Does Plasma Reduce Bleeding in Patients Undergoing Invasive Procedures
Phase: PHASE3
Conditions: Blood Coagulation Disorders, Hemorrhage
Sponsor: Rutgers, The State University of New Jersey

Does Plasma Reduce Bleeding in Patients Undergoing Invasive Procedures 
NCT02637427 
December 19, 2017 

1 
 
 
 
   
 
 
 
Title of Project: 
Does Plasma Reduce Bleeding in Patients Undergoing Invasive 
Procedures 
 
 
 
Principal Investigator: 
Jeffrey L Carson, MD, Rutgers University 
 
 
 
Funding Source(s): 
National Heart, Lung, and Blood Institute (NHLBI), National 
Institutes of Health (NIH) 
 
 
Co-Investigators 
Paul Ness, MD, Johns Hopkins University 
Darrell Triulzi, MD, University of Pittsburgh 
Terry Gernsheimer, University of Washington 
Monica Pagano, University of Washington   
Maria Mori Brooks, PhD, University of Pittsburgh  
Claire Philipp, MD, Rutgers University 
Lauren Hogshire, MD, Rutgers University 
 
Arthur Bracey, MD, Baylor College of Medicine 
 
1. Purpose/Specific Aims 
 
Patients with prolonged clotting times (INR ≥1.5), who are to undergo invasive procedures (e.g., 
central venous catheter placement, endoscopy, bronchoscopy, cystoscopy, angiography), may be 
at increased risk of bleeding for which physicians commonly order pre-procedure plasma 
transfusion.  However the efficacy of prophylactic plasma transfusion has not been established.  
This pilot study will determine the feasibility and optimal study design of a large randomized 
NIH-Defined Phase III Clinical Trial that will provide critical clinic evidence to guide 
transfusion practice.  
 
 1.1 Objectives  
  
Objective 1: To evaluate the feasibility of a research protocol that will lead to a large-scale 
clinical trial designed to evaluate the effectiveness of plasma in patients with prolonged INR 
undergoing an invasive procedure.   
   
 To determine the eligibility and enrollment rate into the study protocol  
 To assess the patient characteristics of patients enrolled in this trial.  
 To determine adherence rates for the plasma transfusion protocol and test methods to 
minimize protocol violations.  
 To establish frequencies of bleeding, transfusion associated cardiac overload (TACO), 
and transfusion related acute lung injury (TRALI) in patients enrolled in this pilot study 
to calculate sample size for large definitive trial. 
 

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Objective 2: To compare the risk of major bleeding and complications in patients with an 
INR of 1.5 to 2.5 undergoing an invasive procedure who are randomly allocated to receive 
plasma versus no treatment.  
 
 To compare the risk of major bleeding defined as drop in hemoglobin level 2 g/dL or 
greater, mean hemoglobin concentration, and use of red blood cell transfusion in patients 
randomly assigned to plasma compared to no treatment.   
 To determine if use of plasma is associated with higher rate TACO, TRALI, infection, 
transfer to ICU and ICU days, mortality, or length of hospital stay compared to no 
treatment. 
 
  
1.2 Hypotheses  
 
The primary study hypothesis is that prophylactic plasma transfusion in patients with INRs 
between 1.5 and 2.5 will reduce post procedure major bleeding (drop in hemoglobin of 2 
g/dL or greater) compared to patients who do not receive plasma.   
 
 
2. Background and Significance 
 
Plasma from whole blood is a frequently administered blood product,1,2 and its usage in the U.S. 
approaches 4 million units transfused annually.3  Recent data demonstrate that relative to red 
blood cell transfusion, the number of plasma units transfused in the United States is higher than 
in other countries with advanced medical care.1,2 Plasma may be used to manage active bleeding 
(e.g. trauma) or prophylactically to reduce risk of bleeding. The transfusion of plasma prior to an 
invasive procedure in order to correct a perceived bleeding risk is common, and in a recent 
survey of plasma transfusion approximately 30% of requests for plasma were for patients 
scheduled to undergo an invasive procedure.4 However, there is no definitive clinical trial 
evidence to substantiate this practice. 
  
Fresh frozen plasma (FFP) contains all of the coagulation factors and proteins present in whole 
blood but slightly diluted by the anticoagulant solution used to collect the blood. Technically, 
fresh frozen plasma is plasma placed in an -18o to -30o C freezer within 8 hours of phlebotomy. 
Each unit is derived from single donor and is about 250cc. Frozen Plasma (PF24) is plasma that 
is frozen within 24 hours of phlebotomy and is often used interchangeably with fresh frozen 
plasma.  Frozen plasma 24 has the same levels of clotting factors as fresh frozen plasma except 
for factor VIII levels, which are 65% to 80% of normal levels. Thawed Plasma is made by 
thawing fresh frozen plasma or frozen plasma 24 and then storing it up to 5 days at 1-6 o C. All 
factors remain stable at refrigerator temperatures except factor V that declines to approximately 
80% of normal and factor VIII to 50% normal. Thawed plasma is used interchangeably with 
fresh frozen plasma or frozen plasma 24.  This protocol uses “plasma” to refer to fresh frozen 
plasma, frozen plasma 24 or thawed plasma. 
   
In general, hemostasis is considered adequate if the factor concentrations are 25% to 30% of 
normal.5  Since plasma volumes are 40 cc/Kg, a dose of 10-15cc/kg is required (assuming 
coagulation factor level equal to 0). Thus, three to five units are required in the average patient.  

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In general, each unit of plasma is infused over 30-60 minutes (3-6cc/kg/hour) in patients with 
reasonable cardiac function and up to a maximum of 4 hours per unit in patients with reduced 
left ventricular function (1 cc/kg/hour). 
 
Clinicians usually assess blood coagulation (and hence the need for plasma) by the results for in 
vitro tests of prothrombin time (PT), activated partial thromboplastin time (PTT), and platelet 
count.  The prothrombin time evaluates the extrinsic pathway and may be prolonged with 
Vitamin K deficiency due to use of warfarin, poor nutrition, antibiotics, liver disease, or many 
other less common disorders. The prothrombin time is also reported as INR (International Ratio), 
which adjusts for different sensitivities of reagents used for the test.  A normal INR is 1.0 and 
INR from 2.0-3.0 is in the therapeutic range for patients treated with the anticoagulant warfarin 
(Coumadin). Patients with INR from 1.5-2.5 may be at increased risk of bleeding especially after 
an invasive procedure.  The PTT is used to evaluate the intrinsic system and to monitor treatment 
with unfractionated heparin. The PTT is prolonged in patients with factor deficiencies of the 
intrinsic system. 
 
 When deciding to use plasma prophylactically or prior to an invasive procedure, the clinician 
makes several assumptions. The first assumption is that elevated laboratory measures of 
coagulation such as prothrombin time and INR confer an increased risk of bleeding. However, 
prothrombin time and INR were never validated for use in this setting. Highlighting this point, a 
recent systematic review assessed whether abnormalities in pre-procedure coagulation tests 
correlated with an increased risk of bleeding.6 Analysis of 24 observational studies and 1 RCT 
included nearly 2000 procedures performed on patients with abnormal coagulation studies and 
concluded that there is not sufficient data to support PT and INR as predictors of bleeding risk. 
 
A second assumption that the clinician makes when deciding to transfuse plasma is that 
administration of plasma will improve the INR value and thereby reduce the procedure’s risk of 
bleeding complications. In fact, there is surprisingly little evidence to support the ability of 
plasma to correct an abnormal INR.7,8 Given that the INR of plasma can be as high as 1.3, 
transfusion will have little effect on a minimally elevated INR. This point is emphasized by a 
prospective study evaluating the effectiveness of transfusing plasma to correct an increased INR 
in patients with a mildly prolonged PT (13.1 to 17 seconds).9 Of 121 patients studied, <1% 
normalized their INR and only 15% demonstrated improvement at least halfway to normal. It is 
important to emphasize that pre-procedural doses of plasma are often inadequate to consistently 
correct coagulation factor deficiencies. Highlighting this point, a recent study of plasma use in 
the critical care setting observed that prophylactic transfusions were often given at 10 mL/kg or 
under, while evidence suggests that correction of low coagulation factor levels may require 
plasma doses as high as 30 mL/kg (approximately 8 units).10,11 Data from analysis of plasma use 
in 10 hospitals also shows that plasma is usually under dosed (see below).12 
 
Given the paucity of high quality evidence to guide prophylactic transfusion of plasma, in 2010 
the AABB published practice guidelines to assist practitioners.2,13 Importantly, no studies of 
nonsurgical invasive procedures met review inclusion criteria. Acknowledging this lack of data 
regarding peri-procedural management of patients with abnormal coagulation parameters, the 
Society of Interventional Radiology recently published consensus guidelines.14 These guidelines 
recommend that in the absence of warfarin treatment or liver disease, pre-procedure INR testing 
be conducted only prior to procedures with moderate to high bleeding risk. In patients scheduled 

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to undergo moderate or high bleeding risk procedures, these guidelines recommend that the INR 
be corrected to <1.5, although this recommendation was derived by Delphi consensus of expert 
practitioners not high quality evidence from randomized clinical trials.14 
 
We know of three clinical trials that evaluated the use the plasma prior to an invasive procedure 
outside the operating room.6,15,16 The only published trial found no difference in bleeding in 72 
patients with either prolonged protime or thrombocytopenia undergoing percutaneous 
dilatational tracheotomy.17 The other two trials did not successfully recruit  (ICU patients (N=81 
of 400)18 and hepatic procedures (N=3 of 1172).  This experience highlights the need to expand 
eligibility criteria and for a pilot study to demonstrate feasibility.   
 
Clinicians must also consider the adverse effects of plasma.  The risks of transfusion virus 
transmission are similar to a red blood cell transfusion, which has decreased greatly throughout 
the past two decades.19,20 Currently, the transmission of infectious diseases by blood is rare.  
However, non-infectious risks are more common.  Transfusion associated circulatory overload 
(TACO) is of greatest concern, and may be under-recognized.  A prospective surveillance study 
of the risk of TACO in patients receiving plasma found a 5% incidence.21 A similar risk has been 
reported with red blood cell transfusion, also estimated to be from 1% to 6%.22-24 The per unit 
risk of transfusion related acute lung injury (TRALI) associated with plasma is declining and is 
estimated to be on the order of 1:12,000.25  Recalling that pre-procedural plasma is typically 
under-dosed, it stands that larger volumes of plasma would confer increased risk to patients 
receiving plasma in order to correct a perceived coagulopathy prior to a procedure. Thus it is 
critical to define whether the current practice to provide plasma when correctly dosed is doing 
more harm than good or whether this risk can be easily managed with a prophylactic dose of 
diuretic. 
  
Despite the absence of data, there are several reasons why clinicians frequently use plasma prior 
to invasive procedures.  First, a markedly prolonged coagulation tests clearly increase the risk of 
bleeding so that it is reasonable to anticipate that modest INR (1.5-2.5) may also increase risk of 
bleeding. Second, it is possible that plasma may benefit a subset of patients with modest 
prolongations of PT/INR such as those with thrombocytopenia or platelet dysfunction. Third, 
there is a common concern of medicolegal consequences of performing a procedure in the face 
of an “abnormal” coagulation test result. Fourth, there are no high quality trials that prove that it 
is beneficial and/or safe not to give plasma.  Supporting the rationale to give plasma is findings 
from plasma epidemiology study that shows about 20% of patients have a drop in hemoglobin 
greater than 2 g/dL after procedure.26 Thus, despite the ongoing campaign to reduce plasma use 
and the generation of many sets of clinical guidelines suggesting its lack of efficacy without 
clinical trial evidence, it may be that the problem is not that plasma is not indicated but rather the 
dose of plasma is too low and ineffective 9,12  
 
Conclusions: 
Plasma is widely used before invasive procedures in patients with moderately prolonged INR 
with the expectation that bleeding will be prevented or reduced. Yet there are no randomized 
clinical trials that demonstrate plasma is efficacious… using the proper dose….or prove that is 
safe not to administer plasma.  Furthermore, there are no trials that describe how common or 
clinically important are the side effects of plasma. Thus, a large pragmatic clinical trial is needed 
to definitively establish or refute the efficacy and safety of properly dosed plasma.  Only a high 

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quality clinical trial will provide the essential evidence to demonstrate to clinicians that the risks 
of plasma outweigh the minimal if any hemostatic benefits in patients with moderately prolonged 
INR undergoing an invasive procedure OR show that clinically significant bleeding can be 
reduced with appropriately dosed plasma and that infrequent side effects like TACO than can be 
easily managed with a dose of a diuretic. Because of the challenges in the past of enrolling 
patients into similar trials it is essential that a pilot trial be performed which provides the 
necessary and sufficient experience needed to plan and successfully complete a large multicenter 
trial that provides the essential evidence to guide the transfusion of plasma.  
   
3. Research Design and Methods 
 
We will perform a randomized clinical trial using simplified inclusion criteria along with 
minimal exclusions to ensure implementation of a pragmatic study whose results will be widely 
generalizable.   
 
Eligible study subjects will be randomly allocated to either receive either plasma transfusion 
prior to the invasive procedure, or to no treatment. Treatment arm will be assigned according to a 
1:1 ratio to plasma or no treatment using a permuted block design with variable block sizes of 4 
and 6 and stratified by clinical site and liver disease via a predetermined randomization table.  
The treatment allocation is provided in real time, using the web based study application. 
Treatment assignment is not masked.   
 
Outside of pre-procedure plasma transfusion, all medical care is per treating physician. Each of 
the transfusion strategies is consistent with medically established guidelines for the study 
population, patients with moderately elevated INRs. Study subjects will be followed (via medical 
record review) through the hospitalization. 
 
At time of randomization, a baseline (within 24 hours prior to randomization and plasma 
transfusion) hemoglobin level and INR will be obtained.  Those allocated to plasma will be 
transfused a target dose of 15 cc per kilogram to a maximum dose of 5 units.  Hemoglobin levels 
and INRs will be collected following the procedure and on the following 2 days (if still in the 
hospital). In the rare instances that these laboratory tests have not been ordered for clinical 
reasons, they will be ordered as research tests.  
 
Detailed information related to bleeding and plasma complications within the 2 days following 
the procedure will be abstracted from the medical chart (transfusion of all blood products 
including red blood cells, plasma, platelets and cryoprecipitate), as will hemoglobin levels and 
all red cell or fresh frozen plasma transfusions within 7 days after randomization. Post procedure 
medical events will be recorded. 
 
If, within the 2 post procedure days,  the subject experiences any new cardiopulmonary 
symptoms, relevant sections of the medical record, including progress notes, relevant consults, 
the official interpretation of chest x-rays or CT scans, laboratory studies (BNP, troponin, and 
electrocardiograms), and treatments including diuretics, will be copied.  These records will be 
redacted of all personal health identifiers (PHI) and sent to the Outcome Classifications 
Committee. The Outcome Classifications Committee, comprised of two of the study co-
investigators masked to treatment allocation, will adjudicate occurrence of TACO and TRALI, 

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medically important outcomes which are susceptible to misclassification and bias in this 
unblinded clinical setting. 
 
 
3.1. Duration of Study 
 
The enrollment phase of the study will be 28 months, and each subject entered into the trial 
will be followed through the hospitalization, for up to 30 days. A total of 110 subjects will be 
enrolled.  It will take 3 years to complete the study. 
 
 
3.2 Study Sites 
 
There are 4 clinical sites in the pilot study:  Robert Wood Johnson University Hospital (PI:  
Jeffrey Carson, Co-investigators Lauren Hogshire and Claire Phillip), Johns Hopkins 
University Hospital (PI:  Paul Ness), University of Pittsburgh Medical Center- Presbyterian 
Hospital (PI: Darrell Triulzi) , University of Washington Medical Center (PI: Terry 
Gernsheimer, Monica Pagano), and Baylor St Luke’s Medical Center (PI: Arthur Bracey).  
Each clinical site will have a team composed of PI and clinical site coordinator. 
 
The University of Pittsburgh under the direction of Maria Brooks will generate the 
randomization table used to allocate treatment assignment. 
 
 
3.3 Sample Size Justification  
 
Pilot:  For the enrollment, adherence and event rates needed for planning and feasibility 
analyses, we determined that the width of a 90% confidence interval should be 0.10 or less for 
true proportions equal to 0.10 (or equivalently 0.90) and 0.15 or less for proportions equal to 
0.30 (or equivalently 0.70).  With 110 persons enrolled in the pilot trial, the 90% confidence 
intervals for estimated proportions equal to 0.10, 0.20 and 0.30 will have widths 0.10, 0.13, 
and 0.15, respectively, based on data from the combined sample, and widths 0.15, 0.19, and 
0.22, respectively, based on data from one treatment arm (i.e. n=55).  The 90% confidence 
intervals for estimated means for continuous measures will have precision +/- 0.16*SD for the 
combined sample and +/- 0.22*SD for each treatment arm.  A pilot trial with a total sample 
size of N=110 will have 90% power to detect a difference of 0.62 SD between the mean 
hemoglobin change between the two assigned treatment groups.  For example, estimating that 
hemoglobin change has a SD of approximately 1.0 g/dL, this pilot trial would have 90% power 
to detect difference of 0.62 g/dL in the change of hemoglobin level from baseline to the nadir 
between the two assigned treatment groups.  
 
3.4 Subject Selection  
 
3.4.1 Inclusion Criteria 
 

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A patient is eligible for enrollment when the following criteria are met: 1) 21 years of 
age or older, 2) an INR between 1.5 and 2.5, 3) undergoing an invasive procedure at the 
bedside, endoscopy laboratory, or in radiology. 
 
These criteria will enroll a broad, generalizable group of study subjects with moderately 
prolonged INRs in whom many clinicians transfuse plasma prior to an invasive 
procedure with the expectation that this will lower the risk of bleeding.  The lower 
range of INR (1.5) closely approximates that recommended by Society of Interventional 
Radiology and the upper range (2.5) is below that for which plasma is clearly required.   
Recent data  confirm that a large proportion of plasma is given to patients with INRs in 
this range and thus reflects current practice.26 
 
3.4.2 Exclusion Criteria 
 
Patients will be excluded if any of the following criteria are met: 1) undergoing a 
surgical procedure in the operating room; 2) active bleeding; 3) undergoing a procedure 
involving or proximal to the central nervous system or spinal cord; 4) cardiac 
catheterization, 5) using 4 factor plasma concentrates 6) using direct factor X inhibitors 
and other anticoagulants for which plasma will not correct prolonged INR; 7) platelet 
count less than 40,000/ul, 8) congenital coagulation disorders; 9) acquired disorders 
(i.e., lupus anticoagulant) for which plasma will not correct the disorder; 10) women 
who are pregnant; 11) Patients on intravenous heparin that is not discontinued > 4 hours 
prior to the procedure and; 12)Patients unwillingness to consider blood transfusion. 
. 
 
Patients undergoing surgical procedures in the operating room are excluded because 
blood loss will occur in all these patients regardless of their coagulation status and 
change in hemoglobin level will not be as useful an outcome compared to patients 
undergoing more minor procedures that would not ordinarily lead to significant 
bleeding. Patients undergoing procedures proximal or involving the central nervous 
system are excluded because even minimal blood loss could be dangerous. Patients 
using anticoagulants, for which plasma does not correct INR, as well as those receiving 
4 factor plasma concentrates, are excluded. Patients undergoing cardiac catheterization 
are excluded since they received multiple anticoagulants and platelet inhibitors as part 
of the procedure and patients with platelet counts less than 40,000/ul are excluded since 
these patients may be at greater risk of bleeding.  
 
Patients receiving platelet transfusions prior to the procedure are not excluded.  
However, since a platelet transfusion includes about 300 ccs of plasma, the INR level 
confirming eligibility must be performed after the platelet transfusion. 
 
 
3.4.3 Heparin Treated Patients 
 
In patients on intravenous heparin, it is not possible to stop heparin, check an INR, 
consent, and administer plasma prior to procedure.  Given the minimal effect of heparin 
on INR, patients will be eligible for the trial if the INR is between 1.5 and 2.5 while 

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receiving heparin.  In patients on intravenous heparin, the medication must be stopped > 
4 hours prior to the procedure and plasma will not be started until 4 hours after 
discontinuation of heparin.  An INR will be checked 4 hours after stopping heparin but 
plasma may be administrated without waiting for the results of the INR off heparin. 
Heparin may be restarted after the procedure at the discretion of the clinical team. 
 
4. Study Variables 
 
 
4.1 Independent Variables or Interventions  
 
4.1.1  Interventions  
 
Plasma:  Patients randomized to plasma will receive the standard target dose of 15cc per 
Kg (acceptable range 10-20 cc/Kg) to maximum of five units up to four hours prior to the 
procedure (and 6 hours in patients with documented or clinically suspected reduced 
ejection fraction). We will limit the maximum dose of plasma to five units since this 
emulates what clinicians often do and the concerns about fluid overload from the 
administration of larger doses of plasma. The attending physician will determine the rate 
of administration of the plasma. 
 
No Treatment:  We will compare to the alternative, which is no treatment prior to 
procedure 
 
There are several procedures in place to ensure adherence to the assigned treatment arm.  
Following randomization, the subject’s chart will be labeled in the progress note to 
indicate the assigned transfusion strategy.  The Clinical Site Coordinator will contact 
the attending, house staff, fellow, and nurse to inform them of the patient’s assignment 
and review the protocol. The blood bank will be notified of the subject’s treatment 
assignment and asked to notify study personnel if plasma is ordered for a patient 
assigned to the no-treatment arm. If administration of plasma is a violation of the 
protocol, study staff will contact the ordering physician to discuss transfusion plans and 
to clarify the study protocol.  However, study staff does not approve or disapprove the 
transfusion and will not delay emergent transfusion; the treating physician controls care. 
 
4.2 Dependent Variables or Outcome Measures 
 
Outcomes Assessing Trial Performance and Feasibility: 
   
The primary feasibility outcome will be enrollment rate, overall and by center.  
Secondary outcomes will include a) Eligibility rates overall and by center; b) Adherence 
rates for the plasma protocol, overall and by center; c) Frequencies of proposed study 
outcomes.  With the proposed sample size, this pilot study will only provide an 
approximation of rates. d) Patient characteristics of patients enrolled in this trial 
including the procedures the patients underwent and the location of the procedure (i.e., 
ICU, radiology) 
 
Secondary Outcomes Assessing Treatment Effectiveness and Safety: 

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During the 2 days following randomization, we will compare: 1) Major Bleeding. 2) 
Mean Change in Hemoglobin Level:  This continuous variable will be much more 
sensitive measure of bleeding and will be the primary clinical outcome in the pilot 
study.  3) Red blood cell transfusion:  We will compare the percentage of patients and 
number of red blood cell units transfused between the two arms. 4) Transfusion 
Associated Cardiac Overload (TACO) i.e., congestive heart failure.  5) Transfusion 
Related Acute Lung Injury (TRALI). 6) Change in INR.   We will determine the change 
in INR from baseline to measurement after procedure, day 1, and day 2.  We also will 
determine the frequency in which the post transfusion INR is less than 1.5.  7) Other 
outcomes:  sites and characteristics of major bleeding, all cause in-hospital mortality, 
length of hospital stay from time of randomization to discharge, pneumonia or blood 
stream infection, transfer to intensive care unit, and number of days in intensive care 
unit. 
 
We will also compare plasma and red cell transfusions received between the treatment 
arms during the 7 days following the procedure.  
 
The following criteria will be used to define the secondary outcomes: 
 
Major Bleeding: Major bleeding will be defined as decline of 2 g/dL or more in 
hemoglobin level from the baseline to nadir hemoglobin level within 2 days of the 
procedure.  In patients receiving red blood cell transfusions, the change in hemoglobin 
level (baseline level minus the nadir) will be increased 1 g/dL for each unit transfused. 
 
 Mean Change in Hemoglobin Level:  Mean change in hemoglobin level within 2 days 
will be defined as the difference between the hemoglobin level before and the nadir 
hemoglobin within 2 days of the procedure.  In patients receiving red blood cell 
transfusions, the change in hemoglobin level will be increased 1 g/dL for each unit 
transfused.   
 
Transfusion Associated Cardiac Overload (TACO):  TACO is equivalent to congestive 
heart failure in patients receiving transfusion.  Congestive heart failure will be 
diagnosed by the Outcomes Classification Committee. The essential components are:  
1) Clinical symptoms of heart failure (New or worsening symptoms such as dyspnea, 
orthopnea and two or more signs including edema, pulmonary crackles, tachypnea, S3 
gallop, radiographic evidence of worsening heart failure) 2) Need for 
additional/increased therapy (Initiation of or a significant augmentation in oral therapy 
for the treatment of congestive heart failure or initiation of intravenous diuretic, 
inotrope, or vasodilator therapy and 3) No other non-cardiac etiology for signs or 
symptoms is identified.  
 
Transfusion Related Acute Lung Injury (TRALI):  TRALI will be diagnosed by the 
Outcomes Classification Committee using the Canadian Consensus Conference 
definition.27  The criteria include 1) acute onset, 2) hypoxemia defined as PaO2/FIO2 < 
300 or SpO2 < 90% on room air, 3) bilateral infiltrates on chest radiograph, 3) no 
evidence for circulatory overload, 4) no preexisting acute lung injury before transfusion, 

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5) occurs within 6 hours of transfusion, and 6) no temporal relationship to alternative 
risk factor for acute lung injury.   
 
Pneumonia and Blood Stream Infection: The CDC criteria will be used for clinically 
defined pneumonia based on two or more serial x-rays and blood stream infection. 28,29  
 
Length of stay, Intensive Care Unit days:  The number of days post randomization that 
patient is in the hospital, along with the number of days post randomization the patient 
is in ICU, if applicable, will be collected. 
 
4.3 Chart Review Selection 
 
Local study staff will abstract data for each potential study subject from the medical 
record to assess eligibility and patient demographics. The subject will be identified with 
a unique sequential study identification number. If the subject has any of the exclusion 
criteria, or the treating physician does not agree to enroll subject, or consent is not 
obtained, no further data will be collected. If a consented subject does not undergo a 
procedure (i.e., consent is obtained in anticipation of a procedure which does not occur 
or a procedure is canceled) no data other than the INR level will be collected.  
 
For each consented patient who undergoes a procedure, abstracted data will include: 
baseline medical status and comorbidities; pre-procedure INR, hemoglobin levels and 
plasma transfusions; specific procedure performed and setting; post procedure INR, 
hemoglobin levels, plasma, and red blood cell transfusions; and the clinical data to 
determine the study outcomes listed above.  Other than dates, PHI will not be collected. 
 
 
 
4.4 Risks of Harm  
 
Transmission of infectious diseases (e.g., hepatitis B, hepatitis C, HIV) via plasma 
transfusion is less than 1 in 10,000.  The estimated risk of transfusion associated 
circulatory overload (TACO) is 5% and transfusion related acute lung injury (TRALI) is 
estimated to be on the order of 1:12,000.  
 
The two transfusion strategies are within medically established guidelines for the study 
population.  No compelling evidence shows one approach to be better than the other, 
i.e., a state of equipoise exists.  Physicians commonly believe that patients with 
moderately elevated INR levels are at increased risk for bleeding following an invasive 
procedure, and that plasma transfusion will mitigate that risk.  However there is no 
medical evidence to support this use of plasma.  Furthermore there are risks associated 
the plasma transfusion including TACO and TRALI which could outweigh any 
potential benefit.  Thus, clinical risks to study subjects above those of usual practice are 
not a consideration.  An independent Data and Safety Monitoring Board (DSMB) will 
monitor the study to assure patient safety. 
 
There are no other alternative treatments. 

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4.5 Potential for Benefit 
 
There are no direct benefits to the study participants.  This pilot study will be the first 
step in attaining the essential clinical trial data to understand the true risk of bleeding, and 
the impact of plasma on that risk, for patients with a moderate elevation in INR who 
undergo invasive procedures. 
 
 
5.  Subject Recruitment and Enrollment Considerations 
 
5.1 Subject Recruitment 
 
Potential study subjects are likely to be identified in the intensive care units where 
bedside procedures are performed or via a scheduled procedure by interventional 
radiologists or gastroenterologists and by blood banks.  Study personnel will present the 
trial to the medical staff prior to the initiation of patient recruitment.  Only patients 
whose treating physician has agreed to cooperate with the study protocol will be 
considered for participation.  Study staff will screen the medical records of patients 
identified in these settings (details below) to determine those who have an INR 
measurement in the study range and who are eligible for the study.   
 
1) Intensive Care Unit: Many bedside procedures are performed in the intensive care 
unit and plasma is often administered if the INR is prolonged.  We will identify 
collaborators in all the major ICUs in the hospital and seek help in identifying patients 
eligible for the trial.  We will request that someone from the ICU team contact the 
research nurse with potential subjects.  In addition, the research nurse will visit each 
ICU daily to identify potential patients for the trial. In the ICU setting, consent will be 
sought for all potential subjects likely to undergo a bedside procedure (as compared to 
scheduled for the procedure), as the majority of these patients may require that the 
procedure be performed (e.g., insertion of a swan ganz catheter) urgently.  
2) Interventional Radiology and Endoscopy Laboratory:  A prothrombin time/INR 
along with PTT, and platelet count are required prior to performing most procedures. 
We will review daily the patients scheduled for a procedure.  In any inpatient with an 
INR between 1.5 and 2.5, we will contact the patient’s attending physician and request 
permission to consent the patient.  We will also confirm that the interventional 
radiologist or gastroenterologist/pulmonologist is willing to follow the transfusion 
protocol and perform the procedure if the patient is enrolled in the trial.  
3) Blood Bank:  The research nurse will telephone the blood bank twice daily to determine 
if plasma has been ordered for a patient and the medical record will be reviewed to 
determine eligibility for the trial. 
 
 
5.2 Consent Procedures 
 

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The clinical site coordinator will identify him/herself to the patient as a member of the 
research team and request permission to tell the patient about the study.  The 
coordinator will describe the purpose of the study and the two transfusion strategies 
(plasma transfusion or no transfusion) and the collection of medical information.  If the 
patient agrees to participate in the trial, the signed IRB approved consent form will be 
placed in the medical record and the coordinator will keep make a copy to keep with the 
subject’s study file.  
 
To minimize placing undue pressure on the patient to agree to participate, the person 
obtaining consent will not be directly involved in the patient’s medical care.  It will be 
emphasized that consent is voluntary, that the medical care the patient receives will not 
be influenced by his or her decision, and that, should the patient agree to participate, he 
or she is free to withdraw from the study at any time.  After the study has been introduced, 
the coordinator will leave a copy of the unsigned consent with the patient for 
consideration.  The coordinator will arrange to return at a time convenient for the patient 
to determine his or her participatory status.  If the patient agrees, he or she will sign the 
consent at that time. 
 
 
5.3 Subject Costs and Compensation 
 
The trial is being performed under usual care conditions and there are no costs to the 
subjects for study participation. In the (rare) instance a protocol required hemoglobin or 
INR has not been ordered by the treating physician, the cost of the test will be covered 
by the trial. 
 
There is no compensation to study subjects. 
 
 
 
6.   Data Handling  
 
Study data will be collected and managed using REDCap electronic data capture tools30 
hosted at Rutgers Robert Wood Johnson Medical School. REDCap (Research Electronic 
Data Capture) is a secure, web-based application designed to support data capture for 
research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) automated export procedures for 
seamless data downloads to common statistical packages; and 4) procedures for importing 
data from external sources. 
 
 
Each study subject will be assigned a unique sequential study identification number. Local 
site staff will enter the de-identified study data directly onto the web application via a secure 
web connection with authentication, using the study number to identify the individual 
subject.  Other than dates, the study does not collect PHI.   The REDCap entry module is 
programmed to have real-time data validation and integrity checks.  Access to the electronic 
data is permitted on a need to know basis through user rights assigned by the coordinating 

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center at Rutgers Robert Wood Johnson Medical School.   Staff at the coordinating center 
will download the data from the web application into SAS software and perform all data 
analyses.   
 
The study-wide de-identified database will not be destroyed. 
 
All medical records that are copied as source documentation for adjudication of TACO and 
TRALI will be labeled with the study identification number and striped of identifiers. 
 
Only the staff at the local site will have the link to PHI for the subjects that are enrolled at 
that site. 
 
 
7. Statistical Analysis 
 
Eligibility and Enrollment: The feasibility of enrollment will be evaluated by determining 
1) the number of patients that undergo invasive procedures with an INR between 1.5 and 2.5; 
2) the number of patients that meet the eligibility criteria for the trial 3) the proportion of 
eligible patients that are willing to be randomized and the proportion of eligible patients who 
are enrolled in the trial.  These proportions will be estimated directly as the observed ratio of 
numbers of patients, and 90% confidence intervals will be calculated to understand the likely 
range of values for a larger study with a comparable research protocol.  For each center, the 
reasons why patients are not enrolled including frequencies of individual exclusions and the 
proportion of patients declining participation will be described.    
 
Adherence: Adherence rates for the plasma protocol will be ascertained as the proportion 
of enrolled patients who adhere to the intervention as assigned and the proportion of patients 
who complete the follow-up evaluations for each assigned group, overall and by center.  
Estimated proportions and 90% confidence intervals will be created.   
 
Estimates for Trial Outcomes:  We will estimate the mean change in hemoglobin between 
baseline and the 2 day nadir, the proportion of patients who have a drop in hemoglobin level 
of 2 g/dL or greater defined as major bleeding, as well as the mean change in INR from 
baseline to after the index procedure, baseline to day 1, and baseline to day 2, and the 
proportion of patients in whom the post transfusion INR is less than 1.5 from the observed 
pilot data.  We will also estimate the proportion of patients who during the 2 days following 
randomization experience transfusion associated cardiac overload (TACO), and, as well 
mortality, and the mean length of hospital stay and ICU stay. TRALI is likely to be too rare 
to estimate rates. Estimated proportions and means and 90% confidence intervals will be 
created for each outcome using the data from the entire pilot trial (i.e. combining the data 
from the two assigned treatment arms).  The change in hemoglobin level will be compared 
according to assigned plasma strategy using a Wilcoxon rank sum test with an alpha level of 
0.05.  Absolute and relative differences for continuous levels and event rates by assigned 
treatment will be estimated and 90% confidence intervals will be calculated to identify 
potential treatment differences for safety and for study planning purposes. We will use alpha 
of 0.01 for secondary outcomes to account for multiple comparisons. We will examine the 

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following subgroups:  liver disease, ICU patients, INR 1.5 to 1.75 vs 1.76 to 1.99, 2.0 to 2.5 
and procedure with biopsy vs no biopsy.  
  
Characteristics of Enrolled Sample of Patients: Descriptive statistics, including means, 
standard deviations, medians, ranges, and frequency distributions, will be examined for all 
relevant measures.  Transformations of measures will be considered based on distribution 
diagnostics and outlier analyses.  The baseline characteristics of the patients in the entire trial 
will be described.  Moreover, the characteristics of patients in the two arms of the trial will 
be compared using chi-square statistics for categorical variables and t-tests or Wilcoxon 
rank-sum statistics for continuous variables in order to identify major imbalances that may be 
relevant to the pilot outcome comparisons by assigned treatment.  We will compare INR 
before and 4 hours after discontinuation of heparin. 
 
 
 
 
8. Data and Safety Monitoring  
 
An independent Data and Safety Monitoring Board (DSMB) consisting of members appointed 
by the Principal Investigator and approved by the National Heart, Lung, and Blood Institute 
(NHLBI) will monitor the study, advise the NIH Program Office and provide input to the 
Steering Committee.   Prior to each meeting the members of the DSMB will declare any 
conflicts. In the event of a conflict, the remaining members will determine if conflict limits the 
member’s ability to participate. The DSMB will include experts in transfusion, biostatistics, 
and ethics.   
 
The DSMB will approve the study protocol before patient recruitment is initiated, as well as 
any subsequent changes to the study protocol and consent. The Principal Investigator will 
notify the NIH of all changes and local IRB approval will be required.  The DSMB will monitor 
accruing data, protocol deviations, and SAEs at a formal review half way through (55 patients) 
study enrollment to confirm that the patients in the trial are being cared for safely. 
 
Adverse events will be monitored in two distinct ways: the expedited reporting of deaths 
(within 24 hours of notification) and Serious Adverse Events (SAE) that are unexpected and 
related to the study protocol (within 1 week of notification)to the DSMB members and NHLBI 
staff, and the scheduled reporting of adverse events and study outcome event rates to DSMB 
members at the meeting half way through the study and at the end of the trial. 
 
Adverse events that are study outcomes : 1) Major Bleeding. 2) Mean Change in Hemoglobin 
Level 3) Red blood cell transfusion 4) Transfusion Associated Cardiac Overload (TACO) 
i.e., congestive heart failure, and 5) Transfusion Related Acute Lung Injury (TRALI), will be 
systematically collected.  In addition, clinical sites will submit an SAE report for all 
unexpected serious adverse events that are possibly associated with the study intervention 
and for all deaths.  The DSMB chairperson/medical safety officer will review the SAE report 
and supporting documentation provide by the site (including local investigator assessment of 
relationship to the protocol) to determine whether the event is related to the study 
intervention and whether the event was unexpected.   

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The NHLBI or the DSMB chairperson may decide to convene the entire DSMB to discuss 
issues related to the individual event.   
 
The DSMB will review all reported adverse events and transfusion arm at the regularly 
scheduled meetings. 
 
The DSMB may advise early termination of the trial for safety reasons or make other 
recommendations regarding modifications to the protocol.   
 
Each clinical site will comply with local IRB adverse event reporting. 
 
 
9. Reporting Results 
 
9.1 Individual Results 
 
This study is performed under usual care conditions. Patient care is managed by the treating 
physicians who will notify subjects of medical test results, as they deem necessary.  The 
study staff will not provide any medical results to the subjects. 
 
9.2 Aggregate Results 
 
The study will not notify participants of the trial results. 
 
 
9.3 Professional Reporting 
 
The results of the study will be presented at medical conferences and submitted to peer 
review journals for publication.  
 
 
10. Bibliography 
 
 
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