Management of Venous Thromboembolic Events (VTE) in Patients With Hematologic Disorders and Treatment-Induced Thrombocytopenia: A Pilot Study
Phase: PHASE2
Conditions: Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, B-Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematologic and Lymphocytic Disorder, Hematopoietic Cell Transplantation Recipient, Myelodysplastic Syndrome, Primary Myelofibrosis, Secondary Myelofibrosis, T-Cell Non-Hodgkin Lymphoma, Thrombocytopenia, Venous Thromboembolism
Sponsor: Fred Hutchinson Cancer Center

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FRED HUTCHINSON CANCER RESEARCH CENTER  
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
 
Current version:  3 
Previous version:2 
 
Management of Venous Thromboembolic Events (VTE) in Patients 
with Hematologic Disorders and Treatment-Induced 
Thrombocytopenia:  a Pilot Study 
 
Principal Investigator:   
 David A Garcia, MD, Professor, UW (206-598-5110) 
 
Co-Investigators at FHCRC/UW 
 Roland Walter, MD PhD, Assistant Member, FHCRC, Professor, UW (206-667-7176) 
 Terry Gernsheimer, MD, Professor, UW (206-598-9066) 
 
Study Coordinator FHCRC: 
 Cody Hammer, Clinical Research Coordinator SCCA (206-606-1286); 
email:chammer@seattlecca.org 
 
Data Coordinator FHCRC: 
 Cody Hammer, Clinical Research Coordinator,, SCCA (206-606-1286); email: 
chammer@seattlecca.org 
 
Emergency Phone (24 hours):  
For non-transplant patients: Call the paging operator at the University of Washington Medical Center at 
206-598-6190, and ask for the Fellow on call for Hematology/Oncology. 
For transplant patients: Call the 8NE front desk at the University of Washington Medical Center at 206-
598-8902, and ask for the triaging provider covering the transplant service. 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
Management of Venous Thromboembolic Events (VTE) in Patients with 
Hematologic Disorders and Treatment-Induced Thrombocytopenia:  a Pilot Study 
Protocol Number 
 
Protocol Sponsor 
None 
Trial Phase 
Pilot  
Trial Type 
Noninferiority 
Clinical Indication 
Management of treatment-induced thrombocytopenia during anticoagulation 
Study Objectives 
1) Determine feasibility of an RCT comparing platelet transfusion thresholds 
of 30 x109 vs 50 x109 in anticoagulated patients 
2) Report bleeding outcomes as they would be in a full trial 
3) Report patient reported outcomes as they would be in a full trial 
Study Design 
Randomized controlled trial 
Population 
Adult patients with moderate to severe thrombocytopenia related to the treatment 
of a hematologic malignancy and/or stem cell transplant for a hematologic disorder 
who require anticoagulation for a recently diagnosed venous thrombosis. 
Primary Endpoints 
(1) Feasibility defined as ≥12 patients enrolled over a 1-year period and (2) ≥70% 
compliance with study-determined transfusion threshold at the time of count 
recovery 
Secondary Endpoints 
(1) Number of eligible patients over a 1-year period 
(2) Percentage of eligible patients providing consent 
(3) Progressive or new venous or arterial thrombosis 
(4) Bleeding events by WHO grade 
(5) Platelet transfusions 
(6) PRBC transfusions 
(7) Transfusion related outcomes 
(8) Quality of life (FACT-Th18) 
Type of control 
Institutional standard of care 
Trial Blinding 
Unblinded 
Treatment Groups  
A:  transfusion threshold of 30x109/L 
B:  transfusion threshold of 50x109/L 
Treatment Schedule 
Transfusions will be administered as needed (based upon randomized threshold) 
throughout a single period of treatment-related thrombocytopenia OR 30 days, 
whichever is shorter 
Number of trial subjects 
12 
Estimated duration of trial 
One year 
Duration of Participation 
≤ 63 days 
 
 
 
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ABBREVIATIONS 
CT scan 
Computed tomography scan 
ATE 
Arterial thromboembolism 
HSCT 
Hematopoietic Stem Cell Transplant 
SCCA 
Seattle Cancer Care Alliance 
VTE 
Venous thromboembolism 
AML 
Acute myeloid leukemia 
ALL 
Acute lymphocytic leukemia 
CML 
Chronic myeloid leukemia 
CLL 
Chronic lymphocytic leukemia 
MDS 
Myelodysplastic syndrome 
WHO 
World Health Organization  
DIC 
Disseminated intravascular coagulation  
PT 
Prothrombin time 
PTT 
Partial thromboplastin time  
V/Q 
Ventilation/perfusion scan 
APL 
Acute promyelocytic leukemia 
HLA 
Human leukocyte antigen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Contents 
1.0 
GENERAL INFORMATION ................................................................................................................. 7 
1.1  Protocol Title ...................................................................................................................................... 7 
1.2 Sponsor Information ........................................................................................................................... 7 
1.3  Investigator Information .................................................................................................................... 7 
2.0 
INTRODUCTION TO THE PROTOCOL ................................................................................................. 7 
2.1 Background and Rationale .................................................................................................................. 7 
2.2 Clinical Data to Date ............................................................................................................................ 8 
2.3 Transfusion Threshold Rationale ........................................................................................................ 9 
2.4 Risks/Benefits ...................................................................................................................................... 9 
3.0  OVERVIEW OF CLINICAL TRIAL ............................................................................................................. 10 
3.1 Study Objectives ................................................................................................................................... 10 
3.1.1 Primary Objective ....................................................................................................................... 10 
3.1.2 Secondary Objectives ................................................................................................................. 10 
3.2 Study Population ............................................................................................................................... 10 
3.3 Study Design ...................................................................................................................................... 10 
3.3.1 
Primary Endpoint ................................................................................................................ 10 
3.3.2 
Secondary Endpoints ........................................................................................................... 11 
3.4 Estimated Accrual ............................................................................................................................. 11 
3.5 Funding Source.................................................................................................................................. 11 
4.0 SAFETY CONSIDERATIONS ..................................................................................................................... 11 
4.1 Stopping Rules................................................................................................................................... 11 
5.0 SUBJECT ELIGIBILITY .............................................................................................................................. 11 
5.1 Inclusion Criteria ............................................................................................................................... 11 
5.2 Exclusion Criteria ............................................................................................................................... 12 
6.0 Subject Registration .............................................................................................................................. 12 
7.0 Treatment Plan ..................................................................................................................................... 13 
7.1 Treatment Plan Overview ................................................................................................................. 13 
7.2 Baseline/Pre-Treatment Assessment ................................................................................................ 13 
7.3 Randomization .................................................................................................................................. 13 
7.4 Administration of Transfusions ......................................................................................................... 13 
7.5 Concomitant Medication and Supportive Care Guidelines .............................................................. 14 
7.5.1 Unfractionated heparin (UFH) ................................................................................................... 14 
 
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7.5.2 Low molecular weight heparin (LMWH) .................................................................................... 14 
7.5.3 Anticoagulation Dosing Modifications ....................................................................................... 14 
7.6 Transfusion Delays/Modifications .................................................................................................... 14 
7.7 Duration of Therapy .......................................................................................................................... 15 
7.7.1 Breaking Randomization ............................................................................................................ 15 
7.8 Duration of Follow-Up ...................................................................................................................... 16 
8.0 Subject Evaluation ................................................................................................................................. 16 
8.1 
Primary Endpoint ........................................................................................................................ 16 
8.2 Secondary Endpoints ........................................................................................................................ 17 
8.1 On-Study Clinical Evaluations............................................................................................................ 18 
8.1.1 Inpatient On-Study Visits ........................................................................................................... 18 
8.1.2 Outpatient On-Study Visits ........................................................................................................ 18 
8.1.3 On-Study Visit Procedures ......................................................................................................... 18 
8.1.4 End of Treatment (EOT) Visit Schedule and Procedures............................................................ 19 
9.0 Subject Discontinuation of Active Treatment ....................................................................................... 19 
10.0 Adverse Events .................................................................................................................................... 19 
10.1  
Expedited Reporting Requirements ........................................................................................ 19 
10.2 
Definitions ................................................................................................................................... 20 
10.2.3 
Serious AE (SAE): An adverse event that results in any of the following outcomes: .......... 20 
10.3 Grading Adverse Event Severity ...................................................................................................... 20 
10.4 Monitoring, Recordings, and Standard Reporting of Adverse Events ............................................ 21 
10.5 Adverse Event Recording Period ..................................................................................................... 21 
11.0 Data and Safety Monitoring Plan ........................................................................................................ 21 
12.0 Data Management/Confidentiality ..................................................................................................... 21 
13.0 Statistical Considerations13.1 Study Design ................................................................................... 22 
13.2 Primary/Secondary Endpoints/Hypotheses and Analytical Methods............................................. 22 
13.2 Sample Size and Power ................................................................................................................... 22 
13.3 Ethnic and Gender Distribution Chart ............................................................................................. 23 
Ethnic Category ........................................................................................................................................... 23 
Racial Categories ......................................................................................................................................... 23 
14.0 Investigator Obligations ...................................................................................................................... 23 
15.0 Administrative and Regulatory Considerations .................................................................................. 23 
15.1 Protocol Interpretation and Compliance ........................................................................................ 23 
 
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15.2 Ethical Considerations ..................................................................................................................... 24 
15.3 Informed Consent ........................................................................................................................... 24 
15.4 Institutional Review Board/Ethics Committee ................................................................................ 24 
16.0  Stopping the Study ............................................................................................................................. 25 
References .................................................................................................................................................. 25 
Appendix 1:  Trial Screening, Entry, Randomization, Treatment and Monitoring Flow Diagram .............. 26 
Appendix 2:  Data Collection Throughout the Study .................................................................................. 27 
Appendix 3:  World Health Organization Bleeding Scale ............................................................................ 28 
Appendix 4:  Modified FACT-Th18 Questionnaire ...................................................................................... 30 
Appendix 5:  Suggested Management of Grade 3/4 Hemorrhagic Events ................................................. 36 
 
 
 
 
 
 
 
 
 
4 
 
 
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1.0 GENERAL INFORMATION 
1.1  Protocol Title 
 “Management of Venous Thromboembolic Events (VTE) in Patients with Hematologic Disorders 
and Treatment-Induced Thrombocytopenia:  a Pilot Study.”   
1.2 Sponsor Information 
This is a pilot study and will not be sponsored. 
1.3  Investigator Information 
Principal Investigator:  
Bethany Samuelson, MD Senior Hematology/Oncology Fellow, UW (206-667-7340) 
Co-Investigators 
David A Garcia, MD, Professor, UW (206-598-5110) 
Terry Gernsheimer, MD, Professor, UW (206-598-9066) 
Roland Walter, MD PhD, Assistant Member, FHCRC, Professor, UW (206-667-7176) 
2.0 INTRODUCTION TO THE PROTOCOL 
This document provides in depth background information and serves as a guidance document 
for the proper identification, treatment and maintenance of trial patients.  This study will be 
conducted in compliance with the IRB approved protocol, associated Federal regulations and all 
applicable IRB requirements.  The purpose of this study is to evaluate the feasibility of a 
randomized, controlled trial comparing a platelet transfusion threshold of 30x109/L to 50x109/L 
in anticoagulated patients with treatment related thrombocytopenia.  To date no clinical trial 
has ever investigated the safety and efficacy of any transfusion strategy in this setting.  This will 
be a pilot study in which approximately 12 patients will be enrolled and randomized to one of 
the two potential transfusion thresholds.  Patients will be followed clinically for bleeding, 
thrombotic and transfusion related outcomes.   
 
2.1 Background and Rationale 
Venous thromboembolic disease (VTE) is a common complication of hematologic malignancy.  
The prolonged periods of thrombocytopenia experienced by these patients during curative-
intent chemotherapy and/or hematopoietic stem cell transplant (HSCT) do not appear to 
provide protection against VTE: the rate of symptomatic VTE may be as high as 5% by day 180 
post HSCT.1 Data to guide management of thrombosis in these patients, particularly during 
periods of moderate to severe thrombocytopenia, are sparse.   
The International Society on Thrombosis and Haemostasis (ISTH) has suggested an empirical 
cut-off of 50x109/L as the minimum platelet threshold above which therapeutic anticoagulation 
is considered to be safe.  Accordingly, a recommendation has been made to consider platelet 
 
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transfusion support to maintain a platelet count above this threshold if therapeutic 
anticoagulation is warranted, as in the setting of acute VTE.2  These recommendations, 
however, have been made on the basis of expert consensus, as there is no high-quality 
evidence. 
The only data currently available in the literature comes from very small retrospective studies 
and case series.  These suggest the risk of bleeding (WHO grade 2 or greater) among patients 
with moderate to severe thrombocytopenia is relatively low (between 7.7 and 9.4% over a 3-6 
month period) when patients are initiated on anticoagulation and then transfused toward a 
goal of 40-50x109/L.3,4  Approximately half of these bleeding episodes represent major bleeding 
(3.8% of patients).4   
2.2 Clinical Data to Date 
A recent survey of malignant/nonmalignant hematologists and transfusion medicine experts 
about this topic found a marked degree of variation in proposed transfusion thresholds (ranging 
from 25 to 50x109/L).5  A recent retrospective study of eighty-two SCCA  patients with VTE 
during a period of treatment-related thrombocytopenia demonstrated that most providers 
here manage VTE with therapeutic anticoagulation, adjusting the platelet transfusion goal to 50 
x109/L, often resulting in two or more weeks of frequent platelet transfusions, potentially 
repeated in future treatment cycles.  Bleeding rates (WHO grade 2 or above) were noted to be 
somewhat higher than those previously reported in the literature (37% at 30 days), but 
comparable to or less than rates expected in patients with severe treatment related 
thrombocytopenia (transfusion threshold 10x109/L), which is as high as 70% over a period of 30 
days or less.6  While retrospective assessments of bleeding, particularly grade 2 bleeds, are 
limited and some bleeds are likely missed by this method, we expect this rate of bleeding is 
more representative of actual outcomes than those previously reported in the literature.   
Our retrospective review demonstrated that the vast majority of patients at our institution in 
this situation are transfused to maintain a platelet count ≥ 50x109/L, with the above noted 
bleeding rate.  The majority of bleeds occurred during a time when the platelet count was at or 
above this goal (mean 52 x109/L) although the retrospective nature made it impossible to 
define or compare ‘at risk’ times.  We did, however, note a number of transfusion related 
complications with this strategy including transfusion reactions in 13% of patients and volume 
overload requiring diuretic therapy or dialysis in 37% of patients.   
Patients received a median of 6 transfusions over the 30 days following diagnosis, accompanied 
by both a financial cost and a drain on resources.  While cost data were not collected as a part 
of this study, previous studies have demonstrated increased cost (as high as $5700/patient in 
2014) associated with the use of prophylactic platelet transfusions to target a platelet count of 
10x109/L.7  The higher target of 50x109/L utilized for most patients in our retrospective study 
would naturally cost considerably more, in terms of financial cost to the patients, infusion room 
time and transportation costs (outpatients), prolongation of hospital stays (inpatients) and 
burden on the finite resource of blood products. 
Another relevant issue is that of platelet refractoriness, defined as repeated, inadequate 
response to platelet transfusions.   Rates of platelet refractoriness may be as high as 21.6% 
 
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among inpatients requiring platelet transfusions, adding both to the complexity of caring for 
such patients, particularly if and when bleeding does occur, and to those additional costs 
mentioned above including monetary (increased mean hospitalization cost of $66,000 in the 
year 2000) and resource utilization (17.8 additional units of platelets/patients).8  
Furthermore, platelet refractoriness may be a sign of the bigger issue of alloimmunization 
(defined as platelet refractoriness due to antibodies against antigens found in >25% of platelet 
donors), a major issue among patients undergoing repeated cycles of chemotherapy or stem 
cell transplant, requiring long term platelet support.  Alloimmunized patients require HLA-
matched platelet units from matched/directed donors, adding further to the expense and stress 
on resources.  This is a common problem, affecting approximately five patients on the 
combined leukemia and transplant services at any given time. 
2.3 Transfusion Threshold Rationale 
As indicated above, we have demonstrated medical, financial and resource costs with the 
current institutional approach of transfusing to a threshold of 50x109/L.  We hypothesize that a 
decreased threshold will lead to decreased rates of transfusion-related complications, 
decreased burden on patients who require frequent transfusions in the inpatient and 
outpatient setting and decreased financial and resource burden.  The rationale behind the 
experimental threshold of 30x109/L arises from expert consensus, including experts in 
transfusion medicine and anticoagulation at our own institution and is being used in clinical 
practice at a number of other centers across North America with various anticoagulation 
strategies.9  Furthermore, this lower threshold is the most often used in our own institution for 
patients who are unable to maintain platelet counts >50x109/L.   
2.4 Risks/Benefits 
The primary risk of a decreased platelet transfusion threshold would be that of increased 
bleeding rates.  Platelet-type, or bleeding due to defects of primary hemostasis, tends to be 
primarily mucocutaneous, including epistaxis, gum bleeding and menorrhagia,10 rather than 
into soft tissue, joints or body cavities as with disorders of secondary hemostasis (clotting factor 
deficiencies, including those induced by anticoagulation).  Thrombocytopenic bleeding in the 
unanticoagulated population is largely low grade (WHO grade 2 or less) and rarely requires 
intervention beyond platelet transfusion.6,11   
Potential benefits of a decreased platelet transfusion threshold are numerous.  Objective 
benefits to the individual patient might include decreased rates of transfusion-related 
complications, including transfusion reactions, infections, volume overload and 
alloimmunization.  Subjective benefits of decreased transfusion frequency/requirement might 
include improved sense of well-being and quality of life, particularly for outpatients who may 
require fewer trips for medical care and benefit from increased time at home.  Systemic 
benefits might include decreased overall cost of care and decreased drain on resources, of 
particular importance when blood products are in short supply. 
 
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3.0  OVERVIEW OF CLINICAL TRIAL 
3.1 Study Objectives 
3.1.1 Primary Objective 
1.  To determine feasibility of a randomized controlled trial comparing two different 
platelet transfusion thresholds (50 x109/L vs 30 x109/L) in patients with treatment or 
malignancy-induced thrombocytopenia requiring therapeutic anticoagulation.   
3.1.2 Secondary Objectives 
1. To report outcomes as they would be in a definitive study including: 
a. Progressive or new VTE 
b. Progressive or new ATE 
c. Hemorrhagic events (WHO grade 2 or greater) 
d. A composite of a, b and c. 
e. Major bleeds (WHO grade 3 or 4) 
f. Number of platelet transfusions per patient during the study period 
g. Platelet transfusion related complications (including transfusion reactions, 
alloimmunization and volume overload) 
h. Degree to which platelet target thresholds are achieved 
3.2 Study Population 
The study population will include patients undergoing therapy for hematologic malignancy, 
including HSCT and/or curative-intent chemotherapy in the setting of acute leukemia at the 
Seattle Cancer Care Alliance/University of Washington Medical Center.  All patients must be 
experiencing treatment-related thrombocytopenia during a time period for which their treating 
physician has determined anticoagulant therapy for VTE is necessary and appropriate. 
3.3 Study Design 
This will be a feasibility/pilot study designed to assess the feasibility of a randomized, controlled 
trial, comparing a lower platelet transfusion threshold (30x109/L) to a higher platelet threshold 
(50x109/L) in patients who require anticoagulation for VTE in the setting of treatment-induced 
(either chemotherapy or HSCT) thrombocytopenia for hematologic disease.  
We are targeting an enrollment of approximately 1 patient per month.  Patients will be enrolled 
and randomized in a consecutive fashion to minimize selection bias.  Blinding will not be 
feasible in this study. 
3.3.1 Primary Endpoint 
The primary endpoint of this study will be feasibility of an RCT comparing a lower platelet 
transfusion threshold (30x109/L) to a higher platelet threshold (50x109/L) in patients who 
require anticoagulation for VTE.  To assess feasibility of a multicenter RCT we will evaluate: 
1. Number of patients eligible, reasons for ineligibility 
2. Number of eligible patients approached for the study 
 
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3. Number of patients consenting to enrollment 
4. Number of patients successfully following protocol (defined as receiving transfusions 
‘on protocol’ at the end of the study period) 
This data will then assist in determining the number of centers likely to be required to 
appropriately power a definitive study within 2-3 years. 
3.3.2 Secondary Endpoints 
1. Progressive or new VTE 
2. Progressive or new ATE 
3. Hemorrhagic events (WHO grade 2 or greater) 
4. A composite of a, b and c. 
5. Major bleeds (WHO grade 3 or 4) 
6. Number of platelet transfusions per patient during the study period 
7. Platelet transfusion related complications  
a. transfusion reactions 
b. alloimmunization  
c. volume overload 
8. Percent of days on which subjects are transfused (or transfusions are not given) in 
compliance with the threshold to which they were randomized 
3.4 Estimated Accrual 
We estimate an accrual rate of approximately one patient per month over a 12-month period.  
Based upon historical data we estimate approximately 25-30 patients per year will be eligible 
and are estimating a 45% rate of consent. 
3.5 Funding Source 
This study will be unfunded, but the PI receives salary source from a T32 grant funded by the 
National Institute of Health (T32HL007093). 
4.0 SAFETY CONSIDERATIONS 
4.1 Stopping Rules 
The study will be stopped early if major bleeding (WHO grade 3 or greater) is noted in 3 or 
more patients on the experimental arm once eight patients have been enrolled (and at least 
four randomized to the experimental arm). 
5.0 SUBJECT ELIGIBILITY 
5.1 Inclusion Criteria 
5.1.1 Any patient with non-APL acute leukemia (AML, ALL, biphenotypic leukemia) undergoing 
curative intent chemotherapy  
OR 
Any patient undergoing allogeneic HSCT for a hematologic disorder (including acute leukemia as 
above, CML, CLL, MDS, primary or secondary myelofibrosis, hypereosiniophilic syndromes, 
plasma cell disorders, B-cell or T-cell lymphoma) 
 
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5.1.2 Disease may be measurable or non-measurable 
5.1.3 Age ≥ 18 years of age 
5.1.4 Diagnosis of, symptomatic venous thromboembolism requiring therapeutic-dose 
anticoagulation (unfractionated or low-molecular weight heparin or oral anticoagulants) 
throughout the period of hematopoietic recovery. 
5.1.5 Anticipated platelet count ≤ 50 x109/L for ≥ 5 days within 72 hours of enrollment 
5.1.6 Ability to understand and the willingness to sign a written informed consent document 
5.2 Exclusion Criteria 
5.2.1 Separate episode of VTE or arterial thrombosis within 3 months of enrollment 
5.2.2 Major bleed (WHO Grade 3 or 4) within 6 months of enrollment 
5.2.3 Active bleeding (Grade 2 or higher) at the time of enrollment 
5.2.4 History of intracranial bleeding at any time 
5.2.5 Disorders of hemostasis including von Willebrand Disease, hemophilia, platelet function 
disorders 
5.2.6 Concomitant use of aspirin or non-steroidal anti-inflammatory drugs 
5.2.7 Evidence of disseminated intravascular anticoagulation (DIC) as determined by the 
patient’s primary provider.  
5.2.8 History of alloimmunization (defined as platelet refractoriness with PRA >25%) at the time 
of or prior to enrollment 
5.2.9 Uncontrolled or concurrent illness including, but not limited to, ongoing or active 
infection, unstable angina pectoris. 
5.2.10 Psychiatric illness/social situations that would limit compliance with study requirements.   
 
5.2.11 Pregnant or able to become pregnant and unwilling to use two forms of birth control 
during the study period 
 
6.0 Subject Registration  
Subjects will be identified either by patient care teams or by study personnel and then 
approached by study personnel following discussion with the patient’s attending physician.  To 
complete the registration process, the PI, Fred Hutch/UW Study Coordinator or designee will 
assign a patient study number, register the patient on the study, and enter the patient into the 
Protocol Accrual Tracking System (PATS). A complete, signed, study consent and HIPAA consent 
are required for registration.  
 
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7.0 Treatment Plan 
This study is a single-center, open-label randomized pilot study of a platelet transfusion 
threshold of 30 x109/L vs 50x109/L among patients receiving anticoagulation for, symptomatic 
VTE during periods of thrombocytopenia related to the treatment of hematologic malignancies 
at the Fred Hutchinson Cancer Research Center/University of Washington Seattle Cancer Care 
Alliance. 
7.1 Treatment Plan Overview 
In this pilot study, patients meeting the inclusion/exclusion criteria and their primary 
hematologists are asked whether or not they would agree to participate in the randomized 
treatment assignment (Appendix 1).  Patients agreeable to randomization will be assigned in a 
1:1 ratio to a higher (50x109/L) or lower (30x109/L) platelet transfusion threshold.  For those 
who wish not to be randomized the reason to decline randomization will be recorded, and 
patients will be managed according to the discretion of their primary hematologist. 
7.2 Baseline/Pre-Treatment Assessment 
The following procedures will be obtained at baseline before randomization to establish trial 
eligibility and allow patient characterization.  Results of tests and/or procedures conducted as 
per standard of care will be used to determine study eligibility.   
 Medical history including disease and treatment specifics of both the hematologic 
malignancy and the venous thrombosis, history of bleeding and anti-thrombotic therapy 
including anticoagulation and antiplatelet agents. 
 Targeted physical exam for evidence of bleeding, thrombosis and volume status 
 Most recent complete blood counts (assessed within 3 days of study day 0) 
 Most recent coagulation assays, including PT, PTT (within one week of study day 0) and 
fibrinogen (if available). 
 CT scan, V/Q scan, Doppler ultrasound or other appropriate diagnostic modality to 
document VTE diagnosis. 
7.3 Randomization 
Randomization may be obtained after or up to 72 hours before the platelet count drops below 
50x109/L, as long as the period of thrombocytopenia (platelet count <50x109/L in the absence 
of platelet transfusion support) is anticipated to last for ≥ 5 days.  Following randomization, 
patients will receive platelet transfusions on all days when the morning platelet count is below 
the threshold to which they have been randomized.  Platelet counts should be checked 
according to standard of care (daily while inpatient, ≥ 3 times per week while outpatient).   
7.4 Administration of Transfusions 
The decision to administer a platelet transfusion will be based upon the first platelet count of 
the day (whether inpatient or outpatient).  Transfusions will be administered when the count is 
below the randomized threshold and will be administered according to institutional policy.  
Post-transfusion counts will not be routinely checked unless there is reasonable expectation on 
the part of the subject’s primary providers that a single transfusion will be insufficient to 
achieve a platelet count greater than the specified transfusion threshold.  This would include a 
pre-transfusion platelet count >25x109/L below the transfusion threshold or suspicion of 
alloimmunization or other platelet refractory state.  If the post-transfusion check is below the 
specified threshold, an additional transfusion will be given.   In the instance that a morning 
 
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platelet count is above the designated threshold and a repeat count, performed later in the day 
for clinical reasons (eg prior to a procedure), is below the threshold, transfusion is allowed at 
that time.  Counts should not be repeated in a patient not meeting transfusion criteria on 
morning labs in the absence of another clinical indication. 
Transfusions may be either single-donor apheresis units or pooled units, depending on 
availability and the clinical situation.  Type and volume of each transfusion will be documented. 
 
7.5 Concomitant Medication and Supportive Care Guidelines 
Pre-medications, including acetaminophen, diphenhydramine and hydrocortisone may be 
administered in patients with a history of transfusion reaction.  In the event of a new, 
suspected transfusion reaction, supportive care should be administered urgently according to 
institutional protocol and/or the discretion of the treating provider.   
 
Therapeutic anticoagulation should be given with one of the following agents/dosing strategies. 
 
7.5.1 Unfractionated heparin (UFH) 
Heparin should be administered intravenously and may be given with or without a loading 
bolus(80 units/kg).  The initial infusion should be 18 units/kg/hr and should be titrated 
according to a goal PTT of 60-100 seconds.  Re-bolus for low PTT may be given at provider 
discretion (https://depts.washington.edu/anticoag/home/content/heparin-infusion-guidelines). 
 
7.5.2 Low molecular weight heparin (LMWH) 
LMWH may be administered either as enoxaparin or dalteparin.  Enoxaparin should be 
administered at a dose of 1mg/kg subcutaneously every 12 hours for the first 30 days following 
diagnosis of VTE, after which dosing may be reduced to 1.5mg/kg daily.  Dalteparin should be 
administered at a dose of 200 units/kg for a minimum of 30 days following diagnosis of VTE, 
after which dosing may be reduced to 150 units/kg daily. 
 
7.5.3 Anticoagulation Dosing Modifications 
Dosing modifications may be made to the above regimens for low body weight, obesity, or 
renal impairment according to the appropriate algorithms found at 
https://depts.washington.edu/anticoag/home/.   
 
If temporary discontinuation of anticoagulation or reduction to prophylactic dosing is 
considered to be necessary by the treating provider (such as in the peri-operative or peri-
procedure setting), these changes may be made at the provider’s discretion for up to a 72 hour 
period.  If anticoagulation must be held or given at a lower dose for longer than 72 hours, 
randomization will be broken and transfusions will be administered at the discretion of the 
managing provider(s).  The new threshold and anticoagulation regimen will be noted and the 
patient will be followed for outcomes until the conclusion of a 30-day period from the date of 
randomization.   
 
7.6 Transfusion Delays/Modifications 
The transfusion threshold may be temporarily increased (for up to 72 hours) if a higher platelet 
count is required for safety in the setting of a procedure (including lumbar puncture and central 
 
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line placement).  Transfusions according to the randomized threshold should resume once the 
procedure has been completed and bleeding risk has returned to baseline as determined by the 
proceduralist and/or the subject’s primary provider.   
 
Transfusion thresholds may also be temporarily increased for minor bleeding events which do 
not meet criteria for grade 3 or 4 bleeding but are bothersome to the patient (e.g. brief but 
recurrent episodes of epistaxis, vaginal bleeding).  If benefit is achieved and the patient or 
provider feel an increased transfusion threshold is required beyond 72 hours, or if this occurs 
on three or more occasions during the study period, randomization will be broken and 
transfusions will be administered at the discretion of the managing provider(s).  The new 
threshold will be noted and the patient will be followed for outcomes until the conclusion of a 
30-day period from the date of randomization.   
 
If post-transfusion thresholds are checked and patients are noted to be platelet refractory 
(defined as a <5x109/L increase in platelet count 30 minutes following a transfusion on ≥ 2 
occasions) efforts should be made, according to institutional protocol and at the discretion of 
the provider, to optimize transfusion strategy, including the use of HLA-matched units, if 
necessary.  If the subject remains refractory, despite all available interventions, and unable to 
achieve the targeted platelet threshold, the decision to continue or withhold anticoagulation 
will be made at the discretion of the primary provider and the patient will break randomization 
and be taken off protocol.   
 
Possible reasons for transfusion delay include need for specific (eg HLA-matched in the instance 
alloimmunization develops during the study period) platelets which may not be immediately 
available or lack of resources (ie infusion room beds or nurses).  A delay of no more than 24 
hours will be acceptable in either case.  Should matched platelets not be available for a period > 
24 hours, pooled platelets should be administered.  If matched platelets are unavailable for >48 
hours and/or frequently unavailable the patient will break randomization and be taken off 
protocol.  Anticoagulation may be continued or discontinued according to the managing 
provider. 
 
7.7 Duration of Therapy 
Patients will remain on protocol until (1) the platelet count spontaneously recovers to >50 x109 
for three consecutive days, in the absence of transfusions or (2) for a maximum of 30 days after 
the date of randomization, whichever is shorter.  The study period is defined as the period 
between the first on-study day (post-randomization) with platelet count <50x109 and either of 
these endpoints regardless of whether the patient receives transfusions according to protocol 
or not.  Following conclusion of the study period, transfusion thresholds will be determined by 
each subject’s primary provider. 
 
7.7.1 Breaking Randomization 
Randomization may be broken and the patient taken off protocol for any of the following 
reasons.  In all cases the new threshold will be noted and the patient will be observed for 
primary and secondary outcomes until the completion of the study period. 
 
 
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Randomization will be immediately broken and transfusions managed according to the 
subject’s managing provider(s) for any grade 3 or 4 bleeding event.  The new threshold will be 
noted and the patient will be followed for outcomes until the end of the study period.  If a 
grade 3 event completely resolves in <72 hours, is non-life-threatening, does not require 
permanent discontinuation of anticoagulation and is not reasonably expected to recur (eg 
vaginal bleeding resolved with hormonal therapy, bleeding from a wound which has been 
closed), the patient and primary provider may elect to continue with the randomized threshold.  
 
For subjects in whom discontinuation of anticoagulation is deemed necessary by managing 
providers, randomization will be broken, and a new transfusion threshold will be determined at 
the discretion of the managing team. 
 
7.8 Duration of Follow-Up 
Follow-up after completion of the study period will involve a single, in-person or telephone visit 
which will occur 30 +/- 5 days after the end of the study period.  The visit will include chart 
review, verbal history and, if appropriate, a brief physical exam for evidence of bleeding or 
thrombosis.   
8.0 Subject Evaluation 
 
8.1 Primary Endpoint 
As this is a feasibility study, the primary goal is to determine the number of centers and 
duration of study that would be required to appropriately power a multicenter trial to evaluate 
for noninferiority.  Toward this aim number of patients eligible, reasons for ineligibility, number 
of eligible patients approached for the study number of patients consenting to enrollment and 
number of patients successfully following protocol will be reported and used, according to the 
table below, to design a larger trial  As patients may break randomization and go off protocol 
for a number of reasons (described in section 9.0 below), the proportion of patients remaining 
on protocol at the end of the study period will be a second key measure of feasibility.   
# Eligible patients/year 
% Eligible patients 
consented 
Number of sites 
Years of duration 
< 15 
20-30 
50 
2 
 
30-40 
35 
2 
 
40-50 
28 
2 
15 - 25 
20-30 
25 
2 
 
30-40 
18 
2 
 
40-50 
15 
2 
>25 
20-30 
17 
2 
 
30-40 
12 
2 
 
40-50 
9 
2 
< 15 
20-30 
33 
3 
 
30-40 
24 
3 
 
40-50 
19 
3 
15 - 25 
20-30 
17 
3 
 
30-40 
12 
3 
 
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40-50 
10 
3 
>25 
20-30 
12 
3 
 
30-40 
8 
3 
 
40-50 
7 
3 
 
8.2 Secondary Endpoints 
Secondary endpoints will be monitored and reported as in a full, randomized controlled trial.  
Endpoints will be defined in the following way. 
8.2.1 Progressive or new VTE 
All diagnoses of new or progressive VTE will require imaging confirmation, defined as 
intraluminal filling defect(s) on contrast-enhanced computed tomography (CT) or 
incompressible venous segment(s) on ultrasonography.  In the absence of these studies, a new 
mismatched segmental defect or a greater perfusion defect compared with baseline on a 
ventilation/perfusion (V/Q) scan, will also be considered confirmatory.   A diagnosis of 
progression will require unequivocal extension of thrombus on repeat imaging.  Presence or 
absence of symptoms (including pain and swelling in the setting of VTE, pain, dyspnea, hypoxia, 
tachycardia or hypotension in the setting of PE) will be documented.  Events will be 
independently adjudicated by physicians blinded to the predictor data. 
8.2.2 Progressive or new ATE 
Diagnoses of new ATE will require either (1) documented acute electrocardiographic (EKG) 
changes compatible with myocardial injury and/or serum biochemical changes diagnostic of 
myocardial infarction (2) documented imaging (CT or magnetic resonance imaging (MRI)) 
changes compatible with infarct due to embolism in the presence of a new neurological deficit 
(3) imaging demonstrated intraluminal filling defects in an arterial distribution accompanied by 
symptoms of acute ischemia (acute onset pain, pallor, loss of pulses or other end-organ 
damage). 
8.2.3 Hemorrhagic events (WHO grade 2, 3 or 4) 
Hemorrhagic events will be defined according to the WHO bleeding criteria (Appendix 3).  
Grade 3 events will be defined as events requiring packed red cell transfusions over and above 
the subject’s routine transfusion needs.  This will be determined based on the clinical judgment 
of an investigator.   
8.2.4 Number of platelet transfusions  
Only transfusions administered during the study period will be included.  Transfusions 
administered ‘off protocol’ or inappropriately while ‘on protocol’ will also be counted.  Type 
(apheresis unit or pooled packs) and volume of transfusion will also be noted. 
8.2.5 Platelet transfusion related complications  
 
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Platelet transfusion reactions will be defined as any of the following (1) new onset fever, chills, 
hypoxia, urticarial rash or hemodynamic instability during or within 1-2 hours of administration 
of a transfusion with or without hemolysis (2) transfusion related lung injury (TRALI) defined as 
new onset dyspnea/tachypnea and hypoxia within 6 hours of transfusion, accompanied by 
bilateral pulmonary edema on imaging, with or without fever and hypotension.   
Volume overload will be defined as evidence of edema (pulmonary, extremity or other 
dependent area) on exam and/or imaging, requiring treatment with diuretics and/or dialysis.  
Contribution of platelet transfusions to volume overload will be determined based on the 
clinical judgment of an investigator. 
Alloimmunization will be defined as a combination of platelet refractoriness (as defined in 
section 7.6) accompanied by a panel reactive antibody result of >25%. 
8.2.6 Percent of days on which subjects are transfused (or transfusions are not given) in 
compliance with the threshold to which they were randomized 
Study staff will determine the appropriateness of transfusion management (in accordance with 
the protocol) each on-protocol day of the study period.  The frequency with which transfusions 
are given despite a platelet count above the determined threshold (not including 72 hour 
temporary increases or procedures as outlined in section 7.6) will be documented, as will the 
frequency with which transfusions are not administered within 24 hours after a platelet count 
below the determined threshold.   
8.1 On-Study Clinical Evaluations 
Targeted history and physical exam, bleeding diaries and FACT-Th18 questionnaires (Appendix 
4) will be conducted in the manner outlined below.  Laboratory studies will be conducted per 
standard of care in this institution, which is a minimum of three times per week.   
 
8.1.1 Inpatient On-Study Visits 
While inpatient at the University of Washington Medical Center, patients will be seen three 
times per seven-day period, visits should be as close to every other day as possible and no more 
than 3 days apart.  
 
8.1.2 Outpatient On-Study Visits 
While outpatients, being followed at the Seattle Cancer Care Alliance, patients will be seen 
weekly on the same day as other routinely scheduled care (eg clinic visits, nursing assessments, 
infusion center visits).  Visits should be as close to every seven days as possible and no more 
than 12 days apart. 
 
8.1.3 On-Study Visit Procedures 
The following tests and procedures are completed, although not all tests may be done at each 
visit. 
 Targeted history for symptoms of bleeding or thrombosis 
 Targeted physical exam for symptoms of bleeding or thrombosis, volume overload 
 Most recent complete blood counts (assessed within one day) 
 
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 FACT-Th18 Questionnaire (Appendix 5) will be completed weekly 
 Bleeding diary (Appendix 4) will be reviewed at each visit and collected weekly 
 Additional chart review including but not limited to documentation of suspected 
hemorrhage, thrombosis and/or transfusion reaction, transfusion administration, 
vascular imaging data, administration of anticoagulants, antiplatelet agents, 
antifibrinolytic or other pro-coagulant therapies and/or diuretics, dialysis for volume 
overload. 
 
8.1.4 End of Treatment (EOT) Visit Schedule and Procedures 
This visit will occur on the first outpatient visit following platelet count recovery (within one 
week) or within three days of count recovery in the inpatient setting.  Procedures will include a 
verbal history of any bleeding or thrombotic symptoms, focused physical exam for evidence of 
eithers, FACT-Th18 questionnaire and results of the most recent complete blood count ordered 
by the patient’s provider.   
9.0 Subject Discontinuation of Active Treatment 
 
Randomization may be broken and active treatment discontinued for any of the reasons 
outlined in section 7.7.1.  Additionally, active treatment may be discontinued for any of the 
following reasons.   
9.1 All reasons for discontinuation of treatment must be documented and the study team must 
be notified within 24 hours if a subject discontinues treatment.  Reasons include:   
 
9.1.1 Completion of protocol treatment. 
 
9.1.2 Initiation of any malignancy-directed therapy other than that being given at the time of 
randomization        
 
9.1.3 Withdrawal of consent; the patient may withdraw from the study at any time for any 
reason.  
 
9.1.4 At investigator’s discretion 
 
9.1.5 Pregnancy 
 
9.1.6 Grade 3 or 4 bleed (Appendix 3) 
 
9.1.7 progressive or new VTE or ATE requiring change in antithrombotic management 
 
9.2 For any reason other than withdrawal of consent, subjects will continue to be observed for 
the study period (until platelet count recovery or 30 days from randomization, whichever 
comes first).  They will also have the same 30 day follow up (described in section 7.8) as 
patients who remain on active treatment. 
10.0 Adverse Events 
10.1  Expedited Reporting Requirements 
In accordance with Fred Hutch/UW Cancer Consortium IRB policy, all adverse events (AEs; 
whether occurring on-site or off-site), which in the opinion of the principal investigator (PI) are 
(1) unexpected, and (2) related or possibly related to the research, and (3) serious or suggests 
 
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that the research places research participants or others at a greater risk of physical or 
psychological harm than was previously known or recognized, will be submitted to the IRB 
within ten (10) calendar days of learning of the problem. Both the “Expedited Reporting Form 
for Unanticipated Problems or Noncompliance” and the “Adverse Event Reporting Form”, or 
equivalent forms, will be completed for this reporting.  
 
10.2 
Definitions 
10.2.1 Adverse Event (AE): Any harm or untoward medical occurrence in a research participant 
administered a medical product, medical treatment or procedure even if it does not necessarily 
have a causal relationship with the product, treatment, or procedure. An adverse event can be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medical product, medical 
treatment, or procedure whether or not considered to be related. Mechanisms of obtaining 
information on AE include study visits, hospital progress and discharge notes.  
10.2.2 Related or Possibly Related AE: An AE is “related or possibly related to the research 
procedures” if in the opinion of the principal investigator, it was more likely than not caused by 
the research procedures. AEs that are solely caused by an underlying disease, disorder or 
condition of the subject or by other circumstances unrelated to either the research or any 
underlying disease, disorder or condition of the subject are not “related or possibly related”. If 
there is any question whether or not an AE is related or possibly related, the AE should be 
reported. 
10.2.3 Serious AE (SAE): An adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening adverse event (real risk of dying)  
• Prolongation of hospitalization* 
• Persistent or significant disability/incapacity/or change in psychosocial status 
• Congenital anomaly 
• Requirement of intervention to prevent permanent impairment or damage 
*Hospitalization itself will not be considered a serious adverse event if required for 
complications or treatment of the underlying hematologic malignancy, treatment or comorbid 
conditions.  Hospitalization will be considered a SAE if it fulfills the criteria for a serious and 
unexpected adverse event as otherwise described. 
10.2.4 Unexpected AE: An unexpected adverse event is defined as an event that has a nature or 
severity, or frequency that is not consistent with the applicable investigator brochure, or the 
prior medical condition of the subject or other treatment given to the subject.  “Unexpected,” 
as defined in this study, refers to an adverse experience that has not been previously observed 
and reported in patients requiring anticoagulation and/or experiencing thrombocytopenia. 
10.3 Grading Adverse Event Severity 
All bleeding will be graded in severity according to the WHO criteria (Appendix 3).  All other 
(unexpected) AEs will be graded in severity according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 (http://ctep.cancer.gov). If a CTCAE criterion does not 
exist, the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), 
 
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Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the maximum 
intensity of the adverse event.  
 
10.4 Monitoring, Recordings, and Standard Reporting of Adverse Events 
Only grade ≥2 adverse events will be recorded, graded, and reported as appropriate per 10.1. 
Grade ≤ 3 heme AEs are anticipated for all subjects based upon inclusion criteria, are not 
anticipated to be related to study procedures and will not be reported.  Grade 4 heme AEs will 
be reported, however.  AEs will be collected for the duration that the patient remains on 
protocol. If a subject decides to terminate the study early or breaks randomization or any of the 
reasons described in 7.7.1 their medical record will continue to be followed for AEs for the 
study period as defined in 7.6. AEs that do not meet the requirement for expedited reporting 
will be reported to the IRB as part of the annual renewal of the protocol.  
 
10.5 Adverse Event Recording Period 
AEs will be monitored and recorded in the study database from the first time the subject is 
simultaneously (1) randomized to a transfusion threshold and (2) experiences a platelet count 
<50x109/L to the end of the study period. AEs with an onset date prior to the first day of the 
study period will not be recorded, except in the case of clinically significant worsening of the AE 
during the specified AE monitoring time frame.  
11.0 Data and Safety Monitoring Plan 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, Fred Hutch Clinical Research Support (CRS) coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or Fred 
Hutch employees unaffiliated with the conduct of the study.  Independent monitoring visits 
occur at specified intervals determined by the assessed risk level of the study and the findings 
of previous visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) and the 
Fred Hutch /University of Washington Cancer Consortium Institutional Review Board (IRB).  The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating 
subjects.  The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects.  Approval of committees as applicable 
is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
12.0 Data Management/Confidentiality 
Research data will be recorded in a study-specific, password protected database using a unique 
study ID for each patient to assure patient confidentiality. Data from source documents will be 
transcribed into this database. Source documents are documents where patient data are 
recorded and documented for the first time. They include, but are not limited to, hospital 
 
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records, clinical and office charts, laboratory notes, memoranda, quality of life assessments, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in the clinical trial. There will be no case reports forms (CRFs) used for 
this trial. 
The investigator will ensure that data collected conform to all established guidelines. Each 
subject is assigned a unique subject number to protect subject confidentiality. Subjects will not 
be referred to by this number, by name, or by any other individual identifier in any publication 
or external presentation. The licensed medical records department, affiliated with the 
institution where the subject receives medical care, maintains all original inpatient and 
outpatient chart documents. Patient research files will be maintained under control of the 
Principal Investigator and/or study team and kept in a locked office or file room within a secure 
building. Access to the study database will be restricted by electronic password protection and 
restricted access to computers (i.e., locked offices).  
13.0 Statistical Considerations 
13.1 Study Design 
This is a pilot study of two different platelet transfusion thresholds in patients receiving 
anticoagulation during periods of thrombocytopenia related to the treatment of hematologic 
malignancies.  Patients will be randomized to transfusion thresholds in a 1:1 fashion. 
13.2 Primary/Secondary Endpoints/Hypotheses and Analytical Methods 
The primary endpoints of this study are (1) enrollment and (2) compliance.  Enrollment will be 
described at the end of a 12-month period and (2) compliance will be evaluated as described in 
section 3.3.1.  The secondary endpoints described in sections 3.3.2 will also be reported and 
analyzed with descriptive statistics only.  This trial is not powered to detect statistically 
significant differences between the study arms for these clinically important endpoints.  Rather, 
the primary goal is to establish feasibility for enrollment into a formal trial. 
13.2 Sample Size and Power 
As this study is purely descriptive, it will not be powered to determine efficacy or safety of 
either intervention.  The sample size has been chosen based upon the rate of enrollment 
necessary to establish the feasibility of an appropriately powered study.   
 
A full trial would be a non-inferiority study powered for safety.  The primary outcome would be 
WHO Grade 2 or above bleeding and the study would be powered to identify a relative risk of 
1.4 or greater.  This is based upon trials of anticoagulation, in which RR of 1.4 for bleeding is 
standardly considered to be acceptable.  
 
Based on historical data, we assume a bleeding rate of ≥40% at the higher threshold.  A relative 
risk of 1.4 would correspond to an assumed-true bleeding rate at the lower threshold of 56% 
(.56/.40 = 1.4).  If we assume that the true bleeding rate at the lower threshold is also 40%, 
then with 125 patients per treatment arm, we’ll have approximately 84% power to deem the 
lower threshold non-inferior to the higher threshold (at the one-sided significance level of .05).  
 
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In other words, if the assumed-true bleeding rates in each arm are 40%, then the upper limit to 
the 95% confidence limit for the difference between the estimate bleed rates (bleed rate at 
lower threshold – bleed rate at higher threshold) is below 0.16 with a probability of 0.84.  If we 
assume a true bleeding rate of 60% at the higher threshold, then a relative risk of 1.4 (or less) 
corresponds to an assumed-true rate in the lower threshold of 84% (or less).  If the assumed-
true bleeding rates in both arms is 60%, then 125 patients/arm yield approximately 99% power 
to deem the lower threshold as non-inferior (as defined above).  
Anticipating a two-year enrollment period across fifteen sites, expecting that other sites will 
enroll at a slightly lower rate than the primary site randomization of 12 patients in a one-year 
period at our Center will be a rough benchmark for feasibility (although other factors will be 
considered when judging this approach as feasible for purposes of designing the randomized 
Phase III trial, including compliance with the study protocol and event rate).  
13.3 Ethnic and Gender Distribution Chart 
TARGETED / PLANNED ENROLLMENT:  Number of Subjects 
Ethnic Category 
Sex / Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
5 
7 
12 
Ethnic Category Total of All Subjects 
5 
7 
12 
Racial Categories 
American Indian / Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
0 
0 
0 
White 
5 
7 
12 
Racial Categories:  Total of All Subjects 
5 
7 
12 
14.0 Investigator Obligations 
The PI is responsible for the conduct of the clinical trial at the site and is responsible for 
personally overseeing the treatment of all study subjects. The PI must assure that all study site 
personnel, including sub-Investigators and other study staff members, adhere to the study 
protocol and to all applicable regulations and guidelines regarding clinical trials both during 
and after study completion. 
All subjects are informed of the nature of the program, its possible hazards, and their right to 
withdraw at any time, and each subject signs a form indicating their consent to participate prior 
to receiving any study-related procedures. 
15.0 Administrative and Regulatory Considerations 
15.1 Protocol Interpretation and Compliance 
The procedures defined in the protocol are carefully reviewed by the PI and his/her staff prior 
to the time of study initiation to ensure accurate representation and implementation. Protocol 
 
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amendments, if any, are reviewed and implemented promptly following IRB/EC and relevant 
Competent Authorities approval.  
 
 15.2 Ethical Considerations 
The Investigator agrees to conduct this study in accordance with applicable United States FDA 
clinical trial regulations and guidelines, the ICH (E6) GCP guidelines, the IRB/EC and local legal 
requirements and with the Declaration of Helsinki (1989). The Investigator will conduct all 
aspects of this study in accordance with all national, state, and local laws of the applicable 
regulatory agencies. 
15.3 Informed Consent 
The PI and qualified designees assume the responsibility of obtaining written Informed Consent 
for each subject or the subject’s legally authorized representative before any study-specific 
procedures are performed. 
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to 
participate in the study. To avoid introduction of bias, the Investigator must exercise no 
selectivity with regard to offering eligible subjects the opportunity to participate in the study. 
All candidate subjects will receive a comprehensive explanation of the proposed treatment, 
including the nature of the therapy, alternative therapies available and other factors that are 
part of obtaining a proper Informed Consent. Subjects will be given the opportunity to ask 
questions concerning the study, and adequate time to consider their decision to or not to 
participate. Informed Consent will be documented by the use of a written Consent Form that 
includes all the elements required by ICH guidelines. The form is to be signed and dated by the 
subject or subject's legally authorized representative and by the person who administers the 
consent process. A copy of the signed form will be given to the person who signed it and the 
original signed Consent Form will be maintained with the subject’s study records. If an 
amendment to the protocol changes the subject participation schedule in scope or activity, or 
increases the potential risk to the subject, the Informed Consent Form must be amended. Any 
amended Informed Consent must be reviewed by the Sponsor or designee and approved by the 
IRB/EC prior to use. The revised Informed Consent Form must be used to obtain re-consent 
from any subjects currently enrolled in the study if the subject is affected by the amendment, 
and must be used to document consent from any new subjects enrolled after the approval date 
of the amendment. 
 15.4 Institutional Review Board/Ethics Committee 
The PI will assure that an appropriately constituted IRB/EC that complies with the requirements 
of 21 CFR Section 56 or written assurance of compliance with ICH (E6) guidelines will be 
responsible for the initial and continuing review and approval of the clinical study. Before 
initiation of the study, the PI or designee will forward copies of the protocol and Consent Form 
to be used for the study to the IRB/EC for its review and approval. The PI or designee will also 
assure that all changes in the research activity and all unanticipated problems involving risks to 
human subjects or others will be reported promptly to the IRB/EC, and that no changes will be 
made to the protocol without prior IRB/EC approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. The Investigator or designee will be 
responsible for submitting periodic progress reports to the IRB/EC at intervals appropriate to 
 
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the degree of subject risk involved in the study, but not less than once per year and at the 
completion or termination of the study. 
16.0  Stopping the Study 
 
The investigators may decide to stop the study at any point, for any reason.  The following 
reasons will lead to premature termination of the trial 
 WHO grade 3/4 bleeding rate <30% in the lower transfusion threshold arm following 
enrollment of 8 patients 
 
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Carrier M, Khorana AA, Zwicker J, et al. Management of challenging cases of patients with 
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Campbell PM, Ippoliti C, Parmar S. Safety of anticoagulation in thrombocytopenic patients with 
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Campbell HE, Estcourt LJ, Stokes EA, et al. Prophylactic platelet transfusions in patients with 
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Meehan KR, Matias CO, Rathore SS, et al. Platelet transfusions: utilization and associated costs 
in a tertiary care hospital. Am J Hematol. 2000;64(4):251-256. 
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Miao Y, Soff GA, Parameswaran R, Wills J, Mantha S. Enoxaparin Dose Reduction for 
Thrombocytopenia in Patients with Cancer: A Quality Assessment Study. Blood. 2015;126(23):429-429. 
10. 
Kirchmaier CM, Pillitteri D. Diagnosis and Management of Inherited Platelet Disorders. Transfus 
Med Hemother. 2010;37(5):237-246. 
11. 
Stanworth SJ, Estcourt LJ, Powter G, et al. A no-prophylaxis platelet-transfusion strategy for 
hematologic cancers. N Engl J Med. 2013;368(19):1771-1780. 
  
 
 
 
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Appendix 1:  Trial Screening, Entry, Randomization, Treatment and Monitoring Flow 
Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with thrombocytopenia related to heme 
malignancy and requiring anticoagulation for VTE 
Platelet transfusion threshold 50x109/L 
Platelet transfusion threshold 30x109/L 
Active Management 

Transfuse to goal threshold based on AM platelet count 

Threshold may be temporarily increased pre-procedure 
No bleeding or WHO grade 1 bleeding 
Manage per randomization 
 WHO grade 2 bleeding 
Threshold ≥50x109/L at physician discretion 
Break randomization (transfusion threshold per managing physician) 

Any episode WHO grade 3 or 4 bleeding 

≥ 2 episodes WHO grade 2 bleeding or bleeding requiring plt threshold 
≥50x109/L for 72 hours 

Plt count ≥50x109/L for 72 hours without transfusions or day 30 
Follow-up period 
30 days after breaking randomization 
Randomization 
 
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Appendix 2:  Data Collection Throughout the Study 
 
 
 
Study Period 
Data Collection 
Screening 
Age, gender 
Diagnosis and treatment 
6 month bleeding/thrombosis history 
(including active bleeding) 
If ineligible:  reason for ineligibility 
Consent 
If consent refused:  reason for refusal 
Enrollment 
Malignancy diagnosis and treatment 
Lifetime bleeding/thrombosis history 
Transfusion history 
Anticoagulation plan (per managing physician) 
Weight, CBC, metabolic panel 
Active management 
Daily platelet count 
Platelet transfusion threshold (and reason for 
deviation if present) 
Transfusion data (product, number, response 
when available) 
Daily bleeding assessment 
VTE symptom assessment 
Anticoagulation management (missed or held 
doses) 
30 Day Follow-up 
Platelet count 
Current platelet threshold 
Current anticoagulation plan 
30 day bleeding/thrombosis history 
 
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Appendix 3:  World Health Organization Bleeding Scale 
 
 
 
 
 
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Appendix 4:  Outpatient Bleeding Diary 
Instructions for completing your Bleeding Assessment: 
 
Please complete this checklist in the morning on a daily basis.  
 
Please think about what has happened and changed over the past 24 hours. 
 
If you are concerned about any of your signs or symptoms, contact your doctor: ____________________________ 
 
If you have questions about completing this form, contact your study team:  _____________________________ 
 
Call 911 for life threatening emergencies. 
Who is filling out 
this form? 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
□ Patient 
□ Caregiver 
Locati
on 
Did you 
notice any... 
Each morning, answer questions for yesterday:  Yes – No  – Unsure   
For example, on Monday, tell us about Sunday 
 
 
 
       /___         
Monday 
 
       /___         
Tuesday 
 
       /___         
Wednesday 
 
       /___         
Thursday 
 
       /___         
Friday 
 
       /___         
Saturday 
 
       /___         
Sunday 
Mouth 
Bleeding from 
your gums, 
inside cheeks, 
roof of mouth, 
under tongue or 
lips? 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Yes – more 
than 30 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
 
Blood blisters in 
or around your 
mouth? 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Yes – more 
than 5 
 
Yes – less than 
5 
 
No 
 
Unsure 
Nose 
Bleeding from 
the nose? 
Yes – more 
than 30 
Yes – more 
than 30 
Yes – more 
than 30 
Yes – more 
than 30 
Yes – more 
than 30 
Yes – more 
than 30 
Yes – more 
than 30 
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minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
minutes 
 
Yes – less than 
30 minutes 
 
No 
 
Unsure 
Skin 
Very small red 
or purple spots 
on your skin 
(petechiae, less 
than 1/8 inch 
(about the size 
of a pencil tip) 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
 
If you have 
these spots, 
is it new? 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
 
Bruising greater 
than 1 inch? 
1 inch =  
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
Yes – 1-2 
bruises 
 
Yes – many 
bruises 
 
No 
 
Unsure 
 
Is the bruise 
new? 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
 
If your 
bruise is not 
new, is it 
larger than 
yesterday? 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
Yes          No 
 
If you have 
bruises, how 
big is the 
biggest one? 
 
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
Less than an 
inch 
 
More than an 
inch  
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More than 4 
inches 
 
More than 4 
inches 
 
More than 4 
inches 
 
More than 4 
inches 
 
More than 4 
inches 
 
More than 4 
inches 
 
More than 4 
inches 
 
 
4 inches =  
 
Joints/
Muscles 
Swelling or pain 
in your joints or 
muscles? 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
 
If yes, 
where? 
 
 
 
 
 
 
 
Invasive 
site 
Bleeding or 
oozing near IV 
site, implanted 
port, where you 
had blood 
drawn, or IV 
catheters? 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
 
If yes, 
where? 
 
 
 
 
 
 
 
 
If yes, for 
how long in 
minutes? 
 
 
 
 
 
 
 
Vomit 
Bright red, 
visible bloody 
streaks, clots, 
coffee ground 
like? 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Stool 
Bright red, 
bloody streaks, 
clots, black or 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
Yes – only on 
the tissue 
 
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tarry (sticky 
black)? 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Yes – in the 
toilet, too 
 
No 
 
Unsure 
Urine 
Pink, red, 
bloody drops, 
clots? 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Vaginal   
 
□ Skip if 
male 
 
Vaginal 
bleeding, 
including your 
period? 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Yes – spotting 
only 
 
Yes – flow 
requiring pads 
 
No 
 
Unsure 
Cough 
Are you 
coughing up 
blood? 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Other Bleeding Symptoms 
 
If yes, 
describe
: 
 
 
 
 
 
 
 
 
Blood Transfusions 
Blood 
Transfus
ions 
Red blood cells 
and/or platelet 
transfusions at 
a non-study site 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
Yes  
 
No 
 
Unsure 
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If yes, 
where: 
 
 
 
 
 
 
 
 
 
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Appendix 5:  Modified FACT-Th18 Questionnaire 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
 a bit 
Very 
much 
 
An5 
I have energy  
0 
1 
2 
3 
4 
 
An7 
I am able to do my usual activities 
 
0 
1 
2 
3 
4 
 
Th1 
I bleed easily  
0 
1 
2 
3 
4 
 
Th2 
I bruise easily  
0 
1 
2 
3 
4 
 
Th3 
I worry about problems with bruising or bleeding 
 
0 
1 
2 
3 
4 
 
Th4 
I worry about the possibility of serious bleeding 
 
0 
1 
2 
3 
4 
 
Th5 
I am bothered by nosebleeds  
0 
1 
2 
3 
4 
 
Th6 
I am bothered by bleeding in my gums or mouth 
 
0 
1 
2 
3 
4 
 
Th7 
I am bothered by pinpoint bruising beneath my skin 
0 
1 
2 
3 
4 
 
Th8 
I am bothered by blood in my urine or stool  
0 
1 
2 
3 
4 
 
Th9 
I am inconvenienced by platelet transfusions 
 
0 
1 
2 
3 
4 
 
HI7 
I feel fatigued  
0 
1 
2 
3 
4 
 
Th 
10
I avoid or limit physical activity (because of concern with 
bleeding or bruising)  
 
0 
 
1 
 
2 
 
3 
 
4 
 
Th 
11 
I avoid or limit social activity (because of concern with 
bleeding or bruising)  
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
Th 
I am frustrated by not being able to do my usual activities
 
 
0 
1 
2 
3 
4 
 
Th 
13 
I worry that my treatment will be delayed (because of low 
blood counts)  
 
0 
 
1 
 
2 
 
3 
 
4 
 
Th 
14 
I worry that my treatment dose will be reduced (because 
of low blood counts)  
 
0 
 
1 
 
2 
 
3 
 
4 
 
Th 
For women only: I am bothered by vaginal bleeding  
0 
1 
2 
3 
4 
 
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Appendix 6:  Suggested Management of Grade 3/4 Hemorrhagic 
Events 
Supportive care should be initiated for all grade 3/4 hemorrhagic events.  This may include but not be 
limited to: 
 
Local control measures, including surgical interventions if indicated 
 
Platelet transfusion 
 
PRBC transfusion 
 
Cryoprecipitate in the event of low fibrinogen 
 
IV fluids prior to arrival of the above products for hemodynamic instability 
 
Anti-fibrinolytic agents (e.g. epsilon amino caproic acid or tranexamic acid) 
The decision of whether or not to use more aggressive pro-hemostatic interventions (including 
anticoagulant-specific antidotes, where available) is based on a number of factors, including 
anticoagulant agent and half-life, time since last dose, renal function and location/severity of bleed.  If 
reversal is deemed necessary by the managing provider, suggested approaches may be found at 
https://depts.washington.edu/anticoag/home/sites/default/files/GUIDELINES%20FOR%20REVERSAL%2
0OF%20ANTICOAGULANTS%20February%202016.pdf.  
 
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