Short or Long Infusion Duration for Platelets: The SOLID Platelet Study
Phase: PHASE2
Conditions: Platelet Transfusion Refractoriness (PTR), Thrombocytopenia
Sponsor: National Institutes of Health Clinical Center (CC)

Abbreviated Title:
SOLID 
Protocol #:
19-CC-0005
Version Date:
October 7, 2019
Protocol Title:
Short or Long Infusion Duration for Platelets: The SOLID Platelet Study
NIH Principal 
Investigator:
Willy A. Flegel, MD
Department of Transfusion Medicine 
Clinical Center
Building 10, Rm 1C711
9000 Rockville Pike
Bethesda, MD 20892
Subjects of Study:
Number: Up to 30
Sex: Either
Age Range: 18 – 100 years old

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
10/07/19
PI: Willy A. Flegel, M.D.
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PRECIS
Platelet transfusion can be a life-saving procedure in preventing or treating serious bleeding in patients 
who have low and/or dysfunctional platelets. Treatment of blood cancer and other blood diseases, as well 
as bone marrow transplantation, is not possible without platelet transfusion support.  Unfortunately, 15-
25% of chronically transfused patients’ platelet counts will stop responding to these transfusions, putting 
them at risk for serious bleeding complications. The development of HLA antibodies is responsible for 4-
8% of this platelet transfusion refractoriness. The presence of HLA antibodies is a clinical complication 
that is generally managed by the selection of products that are negative for the antigens for which the 
patient has antibodies. Often, for patients with chronic and ongoing need, this selection is facilitated by 
targeted recruitment of donors with known HLA types (i.e., types that lack antigens cognate to the 
patient’s known antibodies and are thus predicted to be compatible). However, for very broadly HLA-
alloimmunized patients, compatible products may be exceedingly scarce or completely unavailable, 
precluding the ability to consistently provide products the patient will likely increment from. This research 
protocol is designed to evaluate the efficacy of a 4-HOUR continuous infusion of single donor, apheresis 
platelets in overcoming both alloimmune-mediated and non-alloimmune-mediated platelet 
refractoriness. We hypothesize that when we transfuse patients over a long duration, who have platelet 
refractoriness, the platelet counts will increase to higher numbers for an extended period of time in the 
peri-transfusion period when compared to shorter transfusion intervals.

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
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PI: Willy A. Flegel, M.D.
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Table of Contents
1.
OBJECTIVE.............................................................................................................................................6
1.1
Primary Objective:..............................................................................................................................6
1.2
Secondary Objective:..........................................................................................................................6
2.
INTRODUCTION, BACKGROUND, AND SCIENTIFIC JUSTIFICATION.............................................6
3.
STUDY DESIGN.....................................................................................................................................9
3.1
Indication:...........................................................................................................................................9
3.2
Subject Population: ............................................................................................................................9
3.3
Randomized Block Schema:..............................................................................................................10
4.
ELIGIBILITY ASSESSMENT ................................................................................................................10
4.1
Inclusion Criteria...............................................................................................................................10
4.2
Exclusion Criteria..............................................................................................................................11
5.
RESPONSE CRITERIA.........................................................................................................................11
6.
TREATMENT PLAN ............................................................................................................................11
6.1
Pre-Study Evaluation (screening) .....................................................................................................11
6.2
Randomized Block Design.................................................................................................................11
6.3
Treatment Monitoring......................................................................................................................12
7.
BIOSTATISTICAL CONSIDERATIONS ...............................................................................................13
7.1
Sample Size and Study Design..........................................................................................................14
8.
ENDPOINTS........................................................................................................................................14
8.1
Primary Endpoint..............................................................................................................................14
8.2
Study Analysis...................................................................................................................................14
8.3
Stopping Rules..................................................................................................................................15
8.4
Off-Study Criteria (and Subject Replacement) .................................................................................15
9.
SAMPLE COLLECTION, STORAGE AND TRACKING PLAN.............................................................15
9.1
Sample Storage.................................................................................................................................15
9.2
Intended Use ....................................................................................................................................16
9.3
End of Study Procedures ..................................................................................................................16
9.4
Loss or Destruction of Samples ........................................................................................................16
9.5
Future Use ........................................................................................................................................16
10.
DATA AND SAFETY MONITORING..............................................................................................16
10.1
Reporting Research Events...............................................................................................................16
10.2
Definitions ........................................................................................................................................17
10.3
Adverse Transfusion Events Management.......................................................................................19
10.5
Data Management............................................................................................................................20
10.6
Data Sharing .....................................................................................................................................21
11.
HUMAN SUBJECTS PROTECTIONS..............................................................................................21
11.1
Competition between Branch Protocols ..........................................................................................22
11.2
Reimbursement................................................................................................................................22
11.3
Participation of Children...................................................................................................................22
11.4
Participation of Pregnant Females ...................................................................................................22

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PI: Willy A. Flegel, M.D.
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11.5
Participation of Subjects Unable to Provide Informed Consent.......................................................22
11.6
Anticipated Benefit, Risks and Discomforts......................................................................................22
11.7
Risks in Relation to Anticipated Benefit ...........................................................................................23
11.8
Classification of Risk for the Study as a Whole.................................................................................24
11.9
Informed Consent, Consent Documents and Process ......................................................................24
11.10 Conflict of Interest............................................................................................................................24
12.
ALTERNATIVES TO PARTICIPATION............................................................................................25
13.
TECHNOLOGY TRANSFER.............................................................................................................25
14.
REFERENCES...................................................................................................................................25
List of Abbreviations
AUC – Area Under the Curve
CCI – Corrected Count Increment 
CPT – Continuous Platelet Transfusion
PTR – Platelet Transfusion Refractoriness
IBS – Intercept Blood System
DTM – Department of Transfusion Medicine at the NIH Clinical Center
LSS – Laboratory Services Section of DTM
SDP – Single Dose Platelet 

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
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PI: Willy A. Flegel, M.D.
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1.
OBJECTIVE
1.1.
Primary Objective:
To evaluate efficacy of continuous platelet transfusions in overcoming platelet transfusion 
refractoriness, including HLA-alloimmune-mediated refractoriness, in patients with severe 
thrombocytopenia. 
1.2.
Secondary Objective:
To characterize the efficacy of continuous platelet infusion on bleeding outcomes, as measured 
during the peri-transfusion period by daily hemostatic assessments using the World Health 
Organization (WHO) bleeding scale (see section 6.3.4). 
2.
INTRODUCTION, BACKGROUND, AND SCIENTIFIC JUSTIFICATION
Rationale:
Platelet transfusion can be a life-saving procedure in preventing or treating serious complications from 
hemorrhage in patients who have disorders manifesting as thrombocytopenia and/or platelet dysfunction. 
Allogeneic platelet support is indispensable to the treatment of hematological and non-hematological 
diseases. Prophylactic platelet transfusion to prevent bleeding -- rather than waiting to treat active 
bleeding -- is now the standard practice for the treatment of profound thrombocytopenia (with platelet 
counts below 10 x 109 cells/L) and is recommended by various clinical practice guidelines 1-6. Higher 
“triggers” are recommended when invasive procedures are anticipated. In 2011, an estimated 2.1 million 
platelet products were transfused in the USA 7. However, depending on the patient, and disease 
characteristics, 15-25% of patients chronically transfused with leukocyte-reduced blood components will 
ultimately develop platelet refractoriness, making this a major worldwide health problem 8-10. 
Platelet refractoriness is defined by an inadequate post-transfusion platelet count increment and is 
calculated based on pre- and post-transfusion platelet counts, the number of transfused platelets, and the 
patient’s body surface area. The most commonly used definition to establish platelet refractoriness is a 
post-transfusion corrected count increment (CCI) less than 7500/uL 10-60 min following the transfusion 
(CCI1hr), and less than 5000/uL at the 18-24 hrs time points 11, where CCI is calculated as follows: CCI = 
(absolute count increment per μL x body surface area in m2)/number of platelet transfused (x 1011). The CCI 
is also commonly reported as a “unit-less” multiple of 1000 (i.e., a failed CCI1hr would be <7.5). 
Platelet refractoriness is associated with bleeding complications, reduced overall survival and longer 
hospital stays and higher hospital costs 12-14. The National Institutes of Health Clinical Center is a major 
research referral center for hematologic disorders, including severe aplastic anemia (AA), paroxysmal 
nocturnal hemoglobinuria (PNH), congenital thrombocytopenia, and a multitude of premalignant and 
malignant hematological disorders. Patients with these disorders are characterized by pancytopenia, a 
hypocellular bone marrow, and suppression of hematopoiesis, resulting in hypoproliferative 
thrombocytopenia. Further, one treatment modality that many of the Clinical Center’s research protocols 
utilize in the treatment of hematologic and immunologic conditions is hematopoietic progenitor cell 
transplantation (HPCT), which relies on the recovery of the hematopoiesis from engrafting donor 
progenitor cells. However, until patients recover hematopoiesis they remain pancytopenic. 
Thrombocytopenia leads to easy bruisability and purpura, petechiae of the skin and mucous membranes, 
epistaxis, irregular and heavy menses, and gum bleeding. Bleeding can be brisk in the presence of 
accompanying physical lesions, as in gastritis and fungal infection of the lungs. The most feared 
complication of thrombocytopenia is intracranial hemorrhage, which has a high degree of mortality. The 

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primary modality to prevent life-threatening hemorrhage is platelet transfusion 5. However, patients who 
develop platelet refractoriness do not increment appropriately to platelet transfusions. Any intervention 
that augments hemostasis in these patients pending the recovery of hematopoiesis and endogenous 
platelet count would potentially be lifesaving. 
HPCT is not possible without adequate platelet support. While most platelet refractoriness is associated 
with a range of multifactorial non-immune-mediated clinical factors such as fever, sepsis, splenomegaly 
and certain medications, a significant subset of refractoriness is due to antibodies directed against foreign 
HLA antigens that developed as a result of exposure to foreign leukocytes through pregnancy or prior 
transfusion 8,15,16. Management of platelet refractoriness at the Clinical Center focuses on providing 
platelets of HLA types compatible with the recipient’s antibody profile (i.e., platelets that do not contain 
the HLA antigens to which the patient has developed antibodies). Providing HLA matched platelets is 
primarily accomplished via targeted donor recruitment or less frequently purchasing products procured 
from blood collection agency searches at both the regional and national level. However, for very broadly 
HLA-alloimmunized patients, compatible products may be exceedingly scarce or completely unavailable, 
precluding the platelet transfusion support necessary to overcome the patient’s refractoriness. 
While clinical studies have described the phenomenon of platelet alloimmunization in detail, a full 
elucidation of its pathophysiology remains elusive 16. The majority of clinically relevant HLA antibodies have 
been shown to be immunoglobulins G and M (IgG and IgM) that are directed against HLA class I epitopes, 
namely, HLA-A and B antigens. When patients generate IgG and IgM to allogeneic platelets, the destruction 
of platelets occurs by one of the known antibody dependent mechanisms, namely eradication via the Fc 
receptor-expressing phagocytes 17 residing in the reticuloendothelial system (RES) and via complement 
activation 18. However, attempts to reduce the production of HLA antibodies using immunosuppressive or 
immunomodulatory agents (e. g. IVIG, cyclosporine, corticosteroids) typically do not achieve a sustained 
resolution of platelet refractoriness 19-22. Our experience with a pilot trial treating HLA alloimmune-
mediated platelet refractoriness with eculizumab, a monoclonal antibody that inhibits complement-
mediated destruction by binding C5, shows that while preliminarily results indicate some promise in a 
subset of patients, refractoriness persists in others 23. Thus, alternative approaches to manage patients 
who are heavily HLA alloimmunized are in great demand. It is also clear that alloimmunization to HLA 
antigens does not explain all platelet refractoriness and even for immune refractoriness, HLA 
alloimmunization may be a marker for other conditions (platelet-specific antibodies (HPA), non-HLA 
antibodies to antigens on the platelet surface).
Recently, slow, continuous infusion of platelet products (continuous platelet transfusion, CPT) has garnered 
renewed interest as one potential way to manage platelet transfusion refractoriness (PTR) 24-26. In a case 
series of three patients with PTR, Narvios et al reported successful post-transfusion increments after 
administration of platelet concentrates infused over six hours, with one patient, who also had hematuria 
prior to the infusion, experiencing clinical hemostasis 24-hours post-infusion 24. However, details regarding 
the nature of the refractoriness (alloimmune vs non-alloimmune) and the CCI were not reported. In a 
larger, retrospective analysis of 21 patients with PTR, Tzadok et al evaluated the impact of 24-hour CPT -- 
consisting of consecutive transfusions of single-donor apheresis platelets (SDP) half-doses (i.e., comprising 
1.5×10¹¹ platelets each) infused over 4-6 hours each -- on the CCI obtained after 12 and 24-hours post-
transfusion.  The authors found CPT resulted in a statistically significant higher mean CCI at 24 hours (1.16 
vs. 0.37, p<0.05) but not at 12 hours (2.45 vs. 0.36, p=0.058) 25. The HLA/HPA alloimmune status of the 
patients was not reported. Most recently, employing a similar 24-hour CPT method as Tzadok et al, Cid et 
al reported a range of measures (including HLA alloimmune status, bleeding outcomes and median platelet 
counts before and after CPT) in their retrospective analysis of CPT in 14 patients (6 alloimmune-mediated, 

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Protocol Number: 19-CC-0005
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PI: Willy A. Flegel, M.D.
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8 non-alloimmune-mediated). The difference in increments prior to, and after, CPT was not formally 
statistically assessed. However, nine bleeding episodes (WHO grade>2) were present prior to 19 CPT 
infusions and all nine resolved during the 24-hour infusions, notably without any complicating adverse 
transfusion reactions 26. Similar other anecdotal successes with using 24-hour CPT or massive platelet 
transfusion to manage bleeding risk and/or alloimmunization have also been reported 9.
The theoretical underpinnings of how CPT might be effective in augmenting hemostasis and minimizing 
bleeding events, despite PTR -- including alloimmune-mediated PTR, were the subject of recent speculation 
26.  Briefly, it has been observed that transfusion of HLA-incompatible platelets, while not appreciably 
improving hemostasis as measured by 10- and 60-minute post-transfusion forearm bleeding times, 
nevertheless results in increases in deposition of fibrin on the subendothelial surface and in circulating 
thrombin-antithrombin complexes, suggesting a procoagulant effect 27. The volar bleeding times were 
performed with positive capillary pressure. Thus, it is not known to what extent, if any, this apparent 
procoagulant effect may mitigate the overall bleeding diathesis that results from severe 
thrombocytopenia, and, in particular, in tissues with physiologic or low shear rates. Importantly, Tzadok et 
al suggests a proportion of incompatible platelets infused within a 24-hour CPT may escape immune-
mediated clearance mechanisms 25. An alternative hypothesis that derives some support from animal 
studies is that massive platelet transfusion may be able to directly reduce the level of alloimmunization by 
in vivo alloadsorption 9, thus increasing the likelihood of adequate CCI on each sequential platelet 
transfusion from donors sharing a given HLA type.
In general, a fixed 7.1×10⁹ platelets/L/day is necessary to maintain the vascular endothelial integrity 28, 
suggesting that the average 70 kg adult with a total blood volume of ~5L would require ~0.36×10¹¹ 
platelets/day. A 24-hour CPT, consisting of five to six half-dose SDPs (1.5×10¹¹ platelets each) in 24 hours, 
would provide, at minimum, 7.5×10¹¹ platelets/L/day. In PTR, and in particular in alloimmune-mediated 
PTR, the minimum number of transfused platelets needed per unit time to maintain vascular endothelial 
integrity, mitigate bleeding risk, manage hemorrhage or obtain adequate CCIs is unknown. The kinetics of 
platelet survival in patients with PTR, and the increment in circulating platelet count during transfusion, is 
similarly unknown. 
Taken altogether, these data support slow, continuous transfusion as a potential transfusion approach that 
may minimize the number and/or duration of adverse hemorrhagic events and that may result in greater 
platelet increments per unit time than the conventional infusion approach.  Furthermore, there is no 
evidence in the published literature or any reported relevant experience of physicians who treat 
thrombocytopenic patients to suggest that CPT would be deleterious. Therefore there is equipoise in this 
trial design.
This study only utilizes Cerus Intercept Blood System (IBS) single, apheresis donor platelets (SDP) to 
compare two treatment approaches: 4-HOUR continuous infusion (“Long Transfusion”) versus <60-minute 
infusion (“Short Transfusion”). The IBS is an FDA-approved pathogen reduction technology that reduces the 
risk of transfusion-transmitted infections by inactivating a broad range of pathogens such as viruses, 
bacteria and parasites that may be present in donated blood. This technology is the standard of care 
processing for all platelet products collected by the Department of Transfusion Medicine (DTM), 
implemented January 14th, 2016. The 4-HOUR infusion duration was selected as the maximum infusion 
time since it is undesirable for components that contain red cells to remain at room temperature longer 
than 4 hours, and since it is generally recommended for components to complete transfusion within 4 
hours by the FDA-recognized AABB Circular of Information 
(https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G

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PI: Willy A. Flegel, M.D.
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uidances/Blood/UCM364587.pdf, accessed 11/07/2017). Sixty-minutes was selected for the maximum 
duration for the “Short Transfusion” based on retrospective data on platelet transfusion durations and to 
proscriptively not exceed the 300 mL/hour (“or as tolerated”) rate recommended by the AABB Technical 
Manual (18th edition). As each transfusion will use a half-SDP, and since each full SDP is no greater than 390 
mL, the maximum volume in each product issued within this protocol will not exceed 195 mL; thus, 
ensuring that the slowest infusion rate allowed within this protocol for the “Short Transfusion” does not 
exceed 195 mL/hour (that is, is not prescriptively forced to exceed the 300 mL/hour recommended 
standard rate). 
3.
STUDY DESIGN
3.1.
Indication:
Platelet transfusion refractoriness (PTR)
3.2.
Subject Population:
Subjects/Patients with thrombocytopenia (due to congenital causes, bone marrow failure, 
hematologic malignancies, and treatment-related), already enrolled on a primary protocol at the 
NIH CC, who require platelet transfusions, as well as demonstrate PTR diagnosed by the 
following:
Lack of an adequate post-transfusion platelet count increment, defined by CCI <5000/ul at 10-60 
minutes after each of at least 2 consecutive platelet transfusions.
If, in addition to meeting the above criteria for PTR, anti-HLA class 1 type A and/or type B 
antibodies are detected, the PTR will be classified as HLA-alloimmune-mediated. If HPA 
antibodies are detected in the setting of PTR, the PTR will be classified as HPA alloimmune-
mediated.
If neither HLA nor HPA antibodies are detected, the PTR will be classified as non -alloimmune-
mediated. Both alloimmune and non-alloimmunte types of PTR are eligible for this study.
3.3.
Randomized Block Schema:
RANDOMIZATION
Assignment to Group A or Group B
GROUP A: 
LONG transfusion and then SHORT transfusion
GROUP B:
SHORT transfusion and then LONG transfusion
ONE PLATELET PRODUCT POST-IBS = >4.4×10¹¹ TOTAL PLATELETS, DIVIDED INTO 2 DOSES
Dose 1: 
LONG Transfusion
Transfused over 4-HOURS 
(via infusion pump)
Dose 2: 
SHORT Transfusion
Transfused within 60-minutes 
(via infusion pump or gravity) 
12-HOUR BLOCK

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0-HR
2-HR
4-HR
6-HR
8-HR
10-HR
12-HR
LONG
SHORT
0-HR
2-HR
4-HR
6-HR
8-HR
10-HR
12-HR
SHORT
LONG
GROUP A: 
GROUP B: 
ALL PATIENTS WILL HAVE PLATELET COUNTS OBTAINED VIA COMPLETE BLOOD COUNTS (CBC), DRAWN AT THE ABOVE 
SCHEDULED INTERVALS, DURING EACH 12-HOUR BLOCK.
4.
ELIGIBILITY ASSESSMENT
4.1.
Inclusion Criteria

Ability to comprehend the investigational nature of the study and provide informed consent

Thrombocytopenia
a)
Causes of thrombocytopenia may be due to:
1.
Congenital causes
2. Bone marrow 
failure
3. Hematologic 
malignancies
4.
Treatment related
b)
Thrombocytopenia is generally defined as one of the following:
1.
<10K/uL without bleeding
2.
<20K/uL for “complicated prophylaxis” in patient’s determined to be at 
increased risk of bleeding or other complications
3.
<50K/uL with evidence of active bleeding, such as intracranial hemorrhage, GI 
bleeding, pulmonary hemorrhage, uncontrolled epistaxis, hematuria.
The treating provider may change the platelet transfusion threshold based on the clinical 
circumstance, patient population, and/or concurrent primary protocol considerations – 
similar to the PLADO study29. 

Diagnosed with PTR, characterized by the following:
a)
Lack of adequate post-transfusion platelet count increment, defined by, CCI <5000/ul 
at 10-60 min after each of at least 2 consecutive platelet transfusions
b)
Presence of anti-HLA class 1 type A and/or type B antibody, in the setting of PTR, as 
defined above, constitutes the HLA alloimmune-mediated subtype of PTR. Presence 
of one or more HPA antibodies in the setting of PTR, as defined above, constitutes the 
HPA alloimmune-mediated subtype of PTR. Failure to detect HLA or HPA antibodies 
will be categorized as “non-alloimmune-mediated PTR.”
4.2.
Exclusion Criteria

Less than 18-years-old

Lack of ability to obtain informed consent

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
Pregnant female

Presence of ITP/autoimmune thrombocytopenia

Immune platelet refractoriness responsive to treatment with IVIg or eculizumab, or other 
immunosuppressive therapy within the 3 preceding months. This is based on the wide 
variation in the duration therapeutic antibodies, with the upper limit frequently cited as 3 
months.
5.
RESPONSE CRITERIA
Statistically significant difference in the adjusted platelet increment area under the curve (AUC) obtained 
between 0-HOURS and 6-HOURS after the start of the platelet transfusion (Long Transfusion or Short 
Transfusion); this is determined at the interim and final analysis. The interim analysis will include a test of 
the null hypothesis of no difference in efficacy, using a threshold of significance of 0.01, with a threshold 
of 0.04 used for the final analysis. See Study Analysis, Section 8.2 for further details.
6.
TREATMENT PLAN 
6.1.
Pre-Study Evaluation (screening)

Conducted as part of the subject’s primary research protocol:
o
Clinical history and body surface area (BSA)
o
CBC or CBC with differential

Conducted as part of this protocol’s screening:
o
PT/INR and aPTT
o
HLA typing and HLA class I A, B, C antibody screen for HLA alloantibodies
o
HPA antibody screen (“Platelet antibody screen”)
6.2.
Randomized Block Design
6.2.1. Randomization

Upon IRB approval, the randomization schema for the first block for each subject 
will be specified using the “sealed envelope” web application at 
https://www.sealedenvelope.com/simple-randomiser/v1/lists, using the following 
input specifications:
1)
Treatment Groups

Group A: Long Transfusion followed by Short Transfusion in the first 
block

Group B: Short Transfusion followed by Long Transfusion in the first 
block
2)
Block sizes – 4, 6, or 8
3)
List Length – 30
This web application has been used for randomization in various published clinical 
trial studies over the last decade 
(https://scholar.google.com/scholar?q="Sealed+Envelope+Ltd.").

The randomization list will be held by the TSL Operations Coordinator, who will 
reveal the first block assignment (Group A versus Group B) for each subject at the 
time of that subject’s enrollment

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
Only one block per day will be permitted for a subject. Up to two further 
subsequent blocks (one per day) may be administered for a subject, thus bringing 
the total maximum number of blocks per subject to three. Subsequent blocks will 
alternate the sequence of the Long and Short Transfusions. 
6.2.2. Platelet Component Preparation for Block Administration

This study will only utilize platelet components collected in the NIH Clinical Center, 
Department of Transfusion Medicine

Only IBS platelet components that are >4.4×10¹¹ platelets, as measured from a 
sample obtained from the storage container post-transfer from the compound 
adsorption device (CAD) container, will be used; this number was selected in order 
to closely approximate the number of platelets transfused during routine issue of a 
single dose of platelets

2 ml will be withdrawn into a sample pouch or tubing segment, heat sealed, 
detached, and then emptied into a labeled EDTA tube to be submitted to CPS for 
platelet count determination

Each component will be split by dividing the tubing at the point of union, into two, 
roughly equal, “doses”, following established TSL procedures (TSL-SOP-3941)

Each dose will have its weight documented in order to calculate the number of 
platelets in each dose

Each block consists of two doses from one platelet product, one for a Long 
Transfusion duration and one for a Short Transfusion duration: 

Both doses will be gently swirled for ~20 revolutions, every 30-minutes, to 
thoroughly mix the product; this will done by the nursing staff

Both doses will be weighed to ascertain volume 

One dose within each block will be transfused over a LONG duration, over 4-HOURS 
from the time the back is spiked and one dose within each block will be transfused 
over a SHORT duration, within 60-minutes from the time the bag is spiked; both 
transfusions may occur via an infusion pump or by gravity.
6.3.
Treatment Monitoring
6.3.1. CBC Collection
All CBC blood draws will be collected in a 2 ml EDTA tube, after wasting the first 1ml of 
blood drawn. The sample should be obtained via the patient’s peripheral access device, but 
a peripheral venipuncture or draw from the patient’s central access device may be done if 
access the patient’s peripheral line is not feasible. The initial 1 ml sample discard, prior to 
filling the 2ml EDTA tube, is to prevent a false reading by drawing the sample from the same 
line through which the patient is receiving the transfusion.
Patients will have platelet counts obtained by CBCs collected at the following scheduled 
intervals:
1)
Pre-transfusion (0-HOUR) CBC: obtained 15-minutes prior to transfusion start time 
2)
2-HOUR CBC: Obtained +/- 15-minutes of the 2-HOUR mark after the infusion start 
time

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3)
4-HOUR CBC: Obtained +/- 15-minutes of the 4-HOUR mark after the infusion start 
time
4)
6-HOUR CBC: Obtained +/- 15-minutes of the 6-HOUR mark after the infusion start 
time. Also serves as the PRE (0-HOUR) CBC for the subsequent, transfusion; the 
subsequent transfusion will also have scheduled CBCs drawn at q2hr intervals (i.e. 
CBC at 8-HOUR, 10-HOUR, 12-HOUR), collected +/- 15-minutes of each time mark)
CBCs unable to be obtained as indicated will result in an unsuccessful, or “failed,” block. 
Failed blocks will be precluded from further analysis. All attempts will be made to repeat 
the block as soon as clinically possible. Blood draws for other clinical purposes should be 
avoided, but will not result in a failed block unless it/they preclude the aforementioned 
scheduled CBCs needed for this protocol’s treatment monitoring.
From the CBC, platelet value will be used to calculate the platelet AUC using the trapezoid 
rule and adjusted for the absolute number of platelets transfused, on a rolling basis for each 
transfusion.
6.3.2. Documentation and Results Review
Testing for HLA-alloimmune-mediated PTR and HPA-alloimmune-mediated PTR will be 
performed upon enrollment, if not previously completed prior to enrollment. Weight and 
platelet count of the platelet component will be documented concurrently in the DTM 
Transfusion Services Laboratory. Treatment monitoring, including transfusion duration, CBC 
collection times, platelet counts, etc., will be occur concurrently via The SOLID Platelet Study 
Nursing Worksheets (Appendices B and C), the electronic medical record system, Clinical 
Research Information System (CRIS), and the already operational “DTM Platelet Transfusion 
Summary” and “Patient Platelet Count Summary” SQL reports. 
Orders and results will be tracked through CRIS. Should CRIS not be available, the NIH form 
2803-1 will be completed and accompany the specimen; it will be filed in the patient’s 
medical record.
To evaluate the frequency and extent of hemorrhagic complications, bleeding will be assessed by the 
modified World Health Organization bleeding scale (Appendix A). This will be done by the Principal 
Investigator (PI), the Lead Associate Investigator (LAI), or Associate Investigator (AI) using chart 
reviews for bleeding events one day prior to the Transfusion Blocks, the day(s) of the Transfusion 
Blocks, and one day following the Transfusion Blocks. This approach is deemed reasonable in the 
absence of a standardized or consensus method to evaluate bleeding in platelet transfusion clinical 
trials 31. 
Long-term follow-up observations will not be necessary after the study’s completion. 
7.
BIOSTATISTICAL CONSIDERATIONS
This is a two arm, randomized block study.
7.1.
Sample Size and Study Design
We will determine the sample size using the Two-Stage Design. At the first stage, 12 subjects will 
be accrued. An interim analysis will be performed to compare the platelet count AUC values, 
adjusted for the absolute number of platelets transfused (adjusted platelet AUC), between the 
within-block treatment pairs. If the difference is significant at the 0.01 one-sided level favoring 

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the slow infusion technique, then accrual will cease and the null hypothesis rejected. At the 
interim analysis we will also perform a futility analysis. If the conditional power for rejecting the 
null hypothesis at the end of the study is less than 0.3, then accrual will cease. Otherwise, an 
additional 12 subjects will be accrued, bringing the total number of subjects to n=24. To account 
for dropouts, up to 30 subjects will be enrolled. Anticipated dropouts are due to inability to 
tolerate blood draws. 
This design (n=24) has power >80% using the sign test on the matched pairs from the first block 
for each patient under the alternative hypothesis that the probability that a matched pair of 
adjusted platelet AUC values favors the test regimen is 0.80, assuming no tied observations 32. 
The actual analysis will use the Wilcoxon matched pair signed rank test. A mixed model analysis 
for multiple blocks per patient will be performed as a secondary analysis.
8.
ENDPOINTS
8.1.
Primary Endpoint
To evaluate the efficacy of Long Transfusion in overcoming PTR in patients with severe 
thrombocytopenia. 
Efficacy will be measured in terms of the adjusted platelet increment AUC, obtained between 0-
HOURS and 6-HOURS after start of the platelet transfusion. The AUC (i.e., AUC above the pre-
transfusion CBC’s platelet count, minus the AUC below the pre-transfusion CBC’s platelet count, 
which can be a net increment or net decrement) determined by the 0-HOUR, 2-HOUR, 4-HOUR, 
and 6-HOUR CBC platelet concentrations, will be estimated by the trapezoid rule and used as the 
primary outcome measure. 
Adjustment to the measured AUC will be done for the number of platelets transfused during the 
2 transfusion periods (Long and Short Transfusion durations) in 1 block: The weights of the 2 bags 
will be checked to estimate the platelet product volumes; the volumes will be multiplied by the 
post-illumination CBC (obtained after removal of the platelet product from the compound 
adsorption device). 
The outcomes (AUC) will be compared between the 2 transfusion periods within the first block 
for the primary analysis. The null hypothesis for efficacy will be that the adjusted platelet 
increment AUC does not differ between the 2 transfusion periods (Long and Short infusion 
durations).
8.2.
Study Analysis
All subjects who receive one 12-HOUR block of Short and Long infusion duration of platelets will 
be included in the primary analysis.  Every effort will be made to evaluate the subjects before 
transfusion as well as at 2-HOURS, 4-HOURS and 6-HOURS after starting each platelet dose 
infusion. Adverse events will be tabulated by severity and attribution to treatment and disease 
(transfusion reactions will be classified using the CDC NHSN Hemovigilance Module Surveillance 
Protocol, which may be accessed at https://www.cdc.gov/nhsn/pdfs/biovigilance/bv-hv-
protocol-current.pdf ).
Final statistical analysis will be performed once all 24 subjects have completed the end of study 
assessments and all data have been archived for analysis. An interim analysis will be conducted 
after 12 subjects have completed at least one 12-HOUR block of transfusions. The planned 

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analyses will include descriptive statistics on the proportions of platelet response and 2-HOUR to 
6-HOUR platelet increment AUC values, adjusted for number of platelets given. Hypothesis 
testing will utilize Wilcoxon matched pair signed rank test for the primary analysis. Mixed model 
analysis will be employed for multiple blocks per patient and reported descriptively.
The interim analysis will include a test of the null hypothesis of no difference in efficacy using a 
threshold of significance of 0.01, with a one-sided threshold of 0.04 used for the final analysis. 
The interim analysis will also include a futility analysis based on the conditional power for 
rejecting the null hypothesis at the final analysis given the interim results. The futility analysis 
reduces the type I error of the design.
Secondary analysis based on mixed effect regression, and logistic regression analysis will also be 
employed if deemed appropriate.
8.3.
Stopping Rules
At the interim analysis we will perform a futility analysis. If the conditional power for rejecting 
the null hypothesis at the end of the study is less than 0.2, then accrual will cease.
8.4.
Off-Study Criteria (and Subject Replacement)
Patients will be taken off study for the following:

Subject has completed three successful 12-HOUR blocks

Subject no longer requires frequent platelet transfusions, as defined as 5-days of platelet 
transfusion independence

Withdrawal per subject choice
o
Subjects have the opportunity to withdraw from the study; if subjects withdraw, 
they will be replaced, to reach a total of 24 patients

Withdrawal by physician decision
o
Subject will be withdrawn from the study if he/she cannot tolerate blood draws, 
or if subject no longer requires platelet transfusions

Completion of the study
9.
SAMPLE COLLECTION, STORAGE AND TRACKING PLAN
Plasma samples can be stored in the NIH DTM HLA laboratory with an aliquot of each sample separated 
and set aside for the purpose of this study. Samples and data will be stored using codes that we assign. 
Data will be kept in password-protected computers.  Samples will be kept in locked storage. Only study 
investigators will have access to the samples and data.
9.1.
Sample Storage
Research aliquots will be coded by sample number and be stored in a secure freezer in the 
NIH/CC/DTM Laboratory Service Section. Access will be restricted to protocol research staff only 
(i.e., the PI and AIs). All research aliquots will be discarded after testing is performed.
 
9.2.
Intended Use
Aliquots of stored archival plasma from prior clinical use will be extracted and prepared for 
testing against allogenic platelets for platelet crossmatch method validation.
9.3.
End of Study Procedures
Samples will be stored until they are no longer of use for the purposes within the context of this 
study, or until the subject withdraws consent -- at which time they will be destroyed. 

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9.4.
Loss or Destruction of Samples 
Should it become known that a major breech in the plan for tracking and storage of samples has 
occurred, the IRB will be notified by the PI.
9.5.
Future Use
Other investigators may want to study stored samples. If so, the NIH study team may send 
samples to them along with the coded label. Although the study team will not share information 
that can directly identify subjects, they may share information regarding health history, as well as 
general demographic information such as gender, age, and ethnicity. Future studies may need 
health information (such as smoking history or present health status) that is not already known 
about the subjects; if so, the NIH study team will contact subjects for this information.
10. NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
10.1. Definitions
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
10.2. OHSRP Office of Compliance and Training / IRB Reporting 
For all human subjects research in which an NIH IRB is the Reviewing IRB, NIH Principal 
Investigators (PIs) and, as applicable, non-NIH Site PIs/Lead Investigators (further referred to as 
non-NIH investigators), are required to ensure that all reportable events, as defined in NIH   
Policy – 801, are reported to the OHSRP office of Compliance and Training within the time frames 
as specified in the policy.
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
10.3. Clinical Director (CD) Reporting
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to CD.  A separate 
submission is not necessary as reports in iRIS will be available to the Clinical Director.
10.4. NIH Required Data and Safety Monitoring Plan
The clinical research team will meet weekly when patients are being actively treated on the trial 
to discuss each patient. All data will be collected in a timely manner and reviewed by the 
principal investigator or a lead associate investigator. Events meeting requirements for expedited 
reporting as described in section 10.2 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event data on each patient to ensure safety and 
data accuracy. The principal investigator will personally conduct or supervise the investigation 
and provide appropriate delegation of responsibilities to other members of the research staff.
10.5. Adverse Transfusion Events Management

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All adverse transfusion events will be investigated by the study PI. If it is determined that an 
adverse transfusion event is, indeed, related to the study treatment, each adverse transfusion 
reaction will be classified according to the Centers for Disease Control (CDC) April 2018National 
Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance 
Protocol, v2.5.2 (https://www.cdc.gov/nhsn/pdfs/biovigilance/bv-hv-protocol-current.pdf). This 
reference guide includes reaction-specific case definitions, as well as severity, and imputability 
criteria, further outlined below:

Defined Adverse Transfusion Reactions: 
o
Transfusion-associated circulatory overload (TACO) 
o
Transfusion-related acute lung injury (TRALI) 
o
Transfusion-associated dyspnea (TAD) 
o
Allergic reaction (where severity is severe, life threatening, or death)
o
Hypotensive transfusion reaction 
o
Febrile non-hemolytic transfusion reaction (FNHTR) 
o
Acute hemolytic transfusion reaction (AHTR) 
o
Delayed hemolytic transfusion reaction (DHTR) 
o
Delayed serologic transfusion reaction (DSTR) 
o
Transfusion-associated graft vs. host disease (TAGVHD) 
o
Post-transfusion purpura (PTP)
o
Transfusion-transmitted infection (TTI) 
o
Other or Unknown

Severity:
o
Non-severe: Medical intervention (e.g. symptomatic treatment) is required but 
lack of such would not result in permanent damage or impairment of a bodily 
function. 
o
Severe: Inpatient hospitalization or prolongation of hospitalization is directly 
attributable to the adverse reaction, persistent or significant disability or 
incapacity of the patient occurs as a result of the reaction, or a medical or 
surgical intervention is necessary to preclude permanent damage or impairment 
of a body function.
o
Life-threatening: Major intervention required following the transfusion (e.g. 
vasopressors, intubation, transfer to intensive care) to prevent death. 
o
Death: The recipient died as a result of the adverse transfusion reaction. Death 
should be used if death is possibly, probably or definitely related to transfusion. 
If the patient died of a cause other than the transfusion, the severity of the 
reaction should be graded as appropriate given the clinical circumstances related 
to the reaction.

Imputability:
o
Definite: Conclusive evidence exists that the adverse reaction can be attributed 
to the transfusion
o
Probable: Evidence is clearly in favor of attributing the adverse reaction to the 
transfusion.
o
Possible: Evidence is indeterminate for attributing the adverse reaction to the 
transfusion or an alternate cause.
o
Doubtful: Evidence is clearly in favor of a cause other than the transfusion, but 
transfusion cannot be excluded.

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o
Ruled Out: There is conclusive evidence beyond reasonable doubt of a cause 
other than the transfusion.
10.6. Data Management
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. Laboratory values 
from referring home physicians will be entered into the system. The PI, AI(s), research nurses, 
and/or a contracted data manager will assist with the data management efforts to ensure that 
data is verifiable and evaluable. Data will be extracted from CRIS and will be imported 
electronically from CRIS into an in-house database. 
Data will be located in a password protected folder on the Department of Transfusion Medicine 
(DTM) secure G drive. Access will be restricted to PI and AI(s). 

End of Study Procedures:
o
Data and samples will be stored until they are of no longer of scientific value or 
until the subject withdraws consent at which time it will be destroyed

Loss or destruction of data:
o
Should we become aware that a major breech in our plan to protect subject 
confidentiality and trial data has occurred, the IRB will be notified
o
Data will not be sent outside NIH without IRB notification and an executed MTA 
or CTA.

Research use of study data: 
o
The IRB will be notified and the protocol and consent amended if samples and data 
collected under this protocol will be used for research not described in the current 
protocol or if the study records are transferred to another party.

Publication policy:
o
Given the research mandate of the NIH, subject data including the results of 
testing and responses to treatment will be entered into an NIH-authorized and 
controlled research database. Any future research use will occur only after 
appropriate human subject protection institutional approval such as prospective 
NIH IRB review and approval or an exemption from the NIH Office of Human 
Subjects Research (OHSR).
10.7. Data Sharing
Data and samples may be shared with collaborating laboratories at NIH or outside of NIH and/or 
submitted to NIH-designated repositories and databases if consent for sharing was obtained (if 
applicable: or under waiver of informed consent as described below).  Repositories receiving 
data and/or samples from this protocol may be open-access or restricted access. 
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the code will 
not be provided to collaborators, but will remain at NIH.  Data and samples may be shared with 
investigators and institutions with a Federal Wide Assurance (FWA) or operating under the 
Declaration of Helsinki (DoH) and reported at the time of continuing review.  Sharing with 
investigators without an FWA or not operating under the DoH will be submitted for prospective 
IRB approval.  Submissions to NIH-sponsored or supported databases and repositories will be 

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reported at the time of Continuing Review.  Submission to non-NIH sponsored or supported 
databases and repositories will be submitted for prospective IRB approval.
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations.   
11. HUMAN SUBJECTS PROTECTIONS
The investigators will protect the rights and welfare of human research subjects set forth in 45 C.F.R. Part 
46 and 21 C.F.R Part 50, Protection of Human Subjects.
Rationale for Subject Selection: 
Thrombocytopenia leads to petechiae of the skin and mucous membranes, epistaxis, menses that last 
more than a month, and gum bleeding. The most feared complication of thrombocytopenia is intracranial 
hemorrhage, which has a high degree of mortality. The only modality to prevent life threatening 
hemorrhage is platelet transfusion. However, patients who develop platelet refractoriness do not respond 
to platelet transfusions. A subset of this refractoriness is due to HLA antibodies. Data support the 
observation that continuous platelet transfusion (CPT) may overcome transfusion refractoriness and 
result in an adequate number of platelets in circulation to support hemostasis. Therefore, we hypothesize 
that when we transfuse patients who have platelet refractoriness with “Long Transfusion”, the platelet 
counts will increase to higher numbers after these transfusions than intermittent “Short Transfusion” 
platelet infusions, thus decreasing the risk of bleeding complications or ameliorating, if not completely 
resolving, bleeding present prior to enrollment.
Recruitment Effort: 
Strategies for subject recruitment will include announcement to the medical team during rounds. DTM 
consultations are routinely performed for HLA alloimmunized patients thus there is a keen awareness of 
potential candidates for study. If a subject is deemed suitable by the primary medical team for this 
protocol, the patient will be approached by an Investigator for a full explanation of the study. The study 
will be listed on the clinicaltrials.gov, and Clinical Center research studies.
11.1. Competition between Branch Protocols
This protocol currently does not conflict or compete with any other Branch protocols. This 
protocol is targeted to the same patient population as NHLBI protocol 15-H-0015, which has 
completed enrollment and is thus closed. 
11.2. Reimbursement

Reimbursement for protocol participation, travel, food, and lodging will be consistent 
with NHLBI policy.

Payment for participation:  $0
11.3. Participation of Children
Pediatric subjects are excluded, due to the additional confounding that may be introduced when 
additional processing (i.e., volume reduction) is required of the platelet product due to the 
patient’s size. 
11.4. Participation of Pregnant Females
Pregnant women are excluded, because the hypothesis should first be explored in patients 
without incurring any risk for a pregnant woman or her fetus.

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11.5. Participation of Subjects Unable to Provide Informed Consent
Subjects incapable of providing informed consent are excluded, because the hypothesis should 
first be explored to assess whether their prospective participation in the study outweighs any 
potential risk, as per human subjects research protections outlined in NIH SOP-14E, Research 
Involving Adults Who Are or May Be Unable to Consent.
11.6. Anticipated Benefit, Risks and Discomforts
The research risk of the protocol is no greater than minimal risk with the prospect of direct 
benefit, due to the potential for prolonging platelet survival with a 4-HOUR infusion.
11.6.1. Transfusion-Associated Circulatory Overload (TACO)
Volume overload as a result of transfusion occurs in 1-8% of patients who are transfused, or 
one in ~10,000 transfused components, and is generally under-recognized and lacks 
international consensus criteria. However, the CDC NHSN criteria 
(https://www.cdc.gov/nhsn/pdfs/biovigilance/bv-hv-protocol-current.pdf; Hemovigilance 
Module Surveillance Protocol v2.4) define the reaction as 3 or more of the following within 6 
hours of cessation of transfusion:

Acute respiratory distress (dyspnea, orthopnea, cough)

Elevated brain natriuretic peptide (BNP)

Elevated central venous pressure (CVP)

Evidence of left heart failure

Evidence of positive fluid balance

Radiographic evidence of pulmonary edema
A recent review published by an international panel recommends transfusing patients at 
risk of TACO slowly over up to 4 hours, using divided units33. Since this protocol is an 
extended version of the recommended approach, the risk of TACO is mitigated to some 
degree and is not thought to be substantially increased. TACO is treated by stopping the 
transfusion, administering oxygen as needed, and diuretic administration. 
11.6.2. Risks Common to all Blood Products

Uncommon (1-5%) chance)
o
Mild reactions resulting in itching, rash, fever, headaches.

Rare (<1% chance)
o
Respiratory distress (shortness of breath) or lung injury
o
Exposure to blood borne micro-organisms (bacteria and parasites) that 
could result in an infection*
o
Possible effects on the immune system, which may decrease the body’s 
ability to fight infection
o
Exposure to blood borne viruses such as hepatitis B (an inflammatory 
disease affecting the liver)*
o
Shock

Extremely rare (one in a million or less)
o
Exposure to blood borne viruses such as hepatitis C (an inflammatory 
disease affecting the liver)and Human Immunodeficiency Virus (HIV, the 
virus that causes AIDS)*
o
Death

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*The above incidence refers to non-pathogen reduced platelets. At the NIH CC, all 
platelet products collected by DTM are pathogen-reduced via the Intercept Blood 
System; only these products will be used in this study. Pathogen-reduced platelets 
using the Intercept Blood System for Platelets (IBS) has FDA marketing approval for 
pathogen reduction based on demonstrated effectiveness against a range of 
viruses, protozoa, and Gram-positive, Gram-negative, anaerobic and spirochete 
bacteria. Thus, actual rates are likely much lower. 
11.6.3. Risks Related to Blood Tests
Some subjects may experience localized bruising at the site of venipuncture. Some subjects 
may experience a vasovagal response. In order to minimize the potential for fall injuries after 
a blood draw, subjects will be closely monitored for dizziness or lightheadedness before they 
are allowed to stand.
11.7. Risks in Relation to Anticipated Benefit
The investigational nature and objectives of this study, the procedures and treatments involved 
and their attendant risks and discomforts, potential benefits, and potential alternative therapies 
will be carefully explained to the patient or the patient’s surrogate, and a signed informed 
consent document will be obtained.
There is a possibility that a platelet AUC may show a sustained increase via “Long Transfusion”, 
though it is not known at this time. Thus, this study may offer a benefit from participation by 
reducing the risk of bleeding from refractory thrombocytopenia. 
This study is likely to yield generalizable knowledge about the role of slow transfusion in 
ameliorating platelet transfusion refractoriness. 
11.8. Classification of Risk for the Study as a Whole
The research risk of the protocol is no greater than minimal risk with the prospect of direct 
benefit, due to the potential for prolonging platelet survival with a 4-HOUR infusion.
The risks of this study are reasonable in relation to the indirect benefits that will be provided. For 
adult research subjects, the level of risk is greater than minimal risk, as defined in 45 CFR 46.102.
11.9. Informed Consent, Consent Documents and Process
The investigational nature and research objectives of this trial, the procedure and its attendant 
risks and discomforts will be carefully explained to the subject and a signed informed consent 
document will be obtained prior to entry onto this study. Study investigators designated as able 
to obtain consent (asterisked investigators), will obtain informed consent.  
All participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions regarding this study prior to signing.
Informed Consent for Non-English Speaking Subjects

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We anticipate the enrollment of non-English speaking research participants into our study. The 
IRB approved full consent document will be translated into the subject's native language in 
accordance with the Clinical MAS Policy M77-2.
If there is an unexpected enrollment of a research participant for which there is no translated IRB 
approved consent document,  the PI and/or those authorized to obtain informed consent will use 
the short form oral consent process as described in MAS Policy M77-2, 45 CFR 46.117 ( b) (2) and 
21 CFR 50.27 (b) (a).  The English version of the IRB approved consent document will be used as 
the summary of the text to be provided.
We prospectively request the IRB approve the use of the short form consent process in up to five 
of enrollees who are non-English speaking.  We will notify the IRB at the time of continuing 
review of the frequency of the use of the short form process (number per language).   Should we 
reach the threshold of five of participants, we will notify the IRB of the need for an additional use 
of the short form and that we will have the consent document translated into the given inherent 
language.
11.10.Conflict of Interest
The PI assures that each AI listed on the protocol title page received a copy of the NIH’s Guide to 
preventing conflict of interest. Investigators added subsequent to the initial circulation will be 
provided a copy of the document when they were added. Copies of the Conflict of Interest 
Statement were forwarded to the Clinical Director. No initial members of the research team 
reported a potential conflict of interest.
12. ALTERNATIVES TO PARTICIPATION
Subjects receive standard care platelets on this study and do not forego any treatment in order to 
participate in this study. The alternative, therefore, is not to participate.
13. TECHNOLOGY TRANSFER
No technology transfer agreement is in place for this protocol.
14. REFERENCES
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Slichter SJ. Evidence-Based Platelet Transfusion Guidelines. Hematology 2007; 2007(1): 172-8.
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Slichter SJ. Platelet Transfusion Therapy. Hematology/Oncology Clinics of North America 2007; 
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Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice 
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26. Cid J, Guijarro F, Carbasse G, Lozano M. 24-h continuous infusion of platelets for patients with 
platelet transfusion refractoriness. Br J Haematol 2017.
27. Mazzara R, Escolar G, Garrido M, et al. Procoagulant effect of incompatible platelet transfusions 
in alloimmunized refractory patients. Vox Sang 1996; 71(2): 84-9.
28. Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic 
patients. Transfus Med Rev 2004; 18(3): 153-67.
29. Slichter SJ, Kaufman RM, Assmann SF, et al. Dose of prophylactic platelet transfusions and 
prevention of hemorrhage. N Engl J Med 2010; 362(7): 600-13.
30. Tambur AR, Herrera ND, Haarberg KM, et al. Assessing Antibody Strength: Comparison of MFI, 
C1q, and Titer Information. Am J Transplant 2015; 15(9): 2421-30.
31. Estcourt LJ, Heddle N, Kaufman R, et al. The challenges of measuring bleeding outcomes in 
clinical trials of platelet transfusions. Transfusion 2013; 53(7): 1531-43.
32. Nietert PJ, Dooley MJ. The power of the sign test given uncertainty in the proportion of tied 
observations. Contemporary clinical trials 2011; 32(1): 147-50.
33. Delaney M, Wendel S, Bercovitz RS, et al. Transfusion reactions: prevention, diagnosis, and 
treatment. Lancet 2016; 388(10061): 2825-36.
34. INTERCEPT Blood System for Platelets SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED). 
December 18, 2014. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProdu
cts/PremarketApprovalsPMAs/UCM431243.pdf.
35. INTERCEPT® Blood System for Platelets Manufacturer insert. 2016. https://intercept-
usa.com/images/resources/Package_Inserts/INTERCEPT_Blood_System_SV_Platelets_Package_
Insert_v3.1.pdf.

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
10/07/19
PI: Willy A. Flegel, M.D.
Page 24 of 27
APPENDIX A: World Health Organization Bleeding Scale
Grade 1
Grade 2
Grade 3
Grade 4
Oral
Oropharyngeal bleeding – total 
duration of all episodes in previous 24 
hours < 30 minutes*
Petechiae of oral mucosa
Epistaxis – total duration of all 
episodes in previous 24 hours < 30 
minutes*
Oropharyngeal bleeding – total duration of all 
episodes in previous 24 hours > 30 minutes*
Epistaxis – total duration of all episodes in 
previous 24 hours
30 minutes*
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Skin, soft tissue, 
musculoskeletal
Petechiae of skin
Purpura < 1 inch diameter
One or more spontaneous 
hematomas in the soft tissue or muscle 
> 1 inch
Purpura > 1 inch diameter
Spontaneous hematoma in deeper tissues
Joint bleeding (confirmed by aspiration, 
imaging study or other accepted technique)
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Gastrointestinal
Positive stool occult blood test‡
Melanotic stool
Hematochezia – visible red blood mixed in 
stool, not requiring a transfusion
Hematemesis – grossly visible blood in emesis 
or in nasogastric drainage tube (not related or 
secondary to swallowed blood)
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Genitourinary
Any biochemical or microscopic Hb/RBCs 
without red urine‡
Abnormal vaginal bleeding (Unexpected 
bleeding out of normal cycle or bleeding 
heavier than normal or breakthrough 
bleeding (patient on hormonal therapy 
to prevent bleeding)) with spotting
Gross/visible hematuria without need for 
transfusion
Abnormal vaginal bleeding (Unexpected 
bleeding out of normal cycle or bleeding 
heavier than normal or breakthrough bleeding 
(patient on hormonal therapy to prevent 
bleeding)) more than spotting
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Pulmonary
- Hemoptysis – visible blood
- Blood in broncho-pulmonary lavage, or blood 
tinged sputum (excluding those with nose or 
oropharyngeal bleeding)
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Body cavity
- Visible blood in body cavity fluid (e.g. red cells 
apparent in fluid aspirate) short of criteria for 
Grade 3 or 4
Grossly bloody body cavity fluids and organ dysfunction with 
symptoms, and/or need to intervene (e.g. to aspirate), and/or 
need for transfusion
Central nervous 
system
- Retinal bleeding without visual impairment
- Lumbar puncture with blood (>5 RBC/mL in CSF 
on microscopic analysis and non-traumatic 
tap), no symptoms and no visible red color
Lumbar puncture with visible red color in absence of 
symptoms, and non-traumatic tap
Invasive sites
- Bleeding at invasive sites (venipuncture sites, 
intravenous lines or catheter exit sites): active 
oozing at site for a cumulative total of >1 hour 
in the previous 24 hours
Any bleeding requiring RBC transfusion over routine 
transfusion needs†
Hemodynamic 
instability
Any bleeding associated with moderate hemodynamic 
instability (hypotension; >30mmHg fall or >30% decrease in 
either systolic or diastolic blood pressure) and requiring RBC 
transfusion over routine transfusion needs†
Any bleeding associated 
with severe 
hemodynamic instability 
(hypotension; >50mm/Hg 
fall or >50% decrease in 
either systolic or 
diastolic blood pressure, 
with associated 
tachycardia (heart rate 
increase of > 20% for 20 
minutes) and requiring 
RBC transfusion over 
routine transfusion needs
Fatal bleeding from any 
source
Retinal bleeding with 
visual impairment (Visual 
impairment is defined as 
a field deficit, and 
patients with suspected 
visual impairment require 
an ophthalmologic consult 
for documentation)
CNS symptoms with non-
traumatic bloody lumbar 
puncture
CNS bleeding on imaging 
study with or without 
dysfunction
RBC indicates red blood cell; Hb, hemoglobin; CSF, cerebrospinal fluid; Hg, mercury; and CNS, central nervous system †Red cell transfusion must be specifically related to treatment of bleeding within 24 hours of onset of bleeding
* Count actual bleeding (i.e. “running out” or need for basin, Kleenex, towel, etc.) not minor bleeding ‡Not assessed in PLADO

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
10/07/19
PI: Willy A. Flegel, M.D.
Page 25 of 27
APPENDIX B: Protocol Worksheet
The SOLID Platelet Study, Protocol #19-CC-0005
LONG Transfusion followed by SHORT Transfusion
INSTRUCTIONS:
- All CBCs should be collected in a 2 mL EDTA tube; please WASTE the first 1 mL at each sample collection
- CBC collection times may occur (+/-) 15 minutes of the target draw time
- Documenting ‘EXPECTED TIME’ is optional; it is provided as a reference tool for planning the CBC collection and transfusion START / STOP 
Schedule
- Please call Dr. Flegel (DTM, Protocol PI) with any questions, concerns, or if you run in to any problems, at 301.496.5000.
GROUP
BLOCK
Date (mm-dd-yy)
Randomly Assigned ID
EXPECTED TIME
(Optional)
ACTUAL TIME
PLATELETS
(109/L)
HEMOGLOBIN
(g/DL)
1.
PRE (0-HOUR)
i.
START Long Transfusion AFTER CBC collection
ii.
Continue transfusing over 4-HOURS
iii.
Gently Swirl Bag for 20 revolutions every 30-min
A.
CBC COLLECTION
B.
LONG TRANSFUSION START 
2.
2-HOUR  (1b) + 2-HOURS
A.
CBC COLLECTION
3.
4-HOUR (1b) + 4-HOURS - STOP Long Transfusion BEFORE CBC Collection
A.
LONG TRANSFUSION STOP
i.
i
B.
CBC COLLECTION
i.
i
4.
6-HOUR (1b) + 6-HOURS
i.
START Short Transfusion AFTER CBC Collection 
ii.
Also serves as the PRE (0-HOUR) CBC for the Short Transfusion Transfuse for no more 
than 60-minutes
iii.
Gently Swirl Bag for 20 revolutions every 30-minutes
A.
CBC COLLECTION
B.
SHORT TRANSFUSION START 
5.
7-HOUR (4b) + 1-HOUR - STOP Short Transfusion
A.
SHORT TRANSFUSION STOP
6.
8-HOUR (4b) + 2-HOURS
A.
CBC COLLECTION
7.
10-HOUR (4b) + 4-HOURS
A.
CBC COLLECTION
8.
12-HOUR (4b) + 6-HOURS
A.
CBC COLLECTION
TO BE COMPLETED BY DTM
Print Name of RN(s) Completing form 
Signature
Date
1)
2)
PATIENT
CRIS LABEL

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
10/07/19
PI: Willy A. Flegel, M.D.
Page 26 of 27
APPENDIX C: Protocol Worksheets
The SOLID Platelet Study, Protocol # 19-CC-0005
SHORT Transfusion followed by LONG Transfusion
INSTRUCTIONS:
- All CBCs should be collected in a 2 mL EDTA tube; please WASTE the first 1 mL at each sample collection
- CBC collection times may occur (+/-) 15 minutes of the target draw time
- Documenting ‘EXPECTED TIME’ is optional; it is provided as a reference tool for planning the CBC collection and transfusion START / STOP 
Schedule
- Please call Dr. Flegel (DTM, Protocol PI) with any questions, concerns, or if you run in to any problems, at 301.496.5000.
GROUP
BLOCK
Date (mm-dd-yy)
Randomly Assigned ID
EXPECTED TIME
(Optional)
ACTUAL TIME
PLATELETS
(109/L)
HEMOGLOBIN
(g/DL)
1.
PRE (0-HOUR)
i.
START Short Transfusion AFTER CBC collection
ii.
Transfuse for no more than 60-minutes 
iii.
Gently swirl bag for 20 revolutions every 30-minutes
A.
CBC COLLECTION
B.
SHORT TRANSFUSION START 
2.
1-HOUR  (1b) + 1-HOUR - STOP Short Transfusion
A.
SHORT TRANSFUSION STOP
3.
2-HOUR (1b) + 2-HOURS
A.
CBC COLLECTION
4.
4-HOUR (1b) + 4-HOURS
B.
CBC COLLECTION
5.
6-HOUR (1b) + 6-HOURS
i.
START Long Transfusion AFTER CBC Collection 
ii.
Also serves as the PRE (0-HOUR) CBC for the Long Transfusion 
iii.
Continue transfusing over 4-HOURS
iv.
Gently swirl bag for 20 revolutions every 30-minutes
A.
CBC COLLECTION
B.
LONG TRANSFUSION START
6.
8-HOUR (4b) + 2-HOURS
A.
CBC COLLECTION
7.
10-HOUR (4b) + 4-HOURS
A.
LONG TRANSFUSION STOP
B.
CBC COLLECTION
8.
12-HOUR (4b) + 6-HOURS
A.
CBC COLLECTION
TO BE COMPLETED BY DTM
Print Name of RN(s) Completing form 
Signature
Date
1)
2)
PATIENT
CRIS LABEL

The SOLID Platelet Study 
Protocol Number: 19-CC-0005
10/07/19
PI: Willy A. Flegel, M.D.
Page 27 of 27