1 Neither ER-DP + ASA or ASA alone is recommended for patients who are allergic to aspirin or unable to take low-dose aspirin. 2 The recommended antithrombotic agents have not been specifically tested in patients who have experienced a TIA during ASA therapy.
93

There are currently three options for antiplatelet

therapy for secondary stroke prevention. Table

1 summarizes the American Stroke Association’s

recommendations regarding these agents.

These guidelines are similar to those for 

prevention of stroke after completed brain

infarction (26,28).

Alternative therapy is chronic blood transfusion as used in children with SCD. Recently,

surgical bypass has been reported in a patient

with SCD. Surgical procedures that have been

developed to treat moyamoya syndrome may

be considered, due to the similarity in

anatomic location of the arterial disease in

moyamoya and SCD (29). These procedures

may be last-resort options for patients who

cannot be otherwise treated or who continue

to have brain infarction despite medical therapy. However, risk and benefit in this setting

have not been established and no recommendation can be made. 

INTRACRANIAL HEMORRHAGE

Adults with intracerebral hemorrhage should

be approached in the manner outlined above

for children, with the exception that nimodopine is recommended without qualification

for patients with subarachnoid hemorrhage (11). 

SUMMARY OF 

RECOMMENDATIONS

CHILDREN

■ Primary prevention (figure 2). Children

with SCD 2 to 16 years of age should 

be screened for stroke risk using TCD.

(Chronic transfusion should be strongly

considered in those with confirmed 

abnormal TCD.) If TCD is unavailable 

or technically inadequate, or if TCD

results do not meet criteria for treatment 

in the presence of other strong indications

of high risk, consideration should be given

to intervention on an individualized basis

unless enrollment in appropriate treatment

trials is an option.

■ Children with ischemic stroke should

undergo acute evaluation with CT scanning followed by intravenous hydration

and exchange transfusion to reduce 

Hb S to <30 percent total hemoglobin. 

In most cases this should be followed 

by chronic transfusion (figure 1).

■ Children with intracranial hemorrhage

should be evaluated for a surgically correctable lesion. Following this, chronic

transfusion is recommended in cases 

of severe vasculopathy or unrepaired

aneurysm (figure 1). Acute hydration 

and short-term exchange transfusion 

may be beneficial as well.

ADULTS

■ Adults presenting with acute ischemic

stroke should be evaluated for t-PA treatment (figure 3). If t-PA is not used, aspirin

(325 mg) is appropriate. Adults with TIA

or ischemic stroke should be evaluated for

the cause of the ischemia and therapy

should be guided by these findings.

Alternatives include antiplatelet agents and

warfarin. Chronic transfusion is an option,

as used in pediatric stroke prevention.

REFERENCES

1. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al.

Cerebrovascular accidents in sickle cell disease:

rates and risk factors. Blood 1998;91:288-94.

2. Powars DL. Management of cerebral vasculopathy

in children with sickle cell disease. Br J Haematol

2000;108:666-78.
94

Chapter 13: Stroke and Central Nervous System Disease

3. The National Institute of Neurologic Disorders

and Stroke rt-PA Acute Stroke Study Group. Tissue

plasminogen activator in acute ischemic stroke. 

N Engl J Med 1995;333:1581-7.

4. Pavlakis SG. Neurologic complications of sickle

cell disease. Adv Pediatr 1989;36:247-76.

5. Kandeel AY, Zimmerman RA, Ohene-Frempong

K. Comparison of magnetic resonance angiograpy

and conventional angiography in sickle cell disease:

clinical significance and reliability. Neuroradiol

1996;38:409-16.

6. Williams LS, Garg BP, Cohen M, et al. Subtypes 

of ischemic stroke in children and young adults.

Neurol 1997;49:1541-5.

7. Roach ES. Stroke in children. Curr Treat Options

Neurol 2000;2:295-304.

8. Adams RJ, McKie VC, Carl EM, et al. Long-term

stroke risk in children with sickle cell disease

screened with transcranial doppler. Ann Neurol

1997;42:699-704.

9. Powars DR, Conti PS, Wong WY, et al. Cerebral

vasculopathy in sickle cell anemia: diagnostic contribution of positron emission tomography. Blood

1999;93:71-9.

10. Mayberg MR, Batjer HH, Dacey R, et al.

Guidelines for the management of aneurysmal

subarachnoid hemorrhage. Stroke 1994;25:231-2.

11. Broderick JP, Adams HP, Barsan W, et al.

Guidelines for the management of spontaneous

intracerebral hemorrhage. Stroke 1999;30:905-15.

12. Russell MO, Goldberg HI, Hodson A, et al. 

Effect of transfusion therapy on arteriographic

abnormalities and on recurrence of stroke 

in sickle cell disease. Blood 1984;63:162-9.

13. Pegelow CH, Adams RJ, McKie V, et al. Risk of

recurrent stroke in patients with sickle cell disease

treated with erythrocyte transfusions. J Pediatr

1995;126:896-9.

14. Malinow MR, Bostom AG, Krauss RM.

Homocyst(e)ine, diet, and cardiovascular diseases: 

a statement for health care professionals from the

nutrition committee, American Heart Association.

Circulation 1999;99:178-82.

15. Westerman MP, Green D, Gilman-Sachs A, et al.

Antiphospholipid antibodies, proteins C and S,

and coagulation changes in sickle cell disease. 

J Lab Clin Med 1999;134:352-62.

16. Tam DA. Protein C and protein S activity 

in sickle cell disease and stroke. J Child Neurol

1997;12:19-21.

17. Wang WC, Kavaar EH, Tonkin IC, et al. High risk

of recurrent stroke after discontinuance of five to

twelve years of transfusion therapy in patients with

sickle cell disease. J Pediatr 1991;118:377-82.

18. Rana S, Houston PE, Surana N. Discontinuation

of long-term transfusion therapy in patients with

sickle cell disease. J Pediatr 1997;131:757-60.

19. Walters MC, Storb R, Patience M, et al. Impact 

of bone marrow transplantation for symptomatic

sickle cell disease: an interim report. Blood

2000;95:1918-24.

20. Ware RE, Zimmerman SA, Schultz WH.

Hydroxyurea as an alternative to blood transfusions

for the prevention of recurrent stroke in children

with sickle cell disease. Blood 1999;94:3022-6. 

21. Adams RJ, McKie VC, Hsu L, et al. Prevention of

a first stroke by transfusions in children with sickle

cell anemia and abnormal results on transcranial

Doppler ultrasonography. N Eng J Med

1998;339:5-11.

22. Seibert J, Glasier C, Kirby R, et al. Transcranial

Doppler (TCD), MRA and MRI as a screening

examination for cerebrovascular disease in patients

with sickle cell anemia—an eight year study.

Pediatr Radiol 1998;28:138-42.

23. Miller ST, Sleeper LA, Pegelow CH, et al.

Prediction of adverse outcomes in children with

sickle cell disease. N Engl J Med 2000;342:83-9.

24. Moser FG, Miller ST, Bello JA, et al. The spectrum

of brain MR abnormalities in sickle cell disease: 

a report from the cooperative study of sickle cell

disease. Am J Neuroradiol 1996;17:965-72.

25. Kinney TR, Sleeper LA, Wang WC, et al. Silent

cerebral infarcts in sickle cell anemia: a risk factor

analysis. Pediatrics 1999;103:640-5.

26. Wolf P, Clagett GP, Easton JD, et al. Preventing

ischemic stroke in patients with prior stroke and

transient ischemic attack. A statement for health

care professionals from the Stroke Council of the

American Council of the American Heart

Association. Stroke 1999;30:1991-4.

27. Albers GW, Hart RG, Lutsep HL, et al. Scientific

statement: supplement to the guidelines for the

management of transient ischemic attacks. Stroke

1999;30:2502-11.

28. Albers GW, Amarenco P, Easton JD, et al.

Antithrombotic and thrombolytic therapy for

ischemic stroke. Chest 2001;119:300S-320S. 

29. Vernet O, Montes JL, O’Gorman AM, et al.

Encephaloduroarterio-synangiosis in a child with

sickle cell anemia and moyamoya disease. Pediatr

Neurol 1996;14:226-30.
SICKLE CELL EYE DISEASE 14

95

atrophy, retinal hemorrhages, retinal pigmentary changes, and other abnormalities of the

retinal vasculature, macula, choroid, and optic

disc. These clinical findings are readily apparent on dilated ophthalmoscopy, and all occur

due to local vaso-occlusive events but rarely

have visual consequences. 

PROLIFERATIVE DISEASE

Progression to neovascularization or to the

proliferative stage involves the growth of

abnormal vascular fronds that place patients 

at risk of vitreous hemorrhage and retinal

detachment. The initiating event in the pathogenesis of proliferative disease is thought to be

peripheral retinal arteriolar occlusions. Local

ischemia from repeated episodes of arteriolar

closure is presumed to trigger angiogenesis

through the production of endogenous vascular growth factors, such as vascular endothelial

growth factor and basic fibroblast growth factor (1,2). Goldberg has defined five stages of

proliferative retinopathy (3). In stage I, peripheral arteriolar occlusion is present. In stage II,

vascular remodeling occurs at the boundary

between perfused and nonperfused peripheral

retina with the formation of arteriovenous

anastomoses. In stage III, actual preretinal neovascularization occurs. The neovascular fronds

typically assume a shape that resembles the

marine invertebrate Gorgonia flabellum,

known commonly as the “sea fan.” Stage IV 

is defined by the presence of vitreous hemorrhage, and stage V is defined by the presence

of retinal detachment. This last complication

Sickle cell vaso-occlusive events can affect

every vascular bed in the eye, often with devastating visual consequences. Because early

stages of sickle cell eye disease do not usually

result in visual symptoms, the disease can go

undetected unless a formal eye exam is performed by an ophthalmologist. The examination should include an accurate measurement

of visual acuity, assessment of pupillary 

reactivity, careful evaluation of the anterior 

structures of the eye using a slit-lamp biomicroscope, and a thorough examination of 

the posterior and peripheral retina through 

a dilated pupil. This last examination should

include fluorescein angiography. Patients with

sickle hemoglobinopathies should have yearly

eye examinations beginning in childhood and

continuing through adulthood.

CLINICAL FINDINGS

The clinical manifestations of sickle hemoglobinopathies are grouped according to the 

presence or absence of neovascularization in

the eye. The distinction is clinically relevant

because proliferation of new blood vessels on

the retina is the key biological event that sets

the stage for progression to vitreous hemorrhage and retinal detachment. 

NONPROLIFERATIVE DISEASE

Non-neovascular ocular manifestations of sickle

hemoglobinopathies include conjunctival 

vascular occlusions that transform smooth 

vessels into comma-shaped fragments, iris
Chapter 14: Sickle Cell Eye Disease

96

results from mechanical traction created 

by chronic, enlarging fibrovascular retinal

membranes, with or without hole formation

in the retina. 

Although peripheral vaso-occlusion may be

observed as early as 20 months of age (4),

clinically detectable retinal disease is found

most commonly between 15 and 30 years of

age (5). Sickle retinopathy is found more often

and earlier in SCD-SC, but is also common in

SCD-SS and sickle thalassemia. Observational

cohort studies have also shown that stages IV

and V retinopathy occur more often in SCDSC subjects than in those with SCD-SS (6). It

is a paradox that despite the less dramatic systemic consequences of their disease, subjects

with SCD-SC and sickle thalassemia are more

likely than SCD-SS patients to have serious

ocular manifestations. Research has not been

able to explain the reason for this profound

discrepancy in the severity of the retinal and

systemic manifestations among the various

sickle hemoglobinopathies (see the introductory material and chapter 2, Neonatal Screening,

for an overview of disease subtypes).

Diagnosis of proliferative retinopathy requires

examination through a dilated pupil utilizing

a wide-field indirect ophthalmoscope.

Evaluation of retinal blood flow is performed

with fluorescein angiography. Any patient 

identified with retinopathy should be followed

by an ophthalmologist who specializes in 

diseases of the retina. 

TREATMENT

Treatment is reserved for eyes that have 

progressed to proliferative retinopathy, since

patients are at risk for severe visual loss from

bleeding and retinal detachment. Given the

high rate of spontaneous regression and lack 

of progression of neovascularization in some

eyes, the indications for treatment of retinal

neovascularization are not always clear.

Therapeutic intervention usually is recommended in cases of bilateral proliferative disease, spontaneous hemorrhage, large elevated

neovascular fronds, rapid growth of neovascularization, and cases in which one eye has

already been lost to proliferative retinopathy.

The goal is early treatment to induce regression

of neovascular tissue before bleeding and retinal detachment occur. Techniques such as

diathermy, cryotherapy and laser photocoagulation have been used to cause involution of neovascular lesions. Of all of these methods, laser

photocoagulation has the fewest side effects.

If retinal detachment or nonclearing vitreous

hemorrhage is present, surgical intervention 

is usually required. Surgical techniques include

vitrectomy with or without the placement of 

a scleral buckle. Although modern vitreoretinal microsurgery can improve vision for many

patients with advanced sickle retinopathy, 

it should be emphasized that surgery carries 

a significant risk of intraoperative and postoperative complications including severe ocular

ischemia, recurrent hemorrhage, and elevated

eye pressure (7). To minimize the risk of such

complications, partial exchange transfusion

has been recommended prior to surgery, usually with a target of about 50 to 60 percent normal red cells, although there has never been 

a controlled study demonstrating the efficacy

of this maneuver (8). 
97

INDICATIONS FOR 

URGENT OPHTHALMOLOGIC

CONSULTATION

Immediate consultation with an ophthalmologist familiar with the management of individuals with hemoglobinopathies is required for

any individual with a sickle hemoglobinopathy, including sickle trait, who sustains eye

trauma. Anterior segment trauma may result

in hemorrhage into the anterior chamber of

the eye, allowing sickled erythrocytes to clog

the trabecular outflow channels and raise the

intraocular pressure, producing glaucoma. In

patients with sickle hemoglobinopathies, even

a moderate increase in eye pressure may cause

a significant reduction in perfusion of the

optic nerve and retina, putting the eye at risk

for ischemic optic atrophy and retinal artery

occlusion. In such instances patients may

require an emergent surgical washout of the

anterior chamber.

Trauma considerations aside, any patient with

a sickle hemoglobinopathy who has an acute

change in vision always should be referred

immediately to an ophthalmologist for a full

evaluation. 

RECOMMENDATIONS

Beginning in childhood, all patients with 

sickle hemoglobinopathies should have yearly

dilated examinations by an ophthalmologist

with expertise in retinal diseases. Any patient

with a sickle hemoglobinopathy who experiences a change in vision should be referred 

for ophthalmologic consultation immediately.

Central retinal artery occlusion, an event which

usually results in permanent, devastating loss of

vision, is one of the few bona fide ophthalmic

emergencies which demands intervention

within minutes to hours after the onset of

symptoms. Treatment consists of hyperoxygenation combined with rapid reduction of

eye pressure utilizing surgical and medical

techniques. Vision loss from hemorrhage or

retinal detachment also calls for urgent care,

but, unlike acute vascular occlusion, can be

addressed appropriately within 24 to 48 

hours. Any individual with a sickle hemoglobinopathy who sustains ocular or periocular

trauma should be examined immediately by

an ophthalmologist because of the increased

risk of visual loss from elevated eye pressure

associated with hemorrhage into the anterior

chamber (hyphema). 

REFERENCES

1. Cao J, Mathers MK, McLeod DS, et al.

Angiogenic factors in human proliferative sickle

cell retinopathy. Br J Ophthalmol 1999;83:838-46. 

2. Aiello LP. Clinical implications of vascular growth

factors in proliferative retinopathies. Curr Opin

Ophthalmol 1997;8:19-31.

3. Goldberg MF. Classification and pathogenesis of

proliferative sickle retinopathy. Am J Ophthalmol

1971;71:649-55.

4. McLeod DS, Goldberg MF, Lutty GA. Dual perspective analysis of vascular formations in sickle

retinopathy. Arch Ophthalmol 1993;111:1234-45.

5. Condon PI, Serjeant GR. Photocoagulation in 

proliferative sickle retinopathy: results of a 5

year study. Br J Ophthalmol 1980;64:832-40. 

6. Clarkson JG. The ocular manifestations of sickle

cell disease: a prevalence and natural history study.

Trans Am Ophthalmol Soc 1992;90:481-504. 

7. Rednam KRV, Jampol LM, Goldberg MF. Scatter

retinal photocoagulation for proliferative sickle cell

retinopathy. Am J Ophthalmol 1982;93:594-9.

8. Charache S. Eye disease in sickling disorders.

Hematol Oncol Clin North Am 1996;10:1357-62.

ONLINE RESOURCE

http://www.dr4eyes.com/sickle-cell.htm
98
CARDIOVASCULAR MANIFESTATIONS 15

99

the hemoglobin level and indicated cardiac

dilatation. Cardiac dilatation was also dependent on age. When homozygous α-thalassemia2 was present, left ventricular dimensions were

more normal, but wall thickness was increased

(4). This difference was postulated to be a

result of the higher hemoglobin levels caused

by α-thalassemia. Nevertheless, the response

to exercise was not improved, perhaps because

of the properties of abnormal sickle erythrocytes. Pericardial effusions were present in 

10 percent of patients and were also inversely

related to hemoglobin level (3).

As a group, patients with anemia have lowerthan-expected systolic and diastolic blood 

pressures and individuals with SCD are no

exception (5,6). This may be due to renal sodium wasting; however, its cause is not known

for certain. The blood pressure of patients with

SCD is higher than expected given the severity

of their anemia, suggesting the possibility that

they have “relative” hypertension (7). In a

study of 89 patients, there was an association

between higher blood pressures and stroke.

Survival decreased and the risk of stroke

increased as blood pressure rose, even though

the blood pressure at which these risks

increased was below the level defining early

hypertension in the normal population. This

suggested that “relative” hypertension was

pathogenetically important. Increased longevity, a higher prevalence of sickle cell nephropathy, and the consumption of high-calorie,

high-salt diets probably all contribute to the

rising prevalence of absolute hypertension in

CRITICAL REVIEW

Cardiac exam findings are rarely normal in

sickle cell disease (SCD); the heart is usually

enlarged and the precordium hyperactive, systolic murmurs are found in most patients, and

premature contractions are often present in

adults (1). Physical work capacity is reduced

to about half in adults with sickle cell anemia

and 60 to 70 percent in children; this is related to the severity of the anemia. Cardiomegaly

and heart murmurs often raise the question 

of whether or not congestive heart failure is

present. Contractility is normal and overt

congestive heart failure is uncommon, especially in children (2). When heart failure is

present, it often can be related to secondary

causes such as fluid overload. Cardiac output

is increased at rest and rises further with exercise (1). Electrocardiograms often have nonspecific abnormalities and can show signs of

ventricular enlargement. At rest, cardiac index

is 1.5 times normal value, and increases further

during exercise; it is not completely explained

by hemoglobin level or oxygen content, suggesting increased tissue extraction of oxygen.

One study evaluated cardiac function by

echocardiogram in 200 persons with SCD

who were 13 years of age or older (3).

Compared to normal controls, patients had

increased left and right ventricular and left

atrial chamber dimensions, increased interventricular septal thickness, and normal contractility. These dimensions, except for those of

the right ventricle, were inversely related to
100

Chapter 15: Cardiovascular Manifestations

patients with SCD. When this is added to the

apparent risks of even relative hypertension

and the fact that reducing blood pressure in

people without SCD can prevent the consequence of hypertension, it seems reasonable to

consider antihypertensive therapy in patients

with SCD with borderline hypertension. 

RECOMMENDATIONS

Chest pain, a common entity in SCD, often

leads to patients being told they have had a

heart attack. Obvious myocardial infarction is

unusual, but it has been reported. Paradoxically,

coronary artery occlusion is not common, suggesting that small vessel disease is responsible

for the cardiac damage (2). Ischemic heart 

disease can be present in patients with SCD

and should be considered in all individuals

with chest pain (8).

Sudden unexpected and unexplained death is

common in adults with sickle cell anemia (9,10).

Patients with SCD can have autonomic nervous

system dysfunction that may contribute to sudden death. A recent study in 24 patients found

14 patients (58.3 percent) to have cardiovascular autonomic dysfunction based on abnormal

values for at least two cardiovascular autonomic

function tests, whereas 10 (41.7 percent) had

preserved cardiovascular autonomic function.

In contrast, all control subjects had normal 

cardiac autonomic function (9).

Documented congestive heart failure in sickle

cell anemia should be treated with the usual

methods. Severely anemic patients with symptoms of congestive heart failure or angina pectoris may be helped by cautiously increasing

their hemoglobin concentration by transfusion

or, if possible, with hydroxyurea (see chapter

25, Transfusion, Iron Overload, and Chelation

and chapter 26, Hydroxyurea, for general

information about treating anemia).

Currently, no trials in patients with sickle cell

anemia can guide decisions regarding when to

begin antihypertensive treatment, what agents

are most effective, what the blood pressure

goals of treatment should be, and whether

blood pressure reduction can reduce the incidence of stroke or prolong life. A reasonable

approach, based on experience in the general

hypertensive population where the risk of

stroke begins well below the normal blood

pressure of 140/90 mmHg, is to carefully 

evaluate the patient and consider beginning

antihypertensive treatment when systolic blood

pressure rises by 20 mmHg or the diastolic

blood pressure increases by 10 mmHg. When

there is evidence of target organ damage from

heart disease, nephropathy and peripheral 

vascular disease, treatment might be started 

at pressures above 130/85 mmHg. Treatment

at pressures of 120/75 mmHg may be indicated when proteinuria is higher than 1 gram 

per day. ACE inhibitors and calcium antagonists may be especially useful treatments; the

former appears to reduce proteinuria and preserve renal function, and the latter may induce

a higher rate of response in black patients.

Theoretically, diuretics, by causing hemoconcentration, might predispose to vaso-occlusion. In practice, it is not clear whether this

occurs, and their use is not contraindicated.

Diuretic dosing should take into consideration

the additive effects of obligate hyposthenuria

in patients with SCD. β-adrenergic receptor

blocking agents can also be used. Renindependent hypertension can result from focal

areas of renal ischemia. Severe blood pressure

increases in individuals with SCD should be

evaluated thoroughly to exclude this and other

forms of secondary hypertension.
101

REFERENCES

1. Leight L, Snider TH, Clifford GO, Hellems HK. Hemodynamic studies in sickle cell anemia.

Circulation 1994;10:653-62.

2. Covitz W. Cardiac Disease. In: Embury SH, Hebbel RP, Mohandas N, et al., eds. Sickle Cell Disease: Basic Principles and Clinical Practice

.

New York: Lippincott-Raven, 1994:725-34.

3. Covitz W, Espeland M, Gallagher D, et al. 

The heart in sickle cell anemia. The cooperative

study of sickle cell disease (CSSCD). Chest

1995;108:1214-9.

4. Braden DS, Covitz W, Milner PF. Cardiovascular

function during rest and exercise in patients with

sickle-cell anemia and coexisting alpha thalassemia2. Am J Hematol 1996;52:96-102.

5. Johnson CS, Giorgio AJ. Arterial blood pressure 

in adults with sickle cell disease. Arch Intern Med

1981;141:891-3.

6. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med

1997;102:171-7.

7. Rodgers GP, Walker EC, Podgor MJ. Is “relative”

hypertension a risk factor for vaso-occlusive complications in sickle cell disease. Am J Med Sci

1993;305:150-6.

8. Martin CR, Johnson CS, Cobb C, et al.

Myocardial infarction in sickle cell disease.

J Natl Med Assoc 1996;88:428-32.

9. Romero Mestre JC, Hernandez A, Agramonte O,

et al. Cardiovascular autonomic dysfunction in

sickle cell anemia: a possible risk factor for sudden

death? Clin Auton Res 1999;7:121-5.

10. James TN, Riddick L, Massing GK. Sickle cells

and sudden death: morphologic abnormalities of

the cardiac conduction system. J Lab Clin Med

1994;124:507-20.
102
ACUTE CHEST SYNDROME 16

AND OTHER PULMONARY COMPLICATIONS

103

may not be recognized immediately. A major

risk factor for the development of ACS is the

hemoglobin genotype: the highest incidence 

is seen in βs

/βs genotype (12.8 events/100 person-years) and the lowest in βs

/β+ thalassemia

genotype (3.9 events/100 person-years) (4).

ACS is the second most common cause of

hospitalization in sickle cell patients and the

most common complication of surgery and

anesthesia (5). Children have higher incidences of ACS (21 events/100 person-years,

βs

/βs genotype) but lower mortality (<2 percent) than adults (8.7 events /100 person-years

and 4-9 percent mortality) (3,6). In SCD-SS

persons, the incidence of ACS is related to 

low fetal hemoglobin (Hb F) levels and high

steady-state hematocrits and white cell counts,

but not to coexistent α-thalassemia (4).

Children have seasonal variation in ACS 

incidence: lower in the summer, but higher 

in winter when respiratory infections are 

frequent (6). The seasonal pattern is less

marked in adults. Even though the ACS 

usually is self-limited, it can present with or

progress to respiratory failure, characterized 

by noncardiogenic pulmonary edema and

severe hypoxemia. These critically ill patients

need both respiratory support and emergency

transfusions (see below). 

The Multicenter Acute Chest Syndrome 

Study (MACSS) group enrolled 538 patients

with 671 ACS episodes in a comprehensive,

standardized diagnostic and management 

protocol (3). The protocol included bacteriology, virology, and serologic studies, as well as

The lung is a major target organ for acute 

and chronic complications of sickle cell disease

(SCD). Acute chest syndrome (ACS) is a 

frequent cause of death in both children and

adults (1-3) with SCD. Pulmonary problems

not directly related to sickle cell vaso-occlusion, such as pneumonia or asthma, can worsen SCD because local or systemic hypoxia

increases sickle hemoglobin (Hb S) polymerization. Multiorgan failure often is preceded 

or accompanied by pulmonary involvement, 

as observed with fat embolization in pain

episodes. There is more frequent recognition

of chronic pulmonary hypertension in adult

patients, as this complication gives a poor

prognosis even though pulmonary artery pressures are not very high compared to those in

patients with primary pulmonary hypertension. 

Few of the management recommendations

below are based on randomized clinical trials,

since such trials are largely unavailable. The

proposed guidelines are based on reviews of

small case series in the literature, and on consensus among clinicians with experience in

SCD treatment.

ACUTE CHEST SYNDROME

SUMMARY OF THE STATE

OF KNOWLEDGE

ACS is an acute illness characterized by fever

and respiratory symptoms, accompanied by 

a new pulmonary infiltrate on a chest x ray.

Because the appearance of radiographic

changes may be delayed (3), the diagnosis 
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications

104

examination of bronchoscopy-obtained secretions or deep sputum samples. In 108 of 364

episodes (30 percent) with complete diagnostic data, all results were negative, which led,

by exclusion, to the diagnosis of pulmonary

infarction. Fifty-nine of the 364 episodes

(16.2 percent) had pulmonary fat embolization (PFE) defined by the finding of lipidladen macrophages in broncho-alveolar lavage

specimens. About one-third of the PFE cases

showed evidence of infection. Previous studies

on mostly older patients had reported higher

prevalences of PFE (44 to 77 percent) in ACS

(7,8). Patients with PFE tend to be older and

have lower oxygen saturations (3). An infectious agent was identified in 197 episodes (54

percent) but a wide variety of microorganisms

was found, the most common of which were

chlamydia (48 episodes, 13 percent), mycoplasma (44 episodes, 12 percent) and viruses 

(43 episodes, 12 percent). In 30 ACS episodes

(8.2 percent), bacteria were isolated, which

included Staphylococcus aureus, Streptococcus

pneumoniae, and Hemophilus influenzae.

The MACSS reported findings from the first

ACS episode in 128 adults and 409 children

(82 percent with Hb SS genotype) (3). This

study used strict criteria to define ACS: a pulmonary infiltrate consistent with consolidation, plus at least one of the following: chest

pain, fever over 38.5 ̊C, tachypnea, wheezing,

or cough. An earlier series, the Cooperative

Study of Sickle Cell Disease (CSSCD)

enrolled 252 adults and 687 children (76 

percent with SS genotype) who had a total 

of 1722 episodes of ACS (6) defined by the

appearance of a new pulmonary infiltrate on

the chest x ray. Table 1 summarizes findings

from both of these prospective series. 

Clearly, the MACSS enrolled more severely 

ill patients than did the CSSCD, as shown 

by more frequent use of red cell transfusions,

longer hospital stays, and higher death rate,

particularly in adult patients. In the MACSS,

multilobe involvement, history of cardiac disease, and lower platelet counts independently

predicted respiratory failure. Low platelet

counts also were associated with neurologic

complications.

TREATMENT RECOMMENDATIONS

Oxygen

Assessment of blood oxygenation requires determination of baseline arterial blood gases (ABG),

and estimation of the alveolar-arterial (A-a)

oxygen gradient and the PaO2/FiO2 ratio.

Oxygen should be administered to moderately

hypoxemic patients (PaO2 = 70-80 mmHg,

O2 saturation = 92-95 percent) nasally at 

a rate of 2 liters per min. Chronically hypoxemic patients in whom the admission PaO2

is no lower than in their steady state may still

benefit from oxygen because they may not 

tolerate additional hypoxemia due to ACS.

Control of chest pain and incentive spirometry

can prevent hypoventilation in most patients

(9). The efficacy of these interventions should

be checked with repeated ABGs as needed to

monitor the A-a gradient, which appears to 

be the best predictor of clinical severity (10).

Patients with worsening A-a gradients should

be managed in an intensive care unit for adequate cardiorespiratory support. 

Transfusions

Simple transfusions (or exchange transfusions)

decrease the proportion of sickle red cells and

are indicated for the treatment of ACS (3,11)

(see chapter 25, Transfusion, Iron Overload,

and Chelation). Transfusions will increase the
Table 1. Clinical Presentation and Course of Acute Chest Syndrome: Cooperative Study 

of Sickle Cell Disease (CSSCD) and Multicenter Acute Chest Syndrome Study (MACSS) 

Presenting symptoms and signs (percent) CSSCD MACSS

Fever 80 80

Cough 74 62

Chest pain 57 44

Shortness of breath 28 41

Tachypnea 2 45*

Wheezing 11 26

Rales 46 76

Dullness 31 nr**

Normal auscultation 35 nr

X-ray and laboratory findings 

Multiple lobe involvement, adults (percent) 36 59

Multiple lobe involvement, children (percent) 24 74

Pleural effusion, adults (percent) 21 27

Pleural effusion, children (percent) 3 38 

Mean hemoglobin level (g/dL) 7.9*** 7.7

Mean change from steady-state Hb (g/dL) - 0.7 - 0.8

Mean WBC/μL 21.1x103 23.0x103

Mean PaO2 at diagnosis (mmHg) 71**** 70 

Mean O2 saturation at diagnosis (percent) nr 92

Bacteremia (percent) 3.5 nr

Hospital course, treatment, mortality

Respiratory insufficiency, adults (percent on ventilator) nr 22

Respiratory insufficiency, children (percent on ventilator) nr 10

Neurologic event, (percent patients) nr 11

Antibiotics given (percent patients) nr 100

Bronchodilators used (percent patients) nr 61

Transfusions used (percent patients) 26 72

Mean number of units given nr 3.2

Mean hospital stay, adults (days) 10 12.8

Mean hospital stay, children (days) 5.4 9

Death rate, adults (percent) 4.3 9

Death rate, children (percent) 1.1 <2

* Tachypnea was an inclusion criterion in the MACSS but not in the CSSCD series. 

** Not reported. 

*** SCD-SS patients. 

**** Only 56 percent had arterial blood gas determinations.

105
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications

106

oxygen affinity of blood in sickle cell patients

(12). The main indication for transfusion

therapy is poor respiratory function. The 

goal is to prevent progression of ACS to acute

respiratory failure. Two studies, though nonrandomized, demonstrate the effect of blood

transfusion on oxygenation in ACS patients

(table 2).

From the data above, it would appear that

transfusions or exchange transfusions should

be initiated at the first sign of hypoxemia

(PaO2 below 70 mmHg on room air). For

patients with chronic hypoxemia, a drop in

PaO2 of greater than 10 percent from baseline

seems to be a reasonable transfusion trigger.

Transfusions may not be needed if the A-a

oxygen gradient is due to splinting from pain,

that is, if the gradient corrects with analgesia

and incentive spirometry. Transfusion therapy

should not be delayed, particularly in deteriorating patients. Altered mentation in such

patients is often erroneously attributed to opioid excess, delaying the therapy of progressive

acute chest syndrome.

Antibiotics

Intravenous broad-spectrum antibiotics should

be given to febrile or severely ill ACS patients

since it is difficult to exclude bacterial pneumonia or superinfection of a lung infarct. The

MACSS used erythromycin and cephalosporin.

A macrolide or quinolone antibiotic always

should be included because atypical microorganisms are common (3). 

Other measures

Optimal pain control and incentive spirometry

are important to prevent chest splinting and

atelectasis. A randomized controlled study

showed that incentive spirometry reduced 

the risk of development of ACS by 88 percent

in patients hospitalized with thoracic bone

ischemia/infarction (9). Airway hyperreactivity

occurs in up to one-fourth of ACS patients

and is treated with bronchodilators. Fluid

overload should be avoided by the use of 5

percent dextrose in water or 1/2- or 1/4-normal saline, and by limiting the infusion rate to

1.5 times maintenance requirements (3). More

studies are needed to establish the safety and

efficacy of the use of dexamethasone (13) and

other approaches, such as nitric oxide inhalation (14), in the treatment of ACS.

PREVENTION AND PROGNOSIS

The short-term prognosis of ACS with limited

lung involvement and only mild hypoxemia 

is good. Some reports suggest an association

between chronic pulmonary disease and frequent ACS episodes (15,16), but others did

not find long-term lung damage in patients

with recurrent ACS (17). In any case, frequent

ACS episodes or painful events are associated

with shorter lifespans (4). The frequency of

ACS can be reduced by about 50 percent with

hydroxyurea treatment (18). Nonrandomized

observations suggest that transfusion regimens

can prevent ACS. A preliminary report from

the Stroke Prevention Trial in Sickle Cell

Table 2. Mean Room Air PaO2 in ACS before and after Transfusions

Authors Before Transfusion After Transfusion p 

Emre et al. (18) 65 mmHg 86 mmHg 0.0001 (N=16)

Vichinsky et al. (3) 63 mmHg 71 mmHg 0.001 (N=387)
107

Anemia (STOP) showed that patients randomized to receive transfusions had significantly fewer ACS events (2.2/100 personyears), compared to patients in the nontransfused arm (15.7/100 person-years, p<0.001).

SYSTEMIC FAT EMBOLIZATION

SYNDROME

SUMMARY OF THE STATE OF THE ART

Bone marrow infarction and necrosis is 

a known complication of SCD (19). When 

an infarct is massive, necrotic marrow and fat

embolize to the pulmonary vasculature. Fat

droplets can enter the systemic circulation,

which results in systemic fat embolization

(SFE) syndrome. Thus, in addition to respiratory insufficiency, patients can develop multiorgan failure from emboli in organs such as the

brain and kidneys. SFE can affect patients

with even the mildest forms of SCD. Few case

reports are available (20,21), but risk factors for

SFE appear to be a βs

/βc genotype, pregnancy,

and prior corticosteroid treatment. Clinical

signs of SFE vary and depend on the organs

involved and the degree of involvement.

Initially there may be a painful event, but

patients can present with or develop a fever,

hypoxemia, azotemia, liver damage, altered

mental state, or coma. Hematologic signs

include progressive anemia, normoblastemia,

thrombocytopenia, and disseminated intravascular coagulation. A high index of suspicion for

SFE should be maintained, even though this

diagnosis is hard to prove. Fortunately, SFE 

is often preceded or accompanied by pulmonary involvement (severe chest syndrome,

pulmonary fat embolism), so that transfusions

given to hypoxemic ACS patients may prevent

or inhibit its development.

RECOMMENDATIONS

Because SFE is life-threatening but difficult to

recognize, a proposal for management includes

the following:

■ A high index of suspicion for SFE should

be maintained, and all cases of ACS are

considered to be at risk. Treatment of SFE

should not await proof of diagnosis, since

only two premortem findings prove SFE

in sickle cell or trauma patients: detection

of fat droplets within retinal vessels and 

a biopsy of petechiae (22) that shows

microvascular fat. Urine fat stains are

unreliable. Indirect evidence of SFE in

sickle cell patients includes positive fat

stain in bronchial macrophages, lung

microvascular cells, or venous blood buffy

coat (23) and multiple areas of necrosis 

on bone marrow scans. The descriptions 

of these signs are anecdotal in SCD-related

SFE (and in non-SCD patients with fat

emboli due to trauma). 

■ As in cases of severe ACS, support in a

critical care setting is essential to manage

respiratory insufficiency and multiorgan

failure. Case reports suggest that prompt

transfusion or exchange transfusion may

prevent some deaths from SFE (20). Since

fat embolism causes severe hypoxemia

which promotes Hb S polymerization, 

it seems likely that transfused normal

blood will dilute the patient’s sickle cells

and improve pulmonary and systemic

microvascular circulation. Survival in sickle cell patients with SFE has been reported

only in those treated with transfusions.

REACTIVE AIRWAY DISEASE

Airway hyperreactivity (asthma) is not a classical feature of SCD, but transgenic mouse

models of SCD have airway obstruction that

is responsive to albuterol. Cold air challenge
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications

108

induced hyperresponsiveness in 83 percent 

of asymptomatic children with SCD who had

a history of reactive airways (24). Also, two

large prospective studies of ACS described

above reported wheezing in 11 percent (6) 

and 26 percent (3) of patients on admission.

In the latter group, the mean predicted forced

expiratory volume was 53 percent, and 61 

percent of patients were treated with bronchodilators. Twenty percent of ACS patients

improved with bronchodilators and had a 15

percent increase in predicted forced expiratory

volume (3). Like nonhemoglobinopathy subjects, asthmatic sickle cell patients are treated

with inhaled bronchodilators, with or without

inhaled steroids. Steroids can be added systemically to manage acute asthma, but sickle cell

patients should be monitored for the development of vaso-occlusive events.

PULMONARY HYPERTENSION

SUMMARY OF THE STATE OF THE ART

Pulmonary hypertension (PHT), defined as 

a mean pulmonary artery pressure above 25

mmHg, can be secondary to SCD (20), but 

its prevalence is not known. In sickle cell

patients the frequency of chronic lung disease

with cor pulmonale is reported at 4.3 percent.

PHT is probably more frequent in adult

patients (20), although it was not listed as an

underlying condition in 209 adult CSSCD

patients who died during that study (25).

The mechanisms for PHT in SCD are not

known. One or more of the following factors

could be responsible: sickle cell-related vasculopathy, chronic oxygen desaturation or sleep

hypoventilation (26), pulmonary damage from

recurrent chest syndrome (15), repeated

episodes of thromboembolism (27), or high

pulmonary blood flow due to anemia. The 

last reason, combined with decreased lung 

vasculature, also was given as a cause of PHT

in thalassemia intermedia (28). Regardless 

of the exact mechanism, the development of

PHT raises the risk for cor pulmonale, recurrent pulmonary thrombosis, and worsened

hypoxemia, all of which increase the frequency

and severity of vaso-occlusive episodes (pain

events, ACS) in SCD (15).

The diagnosis of PHT should be considered in

sickle cell patients with (a) increased intensity

of the second heart sound, (b) right ventricular

enlargement on chest x ray, EKG, or echocardiogram, or (c) unexplained oxygen desaturation. As PHT worsens, patients complain 

of chest pain and dyspnea, and have hypoxemia at rest. Additional problems are rightsided heart failure, syncope, and a risk of sudden death from pulmonary thromboembolism, 

systemic hypotension, or cardiac arrhythmia.

Unless an echocardiogram shows tricuspid

regurgitation with increased pulmonary artery

pressure, the diagnosis of PHT requires rightsided cardiac catheterization. In a few patients

whose catheterization results were published,

the pulmonary pressures were lower and cardiac outputs (measured by thermodilution)

were higher than in primary PHT (20). 

RECOMMENDATIONS

There is no proven treatment for sickle cellrelated PHT. Therefore, recommendations are

tentative and based mostly on what is known

about the treatment of primary PHT. During

cardiac catheterization, vasodilators or oxygen

may be given to see if they reduce pulmonary

pressure acutely in order to predict the benefit

of long-term administration. Continuous infusion of prostacyclin, a vasodilator and inhibitor

of platelet aggregation, improves pulmonary

artery pressure and survival in primary PHT

(29), and also may be effective in secondary

PHT (30). This drug also causes some patients
109

with SCD-related PHT to respond during 

cardiac catheterization (31), but there are no

published data on long-term use. Other agents

used to treat primary PHT are the calciumchannel blockers nifedipine and diltiazem

(32), and these or similar medications could

be tried in responsive sickle cell patients.

Long-term anticoagulation with warfarin 

[to an international normalized ratio (INR) 

of 2-3] is used in primary PHT because of 

the risk of thromboembolism (29) and also

may be useful for SCD-related PHT (27).

Continuous or nocturnal oxygen therapy

decreases pulmonary artery pressure in patients

who are hypoxemic from various lung disorders. It should be used in SCD-related PHT 

if it lowers pulmonary pressure at cardiac

catheterization, and in chronically hypoxemic

patients (PaO2 <60 mmHg, O2 saturation 

<90 percent). A red cell transfusion program

would help to reduce the incidence of vasoocclusive events, ACS, lung scarring, and 

PHT in some patients. Hydroxyurea would 

be expected to have the same effect, but it

does not seem to prevent the development 

of PHT in SCD.

REFERENCES

1. Gray A, Anionwu EN, Davies SC, et al. Patterns 

of mortality in sickle cell disease in the United

Kingdom. J Clin Pathol 1991;44:459-63.

2. Miller ST, Sleeper LA, Pegelow CH, et al.

Prediction of adverse outcomes in children with

sickle cell disease. N Engl J Med 2000;342:83-9.

3. Vichinsky EP, Neumayr LD, Earles AN, et al.

Causes and outcomes of the acute chest 

syndrome in sickle cell disease. N Engl J Med

2000;342:1855-65.

4. Castro O, Brambilla DJ, Thorington B, et al. 

The acute chest syndrome in sickle cell disease:

incidence and risk factors. Blood 1994;84:643-9.

5. Vichinsky EP, Haberkern CM, Neumayr L, et al. A

comparison of conservative and aggressive transfusion regimens in the perioperative management of

sickle cell disease. N Engl J Med 1995;333:206-13.

6. Vichinsky EP, Styles LA, Colangelo LH, et al.

Acute chest syndrome in sickle cell disease: clinical

presentation and course. Blood 1997;89:1787-92.

7. Vichinsky E, Williams R, Das M, et al. 

Pulmonary fat embolism: a distinct cause 

of severe acute chest syndrome in sickle cell 

anemia. Blood 1994;83:3107-12.

8. Godeau B, Schaeffer, A, Bachir D, et al.

Bronchoalveolar lavage in adult sickle cell patients

with acute chest syndrome: value for diagnostic

assessment of fat embolism. Am J Respir Crit Care

Med 1996;153:1691-6.

9. Bellet PS, Kalinyak KA, Shukla R, et al. 

Incentive spirometry to prevent acute pulmonary

complications in sickle cell diseases. N Engl J Med

1995;333:699-703.

10. Emre U, Miller ST, Rao SP, et al. Alveolar-arterial

oxygen gradient in acute chest syndrome of sickle

cell disease. J Pediatr 1993;123:272-5.

11. Emre U, Miller ST, Gutierrez M, et al. Effect of

transfusion in acute chest syndrome of sickle cell

disease. J Pediatr 1995;127:901-4.

12. Uchida K, Rackoff WR, Ohene-Frempong K, et al.

Effect of erythrocytapheresis on arterial oxygen saturation and hemoglobin oxygen affinity in patients

with sickle cell disease. Am J Hematol 1998;59:5-8.

13. Bernini JC, Rogers ZR, Sandler ES, et al.

Beneficial effect of intravenous dexamethasone 

in children with mild to moderately severe acute

chest syndrome complicating sickle cell disease.

Blood 1998;92:3082-9.

14. Sullivan KJ, Goodwin SR, Evangelist J, et al. Nitric

oxide successfully used to treat acute chest syndrome of sickle cell disease in a young adolescent.

Crit Care Med 1999;27:2563-8.

15. Powars D, Weidman JA, Odom-Maryon T, et al.

Sickle cell chronic lung disease: prior morbidity

and the risk of pulmonary failure. Medicine

(Baltimore) 1988:67:66-76.

16. Santoli F, Zerah F, Vasile N, et al. Pulmonary function in sickle cell disease with or without acute

chest syndrome. Eur Respir J 1998;12:1124-9.

17. Denbow CD, Chung EE, Serjeant GR. Pulmonary

artery pressure and the acute chest syndrome in

homozygous sickle cell disease. Br Heart J

1993;69:536-8.

18. Charache S, Terrin ML, Moore R, et al. Effect of

hydroxyurea on the frequency of painful crises in

sickle cell anemia. N Engl J Med 1995;332:1317-22.

19. Milner PF, Brown M. Bone marrow infarction in

sickle cell anemia: correlation with hematologic

profiles. Blood 1982;60:1411-9.
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20. Castro O. Systemic fat embolism and pulmonary

hypertension in sickle cell disease. Hematol Oncol

Clin NA 1996;10:1289-303.

21. Ballas SK, Pindzola A, Chang CD, et al.

Postmortem diagnosis of hemoglobin SC disease

complicated by fat embolism. Ann Clin Lab Sci

1998;28:144-9.

22. Schonfeld SA, Ploysongsang Y, DiLisio R, et al. 

Fat embolism prophylaxis with corticosteroids. 

A prospective study in high risk patients. Ann

Intern Med 1983;99:438-43.

23. van Hoeven KH, Wanner JL, Ballas SK. Cytologic

diagnosis of fat emboli in peripheral blood during

sickle cell infarctive crises. Diag Cytopathol

1997;17:54-6.

24. Leong MA, Dampier C, Varlotta L, et al. Airway

hyperreactivity in children with sickle cell disease.

J Pediatr 1997;131:278-83.

25. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality

in sickle cell disease. Life expectancy and risk 

factors for early death. N Engl J Med

1994;330:1639-44.

26. Samuels MP, Stebbens VA, Davies, SC, et al. Sleep

related upper airway obstruction and hypoxaemia

in sickle cell disease. Arch Dis Child 1992;67:925-9.

27. Yung GL, Channick RN, Fedullo PF, et al.

Successful pulmonary thromboendarterectomy 

in two patients with sickle cell disease. Am J Respir

Crit Care Med 1998;157:1690-3.

28. Aessopos A, Stamatelos G, Skoumas V, et al.

Pulmonary hypertension and right heart failure 

in patients with β-thalassemia intermedia. Chest

1995;107:50-3.

29. Barst RJ, Rubin LJ, Long WA, et al. A comparison

of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary 

pulmonary hypertension. N Engl J Med

1996;334:296-302.

30. McLaughlin V, Genthner DE, Panella MM, et al.

Compassionate use of continuous prostacyclin 

in the management of secondary pulmonary 

hypertension: a case series. Ann Intern Med

1999;130:740-3.

31. Kaur K, Brown B, Lombardo F. Prostacyclin for

secondary pulmonary hypertension. Ann Intern

Med 2000;132:165.

32. Rich S, Kaufmann E, Levy PS. The effect of high

doses of calcium-channel blockers on survival in

primary pulmonary hypertension. N Engl J Med

1992;327:76-81.
GALL BLADDER AND LIVER 17

111

Ultrasound surveys of patient populations

indicate the onset of cholelithiasis occurs as

early as 2 to 4 years of age and progressively

increases in prevalence with age (4); nearly 

30 percent of patients develop cholelithiasis 

by age 18. African populations appear to have 

a substantially lower prevalence than that of

Jamaican or North American patients (5); this

variation is attributed to differences in dietary

cholesterol or fiber, although other factors

(genetic or environmental) also may have an

influence. Xenobiotics such as the third generation cephalosporins may crystallize in the

gallbladder, and differences in the use of such

antibiotics could account for some of the geographic variation in cholelithiasis frequency.

The coinheritance of α-thalassemia appears 

to reduce the frequency of stones as the result

of a lesser degree of hemolysis (6). Common

duct obstruction is frequently incomplete

because pigment stones are small but they 

still can cause the characteristic biochemical

changes of cholestasis. Gallstones have been

known to pass with or without pancreatitis.

Biliary sludge is a viscous material detectable

by nonacoustic shadowing on ultrasonography

(7) and may be a precursor of gallstone development. Certain antibiotics such as ceftriaxone seem to promote sludge formation.

Studies in patients with SCD indicate that

sludge is often found with stones, but sludge

alone may or may not progress to stone formation. However, the period of followup of

such studies is short (8,9).

Dysfunction of the liver and biliary tract is 

a common complication of sickle cell disease

(SCD) and its variants. Despite nearly 200

reports in the past 15 years on the hepatobiliary aspects of the sickling disorders, the

frequency and pathophysiology responsible 

for hepatic lesions remain unclear.

Hepato-biliary complications of the sickling

disorders can be separated into broad categories of disorders related to hemolysis, the

problems of anemia and transfusion management, the consequences of sickling and vasoocclusion, and diseases unrelated to sickle

hemoglobin (Hb S). These complications of

the sickling disorders are most common in

sickle cell anemia (SCD-SS), but also occur to

a lesser extent in the compound heterozygous

sickle diseases, SCD-SC and the β-thalassemia

syndromes (SCD-S βo thal and SCD-S β+ thal).

CHOLELITHIASIS AND 

BILIARY SLUDGE

Chronic hemolysis, with its accelerated bilirubin turnover, leads to a high incidence of pigment gallstones. Ordinarily, bilirubin levels in

SCD patients do not exceed 4 mg/dL from

hemolysis alone, and the conjugated fraction is

less than 10 percent (1,2). Marked increases in

the unconjugated fraction have been reported

in association with the UDP-glucuronyltransferase genetic defect of Gilbert’s syndrome (3).
Chapter 17: Gall Bladder and Liver

112

ACUTE AND CHRONIC 

CHOLECYSTITIS

Fever, nausea, vomiting, and abdominal pain

are common events with a wide differential

diagnosis, including hepatic, intestinal, pancreatic, vertebral, neurologic, and pulmonary

disorders (table 1).

A careful clinical evaluation is necessary to

establish a clear diagnosis. Biliary scintigraphy

might be helpful, but its use is controversial

because of a high false positive rate and low

positive predictive value. However, it has a

high negative predictive value since a normal

study indicates that the cystic duct is patent.

False positives can result from prolonged fasting, severe hepatocellular disease, extrahepatic

obstruction, chronic cholecystitis, or narcoticinduced spasm of the sphincter of Oddi (10).

The Tc-99 RBC scan may prove more useful

in detecting the hyperemia of acute cholecystitis, but its use with these patients has not

been reported.

Treatment of acute cholecystitis does not 

differ from that for the general population

and consists of antibiotics and general supportive care with consideration for elective

cholecystectomy several weeks after the acute

episode subsides. 

CHOLECYSTECTOMY

Laparoscopic cholecystectomy on an elective

basis in a well-prepared patient has become

the standard approach to symptomatic

patients. However, symptoms attributed to

cholecystitis often persist after cholecystectomy. Because intraoperative cholangiography

(IOC) has a false positive rate estimated at 25

percent, endoscopic retrograde cholangiopancreatography (ERCP) at the time of laparoscopic cholecystectomy is preferred. IOC is

still useful, however, for delineating the anatomy of the cystic duct and its artery. The decision to proceed to cholecystectomy should be

based on the natural history of the disorder in

this patient population. The Jamaican data (4)

provide the strongest argument for a conservative approach, but Jamaican patients seem to

be substantially less symptomatic than are

North American patients. An aggressive

approach provides the benefit of reducing the

risk of the morbid complications of cholelithiasis, as well as eliminating gallbladder disease

as a confounding item in the differential 

diagnosis of right upper quadrant pain. For

asymptomatic patients, the data support a

conservative approach, but there is considerable controversy.

Table 1. Unusual Causes of Right Upper Quadrant 

(RUQ) Pain and Abnormal Liver Tests 

Reported in Sickling Disorders

Biloma

Focal nodular hyperplasia of the liver in children

Fungal ball

Hepatic artery stenosis 

Hepatic infarct/abscess

Hepatic vein thrombosis

Mesenteric/colonic ischemia

Pancreatitis

Periappendiceal abscess

Pericolonic abscess

Pulmonary infarct/abscess

Renal vein thrombosis
113

VIRAL HEPATITIS

Acute viral hepatitis has the same clinical

course in patients with sickling disorders as 

in the general population, but with a higher

peak bilirubin level because of hemolysis. 

Surveys for serologic evidence of hepatitis 

B infection show a wide range of prevalence,

related to the endemicity of the virus as well 

as to past transfusion practices (1). Fulminant

hepatitis occurs with a high mortality in 

0.5 percent of the general population, and

chronicity is inversely related to age. Thus 

vaccination early in life seems to be indicated;

patients with SCD respond as well as the 

general population. 

Similar surveys for hepatitis C infection indicate that this infection is clearly related to

transfusion practice and geographic location

and that chronic hepatitis is as frequent in

patients with SCD as in the general population (11). In the general population, fulminant hepatitis is unusual, but as many as 65

percent will develop chronic hepatitis and cirrhosis. Chronic hepatitis is subtle, with only

25 percent of patients having AST/ALT as

high as twice normal values. In SCD, cirrhosis

occurs, and liver transplants are now being

done (12). Chronic hepatitis C is associated

with extrahepatic manifestations that can 

confound the management of SCD. These

include a cutaneous leucocytoclastic vasculitis

and essential mixed cryoglobulinemia with

purpura, arthralgias, glomerulonephritis, and

peripheral neuropathy.

In studies of patients with persistent elevations

of AST/ALT, biopsy invariably shows evidence

of chronic hepatitis (13,14). Treatment of

chronic viral hepatitis is based upon observations that sustained suppression of viral replication renders patients noninfectious, reduces

the inflammatory process, and slows the 

subsequent development of cirrhosis and

hepatocellular carcinoma. 

Indications for treatment of hepatitis B

include HBsAg positivity for more than 

6 months, HBV DNA positivity, and persistent elevation of ALT or biopsy evidence for

chronic hepatitis.

For hepatitis C, persistent elevation of

AST/ALT, positive PCR for viral RNA, 

or biopsy evidence of chronic hepatitis 

are indications for treatment.

AUTOIMMUNE HEPATITIS 

Autoimmune hepatitis has been reported in 

5 patients (15). It is characterized histologically

by dense T-cell infiltrates in periportal areas

with bridging fibrosis and piecemeal necrosis

and by a marked polyclonal gammopathy. It 

is associated with extrahepatic manifestations

of arthropathy, rash, and leg ulcers. Treatment 

of sickle cell patients with plasma exchange 

has been successful. Data from the hepatology

literature indicate that prednisone and 

azathioprine given for 24 months initially

induce a clinical remission that is followed 

by biochemical, then histological, remission.

HEMOSIDEROSIS/

HEMOCHROMATOSIS

Iron overload develops as a result of frequent

transfusions, although genetic hemochromatosis does occur. Hepatic iron stores can be measured biochemically or by a superconducting

quantum interference device susceptometer,

but this instrument is not widely available.

Magnetic resonance imaging (MRI) comparing the signal intensity of liver, pancreas, and

spleen to that of muscle is useful for detecting

iron overload, but MRI is not very sensitive 
Chapter 17: Gall Bladder and Liver

114

to gradations of iron load. Decrease in signal

intensity from the pancreas is a very useful

index for hemochromatosis. Serum ferritin

levels may be disproportionately elevated 

relative to the degree of iron stores because of

factors such as ascorbate deficiency, inflammation, or liver disease (16). The isotope Ga-67

is carried by transferrin, and Ga-67 citrate

may prove to be useful in the demonstration

of iron overload but requires further study.

The importance of iron load is illustrated 

by results from a study of children receiving

transfusion for the prevention of stroke; their

serum ferritin levels rose 10-fold at an average

followup of 42 months and this increase was

associated with an 8-fold rise in AST/ALT

(17). In a study of women receiving supportive transfusion during pregnancy, incidental

liver biopsy performed during abdominal

surgery showed that two-thirds had significant

hepatocyte iron accumulation after an average

transfusion burden of 13.6 units (18). 

The standard subcutaneous regimens for

deferoxamine therapy successfully chelate

excess iron. Complications of therapy 

include ophthalmic- or oto-toxicity, allergic

reactions, growth failure, and unusual infections (Yersinia, fungi). 

Poor patient compliance is an unresolved

problem. Because poor compliance can be an

issue, periodic intensive intravenous deferoxamine therapy is often given. Aggressive chelation with intravenous doses of 6 to 12 grams

daily has produced rapid declines in serum 

ferritin and ALT, and improvement in cardiac

function and other indices. Adverse effects

have not been noted in short-term therapy,

although zinc excretion is increased (19).

VASCULAR OCCLUSION

The hepatic complications attributed to vascular occlusion encompass a variety of clinical

syndromes for which our understanding of 

the relationships among clinical presentation,

biochemical findings, and histologic features

remains unclear. In many patients, the liver 

is generally enlarged throughout life, especially

when its measurement is adjusted for body

size (20).

Hepatic crisis, or right upper quadrant 

syndrome (RUQ), consists of RUQ pain,

fever, jaundice, elevated AST/ALT, and hepatic

enlargement. It occurs in as many as 10 percent of patients with acute vaso-occlusive crisis

(VOC). The rapid decrease in AST/ALT 

differentiates this condition from the slower

decline characteristic of acute viral hepatitis.

In one study of 30 patients, liver tests taken 

at the time of uncomplicated VOC and 4

weeks later in the steady state showed that 

the alkaline phosphatase level was 30 percent

higher during VOC; ALT was three-fold 

higher, and bilirubin was elevated two-fold,

primarily due to elevation of the conjugated

fraction (21). Treatment with supportive care

was the only modality needed.

RUQ pain and jaundice present a problem 

in differential diagnosis because prominent

abdominal pain is associated with a wide 

variety of conditions that affect SCD patients

(table 1). Additional imaging techniques are

useful in establishing these diagnoses. Hepatic

infarction is seen as a characteristic wedgeshaped, peripherally located hypointense

lesion on CT scan. Single or multiple abscesses have been described with an irregular shape

on CT scan. Focal nodular hyperplasia of 

the liver has been seen with a characteristic

avascular mass on angiography. 
115

HEPATIC SEQUESTRATION

Acute hepatic sequestration, a rarely recognized complication of VOC, is characterized

by a rapidly enlarging liver accompanied by a

decrease in hemoglobin/hematocrit and a rise

in reticulocyte count. The liver is smooth and

variably tender. The bilirubin may be as high

as 24 mg/dL (or even higher) with a predominance of the conjugated fraction. The alkaline

phosphatase can be as high as 650 IU/L or

may be normal; the transaminases may be 

elevated only minimally but are often normal.

Ultrasonography and CT scanning show only

diffuse hepatomegaly. Liver biopsy shows 

massively dilated sinusoids with sickled erythrocytes and Kupffer cell erythrophagocytosis. Intrahepatic cholestasis with bile plugs 

in canaliculi may be seen. Hepatocyte necrosis

is unusual. Recurrence is common. 

Simple transfusion, exchange transfusion, 

or supportive care alone can resolve hepatic

sequestration. In one patient, treated with

simple transfusion, resolution of sequestration

was accompanied by a rapid increase in the

concentration of circulating hemoglobin, 

representing return of sequestered red cells 

to the circulation; this resulted in a fatal acute

hyperviscosity syndrome (22). Because of this

risk with simple transfusion, exchange transfusion is preferred; however, careful monitoring

still is required.

Acute hepatic failure has been reported in 

several cases where massive hepatic necrosis

was seen in the absence of markers for viral

hepatitis. However, clinical and biological 

profiles improved rapidly after exchange 

transfusion therapy.

CHOLESTASIS

Acute and chronic cholestatic syndromes 

have been attributed to a wide variety of 

clinical entities in patients with SCD. 

A benign cholestatic picture has been described

in which there are striking elevations of bilirubin with only modest elevations of alkaline

phosphatase and transaminases; there is no

impairment of hepatic synthetic function, as

reflected by the prothrombin time and activated partial thromboplastin time. The patients

are asymptomatic except for jaundice or 

pruritus. Fever, abdominal pain, and gastrointestinal upset are conspicuously absent. Drug

reactions can be implicated in some cases, 

and measurement of anti-kidney/liver microsomal antibodies can assist in diagnosis. In 

all instances, resolution of cholestasis occurs

within months in the absence of specific 

therapy (1,23).

In contrast, progressive cholestasis in the

absence of cirrhosis has been reported in a

number of cases. These cases are characterized

by RUQ pain, extreme elevation of bilirubin,

striking elevation of alkaline phosphatase, and

variable elevation of transaminases. Renal failure, thrombocytopenia, and severe prolongation of coagulation test results are present.

Liver histology in both benign and progressive

forms of cholestasis shows intrasinusoidal sickling and Kupffer cell hyperplasia with phagocytosis of sickled erythrocytes. Mortality due

to uncontrollable bleeding or hepatic failure 

is common (1,24). All survivors have been

treated with exchange red cell transfusion;

plasmapheresis with fresh frozen plasma and

platelet transfusion support have been used 

to control bleeding due to hemostatic failure. 
Chapter 17: Gall Bladder and Liver

116

RECOMMENDATIONS

Biliary sludge is best managed by serial 

ultrasound examinations at 12- to 24-month

intervals unless cholestasis occurs; at that

point, laparoscopic cholecystectomy is indicted. Elective laparoscopic cholecystectomy has

become the procedure of choice for symptomatic cholelithiasis (25) because of the shortened hospital stay, lower cost, and fewer immediate surgical complications. One approach 

to asymptomatic or minimally symptomatic

cholelithiasis is careful observation until symptoms dictate surgery. Bacteremia, ascending

cholangitis, empyema, and other hyperacute

biliary complications require surgery on 

a more urgent basis, consistent with good 

surgical practice. 

The management of chronic hepatitis is

beyond the scope of this treatise but requires

close coordination with gastroenterologists 

and the judicious use of liver biopsy to guide 

diagnosis and therapeutic decisions. 

Iron overload can be managed by the standard

subcutaneous protocols, but the intensive

intravenous approach is attractive because 

of the claim of improved compliance (19).

The syndromes attributable to intrahepatic

vaso-occlusion appear to be treated best with

exchange red cell transfusion because of the

remote risk of acute hyperviscosity (22).

Plasmapheresis and platelet transfusion support

are useful in cases associated with coagulopathy. 

REFERENCES

1. Johnson CS, Omata M, Tong MJ, et al. Liver

involvement in sickle cell disease. Medicine

(Baltimore) 1985;64:349-56.

2. West MS, Wethers D, Smith J, et al. Laboratory

profile of sickle cell disease: a cross-sectional 

analysis. J Clin Epidemiol 1992;45:893-909.

3. Passon RG, Howard TA, Zimmerman SA, et al.

The effect of UDP-glucuronosyltransferase

(UGTIA) promoter polymorphisms on serum

bilirubin levels and cholelithiasis in patients with

sickle cell anemia. Blood 1999;94(Supp l):645a.

4 Walker TM, Hambleton IR, Serjeant GR.

Gallstones in sickle cell disease: Observations from

the Jamaican cohort study. J Pediatr 2000;136:80-5.

5. Nzeh DA, Adedoyin MA. Sonographic pattern of

gallbladder disease in children with sickle cell

anaemia. Pediatr Radiol 1989;19:290-2.

6. Haider MZ, Ashebu S, Aduh P, et al. Influence of

α-thalassemia on cholelithiasis in SS patients with

elevated Hb F. Acta Haematol 1998;100:147-50.

7. Lee SP, Maher K, Nicholls JF. Origin and fate of

biliary sludge. Gastroenterology 1988;94:170-6.

8. Al-Salem AH, Qaisruddin S. The significance of

biliary sludge in children with sickle cell disease.

Pediatr Surg Int 1998;13:14-6.

9. Walker TM, Serjeant GR. Biliary sludge in sickle

cell disease. J Pediatr 1996;129:443-5.

10. Serafini AN, Spoliansky G, Sfakianakis N, et al.

Diagnostic studies in patients with sickle cell anemia and acute abdominal pain. Arch Intern Med

1987;147:1061-2.

11. Hasan MF, Marsh F, Posner G, et al. Chronic

hepatitis C in patients with sickle cell disease. 

Am J Gastroenterol 1996;91:1204-6.

12. Emre S, Kitibayashi K, Schwartz M, et al. Liver

transplantation in a patient with acute liver failure

due to sickle cell intrahepatic cholestasis.

Transplantation 2000;69:675-6.

13. Mills LR, Mwakyusa D, Milner PF.

Histopathologic features of liver biopsy specimens

in sickle cell disease. Arch Pathol Lab Med

1988;112:290-4.
117

14. Omata M, Johnson CS, Tong MJ, et al. The

pathological spectrum of liver diseases in sickle cell

disease. Dig Dis Science 1986;31:247-56.

15. Chuang E, Ruchelli E, Mulberg AE. Autoimmune

liver disease and sickle cell anemia in children: A

report of three cases. Am J Pediatr Hematol Oncol

1997;19:159-62.

16. Brittenham GM, Cohen AR, McLaren CE, et al.

Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993;42:81-5.

17. Harmatz P, Butensky E, Quirolo K, et al. Severity

of iron overload in patients with sickle cell disease

receiving chronic red blood cell transfusion therapy. Blood 2000;96:76-9.

18. Yeomans E, Lowe T, Eigenbrodt EH, et al. Liver

histopathologic findings in women with sickle cell

disease given prophylactic transfusion during pregnancy. Am J Obstet Gynecol 1990;163:958-64.

19. Silliman CC, Peterson VM, Mellman DL, et al.

Iron chelation by desferoxamine in sickle cell

patients with severe transfusion-induced hemosiderosis: a randomized double-blind study of 

the dose-response relationship. J Lab Clin Med

1993;122:48-54.

20. Serjeant GR. Sickle Cell Disease, 3rd ed. Oxford:

Oxford University Press, 2001.

21. Ojuawo A, Adeoyin MA, Fagbule D. Hepatic 

function tests in children with sickle cell anaemia

during vaso occlusive crisis. Cent Afr J Med

1994;40:342-5.

22. Lee ESH, Chu PCM. Reverse sequestration 

in a case of sickle cell crisis. Postgrad Med J

1996;72:487-8.

23. Buchanan GR, Glader BE. Benign course of

extreme hyperbilirubinemia in sickle cell anemia:

Analysis of six cases. J Pediatr 1977;91:21-4.

24. Shao SH, Orringer EP. Sickle cell intrahepatic

cholestasis: approach to a difficult problem. 

Am J Gastroenterol 1995;90:2048-50.

25. Jawad AJ, Kurban K, El-Bakry A, et al.

Laparoscopic cholecystectomy for cholelithiasis

during infancy and childhood: cost analysis and

review of current indications. World J Surg

1998;22:69-73.

ONLINE RESOURCES

American Association for the Study of Liver Diseases

http://www.aasld.org

The American Gastroenterological Association

http://www.gastro.org

American Liver Foundation

http://www.liverfoundation.org

Centers for Disease Control and Prevention

http://www.cdc.gov

Hepatitis B Coalition

http://www.immunize.org

Hepatitis B Foundation

http://www.hepb.org

Hepatitis Foundation International

http://www.hepfi.org

National Institutes of Health Consensus Statement

http://www.consensus.nih.gov
118
SPLENIC SEQUESTRATION 18

119

episode, and the mortality rate in these

patients may be 20 percent (5). There are no

clear prognostic factors for the occurrence of

ASSC, although the fetal hemoglobin (Hb F)

level at 6 months of age is somewhat lower 

in children who develop this complication 

(3). Although ASSC occurs most commonly

among children with SCD-SS, it has been

reported in 5 percent of children with SCDSC disease at a mean age of approximately 9

years (6) and in adults with SCD-SC disease

and SCD-S β+-thalassemia (7).

TREATMENT OF ACUTE SPLENIC

SEQUESTRATION

The immediate treatment of acute splenic

sequestration is directed toward correction of

hypovolemia with red blood cell transfusion.

Because severe ASSC can be fatal within a few

hours, emergent transfusion is required (see

chapter 25, Transfusion, Iron Overload, and

Chelation). Once transfusion is employed, red

cells sequestered in the spleen are remobilized,

splenomegaly regresses, and the hemoglobin

level increases, often to a level greater than

predicted on the basis of the volume of red

cells administered.

The rate of recurrent splenic sequestration is

high and greatly influences subsequent management, which may be divided into observation only, chronic transfusion, and splenectomy. Indications for these approaches are not

clearly defined. Questions which bear on management decisions include: Does splenectomy

Acute exacerbation of anemia in the patient

with sickle cell disease (SCD) is a significant

cause of morbidity and mortality. The most

common process leading to this complication

is acute splenic sequestration. 

ACUTE SPLENIC SEQUESTRATION

COMPLICATION 

Acute splenic sequestration complication

(ASSC) is caused by intrasplenic trapping of

red cells which causes a precipitous fall in

hemoglobin level and the potential for hypoxic shock. ASSC remains a leading cause of

death in children with SCD. ASSC may be

defined by a decrease of at least 2 g/dL from

the steady-state hemoglobin concentration,

evidence of increased erythropoiesis such as a

markedly elevated reticulocyte count, and an

acutely enlarging spleen. ASSC has been

reported as early as 5 weeks of age (1) and in

adults (2), but in most cases the first episodes

in SCD-SS patients occur between 3 months

and 5 years of age. The attacks are often associated with viral or bacterial infections. Acute

chest syndrome occurred in 20 percent in one

series (3). The usual clinical manifestations are

sudden weakness, pallor, tachycardia, tachypnea, and abdominal fullness. ASSC has been

reported in 30 percent of children with sickle

cell anemia in Jamaica (3) and 7.5 percent 

of children seen at Duke University (4). In

Jamaica, the mortality rate for first attacks was

12 percent (5). Recurrent splenic sequestration

events are common, occurring in approximately 50 percent of those who survive the first
Chapter 18: Splenic Sequestration

120

increase the risk of invasive infection above

that of the patient with functional asplenia?

Does a partial splenectomy allow maintenance

of some splenic function? Does chronic transfusion effectively restore splenic function? 

Does chronic transfusion maintain the spleen’s

potential for sequestration by delaying autoinfarction?

Observation

Children who have ASSC are at risk for 

recurrent, potentially fatal episodes and 

should receive immediate medical attention.

Observation for adults is common because

episodes tend to be mild (8).

Chronic Transfusion

Rao and Gooden (9) treated 11 children with

subacute splenic sequestration with short-term

transfusion for 1 to 3 years. Seven patients had

recurrent sequestration when transfusions were

discontinued near 5 years of age and subsequently underwent splenectomy. There were

no deaths. The authors concluded that the

time gained from short-term transfusion therapy was beneficial in reducing the risk of acute

sequestration and temporarily reversing splenic

dysfunction. In contrast, Kinney et al. (4)

compared short-term transfusion (n=12) with

observation (n=7) and immediate splenectomy

(n=4) in a group of 23 children with ASSC.

Despite a reduction in the concentration of

sickle hemoglobin (Hb S) to less than 30 percent in the chronically transfused patients, 

the risk of recurrent sequestration appeared

unaffected by transfusion. Seven of 10 evaluable patients with chronic transfusion had

recurrences either during the transfusion period

or shortly after transfusion was discontinued;

4 of 7 patients who were observed had recurrences. Overall, splenectomy was performed in

61 percent of patients. The authors concluded

that short-term transfusion to prevent recurrent

splenic sequestration was of limited benefit. 

An intermediate recommendation came from

Grover and Wethers (10), who advised a year

or more of long-term transfusion therapy for

the child with ASSC under age 3 and prompt

splenectomy after the first episode of ASSC 

in the child 5 years of age or older.

Topley et al. (5) reported that one third of

patients with ASSC develop hypersplenism.

They noted that chronic transfusion may 

simply delay episodes of ASSC to a later age

and may not restore splenic function. In fact,

Rogers et al. (11) reported that pitted red cell

counts rose to asplenic levels after an episode

of ASSC and rarely, if ever, returned to values

compatible with normal splenic function.

Splenectomy

Powell et al. (8) described 12 patients with

ASSC. One patient died; 3 patients with

minor episodes had no recurrences, and 

8 patients had prompt splenectomy. The

researchers recommended splenectomy after

the first major episode of ASSC and reasoned

that removal of a poorly or nonfunctioning

spleen does not increase susceptibility to 

infections. Although chronic blood transfusion

can delay splenectomy and temporarily restore

splenic function, these advantages were

thought to be outweighed by the risks of

chronic blood administration. In addition,

Topley et al. (5) suggested that any child 

with a history of one classical episode of 

ASSC or a minor episode followed by the

development of sustained hypersplenism

should undergo splenectomy.

An analysis of 130 Jamaican patients with 

SCD-SS treated by splenectomy (46 for recurrent ASSC), and a control group matched for

sex, age, and duration of followup in a retrospective review by Wright et al. (12) found

that mortality and bacteremic episodes did not

differ between the splenectomy and control

groups. Painful events and acute chest syndrome were more common in the splenectomy
121

group. The authors concluded that splenectomy

does not increase the risk of death or bacteremic illness in patients with SCD-SS and, 

if otherwise indicated, should not be deferred.

Partial splenectomy has been recommended

for children with recurrent ASSC as a means

of preventing further recurrence and retaining

splenic function (13,14). However, one

patient died of overwhelming sepsis when 

this approach was used (15).

EDUCATION

Emond et al. (3) describe a parental education

program in Jamaica to facilitate early diagnosis

of ASSC. The program, which involved more

than 300 children with SCD-SS, led to an

increase in the incidence of ASSC from 4.6 

to 11.3/100 patient-years, probably reflecting

increased awareness of the complication.

However, the mortality rate fell from 29.4/100

events to 3.1/100 events, a dramatic decline

resulting from improved medical management

and earlier detection.

RECOMMENDATIONS

All reports regarding the management of

ASSC (and chronic hypersplenism) were

descriptive, retrospective, and uncontrolled. 

Clinical evidence derived from controlled 

clinical trials is relatively weak. 

The following are current recommendations: 

■ Early education should be provided to 

parents of infants with SCD regarding palpation of the spleen, symptoms of progressive anemia, and appropriate action for

obtaining rapid evaluation and treatment. 

■ Patients who have a life-threatening

episode of ASSC that requires transfusion

support should have a splenectomy shortly

after the event or be placed on a chronic

transfusion program.

■ Alternatively, patients who have a severe

episode of ASSC and are below 2 years of

age should be placed in a chronic transfusion program to keep Hb S levels below

30 percent until a splenectomy can be

considered after 2 years of age. 

■ Patients with chronic hypersplenism also

should be considered for splenectomy. 

REFERENCES

1. Airede AI. Acute splenic sequestration in a fiveweek-old infant with sickle cell disease. J Pediatr

1992;120:160.

2. Solanki DL, Kletter GG, Castro O. Acute splenic

sequestration crises in adults with sickle cell 

disease. Am J Med 1986;80:985-90.

3. Emond AM, Collis R, Darvill D, et al. Acute

splenic sequestration in homozygous sickle cell

disease: natural history and management. J Pediatr

1985;107:201-6.

4. Kinney TR, Ware RE, Schultz WH, et al. 

Long-term management of splenic sequestration 

in children with sickle cell disease. J Pediatr

1990;117:194-9.

5. Topley JM, Rogers DW, Stevens MCG, et al.

Acute splenic sequestration and hypersplenism 

in the first five years in homozygous sickle cell 

disease. Arch Dis Child 1981;56:765-9.

6. Aquino VM, Norvell JM, Buchanan GR. Acute

splenic complications in children with sickle cellhemoglobin C disease. J Pediatr 1997;130:961-5.

7. Orringer EP, Fowler VG Jr, Owens CM, et al. 

Case report: splenic infarction and acute splenic

sequestration in adults with hemoglobin SC disease. Am J Med Sci 1991;302:374-9.

8. Powell RW, Levine GL, Yang Y-M, et al. Acute

splenic sequestration crisis in sickle cell disease:

early detection and treatment. J Pediatr Surg

1992;27:215-9.

9. Rao S, Gooden S. Splenic sequestration in sickle

cell disease: role of transfusion therapy. Am J

Pediatr Hematol Oncol 1985;7:298-301.

10. Grover R, Wethers DL. Management of acute

splenic sequestration crisis in sickle cell disease. 

J Assoc Acad Minor Phys 1990;1:67-70.

11. Rogers DW, Serjeant BE, Serjeant GR. Early rise 

in ‘pitted’ red cell count as a guide to susceptibility

to infection in childhood sickle cell anemia. Arch

Dis Child 1982;57:338-42.
Chapter 18: Splenic Sequestration

122

12. Wright JG, Hambleton IR, Thomas PW, et al.

Postsplenectomy course in homozygous sickle cell

disease. J Pediatr 1999;134:304-9.

13. Svarch E, Vilorio P, Nordet I, et al. Partial splenectomy in children with sickle cell disease and repeated episodes of splenic sequestration. Hemoglobin

1996;20:393-400.

14. Idowu O, Hayes-Jordan A. Partial splenectomy in

children under 4 years of age with hemoglobinopathy. J Pediatr Surg 1998;33:1251-3.

15. Svarch E, Nordet I, Gonzalez A. Overwhelming

septicaemia in a patient with sickle cell βo thalassaemia and partial splenectomy. Br J Haematol

(letter) 1999;104:930.
RENAL ABNORMALITIES IN SICKLE CELL DISEASE 19

123

it may occur later in life. This dysfunction 

in urinary concentrating ability is frequently

associated with nocturia.

As a result of the inability to maximally 

concentrate the urine, patients with SCD 

are more susceptible than are normal individuals to dehydration, a factor that often precipitates vaso-occlusive events. Patients with

SCD should therefore be encouraged to

drink liberal amounts of liquids in order to

compensate for the fluid loss that is brought

on by hyposthenuria.

TUBULE DYSFUNCTION

Defective urinary acidification also is well

described in SCD (3). Typically, however,

patients have normal aldosterone and renin

responses (4). The primary abnormality is 

an incomplete distal renal tubular acidosis

(RTA), and the severity of the acidification

defect is related, at least in part, to the 

severity of the hyposthenuria.

Defects in potassium excretion also are seen 

in SCD. Although not clinically apparent

under normal circumstances, hyperkalemia

does become manifest as overall renal function

deteriorates. In addition, even SCD patients

with normal renal function are at risk for

hyperkalemia following administration of

drugs such as ACE inhibitors, beta-blockers,

and potassium-sparing diuretics (2).

The kidney in patients with sickle cell disease

(SCD) exhibits numerous structural and functional abnormalities, changes that are seen

along the entire length of the nephron. The

medullary region of the kidney is composed 

of renal tubules and medullary blood vessels

that are collectively referred to as the vasa recta

system. The environment of the renal medulla

is characterized by hypoxia, acidosis, and

hypertonicity. Because these conditions 

promote hemoglobin S (Hb S) polymerization

and red cell sickling, this area of the kidney 

is particularly susceptible to malfunction.

Microradioangiographic studies carried out 

on the kidneys of patients with SCD show 

significant loss of the vasa recta. Those few

medullary blood vessels that remain are

markedly dilated with a spiral configuration,

and appear to end blindly (1). Changes are

most marked in patients with homozygous

sickle cell anemia (SCD-SS), but are also seen

in those with compound heterozygous states 

(SCD-SC, thalassemia) and the sickle cell

trait. Table 1 summarizes renal abnormalities

associated with SCD.

HYPOSTHENURIA

Hyposthenuria, an inability to concentrate

urine maximally, is perhaps the most common renal abnormality in SCD (2). In individuals with SCD-SS, hyposthenuria typically becomes apparent during early childhood 

as enuresis, whereas in the other syndromes,
Table 1. Summary of Renal Abnormalities in SCD

Renal Abnormality Comments

Abnormalities in distal nephron function

Hyposthenuria Not due to anemia

Impaired urinary acidification Incomplete distal tubular acidosis

Impaired potassium excretion Occurs despite normal renin/aldosterone

Supranormal proximal tubule function No pathological significance

Increased β-2-microglobulin reabsorption

Increased phosphate reabsorption

Increased uric acid secretion

Increased creatinine secretion

Hemodynamic changes Mediated by prostaglandins

Increased renal plasma flow

Increased glomerular filtration rate

Decreased filtration fraction

Hematuria Occurs in left kidney in 80 percent of cases

Renal medullary carcinoma Requires thorough workup of hematuria

Papillary necrosis Infrequently produces renal failure

Acute renal failure May be associated with rhabdomyolysis 

Urinary tract infection Especially in pregnant women

Glomerular abnormalities With older age or CAR βs

-haplotype

Proteinuria

Nephrotic syndrome

Chronic renal failure

Chapter 19: Renal Abnormalities in Sickle Cell Disease

124

Increased creatinine secretion causes a lower

serum creatinine level and thus an overestimation of the glomerular filtration rate (GFR) 

in SCD-SS patients. Differences of up to 30

percent have been reported when creatinine

clearance is compared to inulin clearance (5).

The significance of this enhanced proximal

tubular function in the pharmacokinetics of

drugs in which tubular secretion is a major

pathway of elimination is uncertain (2).

Despite increased secretion of uric acid,

patients with SCD often have hyperuricemia

and are vulnerable to secondary gout.

HEMATURIA

Hematuria, a common renal abnormality in

SCD, appears to result from the Hb S polymerization and red cell sickling in the renal

medulla. It may be a manifestation of papillary

necrosis. In most cases, bleeding originates

from the left kidney; a small minority of

patients have bilateral kidney involvement (6).

The treatment of hematuria in SCD involves

bed rest, maintenance of a high urinary flow

documented by monitoring of intake and 

output, and, if blood loss is significant, iron

replacement and/or blood transfusion.
125

Vasopressin and epsilon-amino caproic acid

(EACA) have both been used with variable

success (7,8). However, caution must be exercised when using EACA as this antifibrinolytic

agent may predispose to the formation of 

clots that can obstruct the urinary collecting

system. If prolonged and life-threatening

bleeding is coming from one kidney, local

resection of the bleeding segment is preferred.

Unilateral nephrectomy is a last resort since

bleeding may recur from the other kidney.

Hematuria that occurs in SCD is not always 

a consequence of red cell sickling and papillary

necrosis. Other, nonsickling causes also should

be considered. For example, renal medullary

carcinoma in young subjects with SCD and

sickle cell trait (Hb AS) has been reported

(9,10). Therefore, a thorough evaluation is

recommended when hematuria is initially

found in individuals with SCD and Hb AS.

ACUTE RENAL FAILURE

Acute renal failure occurs as a component 

of the acute multiorgan failure syndrome

(AMOFS) in patients with SCD (11). This

syndrome is characterized by the sudden onset

of severe dysfunction of at least two major

organ systems (e.g., kidney, lung, liver) during

an acute painful vaso-occlusive episode in

patients with SCD. The pathophysiology 

of AMOFS appears to be due to diffuse, small

vessel occlusion, which in turn results in tissue

ischemia and organ dysfunction. The renal

failure in this syndrome also may be related 

to the accompanying rhabdomyolysis. Prompt

initiation of transfusion therapy or exchange

transfusion may reverse this syndrome.

GLOMERULAR ABNORMALITIES

AND CHRONIC RENAL FAILURE

Proteinuria, which can progress to the nephrotic syndrome, is the most common manifestation of glomerular injury in SCD patients.

Moreover, as many as 40 percent of SCD-SS

patients with nephrotic syndrome may go 

on to develop end-stage renal disease (ESRD)

(12). Therefore, patients with persistent 

proteinuria should have a urine collection

obtained for the determination of 24-hour 

protein excretion, and a nephrology consultation should be requested for consideration of

other, nonsickling causes of proteinuria and 

possible renal biopsy.

ACE inhibitors ameliorate pathological

changes such as perihilar focal and segmental

glomerulosclerosis. They also decrease urinary

protein excretion in patients with early manifestations of sickle cell nephropathy (13).

Renal insufficiency occurs earlier in SCD-SS

patients than it does in SCD-SC patients (12).

Factors that appear to predict renal failure 

in SCD-SS patients include hypertension, 

proteinuria, increasingly severe anemia, and

hematuria (13). Finally, the risk of renal 

failure is increased in those SCD-SS patients

with the Central African Republic (CAR) 

βs

-gene cluster haplotype.

As there is no proven treatment for sickle cell

nephropathy, every attempt should be made 

to slow its rate of progression. The amount of

proteinuria can be decreased by the administration of ACE inhibitors, and it is conceivable

that the progression of sickle cell nephropathy

may be slowed by a prolonged course of these

drugs. Patients should avoid nonsteroidal antiinflammatory drugs (NSAIDs) because NSAIDs

have been shown to produce significant

declines in the rates of glomerular filtration and

renal blood flow in patients with SCD (5,14).
Chapter 19: Renal Abnormalities in Sickle Cell Disease

126

Effective control of blood pressure has been

reported to slow the progression of ESRD 

in patients with SCD; they should be treated

with standard approaches (15). Optimum 

target blood pressure has not been defined.

Because dehydration can precipitate vasoocclusive events, caution should be exercised

in the use of diuretic agents in an individual

with obligate hyposthenuria. 

Every effort must be made to avoid additional

renal damage due to urinary tract infection.

Infection must be recognized and treated 

vigorously. Followup should be maintained

longer than for patients without SCD.

Although erythropoietin levels are generally

high in steady-state SCD-SS patients, they are

not increased to the level that would be expected for the degree of anemia (16). One explanation for the relatively decreased erythropoietin

levels is the right-shifted hemoglobin-oxygen

dissociation curve seen in SCD patients (17).

Erythropoietin levels in SCD patients fall still

further as renal function worsens, and these

patients may require substantially higher doses

of erythropoietin than are required for patients

with other forms of ESRD (18). If erythropoietin is ineffective, transfusions can be given;

they must be done carefully, however, to avoid

volume overload (see chapter 25, Transfusion,

Iron Overload, and Chelation).

As with all patients who develop ESRD, SCD

patients can be treated with both hemodiaylsis

and peritoneal dialysis, and they can undergo

renal transplantation. Although early reports

suggested poor allograft survival and other disease-specific problems in SCD patients, others

have reported graft and patient survival rates

comparable to those of other nondiabetic

patients (19). A more recent study of renal

transplantation in SCD reported short-term

patient and allograft outcomes comparable 

to other age-matched African Americans.

However, there was a shorter cadaveric graft

survival and high risk of graft loss with longer

followup in the SCD patient group (20).

There was a trend toward improved survival 

in those SCD patients who received transplants compared to those on chronic dialysis.

Although many SCD patients have done 

well after renal transplantation, several unique

complications have been described. Patients

may experience a resumption of frequent 

vaso-occlusive events which presumably are

related to an increase in whole blood viscosity

accompanying a higher hemoglobin level.

Renal infarction, a probable secondary consequence of Hb S polymerization, cell sickling,

and vaso-occlusion, has been reported to 

occur as early as 6 days following transplantation (21). The reappearance of sickle cell

nephropathy in the donor kidney has also

been reported (22).

It is possible that the availability of new

immunosuppressive drugs may further

improve the outcome renal transplantation 

in SCD patients. Hydroxyurea is excreted by

the kidney and thus its use in patients with

renal failure requires careful monitoring. 

SCD patients receiving renal transplants may

benefit from exchange transfusion or even

from periodic phlebotomy, particularly when

hemoglobin levels are high.
127

REFERENCES

1. Statius van Eps LW, Pinedo-Veels C, deVries CH,

et al. Nature of the concentrating defect in sickle

cell nephropathy. Microradioangiographic studies.

Lancet 1970;1:450-2.

2. Allon M. Renal abnormalities in sickle cell disease.

Arch Intern Med 1990;150:501-4.

3. Kontessis P, Mayopoulou-Symvoulidis D,

Symvoulidis A, et al. Renal involvement in sickle

cell-β thalassemia. Nephron 1992;61:10-5.

4. DeFronzo RA, Taufield PA, Black H, et al.

Impaired renal tubular potassium secretion in sickle cell disease. Ann Intern Med 1979;90:310-6.

5. Allon M, Lawson L, Eckman JR, et al. Effects 

of nonsteroidal anti-inflammatory drugs on 

renal function in sickle cell anemia. Kidney Int

1988;34:500-6.

6. Case records of the Massachusetts General

Hospital: Weekly Clinicopathological Exercises. 

N Engl J Med 1985;312:1623-31.

7. John EG, Schade SG, Spigos DG, et al.

Effectiveness of triglycyl vasopressin in persistent

hematuria associated with sickle cell hemoglobin.

Arch Intern Med 1980;140:1589-93.

8. Immergut MA, Stevenson T. The use of epsilon

aminocaproic acid in the control of hematuria

associated with hemoglobinopathies. J Urol

1965;93:110.

9. Herring JC, Schmetz MA, Digan AB, et al. Renal

medullary carcinoma: a recently described highly

aggressive renal tumor in young black patients. 

J Urol 1997;157:2246-7.

10. Coogan CL, McKiel CF Jr, Flanagan MJ, et al.

Renal medullary carcinoma in patients with SCT.

Urology 1998;51:1049-50.

11. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic

complication of severe sickle cell pain episodes. 

Am J Med 1994;96:155-62.

12. Foucan L, Bourhis V, Bangou J, et al. A randomized trial of captopril for microalbuminuria in 

normotensive adults with sickle cell anemia. Am 

J Med 1998;104:339-42.

13. Powars DR, Elliott-Mills DD, Chan L, et al.

Chronic renal failure in sickle cell disease: risk 

factors, clinical course, and mortality. Ann Intern

Med 1991;115:614-20.

14. De Jong PE, de Jong-van den Berg TW,

Sewrajsingh GS, et al. The influence of

indomethacin on renal hemodynamics in 

sickle cell anemia. Clin Sci 1980;59:245-50.

15. Nissenson AR, Port FK. Outcome of end-stage

renal disease in patients with rare causes of renal

failure. I. Inherited and metabolic disorders. Quart

J Med 1989;271:1055.

16. Sherwood JB, Goldwasser E, Chilcote R, et al.

Sickle cell anemia patients have low erythropoietin

levels for their degree of anemia. Blood

1986;67:46-9.

17. Morris J, Dunn D, Beckford M, et al. The haematology of homozygous sickle cell disease after the

age 40. Br J Haematol 1991;77:382-5.

18. Steinberg MH. Erythropoietin for the anemia of

renal failure in sickle cell disease. N Engl J Med

1991;324:1369-70.

19. Chatterjee SN. National study in natural 

history of renal allografts in sickle cell disease 

or trait: a second report. Transplant Proc

1987;19(2 Suppl 2):33-5.

20. Ojo AO, Govaerts TC, Schmouder RL, et al. 

Renal transplantation in end-stage sickle cell

nephropathy. Transplantation 1999;67:291-5.

21. Donnelly PK, Edmunds ME, O’Reilly K. Renal

transplantation in sickle cell disease. Lancet (letter)

1988;2:229.

22. Miner DJ, Jorkasky DK, Perloff LJ, et al.

Recurrent sickle cell nephropathy in a transplanted

kidney. Am J Kidney Dis 1987;10:306-13.

ONLINE RESOURCES

The Sickle Cell Information Center: Problem Oriented

Clinical Guidelines 

http://www.emory.edu/PEDS/SICKLE/prod04.htm

Sickle Cell Disease

http://www.familyvillage.wisc.edu/lib_scd.htm
128
PRIAPISM 20

129

experienced priapism knew that it could be 

a complication of SCD (1). This information

prompted the authors to prepare a brochure

explaining priapism, which was distributed 

to all males and their families. Boys and young

men, as well as their families, need to know

that they should be prepared to seek medical

attention as soon as an episode begins and that

if untreated, priapism can result in impotence

in the future. The males should know that 

a full bladder can trigger priapism, and they

therefore need to urinate regularly. They also

should avoid prolonged sexual activity, which

can trigger an episode. If they have had 

more than one episode, medications can 

be prescribed that may prevent recurrences. 

EVALUATION AND TREATMENT

When evaluating a patient with priapism, the

physician or nurse should document the time

of onset of the episode as well as the presence

of any other inciting factors, such as trauma,

infections, or the use of drugs (e.g., cocaine,

alcohol, psychotropic agents, sildenafil, testosterone) (4-6). A careful physical examination

should reveal a hard penis with a soft glans. 

The goal of therapy is to ease pain, make the

erection go away, and preserve future erectile

function. If treatment is given within 4 to 6

hours, the erection can generally be reduced

with medication and conservative therapy.

Most of the articles in the literature concern

anecdotal reports and few randomized trials

are available. 

Priapism, defined as a sustained, painful, and

unwanted erection, is a well recognized complication of sickle cell disease (SCD) (1-3).

According to one study, the mean age at

which priapism occurs is 12 years, and by the

age of 20, as many as 89 percent of males with

SCD will have experienced one or more

episodes of priapism (1). Priapism in males

with SCD is due to vaso-occlusion, which

causes obstruction of the venous drainage 

of the penis. Priapism can be classified as 

prolonged if it lasts for more than three hours

or stuttering if it lasts for more than a few

minutes but less than three hours and resolves

spontaneously; however, such stuttering

episodes may recur or develop into more prolonged events. Prolonged priapism is an emergency that requires urologic consultation.

Recurrent episodes of priapism can result in

fibrosis and impotence, even when adequate

treatment is attempted. Currently, there is no

single standard of care for the treatment of

priapism; the information provided below 

represents current efforts with respect to the

treatment of this complication of SCD. 

PSYCHOSOCIAL AND 

COUNSELING ASPECTS 

OF PRIAPISM

Beginning in early boyhood, males need to

know that priapism is one aspect of SCD and

that this is not an event that should embarrass

them. One study found that only 7 percent 

of boys and men with SCD who had not
Chapter 20: Priapism

130

ONSET OF PRIAPISM

Patients should be advised to drink extra 

fluids, use oral analgesics, and attempt to 

urinate as soon as priapism begins.

EPISODES LASTING MORE THAN

TWO HOURS

Patients should go to the emergency room to

receive intravenous hydration and parenteral

analgesia. According to one protocol (7), if

detumescence does not occur in 1 hour after

the patient has arrived in the emergency room,

penile aspiration is initiated (procedure should

be performed within 4 to 6 hours from onset

of priapism). The patient receives conscious

sedation and local anesthesia; blood is then

aspirated from the corpus cavernosum with 

a 23-gauge needle followed by irrigation of 

the corpora with a 1:1,000,000 solution of 

epinephrine in saline. In a prospective nonrandomized unblinded study, this procedure was

successful in producing immediate detumescence in 15 males on 37 of 39 occasions (7).

This study was performed in males who were

teenagers or younger and has not been validated in an older population. 

The concomitant use of automated red cell

exchange transfusions to reduce the sickle

hemoglobin (Hb S) level to less than 30 percent can also be considered, especially if early

intervention with irrigation fails (8). It is

unclear if simple transfusion is equivalent 

to exchange transfusion. 

The clinical response to exchange transfusions 

is variable, and side-effects range from headaches

or seizures to obtundation requiring ventilatory

support. The association of SCD, priapism,

exchange transfusion, and neurological events

has been given the name ASPEN syndrome

(9). Recurrent priapism is strongly associated

with the development of impotence, therefore

some physicians transfuse patients as though

they were on a stroke protocol (maintenance 

of Hb S level below 30 percent). These programs should be limited in duration (6 to 12

months), and patients should be assessed often.

If there is recurrence despite aspiration and

local instillation of vaso-active drugs, shunting

may be considered. In this procedure, known

as the Winter procedure, a shunt is created

between the glans penis and the distal corpora

cavernosa with a Tru-cut biopsy needle; this

allows blood from the distended corpora cavernosa to drain into the uninvolved corpus

spongiosa (10). A larger shunt can be created 

if this is not successful.

Additional medications used for reversal of

priapism have included α-agonists and β-agonists such as terbutaline (11-13). Clinicians in

France and West Africa have used an α-agonist

(etilefrine) that can be injected by patients

into the cavernous sinus (12-13); however, 

this agent is not available in the United States.

None of these agents has been validated in 

a well-controlled trial and thus cannot be

endorsed at this time. 

Complications of priapism and treatment

include bleeding from the holes placed in the

penis as part of the aspiration or shunting 

procedures, infections, skin necrosis, damage

or strictures of the urethra, fistulas, and impotence. If impotence persists for 12 months, 

the patient may wish to consider implantation

of a semirigid penile prosthesis (14). 
131

PREVENTING FUTURE EPISODES

There are no large clinical studies documenting ways to prevent priapism. Some physicians

prescribe 30 mg of oral pseudoephedrine

at night as an attempt to prevent further

episodes in those who have had priapism and

have required aspiration and irrigation (7).

Injections of leuprolide, a gonadotropinreleasing hormone analogue that suppresses

the hypothalamic-testicular axis and the production of testosterone, also has also been

used with some degree of success as prophylaxis against further episodes (15). A small

(11 patients) double-blind, placebo-controlled

crossover study found that oral stilbestrol 

in doses of 5 mg daily for 3 to 4 days could

abort episodes of priapism and that much

smaller doses could prevent recurrence (16).

Although hydroxyurea may potentially be of

benefit (17), clinical studies to determine its

efficacy in preventing priapism have not been

performed.

REFERENCES

1. Mantadakis E, Cavender JD, Rogers ZR, et al.

Prevalence of priapism in children and adolescents

with sickle cell anemia. Am J Pediatr Hematol

Oncol 1999;21:518-22.

2. Powars DR, Johnson CS. Priapism. Hematol 

Oncol Clin North Am 1996;10:1363-72.

3. Miller ST, Rao SP, Dunn EK, et al. Priapism 

in children with sickle cell disease. J Urol

1995;154:844-7.

4. Saenz-de-Tejada I, Ware JC, Blanco R, et al.

Pathophysiology of prolonged penile erection associated with trazodone use. J Urol 1991;145:60-4.

5. Kassim AA, Fabry ME, Nagel RL. Acute priapism

associated with the use of sildenafil in a patient

with sickle cell trait. Blood 2000;95:1878-9.

6. Slayton W, Kedar A, Schatz D. Testosterone

induced priapism in two adolescents with sickle

cell disease. J Pediatr Endocrinol Metab

1995;8:199-203.

7. Mantadakis E, Ewalt DH, Cavender JD, et al.

Outpatient penile aspiration and epinephrine irrigation for young patients with sickle cell anemia

and prolonged priapism. Blood 2000;95:78-82.

8. Walker EM Jr, Mitchum EN, Rous SN, et al.

Automated erythrocytopheresis for relief of priapism in sickle cell hemoglobinopathies. J Urol

1983;130:912-6.

9. Rackoff WR, Ohene-Frempong K, Month S, 

et al. Neurologic events after partial exchange

transfusion for priapism in sickle cell disease. 

J Pediatr 1992;120:882-5.

10. Winter CC. Priapism cured by creation of fistulas

between glans penis and corpora cavernosa. J Urol

1978;119:227-8.

11. Lowe FC, Jarow JP. Placebo controlled study of

oral terbutaline and pseudoephedrine in management of prostaglandin E1-induced prolonged 

erections. Urology 1993;42:51-3.

12. Virag R, Bachir D, Floresco J, et al. Ambulatory

treatment and prevention of priapism using alphaagonists. Apropos of 172 cases. Chirurgie

1997;121;648-52.

13. Jarmon JD, Ginsberg PC, Nachmann MM, et al.

Stuttering priapism in a liver transplant patient

with toxic levels of FK506. Urology 1999;54:366.

14. Douglas L, Fletcher H, Serjeant GR. Penile prostheses in the management of impotence in sickle

cell disease. Br J Urol 1990;65:533-5.

15. Levine LA, Guss SP. Gonadotropin-releasing hormone analogues in the treatment of sickle-cell anemia associated priapism. J Urol 1993;150:475-7.

16. Serjeant GR, DeCeulaer K, Maude GH. Stilbestrol

and stuttering priapism in homozygous sickle-cell

disease. Lancet 1985;2:1274-6.

17. Al Jam’a AH, Al Dobbous IA. Hydroxyurea in the

treatment of sickle cell associated priapism. J Urol

1998;159:1642.

GENERAL REFERENCE

Steidle C. Priapism. In: The Impotence Sourcebook.

New York: RGA Publishing Group, 1998.
132
BONES AND JOINTS 21

133

VASO-OCCLUSIVE EVENTS

METAPHYSEAL AND

DIAPHYSEAL INFARCTS

Bones and joints are major sites of pain in

vaso-occlusive events. It is hypothesized that

relative hypoxia in the sinusoids of the marrow

spaces predisposes to sickling and to thrombosis. Sudden infarction causes acute symptoms

and signs that must be differentiated from

those of bacterial infection. Infarction may

occur in any bone, but common sites include

the spine, pelvis, and long bones. Vertebral

infarction may cause collapse of the end plates,

resulting in the so-called “codfish” vertebra.

The most common sites of involvement in the

long bones are the humerus, tibia, and femur

(in that order) (6). The distal segment is most

often involved. 

Local tenderness, warmth and swelling 

are common, as is impaired motion in 

the adjacent joints. In contrast to cases of

osteomyelitis, fever is usually absent or lowgrade, and the white blood cell differential

rarely demonstrates a left shift. Aspiration 

of the affected site yields negative cultures.

Radiographs are unremarkable in the acute

stage. Once healing and remodeling occur,

radiographs demonstrate patchy sclerosis 

and local thickening of the cortices (1). In

metaphyseal and diaphyseal infarcts of the

long bones, long term sequelae are minimal.

Because it may be difficult to differentiate

between acute infarction and acute

Musculoskeletal manifestations of sickle cell

disease (SCD) are common and may lead to

severe morbidity. Bone and joint involvement

result from three main causes: 1) bone marrow

hyperplasia, which causes distortion and

growth disturbance, particularly in the skull,

vertebrae, and long bones; 2) vaso-occlusive

events that lead to infarction of metaphyseal

and diaphyseal bone and to osteonecrosis of

juxta-articular bone; and 3) hematogenous 

bacterial infection that results in osteomyelitis

and septic arthritis.

BONE MARROW HYPERPLASIA

The chronic hemolytic anemia of SCD results

in erythroid hyperplasia. Cellular proliferation

in the marrow spaces results in bone deformities, most notably in the skull where trabeculae may be oriented in a radial pattern (“hair

on-end”), and an increase in the distance

between the inner and outer tables of the

frontal bone, which results in “bossing” 

of the forehead. Growth disturbance in 

the maxilla may result in protrusion of the

incisors and an accentuated over-bite. In 

the long bones, osteopenia may predispose 

to pathologic fractures (1,2). Similar changes

occur in the vertebral bodies, and resulting

compression fractures may lead to flattening

and to kyphotic deformity of the spine (3).

Acetabular protrusion has been noted in one

or both hips of some patients with SCD and

is attributed to osteopenia associated with

marrow hyperplasia (4,5). 
Chapter 21: Bones and Joints

134

osteomyelitis (7), close followup examinations,

blood cultures, aspiration of the affected site,

and repeated white blood cell counts are appropriate until a diagnosis is firmly established.

DACTYLITIS, OR THE

“HAND-FOOT” SYNDROME

Dactylitis, or the “hand-foot” syndrome, is a

limited phenomenon that occurs in the hands

and feet of infants and young children. One to

four extremities may be involved at the same

time. The syndrome presents with pain in the

metacarpals, metatarsals, and phalanges of the

hands and feet. Swelling typically occurs over

the dorsum of the hands and feet, extending

into the fingers and toes. Radiographs eventually reveal periosteal elevation and a moth-eaten

appearance of involved bone (3). Symptoms

usually resolve in 1 to 4 weeks, and the condition results in no long-term sequelae (8). The

patient should receive analgesia and hydration,

and the parents should be given reassurance.

Transfusions, antibiotics and other measures

are usually not necessary. Although it is rare,

infection should be considered if conservative

management yields no benefit. At least one

study has indicated that an episode of dactylitis within the first two years of life, particularly in association with leukocytosis and severe

anemia, may predict severe manifestations of

SCD later in life (9). 

OSTEONECROSIS

Ischemic necrosis of juxta-articular bone arises

from thrombosis of the endarterial vessels and

often leads to painful destruction of the adjacent joint. The femoral and humeral heads 

are most often involved. Osteonecrosis of the

femoral head may occur in any of the genetic

variants of SCD, but is most prevalent in

patients with SCD-SS α-thalassemia (10). 

The mean age at diagnosis varies according 

to genotype; patients with SCD-SS α-thalassemia present at 28 years of age, those with

SCD-SS present at age 36, and those with

SCD-SC present at age 40. The natural history of symtomatic hip disease in SCD patients

who are treated conservatively varies with the

patient’s age. In skeletally immature patients

who are 12 years of age or younger, treatment

with analgesics, nonsteroidal anti-inflammatory

drugs, and protected weight-bearing usually

results in healing and remodeling of the

involved capital epiphysis, similar to what is

observed in Legg-Calve-Perthes disease (1,11).

This approach results in preservation of the

joint despite the persistence of deformity such

as coxa magna and coxa plana (1,12).

In contrast, conservative management of

osteonecrosis usually fails in patients in late

adolescence and in adulthood. Progressive flattening and collapse of the femoral head results

in painful secondary degenerative arthritis.

The use of joint-preserving surgical procedures

such as core decompression and osteotomy 

has been reported anecdotally in sickle cell

patients who have precollapse femoral head

involvement (13). As yet, there have been 

no prospective, randomized studies in sickle

cell patients to critically assess the safety and

efficacy of such procedures. 

Hip arthroplasty is reserved for patients with

advanced disease who are severely symptomatic. Earlier studies have reported high rates

of early and late deep sepsis, mechanical loosening of implants, and high reoperation rates

(14-18). In these studies, there was a high rate

of postoperative events, averaging 10 percent.

In more recent reports, patients have been

treated with newer surgical techniques, including the use of cementless prostheses, and perioperative medical management has received

greater emphasis (19-21). These studies report

lower rates of infection, fewer risky reoperations,
135

and fewer salvage resection arthroplasties.

Despite these encouraging recent reports, 

most orthopedists continue to reserve prosthetic arthroplasty for those patients in whom

all other measures have failed to yield relief. 

Osteonecrosis of the humeral head occurs

commonly in SCD, especially in patients with

femoral head involvement (22). The prevalence

of humeral head osteonecrosis on radiographs

was 28 percent in one population of patients

(23); in another study, 48 percent of adults

with SCD-SS were found to have radiographic

abnormalities suggestive of healed and remodeled osteonecrotic lesions (24). Treatment of

symptomatic humeral head osteonecrosis is

similar to that described for femoral head

osteonecrosis, but because the forces on the

shoulder joint are smaller, morbidity is less

pronounced (25). 

HEMATOGENOUS INFECTION

OSTEOMYELITIS

Blood-borne bacteria may proliferate in the

sinusoids of the marrow spaces where flow 

is sluggish. Previously infarcted bone may 

provide a protected environment for bacterial

infection, and the likelihood of osteomyelitis 

may be increased further by a diminished

immune response in SCD. The prevalence 

of osteomyelitis may be rare or as high as 

61 percent in sickle cell populations (26,27).

The predisposition of sickle cell patients to

salmonella osteomyelitis is well known. 

As noted earlier, acute osteomyelitis must 

be differentiated from acute bone infarction.

Although acute bone “crisis” is much more

common, a high index of suspicion for

osteomyelitis is warranted. Local tenderness,

warmth, and swelling are present in both.

Fever is generally high in acute infection. 

The white blood cell count is often elevated 

in patients with SCD and further elevations

may be seen with infarcts and infection. A 

left shift in the differential is usually present 

in infection, but not in infarction. Positive 

blood cultures frequently accompany acute

osteomyelitis, and a positive culture from local

bone aspiration is diagnostic. Radiographs

rarely reveal bone changes early on, and the

only abnormality may be evidence of soft tissue swelling. Radionuclide bone scans usually

do not differentiate infection from infarction

in the acute phase (6), but marrow scans may

be helpful (28). 

Surgical drainage is the primary treatment

once the diagnosis is made. Intravenous therapy with antibiotics, chosen according to the

sensitivity of the organism, is carried out for 

2 to 6 weeks, depending upon the nature and

extent of the infection. Protected weightbearing and bracing are sometimes required

when there is significant bone destruction.

Chronic undiagnosed infections may involve

bone extensively, resulting in the formation of

a so-called “bone within a bone” radiographic

appearance, reflecting the presence of a shell of

periosteal new bone (involucrum) surrounding

a core of dead bone (sequestrum).

SEPTIC ARTHRITIS

Septic arthritis, like osteomyelitis, may 

result from hematogenous spread of bacteria

or, alternatively, from direct spread from 

a contiguous focus of osteomyelitis. Severe

pain, tenderness, joint swelling, local warmth,

and marked limitation of motion are characteristic findings. 

Septic arthritis must be differentiated from

other types of arthropathy including synovial

infarction, synovitis associated with adjacent

osteonecrosis, and nonspecific synovitis, which

is usually self-limited and rarely progresses to

chondrolysis (29). The use of radiography and
Chapter 21: Bones and Joints

136

magnetic resonance imaging (MRI) in 

diagnosis of symptomatic joints is confined 

to identifying other causes of arthropathy 

once infection is ruled out by aspiration.

Surgical drainage remains the surest means 

of completely evacuating exudates and breaking up loculations that may predispose to 

persistent infection and articular cartilage

destruction. Intravenous antibiotics are

administered, and short-term joint immobilization is carried out, followed by range-ofmotion exercises. Re-aspiration of the joint

confirms adequate suppression of the infection. 

IMAGING MODALITIES 

IN BONES AND JOINTS

Plain radiography is useful in defining established changes of infection, infarction, and

osteomyelitis. However, it is of little or no 

use in diagnosing acute infection or infarction.

Radiography depicts the bone abnormalities

associated with marrow hyperplasia and those

later adaptive changes that result both from

remodeling and from growth disturbances. 

Radionuclide bone imaging is nonspecific 

and therefore of limited value in differentiating

infection from infarction. However, radionuclide marrow imaging has been shown to 

be useful because it has a high likelihood 

of depicting diminished uptake in infarction

and normal uptake in infection (28). 

Ultrasound and MRI have been shown to 

be useful in the diagnosis of acute conditions.

Ultrasound can be used in depicting soft 

tissue conditions such as abscess, particularly

when MRI is not available (30). MRI has 

been shown to depict the early changes of

osteonecrosis (31) and acute bone and joint

abnormalities in children (32). 

REFERENCES

1. Chung SM, Alavi A, Russell MO. Management of

osteonecrosis in sickle cell anemia and its genetic

variants. Clin Orthop 1978;130:158-74.

2. Johanson NA. Musculoskeletal problems in 

hemoglobinopathy. Orthop Clin North Am

1990;21:191-8.

3. Diggs LW. Bone and joint lesions in sickle cell 

disease. Clin Orthop 1967;52:119-43.

4. Martinez S, Apple JS, Baber C, et al. Protrusio

acetabuli in sickle-cell anemia. Radiology

1984;151:43-4.

5. Rijke A, Pope TL Jr, Keats TE. Bilateral protrusio

acetabuli in sickle cell anemia. South Med J

1990;83:328-9.

6. Keeley K, Buchanan GR. Acute infarction 

of long bones in children with sickle cell anemia. 

J Pediatr 1982;101:170-5.

7. Kooy A, de Heide LJ, ten Tije AJ, et al. Vertebral

bone destruction in sickle cell disease: infection,

infarction or both. Neth J Med 1996;48:227-31.

8. Worrall VT, Butera V. Sickle-cell dactylitis. 

J Bone Joint Surg Am 1976;58:1161-3.

9. Miller ST, Sleeper LA, Pegelow CH, et al.

Prediction of adverse outcomes in children with

sickle cell disease. N Engl J Med 2000;342:83-9.

10. Milner PF, Kraus AP, Sebes JI, et al. Sickle cell 

disease as a cause of osteonecrosis of the femoral

head. N Engl J Med 1991;325:1476-81.

11. Washington ER, Root L. Conservative treatment 

of sickle cell avascular necrosis of the femoral head.

J Pediatr Orthop 1985;5:192-4.

12. Hernigou P, Galacteros F, Bachir D, et al.

Deformities of the hip in adults who have sickle

cell disease and had avascular necrosis in childhood.

J Bone Joint Surg Am 1991;73:81-92.

13. Styles LA, Vichinsky EP. Core decompression 

in avascular necrosis of the hip in sickle-cell 

disease. Am J Hemat 1996;52:103-7.

14. Acurio MT, Friedman RJ. Hip arthroplasty 

in sickle-cell haemoglobinopathy. J Bone Joint 

Surg Br 1992;74:367-71.

15. Bishop AR, Roberson JR, Eckman JR, et al. 

Total hip arthroplasty in patients who have sickle

cell hemoglobinopathy. J Bone Joint Surg Am

1988;70:853-5.

16. Clarke HJ, Jinnah RH, Brooker AF, et al. Total

replacement of the hip for avascular necrosis 

in sickle cell disease. J Bone Joint Surg Br 1989;

71:465-70.
137

17. Gunderson C, D’Ambrosia RD, Shaoji H. Total

hip replacement in patients with sickle cell disease.

J Bone Joint Surg Am 1977;59:760-1.

18. Hanker GJ, Nuys V, Amstutz HC. Osteonecrosis

of the hip in sickle cell disease. J Bone Joint Surg Am

1988;70:499-506.

19. Hickman JM, Lachiewicz PF. Results and 

complications of total hip arthroplasties in patients

with sickle-cell hemoglobinopathies. J Arthroplasty

1997;12:420-5.

20. Moran MC, Huo MH, Garvin KL, et al. Total hip

arthroplasty in sickle cell hemoglobinopathy. Clin

Orthop 1993;294:140-8. 

21. Sanjay BKS, Moreau PG. Bipolar hip replacement

in sickle cell disease. Int Orthop 1996;20:222-6.

22. Wingate J, Schiff CF, Friedman RJ. Osteonecrosis

of the humeral head in sickle cell disease. J South

Orthop Assoc 1996;5:101-7.

23. David HG, Bridgman SA, Davies SC, et al. The

shoulder in sickle-cell disease. J Bone Joint Surg Br

1993;75:538-45.

24. Hernigou P, Allain J, Bachir D, et al. Abnormalities

of the adult shoulder due to sickle cell osteonecrosis

during childhood. Rev Rhum Engl 1996;65:27-32.

25. Chung SM, Ralston EL. Necrosis of the humeral

head associated with sickle cell anemia and its

genetic variants. Clin Orthop 1971;80:105-17.

26. Bennett OM, Namnyak SS. Bone and joint manifestations of sickle cell anaemia. J Bone Joint Surg

Br 1990;72:494-9.

27. Mallouh A, Talab Y. Bone and joint infection in

patients with sickle cell disease. J Pediatr Orthop

1985;5:158-62.

28. Rao S, Solomon N, Miller S, et al. Scintigraphic

differentiation of bone infarction from

osteomyelitis in children with sickle cell 

disease. J Pediatr 1985;107:685-8.

29. Schumacher HR, Dorwart BB, Bond J, et al.

Chronic synovitis with early cartilage destruction in

sickle cell disease. Ann Rheum Dis 1977;36:413-9.

30. Sidhu P, Rich PM. Sonographic detection and

characterization of musculoskeletal and subcutaneous tissue abnormalities in sickle cell disease. 

Br J Radiol 1999;72:9-17.

31. Rao VM, Mitchell DG, Steiner RM, et al. Femoral

head avascular necrosis in sickle cell anemia MR

characteristics. Magn Reson Imaging 1988;6:661-7.

32. Rao VM, Sebes JI, Steiner RM, et al. Noninvasive

diagnostic imaging in hemoglobinopathies. Hematol Oncol Clin North Am 1991;5:517-33.
138
LEG ULCERS 22

139

the neighboring skin appears to be healthy, but

as the ulcer persists, the surrounding skin shows

hyperpigmentation with loss of subcutaneous

fat and hair follicles. These ulcers can be very

painful and often are accompanied by reactive

cellulitis and regional (inguinal) adenitis.

A general physical examination should search

for other causes of leg ulcers such as varicose

veins, diabetes mellitus, and collagen vascular

disease. Before therapy, a radiograph of the 

leg is performed to rule out osteomyelitis,

which is rare, even though periosteal thickening is common.

TREATMENT

The number of well controlled trials for treatment of leg ulcers is small, the number of

patients in most of them is too low, and there

have been almost no confirmatory studies.

Methods considered to be effective in more

common conditions (burns, venous stasis, and

diabetic ulcers) have been used, but evidence

of efficacy is often absent. In most cases, the

patient’s history has been used as his control

in a condition notorious for unexplained

remissions and relapses. Thus, most evidence

is relatively weak.

There have been many proposed treatments,

including topical honey or topical granulocyte

macrophage-colony stimulating factor (GMCSF), zinc oxide impregnated dressings (Unna

boots), various types of natural dressings (such

as lyophilized pig skin), synthetic matrices (2)

Between 10 and 20 percent of patients with

sickle cell disease (SCD) due to a homozygous

hemoglobin S (Hb S) genotype (SCD-SS)

develop painful, disfiguring, and indolent leg

ulcers. The ulcers usually appear between ages

10 and 50 years and are seen more frequently

in males than in females. Leg ulcers are rare 

in individuals with SCD-SC, SCD-S β+-thalassemia, and patients under 10 years of age,

but occur in other hemolytic anemias, such 

as thalassemia major. In the United States,

SCD is the main hemoglobinopathy that 

causes leg ulcers.

PATHOLOGIC MECHANISMS

The etiology of leg ulcers is unclear. In sickle

cell anemia, poorly deformable red cells may

cause hypoxia and infarction of distal ankle

skin, which can be ameliorated by increased

fetal hemoglobin (1). Trauma, infection, severe

anemia, and warmer temperatures also may

predispose to ulcer formation. Decreased

blood flow after the ulcer has healed often

results in recurrence.

CLINICAL FINDINGS

Sickle cell ulcers usually begin as small, elevated, crusting sores on the lower third of the 

leg, over the medial or lateral malleolus of the

ankle. Occasionally, ulcers are seen over the

tibia or the dorsum of the foot. They can be

single or multiple. Some heal rapidly, others

persist for years, and others heal only to recur

in the area of scarred tissue. In the early phase,
Chapter 22: Leg Ulcers

140

that foster healing, full-thickness skin flaps

attached with microsurgical techniques, 

parenteral erythropoietin, and intravenous

antithrombin III concentrate. Localized infection is an invariant feature (3), and proposed

approaches range from acetic acid wet-to-dry

dressings to gentle surgical debridement to

systemic antibiotics. Anemia is, of course, 

a problem; most therapeutic regimens involve

transfusion to raise the patient’s hemoglobin

concentration, and some more aggressive 

programs attempt to dilute sickle cells below

some arbitrary limit, as in treatment and 

prevention of stroke.

There are no published trials of various types

of conventional therapy, no reports that assess

the efficacy of transfusion, and no reports 

that compare skin grafting with conventional

therapy aside from comparisons of pretreatment and posttreatment courses in individual

patients. Particularly when evaluating surgical

regimens, it is important to remember that

ulcers heal with bed rest alone, and that relatively prolonged bed rest is often part of postgrafting regimens.

Any treatment for a chronic condition that

causes many patients to be economically 

disadvantaged must be practical and costeffective. Complete bed rest for weeks may 

be effective, but it is not practical; moderately

expensive dressings used for an outpatient

might be cost-effective, but inpatient therapy

probably is not (4). Issues of cost and practicality are not considered in the following

review of several controlled trials, but they

underlie any choice of treatment.

Most of the controlled trials were carried out

by Serjeant and coworkers in Jamaica (5),

where the frequency of ankle ulcers is very

high and their etiology is complex. In the first

trial, 29 patients received either zinc sulfate or

placebo for 6 months in addition to wound

care; 13 cases in the zinc group improved,

compared to 8 in the placebo group. No statistical analysis of the difference was reported.

Later, topical antibiotic spray was compared 

to sodium chloride solution in 28 patients (6);

6 of the control patients were taking oral zinc

sulfate. For ulcers of the same initial size,

those treated with the topical antibiotic were

66 percent smaller (p<0.05) after 8 weeks. 

A later trial compared Solcoseryl, Duoderm,

and conventional therapy (7); patients did not

tolerate Duoderm, and results with Solcoseryl

were not significantly different from conventional therapy.

Perhaps the most useful but frustrating controlled trial of treatment for ankle ulcers was

that of Wethers and coworkers (2). Fifty-five

patients with chronic nonhealing ulcers were

randomized to treatment with or without a 

gel composed of an arginine-glycine-aspartate

(RGD) peptide (a binding site for integrins 

on cell surfaces) and sodium hyaluronate for

cell attachment. Healing was accelerated in

patients treated with the RGD peptide matrix

(p=0.0085), and the gel was as effective in

ulcers of long duration as it was in those of

shorter duration. Although the study appears

to have been well designed, the manufacturer

of the RGD matrix for clinical use is defunct,

and the compound is no longer available.

SUMMARY

Studies to prove the efficacy of treatment of

leg ulcers are difficult to perform. One reason

is that healing depends on blood circulation,

and the cumulative time of bed rest and leg

elevation is not easily monitored. In addition,

the variable extent of wound debridement is

difficult to quantify, and a short period of

dependency could erase any gains made in 

the previous period. Thus, no treatments 

have been proven to work well or consistently.
141

Stated differently, the “strength of evidence”

that any available treatment except bed rest

and wound cleansing is really effective is not

good, a conclusion similar to that of a recently

published comprehensive review (3).

Since the one apparently effective compound 

is unavailable, practice is empirical, rather than

based on firm evidence. Outpatient treatment 

is cheaper than hospitalization and can be

achieved with intermittent clinic visits for

supervision. Some patients will be unable to

follow medical advice if they cannot stay off

their feet because of employment or domestic

duties, afford to buy dressings, or follow

instructions on how to change dressings. 

In such cases, considerable ingenuity on the

part of the physician or nurse may be needed.

The caregiver can provide encouragement 

and understanding, which can help the patient

accept the long duration of treatment.

RECOMMENDATIONS

Ankle ulcers are painful, and the patient

should be given moderately potent analgesics

such as oxycodone. Bed rest and elevation of

the leg to reduce edema are useful, though not

always practical. Wet-to-dry dressings, even 

if applied only 2 or 3 times a day, can provide

gentle debridement; cooperation of patients

increases when they are permitted to dampen

the dressing slightly before removal, since it 

is a painful process. Oral zinc sulfate (200 mg

3 times a day) probably does no harm if it does

not cause nausea, and may be worth using.

Ankle ulcers are always colonized with pathogenic bacteria, usually Pseudomonas aeruginosa,

Staphylococcus aureus, and/or Streptococcus

species (8), and sometimes the ulcers are

acutely infected. The infection also can be 

systemic. In the colonized patient, topical

antiseptics (dressings soaked with dilute acetic

acid, silver sulfadiazine cream, etc.) may be

helpful, but topical antibiotics invite growth

of treatment-resistant strains and should be

avoided. In acutely infected patients, vigorous

systemic antibiotic therapy is indicated.

Periosteal thickening is usually present beneath

the ulcer, but osteomyelitis is unusual.

After pain and swelling have subsided, the use

of Unna boots can be helpful. Patients can be

taught to change the dressing themselves, and

must be instructed to remove it promptly if

swelling recurs. Patients need to know before 

a boot is first applied that a shoe may no

longer fit when the boot is in place, and a

loose sneaker or sandal may fit more easily. 

If there is much exudate, the boot may need 

to be changed 2 or 3 times a week; as ulcers

improve, weekly changes are sufficient. The

ulcer size should be measured at every clinic

visit; seeing the dimensions shrink can provide

encouragement to the patient.

Some ulcers will not heal. Rigorous studies

have not been done to assess the utility of

transfusions for treating leg ulcers (see chapter

25, Transfusion, Iron Overload, and Chelation),

but the ulcers seem to correlate with degree 

of anemia, which suggests transfusions may

help. They should be considered for recalcitrant or recurrent skin ulcers if conservative

therapy fails. If transfusions are used, they

probably should be continued for 3 to 6

months. There is no evidence that a specified

posttransfusion hemoglobin concentration 

or percentage of sickle cells is better than

another, but a hemoglobin concentration

above 10 g/dL with Hb S levels less than 

50 percent can be achieved. 

More complete bed rest, systemic antibiotics,

transfusions, and skin grafts sometimes help.

If split thickness or pinch grafts are to be used,

preoperative preparation of the ulcer bed is

probably quite important. Quantitative bacterial cultures of biopsies of the bed and margin
Chapter 22: Leg Ulcers

142

are advocated by some (9) but not all (10) 

surgeons as a guide to the time for surgery.

Microsurgical attachment of myocutaneous

flaps may sometimes succeed when all else 

fails (11), but this rather heroic procedure 

is not always successful (12).

Because leg ulcers are less common in patients

with high fetal hemoglobin (Hb F) levels, it

would seem logical to try to raise Hb F concentrations. Intravenous arginine butyrate

infusions have been reported to cause rapid

healing of ankle ulcers (13). Hydroxyurea is

not a good choice because it appears to cause

leg ulcers in patients with myeloproliferative

disease (14).

REFERENCES

1. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers

in patients with sickle cell disease. Blood

1989;74:1403-8.

2. Wethers DL, Ramirez GM, Koshy M, et al.

Accelerated healing of chronic sickle-cell leg 

ulcers treated with RGD peptide matrix. 

Blood 1994;84:1775-9.

3. Eckman JR. Leg ulcers in sickle cell disease.

Hem/Onc Clin N Amer 1996;10:1333-44.

4. Cackovic M, Chung C, Bolton LL, et al. Leg 

ulceration in the sickle cell patient. J Am Coll 

Surg 1998;187:307-9.

5. Serjeant GR, Galloway RE, Gueri MC. Oral zinc

sulphate in sickle cell ulcers. Lancet 1970;2:891-2.

6. Baum KF, MacFarlane DE, Maude GH, et al.

Topical antibiotics in chronic sickle cell leg ulcers.

Trans Roy Soc Trop Med Hyg 1987;81:847-9.

7. La Grenade L, Thomas PW, Serjeant GR. 

A randomized trial of solcoseryl and duoderm 

in chronic sickle-cell ulcers. West Indian Med J

1993;42:121-3.

8. MacFarlane DE, Baum KF, Serjeant GR.

Bacteriology of sickle cell leg ulcers. Trans 

Roy Soc Trop Med Hyg 1986;80:553-6.

9. Majewski W, Cybulski Z, Napierala M, et al. The

value of quantitative bacteriological investigations

in the monitoring of treatment of ischaemic ulcerations of lower legs. Int Angiol 1995;14:381-4.

10. Steer JA, Papini RPG, Wilson APR, et al.

Quantitative microbiology in the management of

burn patients II. Relationship between bacterial

counts obtained by burn wound biopsy culture and

surface alginate swab culture, with clinical outcome

following burn surgery and change of dressings.

Burns 1996;22:177-81.

11. Heckler FR, Dibbell DG, McCraw JB. Successful

use of muscle flaps or myocutaneous flaps in

patients with sickle cell disease. Plast Reconst Surg

1977;59:902-8.

12. Richards RS, Bowen CVA, Glynn MFX.

Microsurgical free flap transfer in sickle cell 

disease. Ann Plastic Surg 1992;29:278-81.

13. Sher GD, Olivieri NF. Rapid healing of chronic leg

ulcers during arginine butyrate therapy in patients

with sickle cell disease and thalassemia. Blood

1994;84:2378-80.

14. Best PJ, Daoud MS, Pittelkow MR, et al.

Hydroxyurea-induced leg ulceration in 14 

patients. Ann Intern Med 1998;128:29-32.
143

SPECIAL TOPICS
144
CONTRACEPTION AND PREGNANCY 23

145

IMPACT OF HYDROXYUREA 

ON PREGNANCY

Women and men who are taking hydroxyurea

should use contraceptive methods and discontinue the drug if they plan to conceive a child,

since hydroxyurea has been shown to be teratogenic in animal models. If conception accidentally occurs when either partner is taking

hydroxurea, the couple should be told that

there is a paucity of information on which 

to determine the effect of hydroxyurea on the

fetus. However, in the 14 or 15 cases in which

hydroxyurea was taken throughout pregnancy,

no fetal malformations occurred (3,4).

MANAGEMENT OF PREGNANCY 

PRENATAL CARE

The prenatal assessment visit serves to provide

counseling and outline continued care for the

duration of the pregnancy. The primary focus

is to identify maternal risks for low birth

weight, preterm delivery, and genetic risks for

fetal abnormalities. At this time, the physician

reviews and discusses the behavior and social

patterns that place the patient at risk for sexually transmitted diseases, illicit drug use, alcohol and tobacco use, and physical abuse.

A history of previous cesarean section and

uterine curettage should be obtained at prenatal evaluation because of the correlation of the

occurrence of placenta previa in patients with

In a large multicenter observational study 

(1), the most common complication during

pregnancy for women with sickle cell disease

(SCD) was hypertension (table 1). A high percentage of the pregnancies resulted in preterm

deliveries and infants that were small for gestational age. Pain episodes were not increased

during pregnancy, and of the pregnancies carried to 28 weeks gestation, 99 percent resulted

in live deliveries. This study demonstrated that

pregnancy is not contraindicated for women

with SCD. However, prenatal care for women

with SCD should be managed by a multidisciplinary team that includes an obstetrician,

nutritionist, primary care physician, and 

hematologist. The team must decide who will

be responsible for each aspect of the patient’s

care. Close monitoring, combined with

prompt diagnosis and aggressive treatment 

of complications during the prenatal and

neonatal period by a multidisciplinary team,

will contribute to better outcomes.

CONTRACEPTION

Oral contraceptives, contraceptive agents

administered intramuscularly, and barrier

methods are all acceptable choices for women

with SCD. Few studies have evaluated oral

contraceptives in this population; however,

there is no evidence of adverse effects (2).

Intrauterine devices are not optimal, since they

may be associated with uterine bleeding and

infection, regardless of the presence of SCD.
Chapter 23: Contraception and Pregnancy

146

previous uterine surgery. Adequate nutritional

assessment and the avoidance of precipitating

factors that cause painful events should be outlined with this initial visit as well as all subsequent visits. The patient’s prepregnant weight,

height, and optimal weight gain in pregnancy

will be recorded. Physical exam should also

include determination of splenic size.

Initial comprehensive laboratory studies

include complete blood count with a reticulocyte index, hemoglobin electrophoresis, serum

iron, total iron binding capacity (TIBC), 

ferritin levels, liver function tests, urine examination and culture, electrolytes, blood urea

nitrogen (BUN), creatinine, blood type and

group, red cell antibody screen, and measurement of antibodies to hepatitis A, B, and C, 

as well as to HIV. Rubella antibody titre,

tuberculin skin test, Pap smear, cervical 

smear, and gonococcus culture and screening

for other sexually transmitted diseases, and 

bacterial vaginosis also should be performed. 

Hepatitis vaccine should be administered

when appropriate for patients who are negative for hepatitis B. If asymptomatic bacteriuria is found, the patient should receive

antibiotics in order to prevent urinary tract

infection and pyelonephritis.

Return visits are recommended 2 weeks after

the initial visit. Low-risk patients are scheduled for monthly visits until the second

trimester, when they should be seen every 

two weeks; in the third trimester, they should

be seen every week. 

Table 1. Complications of Pregnancy in Women With Sickle Cell Disease

Maternal Incidence (%) Fetal Incidence (%)

Preeclampsia 14 Miscarriages 6

Eclampsia 1 Stillbirth 1

Pyelonephritis <1 Small for gestational age 21

(<10th percentile) Placenta previa 1

Premature 27 Rupture of membranes 6 (<37 weeks at birth) 

Premature labor 9

Acute anemic event 3

(decrease in hemoglobin

levels by 30 percent of 

baseline)

Maternal mortality 0.45

Data are based on a study of 445 pregnancies in 297 women (predominantly in women with SCD-SS) recorded 

between 1979 and 1986 at 19 centers participating in the Cooperative Study of Sickle Cell Disease (1).
147

RECOGNITION OF PREGNANCY-INDUCED

HYPERTENSION AND DIABETES

For women with SCD, preeclampsia and

severe anemia have been identified as risk 

factors for delivering infants that are small for

their gestational age (1). In the study summarized in table 1, the incidence of preeclampsia

(defined as blood pressure >140/90 mmHg,

proteinuria of >300 mg/2 hours, and pathologic edema), and eclampsia (seizures in addition to features of preeclampsia) in pregnant

women with SCD was 15 percent (1). The

mechanisms for the high incidence of hypertension in this patient population remain

unclear; multiple factors such as placental

ischemia and endothelial injury have been

implicated. Other known risk factors for

preeclampsia, even in women without SCD,

are nulliparity, a history of renal disease or

hypertension, multiple gestation, and diabetes.

Pregnant women with SCD should be

observed closely if blood pressure rises above

125/75 mmHg, if the systolic blood pressure

increases by 30 mmHg, or diastolic blood

pressure increases by 15 mmHg, in association

with edema and proteinuria in the second

trimester. Preeclampsia, which requires 

frequent monitoring, can be treated with 

bed rest at home or in the hospital, if needed.

If preeclampsia is worsening, delivery of the

fetus may be required if the gestational age is

greater than 32 weeks. Expedited delivery is

recommended for uncontrolled hypertension.

INDICATIONS FOR BLOOD

TRANSFUSION DURING PREGNANCY

The role of prophylactic transfusions in pregnancy is controversial. One randomized trial

(5) and a retrospective study (6) concluded

that routine prophylactic transfusions from

the onset of pregnancy do not alter the outcome for the fetus or mother. However, one

additional study, also retrospective in nature,

concluded that prophylactic transfusions, if

initiated at about 20 weeks, may be beneficial

(7). A realistic approach may be to avoid routine prophylactic transfusions for uncomplicated pregnancies but to consider initiation 

of transfusions for women who have complications such as preeclampsia, severe anemia, 

or increasing frequency of pain episodes (8).

Women who have had previous pregnancy

losses or who have multiple gestations may

benefit from the early use of transfusions to

maintain a hemoglobin level above 9 g/dL (8).

Women should receive leukoreduced packed

red blood cells that have been phenotyped for

major and minor antigens. If the primary goal

of transfusions is to reduce the percent of sickle hemoglobin (Hb S), and the hemoglobin

level is high, one approach is to remove 500

mL of whole blood and transfuse 2 units of

packed red blood cells. This procedure can 

be done manually or by automated methods

to obtain a posttransfusion hemoglobin level

ranging between 10 and 11 g/dL and to reduce

the percentage of Hb S to between 30 and 40

percent of the total hemoglobin concentration. 

SICKLE CELL-RELATED EVENTS

DURING PREGNANCY

The clinical problems of SCD, such as newonset seizures, hepatopathy, acute anemia, and

painful episodes should be evaluated and managed for pregnant women in the same fashion

as for women who are not pregnant.

The frequency of previous acute vaso-occlusive

painful events is usually predictive of the events

during pregnancy, although some patients 

may experience an increased frequency of 

pain episodes (9,10). Patients with a chronic

pain syndrome should be identified; they 

may benefit from an individualized care plan.
Chapter 23: Contraception and Pregnancy

148

INTERRUPTION OF PREGNANCY

If interruption of pregnancy is considered at

less than 13 weeks, analgesia rather than anesthesia is usually all that is required for suction

curettage. Beyond 13 weeks, hypertonic urea

solutions are injected into the uterus and contractions are stimulated with prostaglandin F2.

Hypertonic sodium chloride should not be

injected because it can cause sickling. Rh-negative women should receive Rh immunoglobulin after therapeutic or spontaneous abortion.

Newer methods for medical termination of

pregnancy are available, but their use has not

been extensively described in women with

SCD (11).

LABOR, DELIVERY, POSTPARTUM

CARE, AND COUNSELING

Cardiac function can be compromised because

of chronic hypoxemia and anemia. During

labor, fetal monitoring is useful to detect fetal

distress, which can trigger prompt delivery by

cesarean section. If surgery appears imminent,

simple transfusion or rapid exchange transfusion can be of benefit depending on the baseline hemoglobin levels. The postpartum

patient may require transfusion if she has

undergone extensive blood loss during parturition. Venous thromboembolism can also complicate the postpartum course. To prevent this,

early ambulation is initiated. 

Counseling is also an important component 

of postpartum care. Results of the screen for

SCD in the infant should be made available 

to the mother and father, as well as to the

pediatrician. Contraception and plans for

future pregnancies also should be discussed. If 

a woman is considering no future pregnancies,

she can receive preliminary counseling about

tubal ligation for permanent birth control.

REFERENCES

1. Smith JA, Espeland M, Bellevue R, et al.

Pregnancy in sickle cell disease: experience of the

cooperative study of sickle cell disease. Obstet

Gynecol 1996;87:199-203.

2. Freie HMP. Sickle cell disease and hormonal 

contraception. Acta Obstet Gynecol Scand

1983;62:211-7. 

3. Diav-Citrin O, Hunnisett L, Sher GD, et al.

Hydroxyurea use during pregnancy: a case report 

in sickle cell disease and review of the literature.

Am J Hematol 1999;60:148-50.

4. Byrd DC, Pitts SR, Alexander CK. Hydroxyurea 

in two pregnant women with sickle cell anemia.

Pharmacotherapy 1999;19:1459-62.

5. Koshy M, Burd L, Wallace D, et al. Prophylactic

red cell transfusion in pregnant patient with sickle

cell disease. A randomized cooperative study. 

N Engl J Med 1988;319:1447-52.

6. Tuck SM, James CE, Brewster EM, et al.

Prophylactic blood transfusion in maternal sickle

cell syndromes. Br J Obstet Gynaecol 1987;94:121-5.

7. Morrison JC, Morrison FS, Floyd RC, et al. Use 

of continuous flow erythrocytapheresis in pregnant

patients with sickle cell disease. J Clin Apher

1991;6:224-9.

8. Koshy M, Chisum D, Burd L, et al. Management

of sickle cell anemia and pregnancy. J Clin Apher

1991;6:230-3.

9. Koshy M, Burd L, Dorn L, et al. Frequency 

of pain crisis during pregnancy. Prog Clin Biol Res

1987;240:305-11.

10. Koshy M, Leikin J, Dorn L, et al. Evaluation and

management of sickle cell disease in the emergency

department (an 18-year experience): 1974-1992.

Am J Therap 1994;1:309-20.

11. Christin-Maitre S, Bouchard P, Spitz I. Medical

termination of pregnancy. N Engl J Med

2000;342:946-56. 
ANESTHESIA AND SURGERY 24

149

study of aggressive (exchange) versus simple

transfusion in SCD-SS patients, with both

treatments performed to achieve a hemoglobin

level of 10 g/dL. The authors found no difference in complication rates. The protocol specified a minimum of “8 hours of preoperative

hydration, with intraoperative monitoring 

of temperature, blood pressure, electrocardiographic features, and oxygenation.” Postoperative care included the administration of 

oxygen, intravenous hydration, monitoring

with pulse oximetry, and respiratory therapy.

These guidelines are now generally accepted 

as the standard of perioperative care.

Koshy et al. (8), reporting for the Cooperative

Study of Sickle Cell Disease on 717 patients

with SCD-SS, SCD-SC, SCD-S βo-thalassemia,

and SCD-S β+-thalassemia, reported no deaths

in patients under the age of 14 (42 percent 

of the population was under the age of 20).

This nonrandomized study also showed that

postoperative complications increased with

age, with an “estimated odds ratio 1.3 times

increased risk of postoperative complications

per ten years of age, p<0.0001.” Furthermore,

SCD-related complications were more common in those who received regional compared

with general anesthesia and preoperative transfusion resulted in a lower complication rate for

those undergoing low-risk surgery (p=0.006).

Preoperative transfusions were beneficial for

SCD-SC patients undergoing any risk level 

of surgery (p=0.009) (8). Neumayer et al. (9),

reporting on SCD-SC patients in the same

Patients with sickle cell disease (SCD) may

require surgery for complications such as aseptic necrosis or cholelithiasis, or for conditions

unrelated to SCD. Multiple authors (1-5) have

reported that the risk of morbidity and mortality in these patients is greater than in the

general population because of anemia, the

propensity for red blood cells to sickle and

obstruct the microvasculature, the presence of

chronic organ damage in some patients, the

risks of hypoxia, and the effects of asplenia.

Risks have been said to be greater for patients

with SCD-SS or SCD-S βo-thalassemia.

Various suggestions for risk reduction have

been made, including correction of anemia by

simple or exchange transfusion, attention to

hydration and oxygenation, postoperative respiratory care, and selection of less aggressive or

extensive surgical procedures. It also has been

suggested (6) that patients undergoing minor 

surgical procedures (excluding tonsillectomy

and adenoidectomy) may not require transfusion if special attention is paid to oxygenation

and acid-base status. Several recent reports 

of larger series have begun to quantify the

magnitude of risks and provide some guidance

for management (7-9). 

SUMMARY OF THE 

STATE OF THE ART 

Two reports published in 1995 and one in

1998 have added greatly to our understanding

of the magnitude of risk and the management

of surgery in SCD patients. Vichinsky et al.

(7) reported on a multicenter randomized
Chapter 24: Anesthesia and Surgery

150

study reported by Vichinsky (7), observed that

“in patients undergoing intraabdominal procedures, the incidence of sickle-related complications was significantly higher in those SC

patients not transfused prior to their surgery.”

In this study, 60 percent of the patients transfused underwent exchange transfusion. 

Anecdotal data from all three studies suggests

that tonsillectomy and adenoidectomy should

not be considered low-risk procedures. The 

latter procedure, which is often associated

with blood loss, fluid loss, and inability 

to take oral hydration, appears to be more

serious for persons with sickle cell syndromes

than for other individuals.

Outcome data from the three studies are 

summarized in table 1. While some variation

exists in the incidence of acute chest syndrome and the infection/fever complications,

possibly due to differences in definitions, the

incidences of sickle cell pain, cerebrovascular

accident, and death are similar, lending validity to the management principles described in

the three studies.

RECOMMENDATIONS

■ Make sure the operating and anesthesia

teams are aware of the diagnosis of a 

sickle cell syndrome and the need for 

special attention.

■ In patients with SCD-SS and SCD-S 

βo-thalassemia, simple transfusion to

achieve a hemoglobin of 10 g/dL should

be performed before all but the lowestrisk procedures. 

■ For patients with SCD-SC, exchange

transfusions may be needed to avoid complications associated with hyperviscosity.

■ Alloimmunization should be minimized

by giving antigen-matched blood

(matched K, C, E, S, Fy, and Jk antigens). 

■ Patients with SCD, regardless of genotype,

should all receive careful attention, with

preoperative monitoring of intake and

output, hematocrit, peripheral perfusion,

and oxygenation status.

■ Intraoperative monitoring of blood 

pressure, cardiac rhythm and rate, and

oxygenation should be conducted for 

all surgical procedures. 

■ Postoperative care should include attention

to hydration, oxygen administration with

careful monitoring, and respiratory therapy.
151

Table 1. Outcome of Surgery in Patients With Sickle Cell Disease Who Received Perioperative Transfusions

Postoperative Complications (%) 

Ref. Yrs Hb Ages No. of Surgical ACS Pain CVA Infection Death

Procedures /Renal /Fever

Koshy

et al. (8) 1978-88 SS* 0-59 650 2.2 3.5 0.15 4.3 0.46 

Vichinsky

et al. (7) 1988-93 SS* All 604 10.0 5.0 >2.0 6.0 >0.5

Koshy

et al. (8) 1978-88 SC 0-62 81 0.0 2.5 0.0 20.0 0.0

Neumayr

et al. (9) 1988-93 SC** All 92 5.0 3.0 not 9.0 2.0**

reported

ACS = acute chest syndrome.

* Data include SCD-S βo-thalassemia patients. 

** Data include at least one SCD-S β+-thalassemia patient.

REFERENCES 

1. Janik J, Seeler AS. Perioperative management in

children with sickle hemoglobinopathy. Pediatr

Surg 1980;15:117-20.

2. Rutledge R, Groom RD III, Davis JW, et al.

Cholelithiasis in sickle cell anemia: surgical 

considerations. South Med 1986;79:28-30.

3. Gibson JR. Anesthesia for sickle cell diseases 

and other hemoglobinopathies. Sem Anesthesia

1987;IV:27-35. 

4. Ware R, Filston HC, Schultz WH, et al. Elective

cholecystectomy in children with sickle hemoglobinopathies. Successful outcome using a preoperative transfusion regimen. Ann Surg 1988;208:17-22.

5. Esseltine DW, Baxter MRN, Bevan JC. Sickle 

cell states and the anesthetist. Can J Anaesth

1988;35:385-403.

6. Griffin TC, Buchanan GR. Elective surgery on

children with sickle cell disease without preoperative blood transfusion. Pediatr Surg 1993;28:681-5.

7. Vichinsky EP, Haberkern CM, Neumayr L, et al. 

A comparison of conservative and aggressive 

transfusion regimens in the perioperative 

management of sickle cell disease. N Engl J Med

1995;333:206-12. 

8. Koshy M, Weiner SJ, Miller ST, et al. Surgery and

anesthesia in sickle cell disease. Cooperative Study

of Sickle Cell Disease. Blood 1995;66:3676-84. 

9. Neumayr L, Koshy M, Haberkern C, et al. 

Surgery in patients with hemoglobin SC disease.

Preoperative transfusion in sickle cell disease study

group. Am J Hematol 1998;57:101-8.

ONLINE RESOURCE

Sickle Cell Information Center 

(anesthesia and transfusion guidelines)

http://www.emory.edu/PEDS/SICKLE 
152
TRANSFUSION, IRON OVERLOAD, AND CHELATION 25

153

EPISODIC TRANSFUSIONS

MANAGEMENT OF SEVERE ANEMIA

In severely anemic patients, simple transfusions

should be used without removal of any blood

from the patient. The most common causes 

of acute anemia are acute splenic sequestration

(described in chapter 18, Splenic Sequestration)

and transient red cell aplasia (see chapter 12,

Transient Red Cell Aplasia). A third form of

acute anemia, called hyperhemolysis, is associated with infection (see chapter 11, Infection),

acute chest syndrome (see chapter 16, Acute

Chest Syndrome and Other Pulmonary

Complications), and particularly, malaria. 

In patients hospitalized for pain episodes and

other events, the Hb concentration may fall

well below the admission value. If the patient

is stable and the reticulocyte count high 

(>20 percent or >250,000/μL), transfusions

can be deferred. In general, patients should 

be transfused if there is sufficient physiological

derangement to result in heart failure, dyspnea,

hypotension, or marked fatigue. Such symptoms tend to occur during an acute illness

when hemoglobin falls under 5 g/dL. Patients

with an acute event associated with falling

hemoglobin can die suddenly from cardiovascular collapse and should be monitored closely.

Used correctly, transfusion can prevent organ

damage and save the lives of sickle cell disease

(SCD) patients. Used unwisely, transfusion

therapy can result in serious complications.

The choice of several methods, such as simple

transfusion, partial exchange transfusion, and

erythrocytapheresis, depends on the specific

requirements of the patient. Except in severe

anemia, exchange transfusion offers many 

benefits and should be made available.

Once a decision is made to transfuse, the type

of red cells to be given is specified and goals

are set for the final posttransfusion hematocrit

and percent sickle hemoglobin (Hb S) desired.

In general, phenotypically matched, sicklenegative, leukodepleted packed cells are the

blood product of choice, and a posttransfusion

hematocrit of 36 percent or less is recommended, since a higher value theoretically causes

hyperviscosity, which is dangerous to sickle

cell patients. A comprehensive transfusion

protocol should include accurate records of

the patient’s red cell phenotype, alloimmunization history, number of units received, serial

Hb S percentages, and results of monitoring

for infectious diseases and iron overload. 

Transfusions are used to raise the oxygencarrying capacity of blood and decrease the

proportion of sickle red cells. Clinically, they

will improve microvascular perfusion of tissues.

Transfusions usually fall into two categories:

episodic, acute transfusions to stabilize or reverse

complications, and long-term, prophylactic

transfusions to prevent future complications (1). 
Chapter 25: Transfusion, Iron Overload, and Chelation

154

MANAGEMENT OF SUDDEN

SEVERE ILLNESS

Leading causes of death in SCD, such as 

acute chest syndrome (see chapter 16, Acute

Chest Syndrome and Other Pulmonary

Complications), stroke (see chapter 13, 

Stroke and Central Nervous System Disease),

sepsis, and acute multiorgan failure often are

accompanied by a falling hemoglobin level. 

Transfusions can improve tissue oxygenation

and perfusion and are indicated in seriously ill

patients to potentially limit areas of vaso-occlusion. Controlled clinical trials to evaluate transfusions in most life-threatening situations have

not been performed, so medical practice is

based mainly on clinical observations. However,

limited studies indicate that aggressive transfusion regimens may improve recovery of organ

function and survival in instances of acute 

multiorgan failure (2). In general, the goal is 

to maintain a Hb S level below 30 percent. 

PREPARATION FOR

GENERAL ANESTHESIA

A multi-institution study recently compared

perioperative complications among sickle cell

patients undergoing major surgery (e.g., cholecystectomy) (3). Patients were randomized 

to an aggressive transfusion arm (to decrease 

Hb S to below 30 percent) or a conservative

transfusion arm (with Hb S at about 60 percent, total Hb corrected to 10 g/dL). The

groups also were compared to patients who

did not receive any perioperative transfusions.

Complications occurred in all groups but were

substantially more frequent in nontransfused

patients. There was no difference between 

the conservatively and aggressively transfused

patients with respect to perioperative complications; however, the latter group had a higher

alloimmunization rate. 

Thus, there is good evidence to recommend

that sickle cell patients be transfused before

major surgery. Anemia should be corrected 

to a Hb concentration of about 10 g/dL and

the Hb S level should be approximately 60

percent or lower. Although practice guidelines

have not been established, it is generally

acceptable to omit preoperative transfusions 

in healthy SCD-SC patients and stable SCDSS patients who undergo minor surgery (see

chapter 24, Anesthesia and Surgery).

CHRONIC TRANSFUSION

THERAPY 

Chronic transfusion therapy is indicated 

when avoidance of potentially serious medical

complications justifies the risks of alloimmunization, infection, and iron overload (4,5).

The goal is to maintain the Hb S level

between 30 and 50 percent, depending on 

the specific problem. Transfusions are usually

repeated every 3 or 4 weeks. While simple

transfusions may be used, red cell pheresis 

or exchange transfusions may help to decrease

the risk of iron overload (6).

Chronic transfusion therapy may be warranted

for the primary prevention of stroke and 

prevention of stroke recurrence (see chapter

13, Stroke and Central Nervous System

Disease). It may also be used to treat chronic

debilitating pain (see chapter 10, Pain), pulmonary hypertension (see chapter 16, Acute

Chest Syndrome and Other Pulmonary

Complications), and anemia associated with

chronic renal failure (see chapter 19, Renal

Abnormalities in Sickle Cell Disease). In

patients with chronic heart failure, transfusion

therapy may assist cardiac treatments and

improve quality of life (see chapter 15,

Cardiovascular Manifestations).
155

CONTROVERSIAL INDICATIONS

Transfusions are sometimes suggested for conditions in which efficacy is unproven, but may

be considered under extreme circumstances 

as described in chapter 20, Priapism; chapter

22, Leg Ulcers; and chapter 23, Contraception

and Pregnancy. 

PREPARATION FOR INFUSION

OF CONTRAST MEDIA

In the past, sickle cell patients were at increased

risk of sickling when given hypertonic contrast

media for radiographic examinations. To 

eliminate this problem, transfusion was recommended beforehand, but new agents, such

as gadolinium and nonionic contrast media,

now lower the risk.

MANAGEMENT OF “SILENT” CEREBRAL

INFARCT AND/OR NEUROCOGNITIVE

DAMAGE

Subclinical infarcts detected by magnetic 

resonance technology often are associated with

neurocognitive defects. Patients who have subclinical infarcts appear to have a higher incidence of strokes, but the efficacy of preventive

transfusion has not been evaluated in these

patients. Until rigorous controlled trials are

conducted, routine chronic transfusion therapy

cannot be recommended.

INAPPROPRIATE INDICATIONS 

AND CONTRAINDICATIONS 

The following conditions alone do not justify

transfusion:

■ Chronic steady-state anemia. Most

patients with SCD are relatively 

asymptomatic from their anemia and 

do not require transfusions to improve

oxygen delivery.

■ Uncomplicated acute pain episodes.

■ Infections.

■ Minor surgery that does not require 

prolonged general anesthesia (e.g.,

myringotomy).

■ Aseptic necrosis of the hip or shoulder

(except when surgery is required).

■ Uncomplicated pregnancies.

TYPES OF BLOOD PRODUCTS 

TO BE USED 

Standard bank blood is appropriate for

patients with SCD. The “age” of the blood

(time since collection) is usually not important, as long as it is within limits set by the

transfusion service. Exchange transfusion 

with blood less than 5 days old (less than 3

days old for small infants) helps in acute situations requiring immediate correction of oxygen-carrying capacity. All blood should be

screened for the absence of sickle hemoglobin;

a solubility test is adequate. This eliminates

blood with sickle cell trait, which can confuse

later measurements of the proportion of sickle

cells or Hb S. The antigenic phenotype of the

red cells (at least ABO, Rh, Kell, Duffy, Kidd,

Lewis, Lutheran, P, and MNS groups) should

be determined in all patients older than 6

months of age. A permanent record of the

phenotyping should be maintained in the

blood bank to optimize matching, and 

a copy of the record should be given to the

patient or family. All patients with a history 

of prior transfusion should be screened for 

the presence of alloantibodies. The efficacy 

of a chronic transfusion program should be

assessed periodically by determination of the

proportion of Hb S by quantitative hemoglobin electrophoresis as well as the hemoglobin

concentration or hematocrit.

There are several causes of the high prevalence of alloimmunization in SCD, and phenotypic incompatibility between the donor
Chapter 25: Transfusion, Iron Overload, and Chelation

156

and recipient is a major factor (7). Limited

matching for E, C, and Kell antigens is usually

performed, unless patients have antibodies (8).

Prestorage leukodepletion of red cells is 

standard practice to reduce febrile reactions,

platelet refractoriness, infections, and cytokineinduced complications (9). Washed red cells

should be reserved for patients who had allergic reactions after prior transfusions. Irradiated

blood should be considered in patients likely

to be candidates for bone marrow transplantation, but relatives should not be used as blood

donors for children who are such candidates.

The use of autologous blood transfusions in

SCD should be avoided. Red cell substitutes

are experimental and generally not indicated.

TRANSFUSION METHODS

Simple transfusions can be used for acute 

anemia or hypovolemia. Packed red cells 

are preferred, except when marked volume

expansion is needed.

CHRONIC SIMPLE TRANSFUSION

Once a sufficient level of transfused normal

cells [60-70 percent normal hemoglobin (Hb

A)] is achieved, simple transfusions every 2 to

4 weeks may maintain this proportion of normal cells for years. The level of Hb A must be

monitored regularly by quantitative hemoglobin electrophoresis. Significant variation in

transfusion requirements for each patient is

common, but the pretransfusion hematocrit

should be between 25 and 30 percent. The

posttransfusion hematocrit should be 36 percent or less to prevent hyperviscosity, especially

for initial transfusions.

EXCHANGE TRANSFUSION

Exchange transfusion is used to remove sickle

cells and replace them with normal red cells

without increasing whole blood viscosity or

chronic iron burden (6,10). The volume of

blood needed can be calculated from the

patient’s weight, initial hematocrit, target

hematocrit, and desired percentage of Hb A.

An adult exchange usually takes about 6 to 8

units, and children require about 50 to 60

mL/kg of blood. Whole blood or packed cells

reconstituted to hematocrits of 30 to 40 percent are used to conserve units, but exchanges

will take longer than with packed cells alone.

Blood can be removed from the adult patient 

in 500 mL aliquots, followed by infusion of

500 mL of reconstituted blood, repeated for 

6 to 8 cycles, or another schedule can be used.

The following is an example:

Step 1. Bleed one unit (500 mL) of blood

from patient, infuse 500 mL of saline.

Step 2. Bleed a second unit from the patient,

infuse two units of blood.

Step 3. Repeat steps 1 and 2; if the patient has

a large red blood cell mass, repeat once more.

For children, smaller, more precise volumes

should be calculated and used in order not 

to remove or transfuse too much blood at one

time. In some patients, whole blood can be

taken from one arm at the same time that

donor cells are transfused into the other. 

For adults, this procedure can be performed 

in 500 mL units, whereas in children, smaller

amounts are practical. Automated erythrocytapheresis is safe and is being used fairly often

because it prevents iron overload, despite 

concerns about increased red cell utilization,

venous access, and increased cost. When

exchange transfusion is performed, the final

hemoglobin value should not exceed 10 to 12

g/dL to avoid hyperviscosity, and the percentage of Hb A should meet the goals of therapy.
157

TRANSFUSION COMPLICATIONS 

Transfusion complications, such as 

alloimmunization, hyperviscosity, and relative

hypertension, may be higher for sickle cell

patients than for members of the general 

population (1). Transfusions have precipitated

pain episodes, strokes, and acute pulmonary

insufficiency. 

VOLUME OVERLOAD

This condition occurs when a large volume 

of blood is transfused too quickly. Congestive

heart failure and pulmonary edema tend to

occur in patients who have cardiac dysfunction or poor cardiac reserve. Administration 

of intravenous furosemide, partial removal 

of red cell supernatant fluid before transfusion,

and a slow transfusion rate can help to prevent

this problem.

ALLOIMMUNIZATION AND DELAYED

HEMOLYTIC TRANSFUSION REACTIONS

The incidence of alloimmunization to red

blood cell antigens in transfused patients with

sickle cell anemia is approximately 20 to 25

percent, which is greater than in the general

population (7). This condition causes difficulty

in obtaining compatible blood and results in 

a high incidence of delayed hemolytic transfusion reactions (12,13). Reactions occur 5 

to 20 days after transfusion and are due to

antibodies undetectable at the time of compatibility testing. More than 30 percent of

antibodies disappear with time, but recipients

can mount anamnestic responses to further

stimulation by transfusion. Delayed hemolytic

transfusion reactions may cause severe anemia,

painful events, and even death.

ACUTE HEMOLYTIC

TRANSFUSION REACTIONS

The causes of acute hemolytic transfusion

reactions in sickle cell patients are not different from those in other patients. Major

hemolytic reactions occur mainly with major

blood group (ABO) mismatches and must be

treated aggressively to maintain blood pressure

and glomerular filtration. Most reactions can

be prevented by avoiding clerical and sample

identification errors in the cross-matching and

transfer of units from the donor site to the

patient. Minor hemolytic reactions occur

when the amount of antibody in the patient’s

serum is limiting and causes the transfused

blood to disappear over several days, followed

by hyperbilirubinemia. The hematocrit

decreases, but no further treatment is needed

unless the hematocrit falls greatly.

Any of these reactions, particularly the delayed

variety, can initiate a pain episode in patients

with SCD. In all cases, a patient’s blood

should be examined very carefully by

immunohematologists to document the antibody or antibodies responsible for the reaction. The patient must be told of the complication and be given a card describing the antibodies found.

Alloimmunization and hemolytic transfusion

reactions can be reduced by:

■ Acquiring and maintaining adequate

records of previous transfusions and 

complications arising from them.

■ Limiting the number of transfusions

administered.

■ Screening for newly acquired antibodies 

1 to 2 months after each transfusion 

to detect transient antibodies that cause 

a subsequent delayed reaction.
Chapter 25: Transfusion, Iron Overload, and Chelation

158

■ Diminishing the opportunities for alloimmunization because of a mismatch in 

the antigens of donors and patients (14). 

This may be accomplished by:

– Typing the patient before transfusion 

(if this has not already been done) for Rh

and Kell blood group antigens to avoid

transfusion of cells with these antigens

(particularly E, C, and Kell) if the patient

lacks them.

– More extensive antigen matching in

patients who are already alloimmunized.

– Increasing the numbers of AfricanAmerican blood donors because of the

similarity of their blood cell antigenic 

phenotypes. Family members and community groups can assist in accomplishing

this objective.

Patients alloimmunized to one red cell antigen

are more likely to become alloimmunized to

others. Transfusions should be given only for

clearcut indications, and care should be taken

in the selection of units of blood. Patients

should be counseled to advise any new physician of their history of alloimmunization and

to carry a card or identification bracelet that

lists their red blood cell phenotype and any

identified antibodies.

AUTOIMMUNE ANEMIA FOLLOWING

ALLOSENSITIZATION

In a highly alloimmunized patient, a syndrome

of autoimmune hemolytic anemia may occur.

In this case, the patient may become more 

anemic than before transfusion, and the direct

antiglobulin (Coombs’) test remains positive

even after the incompatible transfused cells

have been destroyed. Autoimmune anemia

occurs because the recipient produces antibodies against self-antigens, which may persist up 

to 2 to 3 months before disappearing. Further

transfusion is complicated by the autoimmune

antibody and requires special blood bank tests

to find the least incompatible units for transfusion. Although transfusion may be necessary in

some patients, an alternative course may be to

avoid transfusion and to administer corticosteroids, large doses of erythropoietin, and possibly intravenous immune globulin.

ALLOANTIBODIES TO WHITE CELLS,

PLATELETS, AND SERUM PROTEINS

Patients who are transfused may become

alloimmunized to antigens present on leukocytes or platelets but absent from red blood

cells. Such antibodies may cause febrile reactions that can be prevented by the removal 

of leukocytes by filtration or washing. These

antibodies, and those for serum proteins, 

can cause allergic reactions that can be prevented by prophylaxis with an antihistamine

(Benadryl®), leukodepletion, or removal 

of plasma.

INFECTION

Hepatitis and other transfusion-transmitted

viral diseases in blood occur with the same 

frequency in sickle cell patients as in other

patients who receive transfusions. The consequences may be more severe with concurrent

SCD, however. Patients who have received

multiple transfusions should be monitored

serially for hepatitis C and other infections

(15,16). Parvovirus occurs in 1 in every 40,000

units, and is associated with acute anemic

events and multiple sickle cell complications. 

Transfusion-induced bacterial infections are

uncommon. Repeatedly transfused hemoglobinopathy patients are particularly vulnerable

to Yersinia entercolitica and bacteremia from

poor skin cleansing before phlebotomy. All

patients who develop fever after transfusion

need to be assessed immediately for potential

bacterial infection. 
159

IRON OVERLOAD 

AND CHELATION

Iron overload in sickle cell patients is often

undetected or not treated. In contrast to thalassemia patients, most patients are iron overloaded because of intermittent transfusions

throughout their lives. There is no evidence

that SCD patients are spared the fatal consequences of iron overload. Therefore, a comprehensive program to monitor and treat iron

overload is necessary.

There is no simple test to determine iron 

overload. Measurement of serial serum ferritins may help but can be unreliable because

ferritin is an acute phase reactant and values

are altered by liver disease, inflammation, 

and vitamin C stores. Liver biopsy is the most

accurate test for iron overload and can be 

performed safely by an experienced physician.

The sample should be of adequate size and

sent to a reference lab familiar with liver iron

quantitation. Some programs recommend liver

biopsies at the start of chelation and every 2

years thereafter. As a noninvasive method, the

superconducting quantum interference device

(SQUID) is acceptable for quantitating liver

iron (10). There is progress with MRI and 

CT, but their clinical use is unproven. The

best indication to begin chelation therapy is 

a rise in liver iron stores to 7 mg/g dry weight.

Alternatively, cumulative transfusions of 120

cc of pure red cells per kilogram of body

weight can be used (5). Serum ferritin levels

above 1,000 ng/mL in the steady state are

helpful, but the risk of under- and overtreatment occurs. All iron-overloaded patients

should be followed at comprehensive sickle

cell centers that can monitor organ toxicity

and provide ongoing education and support.

Exchange transfusions and chelation therapy

are the only two accepted methods to manage

transfusion-related iron overload. Phlebotomy

will remove iron in abnormal red cells, which

are replaced by normal red cells. The initial

dose of the chelator deferoxamine (DesferalTM)

is 25 mg/kg per day, over 8 hours subcutaneously (17); dose and duration of infusion

can be increased, depending on patient age and

iron load. Supplementation with vitamin C,

100 to 200 mg per day, may help to increase

excretion, especially in those who are vitamin

C deficient. New methods of delivery, including twice-daily subcutaneous injections and

intravenous home parenteral access, are being

studied. Deferoxamine is generally safe, but has

been associated with ototoxicity, eye toxicity,

allergic reactions, growth failure, unusual infections, and pulmonary hypersensitivity; therefore, patients should be monitored annually for

growth and eye toxicity. Iron chelation always

should be discontinued during an acute infection. Other chelators are experimental and are

not recommended at this time.

REFERENCES

1. Ohene-Frempong K. Indications for red cell 

transfusion in sickle cell disease. Sem Hematol

2001;38(Suppl 1):5-13.

2. Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic

complication of severe sickle cell pain episodes. 

Am J Med 1994;96:155-62.

3. Vichinsky EP, Haberkern CM, Neumayr L, et al. 

A comparison of conservative and aggressive transfusion regimens in the perioperative management

of sickle cell disease. The Preoperative Transfusion

in Sickle Cell Disease Study Group. N Engl J Med

1995;333:206-13.

4. Styles LA, Vichinsky E. Effects of a long-term

transfusion regimen on sickle cell-related illnesses.

J Pediatr 1994;125:909-11.

5. Vichinsky E. Guest editor. Consensus document

for transfusion-related iron overloads. Sem Hematol

2001;38(Suppl 1):2-4.
Chapter 25: Transfusion, Iron Overload, and Chelation

160

6. Singer ST, Quirolo K, Nishi K, et al. Erythrocytapheresis for chronically transfused children with

sickle cell disease: an effective method for maintaining a low hemoglobin S level and reducing iron

overload. J Clin Apheresis 1999;14:122-5.

7. Rosse WF, Gallagher D, Kinney TR, et al.

Transfusion and alloimmunization in sickle cell 

disease. The Cooperative Study of Sickle Cell

Disease. Blood 1990;76:1431-7.

8. Sosler SD, Jilly BJ, Saporito C, et al. A simple, practical model for reducing alloimmunization 

in patients with sickle cell disease. Am J Hematol

1993;43:103-6 

9. Brand A. Passenger leukocytes, cytokines, and transfusion reactions. N Engl J Med 1994;331:670-1.

10. Brittenham GW, Cohen AR, McLaren CE, et al.

Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993;42:81-5.

11. Pegelow CH, Colangelo L, Steinberg M, et al.

Natural history of blood pressure in sickle cell 

disease: risks for stroke and death associated with

relative hypertension in sickle cell anemia. Am J

Med 1997;102:171-7.

12. King KE, Shirey RS, Lankiewicz MW, et al.

Delayed hemolytic transfusion reactions in sickle

cell disease: simultaneous destruction of recipients’

red cells. Transfusion 1997;37:376-81.

13. Petz LD, Calhoun L, Shulman IA, et al. The sickle

cell hemolytic transfusion reaction syndrome.

Transfusion 1997;37:382-92.

14. Tahhan HR, Holbrook CT, Braddy LR, et al.

Antigen-matched donor blood in the transfusion

management of patients with sickle cell disease.

Transfusion 1994;34:562-9.

15. Hasan MF, Marsh F, Posner G, et al. Chronic

hepatitis C in patients with sickle cell disease. 

Am J Gastroenterol 1996;91:1204-6.

16. Schreiber GB, Busch MP, Kleinman SH, et al. 

The risk of transfusion-transmitted viral infections.

The Retrovirus Epidemiology Donor Study. 

N Engl J Med 1996;334:1685-90.

17. Silliman CC, Peterson VM, Mellman DL, et al.

Iron chelation by desferrioxamine in sickle cell

patients with severe transfusion-induced hemosiderosis: a randomized, double-blind study of 

the dose-response relationship. J Lab Clin Med

1993;122:48-54.
FETAL HEMOGLOBIN INDUCTION 26

161

F expression without gene hypomethylation,

and hydroxyurea is one example that supports

erythroid regeneration as a mechanism of Hb

F induction.

Hydroxyurea is a ribonucleotide reductase

inhibitor, which blocks ribonucleoside conversion to deoxyribonucleotides and prevents

DNA synthesis. In anemic primates, hydroxyurea increased Hb F levels, and in early studies in two patients with sickle cell anemia, 

hydroxyurea increased F-reticulocytes and 

Hb F concentrations. An important pilot 

trial defined effective dosages, found increased

Hb F in most, but not all, compliant patients,

and revealed little short-term toxicity. 

5-AZACYTIDINE 

5-azacytidine is an antineoplastic agent that

inhibits methylation of cytosines in DNA.

Studies on gene regulation had suggested that

methylation resulted in repression of transcription and that hypomethylation was associated

with active gene expression. It was observed

that the inactive gene becomes methylated

during the developmental switch from γ-globin to β-globin production in erythroid cells.

The administration of 5-azacytidine caused 

a marked increase in Hb F in baboons. These

results prompted limited clinical trials, which

demonstrated significant but less dramatic

induction of Hb F in patients with SCD. 

The antiproliferative activity of this drug may

have led to the proposed use of hydroxyurea.

Enhanced concentrations of hemoglobin F

(Hb F) can inhibit sickle hemoglobin (Hb S)

polymerization and red cell sickling and

improve the clinical course of sickle cell disease (SCD). In populations such as Bedouin

Arabs from the Saudi peninsula and certain

tribes from central India, patients homozygous

for SCD have elevated amounts of Hb F and

fairly mild clinical manifestations. In a cooperative study of the natural history of patients

with sickle cell anemia in the United States,

the frequency of pain episodes correlated

inversely with the Hb F concentration. Based

on these epidemiologic studies and understanding the biophysics of Hb S polymerization, a search was launched for pharmacologic

agents that could reverse the switch from 

γ- to β-globin chain synthesis in erythroid 

precursors. The first “hemoglobin switching”

agent was the nucleoside analog 5-azacytidine

(1), which was followed by butyrate derivatives as compounds which increase Hb F gene

expression. Other drugs, such as hydroxyurea

and erythropoietin, alter maturation of erythroid precursors and promote Hb F production indirectly.

The small amount of Hb F in adults is found

in rare erythrocytes called F-cells. Rapid erythropoiesis induces F-cell production, probably due to commitment of early progenitors

that contain factors that favor γ-globin expression and faster maturation and release into the

circulation. Many cytotoxic drugs induce Hb
Chapter 26: Fetal Hemoglobin Induction

162

BUTYRATE

Butyrates appear to modulate globin-gene

expression by direct binding to transcriptionally active elements, and by inhibition of 

histone deacetylase, histone hyperacetylation,

and changes in chromatin structure. In sickle 

cell anemia, early trials of butyrate given by

continuous infusion over 2 or 3 weeks were

inconclusive, but newer studies with pulse

butyrate treatment are encouraging. When

arginine butyrate was given once or twice

monthly, 11 of 15 sickle cell patients responded

with a mean rise in Hb F from 7 percent to

21 percent, a level maintained in some people

for 1 to 2 years. The studies also suggested

butyrate and hydroxyurea are synergistic 

without cross-resistance; pretreatment with

hydroxyurea may select a population of erythroid precursors with active γ-globin genes 

and make them responsive to butyrate. 

Butyrate does not seem to be cytotoxic, 

but its use is experimental.

HYDROXYUREA IN 

SICKLE CELL ANEMIA

CLINICAL AND HEMATOLOGIC EFFECTS

A pivotal multicenter efficacy trial of hydroxyurea in 299 adults with sickle cell anemia

showed that hydroxyurea reduced by nearly

half the frequency of hospitalization and the

incidence of pain, acute chest syndrome, and

blood transfusions (2). In good responders,

hemolysis and leukocyte counts fell, and

hemoglobin concentrations increased. 

Hb F increased from a baseline of 5 percent 

to about 9 percent after 2 years of treatment;

Hb F increased to a mean of 18 percent in 

the top 25 percent of Hb F responders and 

to 9 percent in the next highest 25 percent,

but changed little in the lower half of Hb F

responders. These results may not be typical 

of all patients because the patients in the 

study had a mean age of about 30 years, had

severe disease, and were treated to the brink of

myelotoxicity. After treatment, some individuals

had improved physical capacity and aerobic 

cardiovascular fitness. A modest improvement

in general perceptions of health and social

function and recall of pain was found.

Moreover, hydroxyurea was cost-effective 

and clinically beneficial.

Studies of hydroxyurea in infants, children,

and adolescents lag behind adult studies in 

the appraisal of clinical efficacy. Most patients

reported were adolescents or teenagers treated

in unblinded pilot studies, although 25

patients with a median age of 9 years were

treated in a single-blinded crossover study

with drug or placebo. In all trials, Hb F

increased from about 5 percent before treatment to about 16 percent after 6 months 

to a year of treatment.

A trial of 84 children with a mean age of 10

years gave results similar to those in adults (3).

Sixty-eight patients reached the maximally tolerated dose, and 52 patients completed a year

of treatment. About 20 percent of enrolled

patients withdrew from the study, predominantly because of lack of compliance. Baseline

Hb F of 6.8 percent increased to 19.8 percent

(range, 3.2-32.4 percent). Mean cell volume

(MCV) and hemoglobin concentration

increased, and the leukocyte count fell. These

changes, apparent after 6 months of treatment,

were sustained at 24 months. The increment in

Hb F was variable, but unlike the adults, the

young patients with the highest baseline Hb F

concentration had the highest Hb F levels with

treatment, and the drop in leukocyte count did

not predict the rise in Hb F.
163

Twenty-nine infants, with a median age of 

14 months, were treated with hydroxyurea at 

a dose of 20 mg/kg for 2 years, escalating to

30 mg/kg thereafter. After 2 years, all parents

elected to continue treatment, and 19 children

completed a median treatment period of 148

weeks. Changes in hemoglobin concentration,

MCV, Hb F, and leukocyte count were compared with the changes observed in a historical

control group. Hemoglobin increased from

8.5 to 8.9 g/dL (predicted, 8.2 g/dL), MCV

increased from 82 to 93 fL (predicted, 88 fL),

and Hb F fell from 21.3 to 19.6 percent 

(predicted, 12.3 percent). Functional asplenia

was found in 24 percent of patients before

treatment and in 47 percent after treatment 

(predicted, 80 percent). Nine patients were

dropped from the study because of poor 

compliance or parental refusal to continue;

one child died of splenic sequestration. One

patient had a transient ischemic attack, one

had a mild stroke, eight had episodes of acute

chest syndrome, two had splenic sequestration,

and three had episodes of sepsis. Growth was

normal. Despite moderate levels of Hb F,

acute complications of sickle cell anemia still

occurred in these very young patients. Perhaps

functional asplenia is delayed by treatment,

but risks of splenic sequestration and other

complications may persist.

MORTALITY AND MORBIDITY

The best data on the complications of hydroxyurea treatment and its effect on morbidity and

mortality come from the followup of patients

in the Multicenter Study of Hydroxyurea in

Sickle Cell Disease. After 8 years of followup

the data strongly suggest that treatment of

moderately-to-severely affected adults with

sickle cell anemia with hydroxyurea is associated with reduced mortality. Twelve strokes have

occured, 9 in patients with more than 1 year

of hydroxyurea treatment, 2 in patients with

less than 1 year of drug exposure, and 1 in 

a patient who never received hydroxyurea.

New adverse effects have not been found.

Pulmonary disease was the most common

cause of death. 

We do not know whether hydroxyurea will

prevent or reverse organ damage (4). After 1

year of treatment, splenic function in a group

of children who averaged 12 years of age did

not change. Of 10 patients with sickle cell

anemia who received hydroxyurea for 21

months and had an increase in Hb F from 

8 to 17 percent, only 1 recovered splenic 

function. In another prospective study, some

patients had partial return of splenic function,

possibly related to Hb F levels. Splenic regeneration was reported in 2 adults with sickle

cell anemia who had Hb F levels of about 

30 percent after hydroxyurea treatment.

Hydroxyurea does not appear to prevent 

the cerebrovascular complications of SCD.

However, in children ages 5 to 15 years without a history of overt CVA and with more

than three painful episodes yearly, hydroxyurea

maintained cognitive performance comparable

to sibling controls. Performance was found 

to deteriorate in untreated patients.

ADVERSE EVENTS

Long-term effects of hydroxyurea are still

poorly defined. The multicenter trial had

power to detect only 100-fold increases in the

incidence of leukemia or cancer. Hydroxyurea

has been given to 64 children with cyanotic

congenital heart disease for a mean duration

of more than 5 years without any reports of

malignancies. In myeloproliferative disorders,

however, the drug may have helped to transform premalignant conditions into acute

leukemia in about 10 percent of patients.

There are at least three patients with SCD

treated with hydroxyurea who developed
Chapter 26: Fetal Hemoglobin Induction

164

CONCLUSION

Hydroxyurea is a valuable adjunct in the 

treatment of severe SCD, although its clinical

effectiveness for individuals with SCD has 

not yet been reported. Meanwhile, it must 

be used carefully with full appreciation of its

toxicity and possible long-term adverse effects.

Many questions about its use and effects

remain unanswered. Hydroxyurea is not the

final solution in the pharmacologic therapy 

of SCD, but it is a promising start.

REFERENCES

1. DeSimone J, Heller P, Hall L, et al. 5-Azacytidine

stimulates fetal hemoglobin synthesis in anemia

baboons. Proc Natl Acad Sci USA 1982;79:4428-31.

2. Charache S, Terrin ML, Moore RD, et al.

Multicenter Study of Hydroxyurea in Sickle Cell

Anemia. Effect of hydroxyurea on the frequency of

painful crises in sickle cell anemia. N Engl J Med

1995;332:1317-22.

3. Kinney TR, Helms RW, O’Branski EE, et al. Safety

of hydroxyurea in children with sickle cell anemia:

results of the HUG-KIDS study, a phase I/II trial.

Blood 1999;94:1550-4. 

4. Steinberg MH. Management of sickle cell disease.

N Engl J Med 1999;340:1021-30.

5. Rodgers GP, Dover GJ, Uyesaka N, et al.

Augmentation by erythropoietin of the fetalhemoglobin response to hydroxyurea in sickle 

cell disease. N Engl J Med 1993;328:73-80.

leukemia, two after 6 and 8 years of treatment.

Cellular changes that may precede neoplastic

transformation, such as increases in chromosome breakage, recombination, and mutations,

have not been reported in hydroxyurea-treated

sickle cell patients.

Adverse effects on growth and development

have not been reported. Whether continuous

drug exposure at a very young age will be

especially hazardous or beneficial is not

known. Contraception should be practiced 

by both women and men on hydroxyurea, 

and the uncertain outcome of an unplanned

pregnancy should be discussed frankly.

Pregnancy resulting in infants without malformaions has been reported in at least 15

women receiving hydroxyurea; most mothers

had myeloproliferative disorders, but 6 had

sickle cell anemia.

TREATMENT PROTOCOL

Table 1 summarizes the treatment protocol

and points that should be considered when

using hydroxyurea as a treatment for patients

with sickle cell anemia.

COMBINATIONS 

OF HB F INDUCERS 

When both hydroxyurea and erythropoietin

were given to patients with sickle cell anemia,

an increment in Hb F concentration beyond

that seen with hydroxyurea alone occurred (5).

It is conceivable that combination therapy

with butyrate and hydroxyurea and/or erythropoietin may provide additive effects on

Hb F production, although verification of this

conclusion must await the results of appropriate clinical trials.
165

Table 1. Hydroxyurea in Sickle Cell Anemia

Indications for Treatment

Adults, adolescents, or children (after consultation with parents and expert pediatricians) with sickle cell

anemia or SCD-S βo-thalassemia and frequent pain episodes, history of acute chest syndrome, other severe

vaso-occlusive events, or severe symptomatic anemia. Initial high levels of Hb F (e.g., >10 percent) do not

preclude favorable responses to therapy.

Baseline Evaluation

Blood counts, red cell indices, percent Hb F, serum chemistries, pregnancy test, willingness to follow 

treatment recommendations, nonparticipation in a chronic transfusion program.

Initiation of Treatment

Hydroxyurea, 10-15 mg/kg/day in a single daily dose for 6-8 weeks; CBC every 2 weeks; percent Hb F 

every 6-8 weeks; serum chemistries every 2-4 weeks.

Continuation of Treatment

If no major toxicity, escalate dose every 6-8 weeks until the desired endpoint is reached.

Treatment Endpoints

Less pain, increase in Hb F to 15-20 percent, increased hemoglobin level if severely anemic, 

improved well-being, acceptable myelotoxicity.

Failure of Hb F (or MCV) To Increase

Consider biological inability to respond to treatment or poor compliance with treatment. Increase dose

very cautiously to a maximum dose of 35 mg/kg/day. In the absence of transfusion support or concurrent

illness suppressing erythropoiesis, a trial period of 6-12 months is probably adequate.

Cautions

Special caution should be taken in patients with compromised renal or hepatic function. Contraception

should be practiced by both men and women since hydroxyurea is a teratogen and its effects during 

pregnancy are unknown. After a stable, nontoxic dose of hydroxyurea is reached, blood counts may be

done at 4-8 week intervals. Granulocytes should be ≥ 2,500/μL, platelets ≥ 95,000/μL.
166
HEMATOPOIETIC CELL TRANSPLANTATION 27

167

nation of SCD. In the decade and longer that

followed, there was considerable discussion

about who should be considered and when

they should be referred for transplantation

(13-15). The first limited series of patients

who underwent transplantation because 

they had SCD comprised a group of families

from Africa living at the time in Belgium (4).

Based in part on the very good outcome 

experienced by these initial patients, several

multicenter phase II studies for children with

symptomatic SCD were conducted in North

America and Europe (7,9). It was reasoned

that children might have a superior outcome

compared to adult patients because of children’s lower risk of transplant-related complications such as graft-versus-host disease

(GvHD) and because of a presumed lower

burden of sickle-related organ damage. The

inclusion and exclusion criteria for enrollment

adapted from one multicenter study (7) are

summarized in table 2.

RESULTS OF HCT FROM HLAIDENTICAL SIBLING DONORS

Approximately 150 patients have undergone

HCT from HLA-identical siblings worldwide

(9,10,16,17). The combined results of three

studies have demonstrated that transplantrelated mortality is about 5 percent, and that

more than 90 percent of patients survive.

Approximately 85 percent survive free from

SCD after transplantation with a period of

followup that extends to 11 years, but about

10 percent of patients experience recurrence 

Hematopoietic cell transplantation (HCT) 

has curative potential for a broad spectrum of

genetic disorders, including sickle cell disease

(SCD) (1). The goal is to eliminate the sickle

erythrocyte and its cellular progenitors and

replace them with donor hematopoietic

pluripotent stem cells that give rise to erythrocytes that express no sickle hemoglobin (Hb

S), thereby reducing Hb S levels to those associated with the trait condition. The possibility

of preventing serious complications from SCD,

which can cause extensive morbidity and early

death, is balanced by the risk of severe adverse

events after transplantation. The first case

reports of successful outcomes after transplantation have been extended by several multicenter investigations (table 1). To date, nearly all

transplants have utilized HLA-identical sibling

donors, which has limited the number of eligible sickle cell patients. Thus, there are no randomized, controlled studies that support this

therapeutic option for SCD. However, with

the development of new therapies that prevent

and treat graft-versus-host and host-versus-graft

reactions, it is likely that transplantation will

take on added importance for selected patients

with SCD. 

INDICATIONS FOR HCT

The first published reports of HCT for SCD

involved patients who had other hematological

or genetic disorders that were the primary

indication for transplantation (2,3). From this

initial experience it was learned that engraftment of donor cells was associated with elimi-
Chapter 27: Hematopoietic Cell Transplantation

168

Table 1. Supporting Evidence for HCT for Sickle Cell Disease

Study Description References

Case reports Johnson et al. (2), Milpied et al. (3)

Patient series Vermylen et al. (4,5)

Proposal of HCT trial Thomas (6)

Collaborative HCT trial Walters et al. (7)

Collaborative HCT trial in Europe Vermylen and Cornu (8)

Long-term impact of HCT Vermylen et al. (9), Walters et al. (10)

UCB report Brichard et al. (11), Minero et al. (12)

Table 2. Eligibility Criteria for HCT for Sickle Cell Disease

Inclusions

Patients < 16 years of age with sickle cell anemia (SCD-SS or SCD-S βo-thalassemia) 

One or more of the following complications:

Stroke or central nervous system (CNS) event lasting longer than 24 hours

Impaired neuropsychologic function and abnormal cerebral magnetic resonance imaging (MRI) scan

Recurrent acute chest syndrome or Stage I or II sickle lung disease

Recurrent vaso-occlusive painful episodes

Sickle nephropathy [glomular filtration rate (GFR) 30-50 percent of predicted normal]

Osteonecrosis of multiple joints

Exclusions

Patients >16 years of age

HLA-non-identical donor

One or more of the following conditions:

Lansky performance score <70 percent

Acute hepatitis or biopsy evidence of cirrhosis

Renal impairment (GFR <30 percent predicted normal)

Stage III or IV sickle lung disease
169

of SCD. Neurologic complications, such as

seizures, occurred frequently after transplantation, leading to the development of preventive

measures (18-20). 

Among patients who had stable engraftment

of donor cells, there were no subsequent sickle

cell-related clinical events, and there was stabilization of preexisting sickle cell-related organ

damage (9,10,21). There was also recovery 

of splenic function (22). Some patients 

developed mixed donor-host hematopoietic

chimerism after transplantation that was stable

(23). Of interest, these patients also had no

symptoms from SCD. 

About 5 percent of patients developed Grade

III acute or extensive chronic GvHD; the 

others had no graft-vs-host response or mild

GvHD. Primary and secondary amenorrhea

were common among females after transplantation and it is likely that most patients will 

be infertile (9,10). The risk of secondary cancers after HCT remains uncertain, but it is

estimated to be less than 5 percent (24). Linear

growth was normal or accelerated after transplantation in the majority of patients (9,10).

ALTERNATIVE SOURCES 

OF STEM CELLS

Umbilical cord blood (UCB) and hematopoietic cells from volunteer donors represent

alternative sources of hematopoietic stem cells

that might increase the number of donors 

for SCD patients. Successful hematological

reconstitution has been observed after UCB

transplantation for SCD (11). However, there

are no published reports of transplantation 

to treat SCD using UCB from volunteer, 

unrelated donors. 

There is evidence to suggest that the incidence

of GvHD is lower after UCB transplantation

than after bone marrow transplantation (25).

This advantage is balanced by somewhat

lengthier periods for hematopoietic engraftment and perhaps a higher rate of graft rejection, especially when nonidentical donors 

are used and when cell doses are low (26).

Strategies for transplantation from unrelated

volunteer stem cell donors will need to overcome histocompatibility barriers associated

with higher rates of GvHD and graft rejection. There are no established protocols for

transplantation from alternative sources of

stem cells; however, pilot clinical investigations are being designed.

HCT FOR ADULTS

There is very limited information about the

outcome after HCT among adult patients.

However, they might have a higher risk of

dying due, in part, to the increased frequency

of GvHD in adults (27). Compared to

younger patients with β-thalassemia major,

adult patients had an increased risk of dying

after HLA-identical bone marrow transplantation (28), but ethnic factors might have contributed to the risk. The use of nonmyeloablative preparation before HCT may lower the

risk of complications (29). The intent is to

establish stable donor-host hematopoietic

chimerism after transplantation, which might

provide a significant clinical benefit. If successful, the nonmyeloablative approach might

improve the safety profile of HCT for older

individuals who have advanced organ damage

from SCD. Several investigations have been

initiated to test this hypothesis.

SUMMARY OF THE 

STATE OF THE ART

Currently, HCT is the only therapy for 

SCD that has curative potential. The results 

of transplantation are best when performed 

in children with a sibling donor who is 
Chapter 27: Hematopoietic Cell Transplantation

170

REFERENCES

1. Parkman R. The application of bone marrow 

transplantation to the treatment of genetic diseases.

Science 1986;232:1373-8.

2. Johnson FL, Look AT, Gockerman J, et al. Bonemarrow transplantation in a patient with sickle-cell

anemia. N Engl J Med 1984;311:780-3.

3. Milpied NHJ, Garand R, David A. Bonemarrow transplantation for sickle-cell anaemia.

Lancet (letter) 1988;2:328-9.

4. Vermylen C, Fernandez Robles E, Ninane J, et al.

Bone marrow transplantation in five children with

sickle cell anaemia. Lancet 1988;1:1427-8.

5. Vermylen C, Cornu G, Philippe M, et al. Bone

marrow transplantation in sickle cell anaemia. 

Arch Dis Child 1991;66:1195-8.

6. Thomas ED. The pros and cons of bone marrow

transplantation for sickle cell anemia. Sem Hematol

1991;28:260-2.

7. Walters MC, Patience M, Leisenring W, et al. 

Bone marrow transplantation for sickle cell disease.

N Engl J Med 1996;335:369-76.

8. Vermylen C, Cornu G. Bone marrow 

transplantation for sickle cell disease. The

European experience. Am J Pediatr Hematol

Oncol 1994;16:18-21.

9. Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation for sickle cell

anaemia: the first 50 patients transplanted in

Belgium. Bone Marrow Transplant 1998;22:1-6.

10. Walters MC, Storb R, Patience M, et al. Impact 

of bone marrow transplantation for symptomatic

sickle cell disease: an interim report. Blood

2000;95:1918-24.

11. Brichard B, Vermylen C, Ninane J, et al.

Persistence of fetal hemoglobin production after

successful transplantation of cord blood stem cells

in a patient with sickle cell anemia. J Pediatr

1996;128:241-3.

12. Miniero R, Rocha V, Saracco P, et al. Cord blood

transplantation (CBT) in hemoglobinopathies.

Eurocord. Bone Marrow Transplant 1998;22(Suppl

1):S78-9.

13. Nagel RL. The dilemma of marrow transplantation

in sickle cell anemia. Sem Hematol 1991;28:233-4.

14. Davies SC. Bone marrow transplantation for sickle

cell disease. Arch Dis Child 1993;69:176-7.

HLA-identical. While there appears to be 

a considerable benefit to those who survive

with stable engraftment of donor cells, there

are also significant health risks associated with

this treatment. Thus, careful discussions with

families by health care professionals experienced in the care of patients with SCD and

with HCT should be conducted to establish

informed consent for this procedure.

HCT is reserved for those patients who have

experienced significant complications caused

by SCD, such as stroke and recurrent episodes

of acute chest syndrome or pain. In the future,

identification of clinical or genetic markers

that reliably predict an adverse outcome may

permit the application of HCT before significant clinical complications occur. Efforts are

ongoing to expand donor availability by overcoming graft-versus-host and host-versus-graft

reactions and to diminish the toxicity of 

HCT by using nonmyeloablative preparations

to establish stable donor-host hematopoietic

chimerism. If successful, these efforts could

expand the role of HCT in treating patients

with SCD.

RECOMMENDATIONS

Children with SCD who experience significant, noninfectious complications caused 

by vaso-occlusion should be considered for 

HCT, and if full siblings are available, HLA

typing should be performed. Families should

be counseled about the collection of UCB

from prospective siblings (30). For severely

affected children who have HLA-identical 

sibling donors, families should be informed

about the benefits, risks, and treatment alternatives such as HCT. There are no comparative studies that would permit clinicians to

recommend one intervention, such as chronic

red blood cell transfusions or hydroxyurea

treatment, over another.
171

15. Platt OS, Guinan EC. Bone marrow transplantation in sickle cell anemia—the dilemma of choice.

N Engl J Med 1996;335:426-8.

16. Giardini C, Galimberti M, Lucarelli G, et al. 

Bone marrow transplantation in sickle-cell 

anemia in Pesaro. Bone Marrow Transplant

1993;12(Suppl 1):122-3.

17. Bernaudin F. Resultats et indications actuelles 

de l’allogreffe de moelle dans la drepanocytose.

Path Biolog 1999;47:59-64.

18. Walters MC, Sullivan KM, Bernaudin F, et al.

Neurologic complications after allogeneic marrow

transplantation for sickle cell anemia. Blood

1995;85:879-84.

19. Ferster A, Christophe C, Dan B, et al. Neurologic

complications after bone marrow transplantation

for sickle cell anemia. Blood 1995;86:408-9.

20. Abboud MR, Jackson SM, Barredo J, et al.

Neurologic complications following bone marrow

transplantation for sickle cell disease. Bone Marrow

Transplant 1996;17:405-7.

21. Hernigou P, Bernaudin F, Reinert P, et al. Bonemarrow transplantation in sickle-cell disease. 

Effect on osteonecrosis: a case report with a fouryear follow-up. J Bone Joint Surg 1997;79:1726-30.

22. Ferster A, Bujan W, Corazza F, et al. Bone marrow

transplantation corrects the splenic reticuloendothelial dysfunction in sickle cell anemia. Blood

1993;81:1102-5.

23. Sullivan K, Walters MC, Patience M, et al.

Collaborative study of marrow transplantation for

sickle cell disease: aspects specific for transplantation of hemoglobin disorders. Bone Marrow

Transplant 1997;19(Suppl 2):102-5.

24. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid 

cancers after bone marrow transplantation. 

N Engl J Med 1997;336:897-904.

25. Rocha V, Chastang C, Souillet G, et al. Related

cord blood transplants: the Eurocord experience

from 78 transplants. Eurocord Transplant Group.

Bone Marrow Transplant 1998;21(Suppl 3):S59-62.

26. Gluckman E, Rocha V, Boyer-Chammard A, 

et al. Outcome of cord-blood transplantation 

from related and unrelated donors. Eurocord

Transplant Group and the European Blood and

Marrow Transplantation Group. N Engl J Med

1997;337:373-81.

27. Sullivan KM, Agura E, Anasetti C, et al. 

Chronic graft-versus-host disease and other late

complications of bone marrow transplantation.

Sem Hematol 1991;28:250-9.

28. Lucarelli G, Clift RA, Galimberti M, et al. 

Bone marrow transplantation in adult thalassemic

patients. Blood 1999;93:1164-7.

29. Storb R, Yu C, Sandmaier BM, et al. Mixed

hematopoietic chimerism after marrow allografts.

Transplantation in the ambulatory care setting.

Ann N York Acad Sci 1999;872:372-6.

30. Lubin BH, Eraklis M, Apicelli G. Umbilical cord

blood banking. Advan Pediatr 1999;46:383-408.
172
GENETIC MODULATION OF PHENOTYPE

BY EPISTATIC GENES

28

173

gene cluster haplotypes, chromosome 6 locus),

and 2) the copresence of α-thalassemia. These

known factors explain only a small fraction 

of the diversity of sickle cell anemia, however.

Other epistatic genes must exist, and based 

on our knowledge of the pathophysiology of

SCD, candidate genes have been suggested (3). 

FETAL HEMOGLOBIN 

MODULATION OF 

SICKLE CELL ANEMIA 

THE β-GLOBIN GENE CLUSTER

AND GLOBIN GENE SWITCHING

Hb F levels in sickle cell anemia vary over two

orders of magnitude. Initially only very high

levels of Hb F were considered capable of

influencing the phenotype of sickle cell anemia (4,5), but any increment in Hb F appears

to be clinically and perhaps therapeutically

important (6).

Hemoglobin gene switching is the process of

sequential globin gene activation and inactivation. It involves complex interactions of stagespecific transcription factors, chromosomal

gene order, gene proximity to the β-globin

locus control region (LCR), cis-acting sequences

that positively and negatively regulate transcription, and erythroid-specific and ubiquitous trans-acting factors (7). By interacting

with promoters of the β-like globin genes, 

the LCR plays a critical role in gene expression;

polymorphisms in some of their sequences 

A unique mutation is responsible for sickle

hemoglobin (Hb S), but sickle cell disease

(SCD) is clinically pleiotropic and can be 

considered a multigene disease. Polymerization

of Hb S can injure red cells and cause a cascade of pleiotropic effects that determines the

clinical picture (1,2). Some patients are always

sick, and others infrequently ill. What is the

basis of this variability? An environmental

effect on the course of SCD is dramatically

apparent in tropical Africa. Provided there is

good access to medical care, survival to adulthood and a decent quality of life is possible.

Still, SCD in Africa remains a childhood 

disease since premature death, often from

malaria, is common.

Most of the pleiotropic effects result from 

the activity of other genes—which also may 

be polymorphic—that differ among patients.

These epistatic (or modifier) genes may

account for the interindividual variation that

characterizes SCD. Another source of genetic

variation in SCD derives from the multicentric origin of the Hb S gene. Because it arose

more than once, the gene had the opportunity

to interact with different (polymorphic) linked

genes, particularly the two γ-globin genes that

ameliorate SCD through expression of fetal

hemoglobin (Hb F).

The two best understood genetic factors that

influence the clinical expression of the Hb S

mutation are 1) those linked to the synthesis

of fetal hemoglobin (Hb F) (gender, β-globin
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes

174

are considered vital elements of γ-globin gene 

regulation in sickle cell anemia. Nevertheless,

the full picture of this process is not known. 

β-GLOBIN GENE CLUSTER

HAPLOTYPES—EFFECTS ON HB F

LEVELS, HEMATOLOGY, AND

CLINICAL COURSE

Four β-globin gene cluster haplotypes are

linked with the independent emergence of four

βs genes in Africa. The three most common are

the Senegal haplotype in Atlantic West Africa,

the Benin haplotype in central West Africa,

and the Bantu haplotype in all Bantu-speaking

African societies (equatorial and southern

Africa) (8). The Arab-Indian haplotype is

found in the Middle East and India.

Although β-globin gene cluster haplotypes 

are convenient markers for genetic regulators

of γ-globin gene expression, most polymorphic

endonuclease restriction sites used to assign a

haplotype have no known role in the differential transcription and temporal regulation of

these genes. An exception is the Xmn I site

that is 5' to the Gγ-globin gene in the Senegal

and Arab-India haplotypes (9-11). This site is

strongly associated with high expression of the

Gγ-globin gene compared with the Aγ-globin

gene. In adults and neonates lacking the Hb S

gene, this polymorphism is associated with

small but significant increases in the synthesis

of Hb F and Gγ-globin chains. More recently,

twin studies have implicated it as a major 

factor in defining the level of Hb F expression

(see below).

Considerable variation also exists among

patients who have Senegal or Arab-India 

haplotypes, although they tend to have higher

Hb F levels than those who have Benin and

Bantu haplotypes. A patient’s sex, in addition

to his or her haplotype, also may modulate

Hb F production (12). 

Most of the detailed and larger studies of the

clinical and hematological effects of haplotype

in sickle cell anemia have been in regions

where the Hb S gene arrived by gene flow.

After many years of miscegenation, patients

are commonly haplotype heterozygotes, 

complicating the interpretation of potential

associations of haplotype with phenotype.

Therefore, reports of the clinical and hematological effects of haplotype in sickle cell 

anemia should be interpreted carefully. Often

too few patients are studied, the patients’ ages 

differ among series, clinical events are not

sharply defined, age-dependence of their 

phenotype is not considered, and the distinction between haplotype homozygotes and 

heterozygotes is not clearly drawn. 

In longitudinal studies from the United States,

the Senegal haplotype was associated with

fewer hospitalizations and painful episodes. 

The relationship between the Senegal haplotype and reduced frequency of acute chest 

syndrome was of marginal significance. The

Bantu haplotype was associated with the highest incidence of organ damage and was strongly associated with renal failure in a study that

used robust statistics and a large number of

patients (13-15). Most work suggests that the

Arab-India haplotype is associated with milder

disease, although vaso-occlusive events are not

rare. In India the almost fixed (approaching

100 percent) haplotype frequency of α-thalassemia adds considerably to the benign 

picture of SCD (16).
175

HB F MODULATION UNLINKED TO

THE β-GLOBIN GENE CLUSTER: GENDER

EFFECTS AND ROLE OF CHROMOSOMAL

SITES OTHER THAN CHROMOSOME 11

Hb F is restricted to a subset of red cells,

called F-cells, whose numbers are determined

genetically, although exactly how is unknown.

There are likely to be genetic determinants 

of Hb F level not linked to the β-globin gene

cluster that influence Hb F concentrations 

in sickle cell anemia. The Hb F level in sickle

cell anemia is set by the number of F-cells, the

amount of Hb F per F-cell, and the differential survival of F-cells and non-F-cells (17).

Family studies have shown that this considerable variation is inherited, but the number of

genes involved and the mode of inheritance

are largely unknown. Identical-twin studies

showed that the heritability of F-cell numbers

is very high and that gender, age, and the -158

T-to-C mutation 5' to the Gγ-globin gene

account for close to 40 percent of the variance. 

Other trans-acting autosomal loci, termed

quantitative trait loci (QTL), also appear to

influence the amounts of Hb F in F-cells (18).

Two such QTLs have been mapped by linkage

analysis, one to chromosome 6q23 (19).

Genetic studies originally localized this QTL

to a region approximately 4 Mb or 11 cM

between markers D6S408 and D6S292. More

recently, novel polymorphic markers plus

existing markers have further localized the

QTL within an interval of 0.8-1 Mb between

D6S270 and D61626 (20). Further analysis

suggests an additional QTL on chromosome 8q

(20). It is clear that further QTLs affecting the

expression of Hb F will be found in the future.

The second possible F-cell production locus

(FCP) is X-chromosome-linked and has been

localized between DXS143 and DXS16 within

the short arm of chromosome X (Xp22.3-

22.20) (21). The FCP locus may account, 

in part, for the higher Hb F levels in females

compared to males, an observation found in

both the normal population and in patients

with sickle cell anemia. More recent multipoint linkage analysis with seven polymorphic

markers has further localized the FCP within

2 to 3 cM between DXS452 and APXL, with

a maximum LOD score of 3.3.

α-THALASSEMIA 

α-thalassemia in individuals of African descent

is usually a result of the deletion of one or 

two α-globin genes. Missing even two of the

normal complement of four α-globin genes is

not clinically significant in normal individuals.

About a third of African Americans carry an

α-globin gene deletion, and this prevalence 

is even higher in some populations, so αthalassemia and sickle cell anemia frequently

coexist (22).

The hematological and clinical consequences

of interactions between these two disorders

have been studied intensively. The presence 

of α-thalassemia with sickle cell anemia is

associated with less hemolysis, higher hemoglobin concentration, lower mean corpuscular

volume (MCV), and lower reticulocyte count,

when compared to individuals with normal 

α-globin gene numbers. α-thalassemia does

not appear to modify the effect of haplotype

on Hb F levels in sickle cell anemia despite an

early report to the contrary, but it can further

ameliorate the disease. Therefore, it is unlikely

that any clinical benefit α-thalassemia confers

upon sickle cell anemia is mediated through

its effect on Hb F level.

α-thalassemia has a strong effect upon the

phenotype of sickle cell anemia by reducing

the erythrocyte Hb S concentration. Hb S

polymerization depends on hemoglobin 

concentration, so concurrent α-thalassemia

should diminish the polymerization potential
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes

176

of sickle hemoglobin in sickle cell anemia.

When these conditions coexist, there is less

hemolysis, and anemia is less severe. Clinically,

the copresence of α-thalassemia and sickle cell

anemia is a paradoxical outcome. Vaso-occlusive events appear undiminished in SCD with

α-thalassemia, and in some studies, even

appeared to be increased. Fewer dense and

poorly deformable cells as a result of α-thalassemia raise the packed cell volume (PCV),

and because the cells contain Hb S, blood 

viscosity is increased. Raising the number of

sickle cells, as occurs with α-thalassemia, might

promote vaso-occlusion since younger sickle

cells are more adherent (a critical phenomenon in painful episodes) (23). On the other

hand, a higher PCV may have beneficial

effects in some organs, so that skin ulcers 

of the leg, childhood stroke, and retinal 

vascular disease may be less common in 

carriers of α-thalassemia and sickle cell anemia. The effect of α-thalassemia on cellular,

hematological, and clinical aspects of sickle

cell anemia have been reviewed recently (22).

Some but not all studies suggest that the 

combination of α-thalassemia and sickle cell

anemia may increase survival (24). A recent

followup study of the age-dependency of 

α-globin gene frequency is compatible with

the following interpretation: as medical care

improves, the advantage of α-thalassemia on

survival disappears, a phenomenon that could

explain the contradiction in the available data. 

INTERACTIONS OF β-GLOBIN

GENE HAPLOTYPE AND 

α-THALASSEMIA

Some studies have examined how α-thalassemia

interacts with different β-globin gene haplotypes to modify the hematological and clinical

picture of sickle cell anemia (12,25,26). Most

often there is little interaction besides minor

reductions in MCV and reticulocyte count and

increases in PCV. One exception was a study

of two western Indian populations with high

Hb F levels in which the coexistence of α-thalassemia was associated with milder disease (16).

HEMOGLOBIN A2

Hb A2, the tetramer of α- and δ-globin

chains, impairs the polymerization of Hb S 

to the same extent as the γ-globin chain of 

Hb F. When Hb A2 and Hb F levels are high,

the combination of these two hemoglobins

may potentially modulate SCD and cause 

a mild phenotype.

ERYTHROCYTE G-6-PD DEFICIENCY

Glucose-6-phosphate dehydrogenase (G-6-

PD) deficiency is common in sickle cell anemia. In a study of 800 males over age 2 with

SCD, G-6-PD deficiency was not associated

with differential survival, reduced hemoglobin

levels, increased hemolysis, more pain episodes,

septic episodes, or a higher incidence of acute

anemia episodes (27,28). It now seems clear

that there is little, if any, modulation of the

phenotype of sickle cell anemia by coincident

G-6-PD deficiency, particularly in males

where the expression of this X-linked trait 

is most apparent. 

INHERITED DISORDERS 

OF THROMBOSIS 

Some have postulated that thrombosis and

hemostasis could play roles in the pathophysiology of SCD. Coincidental mutations that

favor blood coagulation or thrombosis could

influence disease phenotype (29), particularly

the occurance of SCD-related stroke.
177

Recent studies attempting to relate the presence of mutations in genes for factor V,

platelet glycoprotein IIIa, and 5,10 methylenetetrahydrofolate reductase (MTHFR) to

the pathogenesis of specific complications of

SCD have had disparate results. In one report,

a C→T mutation at position 677 of the

MTHFR gene that is associated with enzyme

thermolability and a putative hypercoagulabile

state due to hyperhomocystenemia was found

in 36 percent of 45 adults with SCD and

osteonecrosis but in only 13 percent of 62

SCD patients without osteonecrosis—a significant difference (30). However, smaller studies

reported that the same mutation was not associated with vascular complications of SCD,

including osteonecrosis and stroke (31-33).

Studies of the platelet glycoprotein IIIa gene

have not found a link between a C→T mutation at position 1565 (which is associated 

with premature coronary artery disease) and

osteonecrosis. Factor V Leiden, a common

cause of thrombosis in Caucasians, is rare in

African Americans; limited studies have not

linked this mutation to stroke in SCD.

High levels of antiphospholipid antibodies

were found in patients with SCD and individuals with sickle cell trait (33), but no relationship to disease complications was noted.

Clearly, further work is needed to resolve 

the role of genetic risk factors for thrombosis,

many of which have been examined only 

in pilot studies or reported in abstract.

The potential genetic contribution to stroke

risk in SCD can be estimated from clinical

stroke risk observed in sibling pairs with SCD.

In 210 pairs among 2,353 patients with SCD,

167 pairs had no history of stroke, 33 pairs

had a stroke in one sib, and 10 pairs had history of stroke in both sibs (34).

A case-control candidate gene association study

involving patients with SCD and ischemic

stroke suggested an association with ischemic

stroke and angiotensinogen repeat alleles 

3 and 4 (p<0.05) and plasminogen activator

inhibitor (PAI-I) 4/4 alleles (p<0.01) (35). 

GENETIC PREDICTION 

OF PHENOTYPE IN 

SICKLE CELL ANEMIA 

As with other diseases, the sickle cell diseases

are variable in their presentation due to differences in the genetic makeup and the environmental exposure of the affected individual.

Although the exact genes have yet to be identified, extensive advances in understanding the

pathophysiology of SCD suggest that genes

involved in numerous mechanisms might have

epistatic potential in SCD. These include: 

1. Genes involved in the adhesion of young

sickle cells to the vascular endothelium

(e.g., genes related to integrin and other

adhesive molecules).

2. Genes that affect the density of sickle cells,

including transporter genes such as those

involved in Ca-dependent K efflux, K:Cl

cotransport, Na/H exchange.

3. Genes involved in thrombosis, 

particularly in sickle cell stroke.

4. Genes involved in angiogenesis, 

particularly in sickle cell retinopathy.

5. Genes involved in hemopoiesis, 

particularly marrow response to anemia.

6. Genes involved in vascular reactivity, 

particularly genes involved in the effects 

of endothelin and NO.
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes

178

Eventually, researchers may develop a reliable

method of predicting severity of disease. This

would allow better grounds for decisions 

pertaining to termination of pregnancy in 

the context of prenatal diagnosis and the

establishment of risk/benefit ratios when 

contemplating bone marrow transplantation,

chemotherapeutic manipulation of Hb F 

level, and even gene therapy, all of which 

have potentially serious complications. 

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MH, Forget BG, Higgs DR, et al., eds. Disorders 

of Hemoglobin: Genetics, Pathophysiology, Clinical

Management. Cambridge, UK: Cambridge

University Press, 2001. 

2. Nagel RL. Severity, pathobiology, epistatic effects,

and genetic markers in sickle cell anemia. Semin

Hematol 1991;28:180-201. 

3. Nagel RL, Platt O. Pathophysiology of sickle cell

anemia. In: Steinberg MH, Forget BG, Higgs 

DR, et al., eds. Disorders of Hemoglobin: Genetics,

Pathophysiology, Clinical Management. Cambridge,

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4. Noguchi CT, Rodgers GP, Serjeant G, et al. Levels

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5. Powars DR, Weiss JN, Chan LS, et al. Is there 

a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood

1984;63:921-6. 

6. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality

in sickle cell disease. Life expectancy and risk factors

for early death. N Engl J Med 1994;330:1639-44. 

7. Weiss M, Blobel G. Nuclear factors that regulate

erythropoiesis. In: Steinberg MH, Forget BG,

Higgs DR, et al., eds. Disorders of Hemoglobin:

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8. Nagel RL, Steinberg MH. Genetics of the βs gene:

Origins, genetic epidemiology, and epistasis in 

sickle cell anemia. In: Steinberg MH, Forget BG,

Higgs DR, et al., eds. Disorders of Hemoglobin:

Genetics, Pathophysiology, Clinical Management.

Cambridge, UK: Cambridge University Press, 2001. 

9. Gilman JG, Huisman TH. DNA sequence 

variation associated with elevated fetal Gγ globin

production. Blood 1985;66:783-7. 

10. Nagel RL, Fabry ME, Pagnier J, et al.

Hematologically and genetically distinct forms of

sickle cell anemia in Africa. The Senegal type and

the Benin type. N Engl J Med 1984;312:880-4. 

11. Labie D, Srinivas R, Dunda O, et al. Haplotypes

in tribal Indians bearing the sickle gene: evidence

for the unicentric origin of the beta S mutation

and the unicentric origin of the tribal populations

of India. Hum Biol 1989;61:479-91. 

12. Steinberg MH, Hsu H, Nagel RL, et al. Gender

and haplotype effects upon hematological manifestations of adult sickle cell anemia. Am J Hematol

1995;48:175-81. 

13. Powars DR. Sickle cell anemia: βS-gene-cluster

haplotypes as prognostic indicators of vital organ

failure. Semin Hematol 1991;28:202-8.

14. Powars DR. βS-gene-cluster haplotypes in sickle

cell anemia. Clinical and hematologic features.

Hematol Oncol Clin N Am 1991;5:475-93.

15. Powars DR, Elliott-Mills DD, Chan L. Chronic

renal failure in sickle cell disease: risk factors, 

clinical course, and mortality. Ann Intern Med

1991;115:614-20. 

16. Mukherjee MB, Lu CY, Ducrocq R, et al. Effect 

of α-thalassemia on sickle-cell anemia linked to 

the Arab-Indian haplotype in India. Am J Hematol

1997;55:104-9. 

17. Dover GJ, Boyer SH, Charache S, et al. 

Individual variation in the production 

and survival of F cells in sickle-cell disease. 

N Engl J Med 1978;299:1428-35. 

18. Garner C, Tatu T, Reittie JE, et al. Genetic influences on F cells and other hematologic variables: A

twin heritability study. Blood 2000;95:342-6.

19. Game L, Close J, Stephens P, et al. An integrated

map of human 6q22.3-q24 including a 3-Mb highresolution BAC/PAC contig encompassing a QTL

for fetal hemoglobin. Genomics 2000;64:264-76.

20. Tang W, Smith K, Dover G. The F-cell production

locus is mapped between DXS 452 and APXL, and

interval of 2-3 cM on Xp22.2. Abstract. The 12th

Conference on Hemoglobin Switching. 2000. 

21. Dover GJ, Smith KD, Chang YC, et al. Fetal

hemoglobin levels in sickle cell disease and normal

individuals are partially controlled by an X-linked

gene located at Xp22.2. Blood 1992;80:816-24.
179

22. Steinberg MH. Compound heterozygous and other

sickle hemoglobinopathies. In: Steinberg MH,

Forget BG, Higgs DR, et al., eds. Disorders of

Hemoglobin: Genetics, Pathophysiology, Clinical

Management. Cambridge, UK: Cambridge

University Press, 2001. 

23. Adekile AD, Tuli M, Haider MZ, et al. Influence

of α-thalassemia trait on spleen function in sickle

cell anemia patients with high Hb F. Am J Hematol

1996;53:1-5. 

24. Mears JG, Lachman HM, Labie D, et al. α-thalassemia is related to prolonged survival in sickle

cell anemia. Blood 1983;62:286-90. 

25. Rieder RF, Safaya S, Gillette P, et al. Effect of βglobin gene cluster haplotype on the hematological

and clinical features of sickle cell anemia. Am J

Hematol 1991;36:184-9. 

26. Steinberg MH, Embury SH. α-thalassemia 

in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood

1986;68:985-90. 

27. Steinberg MH, West MS, Gallagher D, et al.

Effects of glucose-6-phosphate dehydrogenase 

deficiency upon sickle cell anemia. Blood

1988;71:748-52. 

28. Bouanga JC, Mouélé R, Préhu C, et al. Glucose6-phosphate dehydrogenase deficiency and

homozygous sickle cell disease in Congo. Hum

Hered 1998;48:192-7. 

29. Francis JR, Hebbel RP. Hemostasis. In: Embury

SH, Hebbel RP, Mohandas N, et al., eds. Sickle

Cell Disease: Basic Principles and Clinical Practice.

New York: Lippincott-Raven, 1994:299-310. 

30. Kutlar A, Kutlar F, Turker I, et al. The methlylene

tetrathydrofolate reductase (C677T) mutation as 

a potential risk factor for avascular necrosis (AVN)

in sickle cell disease. Hemoglobin 2001:25:213-7. 

31. Zimmerman SA, Ware RE. Inherited DNA mutations contributing to thrombotic complications in

patients with sickle cell disease. Am J Hematol

1998;59:267-72. 

32. Andrade FL, Annichino-Bizzacchi JM, Saad STO,

et al. Prothrombin mutant, factor V Leiden, and

thermolabile variant of methylenetetrahydrofolate

reductase among patients with sickle cell disease 

in Brazil. Am J Hematol 1998;59:46-50. 

33. Nsiri B, Ghazouani E, Gritli N, et al. Antiphospholipid antibodies: lupus anticoagulants, anticardiolipin and antiphospholipid isotypes in patients

with sickle cell disease. Hematol Cell Ther

1998;40:107-12. 

34. Driscoll MC, Hurlet A, Berman B, et al. Stroke

risk in sibling pairs with sickle cell disease. Am J

Hum Genet 1999;65:A201. 

35. Tang DC, Prauner R, Liu W, et al. The

angiotensinogen GT dinucleotide repeat is 

associated with stroke in children with sickle 

cell anemia. Abstract. National Sickle Cell 

Disease Center Meeting. 1999.
180
HIGHLIGHTS FROM FEDERALLY FUNDED STUDIES 29

181

risk factors responsible for the increased morbidity and early mortality of SCD (table 1).

Below are just a few of the findings from the

CSSCD studies, which have resulted in 39

papers (1-39).

LABORATORY REFERENCE VALUES

The CSSCD described reference values and

hematologic changes from birth to 5 years 

of age (2). Anemia was observed by 10 weeks 

of age in infants with SCD-SS and was associated with a rising reticulocyte count, exceeding

12 percent by 5 years of age. The fetal hemoglobin (Hb F) concentration in SCD-SS infants

declined more gradually than did that of infants

with SCD-SC. Infants with SCD-SS had evidence of abnormal splenic function after 6

months of age, and by 1 year, 28 percent of

SCD-SS infants had evidence of poor splenic

function. By the time the children had reached

3 years of age, this percentage had increased to

78 percent for SCD-SS children and 32 percent

for those with SCD-SC. Children with SCDSC were mildly affected, and displayed mild

anemia (10.5 g/dL), slightly elevated mean

reticulocyte counts (3 percent), and fetal hemoglobin levels (3 percent) during early childhood. 

PAINFUL EVENTS

One of the major accomplishments of the

CSSCD was an analysis of the epidemiology

of pain episodes (3). The natural history of

3,578 individuals ranging in age from newborns to 66 years was evaluated. The average

pain rate was 0.8 episode per person-year in

Many of the observational studies and therapeutic trials that have contributed to the

understanding of syndromes associated with

sickle cell disease (SCD) have been federally

funded. This chapter highlights some of the

research funded by the National Heart, Lung,

and Blood Institute (NHLBI) that has led to 

a clearer understanding of the clinical course

of SCD and appropriate interventions to

reduce morbidity. Specifically, it describes 

a large multi-year observational study, known

as the Cooperative Study of Sickle Cell

Disease (CSSCD), as well as several interventional clinical trials. The discussions are not

inclusive but rather highlight successful efforts

in the study and treatment of the disorder.

COOPERATIVE STUDY OF SICKLE

CELL DISEASE—EPIDEMIOLOGY

COHORT STUDY

The CSSCD, started in 1979 after years 

of planning, was a large multi-institutional

prospective study of the clinical course of

SCD (1). The recruitment goals included individuals with major phenotypes of sickle cell

disease (SCD-SS, SCD-SC, and SCD-S β+/o

thalassemia); 3,200 subjects, with an SCD-SS

sample of 2100; individuals from different

geographic areas (including rural areas); and

inclusion of individuals at all stages of life

(including newborns and pregnant women).

The CSSCD completed its third phase in

1999; it followed the newborn cohort of 694

children who were identified through screening programs. The CSSCD has identified the
Chapter 29: Highlights From Federally Funded Studies

182

sickle cell anemia (SCD-SS), 1.0 episode 

per person-year in SCD-S βo-thalassemia, 

and 0.4 episode per person-year in SCD-SC

β+-thalassemia and SCD-SS β+-thalassemia. 

The rates varied widely within each of these

four groups. Thirty-nine percent of persons

with sickle cell anemia had no episodes of

pain, and 1 percent had more than six episodes

per year. The 5.2 percent of persons with 3 

to 10 episodes per year had 32.9 percent of 

all episodes. Among persons over the age 

of 20, those with high pain rates tended to 

die earlier than did those with low pain rates.

High pain rates were associated with high

hematocrit and low Hb F levels, and α-thalassemia had no effect on pain rates apart 

from its association with an increased hematocrit. The data indicated that the Hb F level

was predictive of the pain rate, prompting

attempts to increase Hb F levels with pharmacologic agents such as hydroxyurea.

Table 1. Risk Factors for Major Organ Dysfunction or Event (Results from the CSSCD)

Condition (Reference) Associated Risk Factors*

Painful events (3) ↓ Hb F

↑ hematocrit (Hct)

Premature death (3) ↑ painful event rate

Leg ulcers (4) ↓ Hb F concentration

Splenic sequestration (12) ↓ Hb F concentration

Osteonecrosis, femoral head (13) ↑ painful episodes

↑ Hct

↓ mean cell volume (MCV)

Infarctive stroke (17) acute chest syndrome

prior transient ischemic attack (TIA)

↓ Hb concentration

↑ systolic blood pressure

Hemorrhagic stroke (17) ↓ Hb concentration

↑ white blood cell count (WBC)

Silent infarct (18) ↓ Hb concentration

↑ WBC

↓ splenic function

Senegal globin haplotype

Acute chest syndrome (19) ↓ Hb concentration

↓ Hb F concentraion

↑ steady state WBC

Sickle cardiomyopathy (21) ↓ Hb concentration

↑ age

* ↓=decreased, ↑=increased
183

MAJOR ORGAN DYSFUNCTION

Leg Ulcers 

The incidence of leg ulcers was evaluated at

study entry in 2,075 persons 10 years and

older between 1979 and 1986 (4). Leg ulcers

were most prevalent in persons with SCD-SS

and SCD-SS α-thalassemia. Prevalence rates

per 100 persons were: SCD-SS (4-5 α genes)

= 4.97; SCD-SS (2-3 α genes) = 3.9; SCD-SS

unmapped = 1.5; SCD-S βo-thalassemia = 0.9.

Individuals with SCD-SC and SCD-S β+-thalassemia did not have leg ulcers at entry. The

incidence rates of leg ulceration among males

were significantly higher than among females

(15 versus 5 per 100 person-years). Persons

who had SCD-SS experienced a sharp increase

in incidence of leg ulcers after the second

decade of life. At any given total hemoglobin

concentration, rates were lower in individuals

with fetal hemoglobin (Hb F) levels greater than

5 percent.

Osteonecrosis of the Humeral Head 

Osteonecrosis of the humeral head was determined in a study of 2,524 persons in the

CSSCD cohort (5). At entry, 5.6 percent had

radiologic evidence of osteonecrosis in one or

both shoulders. The highest age adjusted incidence rates were observed in SCD-SS persons

with concomitant α-thalassemia (4.9 per 100

person-years), followed by SCD-S βo-thalassemia (4.8 per 100 person-years), SCD-SS

without α-thalassemia (2.5 per 100 personyears), and SCD-SC (1.7 per 100 personyears). Most were asymptomatic, with 20.9

percent reporting pain or limited range of

motion at time of diagnosis. 

ALLOIMMUNIZATION RISKS

OF TRANSFUSION

In 1,814 persons with SCD who had been

transfused, the rate of alloimmunization to

erythrocyte antigens was 18.6 percent (6). 

The rate of alloimmunization increased exponentially with increasing numbers of transfusions. However, the rate of alloimmunization

in persons whose first transfusion occurred 

at less than 10 years of age was less than

expected based on the number of transfusions

administered.

DEMOGRAPHICS

An analysis of socioeconomic status of 3,538

African-American SCD persons enrolled in

the CSSCD revealed the following: there were

fewer two-parent families than in the total

United States black population (USBP) (40

percent versus 54 percent); twice as many 

persons of both sexes with SCD worked in

white-collar positions; a higher percentage of

SCD persons were unemployed and disabled

(compared to the USBP); and men with 

SCD patients had lower median incomes 

than all black males in the United States (7).

The percentage of high school graduates was

similar (71 percent SCD versus 75 percent

USBP), and female heads of household

employed full time earned about the same

salary as USBP females.

CLINICAL TRIALS IN 

SICKLE CELL DISEASE

Interventional trials grew partly from needs

and observations related to the CSSCD.

Examples of clinical trials funded by the

NHLBI are described below and are summarized in table 2.
Chapter 29: Highlights From Federally Funded Studies

184

PROPHYLACTIC PENICILLIN STUDIES

I & II (PROPS I & PROPS II)

The Prophylactic Penicillin Study (PROPS I),

one of the first multicenter clinical trials, was

initiated in 1983 to test the effectiveness of

prophylactic oral penicillin in the prevention

of severe pneumococcal infections in young

children under 3 years of age with SCD (8,9).

The multicenter randomized double-blind

placebo-controlled trial demonstrated an 84

percent reduction in the incidence of infection

in children who received oral penicillin twice

daily, compared to the placebo group. It indicated that all neonates should be screened 

for sickle hemoglobinopathies, and those 

with sickle cell anemia should be placed on

prophylactic penicillin by 4 months of age. 

Penicillin Prophylaxis in Sickle Cell Disease 

II (PROPS II) demonstrated that penicillin 

prophylaxis can be stopped safely after age 5

because no significant benefit was found in comparing the placebo and penicillin groups (40).

HYDROXYUREA PHASE II TRIAL

Based on the findings that persons with poorer

prognoses often had lower fetal hemoglobins

(table 1), a multicenter safety and dosing

study of hydroxyurea was undertaken in adults

to determine responsiveness of fetal hemoglobin levels and toxicity (41). Forty-nine persons

were enrolled, and 32 of them were still

receiving therapy at the end of the study.

Eighteen persons were treated for 24 months

or longer, and 11 completed 16 weeks of 

therapy at a maximally tolerated dose (MTD).

Hb F levels ranged from 1.9 percent to 26.3

percent, with the most significant predictors

of Hb F levels being last plasma hydroxyurea

level, initial white blood cell count, and initial

Hb F level. No serious toxicities were observed,

significant bone marrow depression was avoided, and chromosome abnormalities after 2

years of treatment were no greater than those

observed before treatment. Hemoglobin 

concentrations increased, as did body weight.

There was a suggestion of clinical benefit,

although the study was uncontrolled and

open-label and therefore was not designed 

to test therapeutic efficacy. This study was 

followed by the Multicenter Study of

Hydroxyurea in Sickle Cell Anemia (MSH

Trial), the first randomized double-blind trial

to test the efficacy of an agent in decreasing

the rate of painful events.

MULTICENTER STUDY OF

HYDROXYUREA IN SICKLE CELL

ANEMIA (MSH TRIAL) 

The randomized, double-blind, placebo controlled MSH Trial conducted at 21 clinic centers (42,43) found that hydroxyurea decreased

painful sickle cell episodes or crises, hospitalizations for painful episodes, acute chest syndrome, and total number of units of blood

transfused by approximately 50 percent. In

1998, as a result of this trial, hydroxyurea

became the first agent to be approved by the

Food and Drug Administration for the prevention of painful episodes in adults with 

sickle cell anemia.

A contract to follow the MSH patient cohort,

a phase IV study, began in February 1996.

Only persons involved in the MSH Trial 

were recruited for this study, and they are

being followed for long-term morbidity 

and mortality in association with long-term

hydroxyurea usage.

Ancillary studies in the MSH Trial have

explored factors responsible for genetic modulation of γ-globin gene expression (44) and

effects of hydroxyurea administration on body

weight and exercise performance (45). An

analysis of the cost-effectiveness of hydroxyurea

has shown that individuals with SCD who
185

received the drug had an average yearly lower

cost of health care than did those originally

randomized to receive placebo (46). Other

areas being explored by the MSH investigators include effects of hydroxyurea usage on

quality of life and the effect of hydroxyurea

on analgesia use.

PHASE I/II STUDY OF HYDROXYUREA

IN CHILDREN (PED HUG)

Children between the ages of 5 and 15 years

with sickle cell anemia were entered into a

multicenter safety and dosing study of hydroxyurea in 1994 (47). A total of 84 children

were enrolled, 68 reached MTD, and 52 were

treated at MTD for 1 year. This study demonstrated significant increases in hemoglobin

concentration, Hb F levels, and decreases 

in white blood cell, neutrophil, platelet, and

reticulocyte counts. Laboratory toxicities were

transient and were reversible with cessation of

hydroxyurea, as had been seen in adults. This

study set the stage for the design of phase III

trials of hydroxyurea in even younger children

to determine whether hydroxyurea can prevent

chronic end-organ damage.

PERIOPERATIVE TRANSFUSION STUDY

Perioperative transfusions are used frequently

to prevent morbidity in patients with sickle cell

anemia. A prospective multicenter study that

ran from 1988 to 1993 randomly assigned 692

patients to receive either exchange transfusions

to decrease their Hb S levels below 30 percent

or simple transfusions to increase their hemoglobin levels to 10 g/dL (48). The conservative

transfusion regimen was as effective as exchange

transfusion in preventing perioperative complications, and the conservative regimen was

associated with a much lower rate of transfusion-associated complications. In addition to

decreasing morbidity for patients undergoing

surgical procedures, simple transfusions 

are associated with significant cost savings.

STROKE PREVENTION TRIAL IN

SICKLE CELL ANEMIA (STOP TRIAL)

Stroke is the second leading cause of death 

in children with SCD. In the STOP trial, an

investigator-initiated multicentered trial funded by the NHLBI, children between the ages

of 2 and 16 who were at risk for first-time

stroke, as determined by having transcranial

Doppler velocity greater than 200 cm/sec,

were randomized to receive either periodic

transfusions to maintain the Hb S level below

30 percent or standard supportive care (49).

An interim analysis demonstrated that periodic transfusions were efficacious in preventing

first-time stroke in the children randomized 

to the transfusion arm. At the end of the trial,

all participants were offered periodic transfusion therapy. The main side effects of the

transfusion therapy were iron accumulation

and alloimmunization, although the rate of

occurrence was low. A new trial, known as

STOP II, is now in place to determine whether

transfusions need to be continued indefinitely

or if they can be stopped after some period of

time when risk of stroke has diminished. 

SUMMARY

The trials discussed are examples of only some

of the major clinical efforts in SCD research.

The NHLBI funds 10 Comprehensive Sickle

Cell Centers, whose mission is to perform

basic research in SCD, conduct clinical studies,

and provide community outreach and education.

It also supports a variety of other endeavors. 
Chapter 29: Highlights From Federally Funded Studies

186

Table 2. NHLBI-Sponsored Clinical Trials in Sickle Cell Disease

Trial Therapy Tested (Type of Trial) Outcome (Reference)

PROPS I Prophylactic penicillin in infants Pneumococcal sepsis prevented

(Phase III) in infants (8)

PROPS II Prophylactic penicillin in children Penicillin prophylaxis can be safely

(Phase III) stopped at age 5 (40)

Hydroxyurea Hydroxyurea in adults Hydroxyurea can be safely given to

Phase II Trial (Phase II) adults with SCD-SS (41)

MSH Trial Hydroxyurea in adults with Hydroxyurea lowered rate of painful

severe sickle cell anemia events, blood transfusions, acute 

(Phase III) chest syndrome, and hospitalizations 

by 50 percent (42,43)

PED HUG Hydroxyurea in children Hydroxyurea can be safely given 

(HUG KIDS) (Phase II) to children between the ages of 5 

and 15 (47)

Perioperative Simple blood transfusions to raise the Simple blood transfusions can be safely 

Transfusion Trial total Hb level to 10 g/dL regardless of Hb S given during the perioperative period 

concentration, compared to aggressive to raise Hb concentration to 10 g/dL (48)

blood transfusions to suppress Hb S level 

to below 30 percent at time of surgery 

in children and adults 

(Phase III)

STOP Trial Blood transfusions to prevent stroke First-time stroke can be prevented 

in children in children found to be at risk by periodic

(Phase III) blood transfusions to suppress Hb S 

concentraion to less than 30 percent (49)
187

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National Heart, Lung, and Blood Institute

NIH Publication No. 02-2117

Originally Printed 1984

Previously Revised 1989, 1995

Reprinted June 1999

Revised June 2002 (Fourth Edition)