Unfractionated Heparin in Acute Chest Syndrome: A Pilot Feasibility Randomized Controlled Trial of Unfractionated Heparin vs. Standard of Care in Acute Chest Syndrome
Phase: PHASE2
Conditions: Acute Chest Syndrome, Sickle Cell Disease
Sponsor: Craig Seaman

Protocol Title: Feasibility Study of Unfractionated Heparin in Acute Chest Syndrome 
 
NCT: NCT02098993 
 
 
PRINCIPAL INVESTIGATOR:  
Craig D. Seaman, MD, MS 
 
 
 
 
 
Assistant Professor of Medicine 
Department of Medicine 
 
 
 
 
 
University of Pittsburgh  
 
 
 
 
 
Associate Director HCWP 
 
 
 
 
 
3636 Blvd of the Allies 
 
 
  
Pittsburgh, PA 15213 
 
 
 
 
 
Telephone: 412-209-7308 
 
 
CO-INVESTIGATORS:      
Margaret Ragni, MD, MPH          
Enrico Novelli, MD, Assistant Professor of Medicine        
Professor of Medicine        
 
Greg Kato, MD, Professor of Medicine 
University of Pittsburgh     
 
Mark Gladwin, MD, Professor of Medicine 
Director HCWP                  
 
Vascular Medicine Institute 
3636 Boulevard Allies        
 
BST E1240 
Pittsburgh, PA 15213          
 
200 Lothrop St. 
 
 
 
 
 
Pittsburgh, PA, 15261 
 
 
 
 
SOURCE OF SUPPORT:      
Vascular Medicine Institute 
 
University of Pittsburgh Medical Center 
 
 
Updated: 5/8/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
Abstract 
 
This is a single-center, randomized controlled, open-label, pilot study to determine the feasibility of 
performing a larger multicenter phase III trial to assess the effects of unfractionated heparin (UFH) in acute 
chest syndrome (ACS). Adult patients with sickle cell disease (HbSS, SC, or Sβ0) aged 18 years or older 
admitted to the University of Pittsburgh Medical Center (Presbyterian, Montefiore, Magee, Shadyside) hospitals 
with a diagnosis of ACS will be eligible for screening to participate in the trial. Subjects meeting inclusion and 
exclusion criteria and consenting to study will be randomized within 24 hours of diagnosis to one of two 
treatment arms, Arm A, anticoagulation and standard of care, or Arm B, no anticoagulation and standard of 
care. Weight-adjusted UFH will be given at doses of 80 units per kilogram followed by 18 units per kilogram per 
hour intravenously for 7 days, or until discharge, if discharge is shorter than 7 days. UFH will be monitored by 
standard protocol to maintain the anti-Xa UFH level in the therapeutic range per institutional guidelines. 
Standard of care will include intravenous fluids, antibiotics, supplemental oxygen, incentive spirometry, pain 
medication, red blood cell transfusions, and exchange transfusion. Prespecified feasibility criteria consists of 
the ability to enroll potential study participants, which includes the timely notification of hospitalized patients 
with ACS, the capacity to consent eligible individuals, and the ability to appropriately randomize screened 
patients within 24 hours of diagnosis. Additional feasibility objectives involve ensuring appropriate inclusion 
and exclusion criteria, proper administration of the study drug, and the ability to completely and accurately 
collect clinical data of interest. The final aim of our pilot study is to provide preliminary data, with respect to 
treatment effect and variance, to allow sample size calculation in a larger trial given the lack of data available 
to help guide this process. All clinical outcomes, except the number of red blood cell transfusions administered, 
will be defined as beginning with randomization and measured in hours. The primary clinical outcome is 
duration of hospitalization. Secondary clinical outcomes include the duration of hypoxemia, duration of fever, 
duration of leukocytosis, duration of moderate to severe pain, total dose of opioids, and the number of red 
blood cell transfusions administered. Additional clinical outcomes will include the rate of transfer to the 
intensive care unit, requirement for mechanical ventilation, and development of multiorgan dysfunction 
syndrome. Further data collected will include demographics and medical information. A sample size of 20 
subjects for the pilot study is based on clinical rather than statistical considerations and should provide a 
preliminary estimate of primary and secondary clinical outcomes and assess prespecified feasibility criteria as 
detailed above. This is a pilot feasibility study, so comparisons will be descriptive, including frequencies and 
percentages for categorical variables and mean, median, range, and standard deviation for continuous 
variables. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
1.0 Objective and Specific Aims 
 
The purpose of this single-center, randomized controlled, open-label, pilot study is to determine the 
feasibility of performing a larger multicenter phase III trial to assess the effects of unfractionated heparin (UFH) 
in acute chest syndrome (ACS). Specific feasibility criteria include the ability to enroll potential study 
participants, which entails the timely notification of all hospitalized patients diagnosed with ACS, the capacity to 
consent eligible individuals, and the ability to appropriately randomize screened patients within 24 hours of 
diagnosis. Additional feasibility objectives involve ensuring appropriate inclusion and exclusion criteria, proper 
administration of the study drug, and the ability to completely and accurately collect clinical data of interest. 
The final aim of our pilot study is to provide preliminary data, with respect to treatment effect and variance, for 
future sample size calculations given the lack of existing data to help guide this process. The primary clinical 
outcome is duration of hospitalization. Secondary clinical outcomes include the duration of hypoxemia, duration 
of fever, duration of leukocytosis, duration of moderate to severe pain, total dose of opioids, and the number of 
red blood cell transfusions administered. Additional clinical outcomes will include the rate of transfer to the 
intensive care unit (ICU), requirement for mechanical ventilation, and development of multiorgan dysfunction 
syndrome (MODS).  
 
2.0 Background and Significance 
2.1 Background 
Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy caused by a glutamic acid to 
valine substitution at the sixth codon of the beta globin gene resulting in the production of mutant hemoglobin S 
that is prone to intraerythrocytic polymerization and subsequent microvascular occlusion clinically manifested 
as episodes of severe pain, organ damage, and early death.1,2 SCD affects approximately 75,000 to 100,000 
African Americans in the United States.3 The second leading cause of admission to the hospital and leading 
cause of mortality in SCD is ACS, defined as a new pulmonary infiltrate associated with fever, chest pain, and 
signs and symptoms of pulmonary disease, such as cough, dyspnea, and tachypnea.4 While a frequent cause 
of hospitalization in SCD, 48% of ACS episodes are diagnosed following a hospital admission for another 
reason, typically vasooclusive crises in nearly 75% of instances, usually occurring within 3 days.5 The 
incidence of ACS in adults is 8.8 per 100 patient years.4  Nearly ½ of all patients with SCD will develop ACS at 
least once with a smaller subset suffering multiple episodes.4 Repeated episodes of ACS are associated with 
the development of chronic lung disease and early death.4 ACS is responsible for 25% of deaths from SCD.4 
The rate of death in ACS is 9% in adults.5 
 
Recently, the role of thrombosis in SCD has been the subject of greater investigation. Nearly every 
component of hemostasis, including platelet function and the procoagulant, anticoagulant, and fibrinolytic 
systems, are altered in the direction of the procoagulant phenotype, in SCD.6 The pathogenesis of the 
thrombophilic state in SCD is multifactorial and involves every aspect of Virchow’s triad, increased 
coagulability, endothelial dysfunction, and impaired blood flow, resulting in a very thrombogenic environment.7 
Specific mechanisms of hypercoagulability include the loss of normal membrane phospholipid asymmetry from 
repeated cycles of sickling and unsickling resulting in abnormal phosphatidylserine exposure which is 
associated with increased levels of markers of thrombin generation and increased endothelial tissue factor 
expression.6 Additionally, free plasma hemoglobin from hemolysis in SCD scavenges nitric oxide, which 
normally inhibits platelet activation and aggregation, resulting in chronic platelet activation.8 Sickled red blood 
cells (RBCs) result in microvascular occlusion and subsequent ischemia precipitating endothelial injury as well 
as impaired blood flow.4 There is a 50 to 100-fold increase in the incidence of PE in hospitalized SCD patients 
compared with the general population.9  
 
The pathogenesis of ACS is complex and not entirely understood with multiple etiologies likely 
contributing simultaneously in any one particular episode. The most common etiologies of ACS include 
infection, infarction due to pulmonary vascular occlusion, and fat embolism.5 Pulmonary vascular occlusion 
may be microvascular, due to thrombosis or sickled RBCs, or occur in larger vessels as seen with PE.4 

Additionally, fat embolism can result in pulmonary vascular occlusion.4 Infarction is the second leading cause 
of ACS and one of the leading causes of death in ACS.5   
 
Pulmonary vascular occlusion due to thrombosis is becoming increasingly more recognized as an 
important player in the pathogenesis of ACS. There is a 17% prevalence of pulmonary artery thrombosis in 
patients admitted to the hospital with ACS.10 At autopsy, 38.1% of patients had PE and 28.5% of patients had 
pulmonary microvascular thrombi defined as <1 millimeter in size and undetectable with current computed 
tomography (CT) techniques.11 Pulmonary artery thrombosis in ACS may be more of a local rather than 
embolic phenomenon evidenced by one study that found none of the individuals diagnosed with ACS and 
pulmonary artery thrombosis had a concurrent lower extremity deep venous thrombosis (DVT).10 This is in 
contrast to data that shows approximately 45% of pulmonary emboli in the general population are associated 
with lower extremity DVTs.10 
 
UFH decreases sickle cell adhesion to the endothelium under static conditions as well as P-selectin 
mediated flow adherence of sickle cells to thrombin treated human vascular endothelial cells.4 A few studies 
have evaluated the use of anticoagulation in SCD with varying results.  One randomized, double-blind, 
placebo-controlled study of patients with SCD during vasooclusive (VOC) crises treated with tinzaparin 
resulted in a significant reduction in duration of hospitalization, duration of VOC, and the number of days with 
the most severe pain scores.12 Another randomized, double-blind, placebo-controlled trial is evaluating 
hypercoagulable markers and pain scores in hospitalized SCD patients treated with dalteparin versus 
placebo.13 This trial is open and enrolling patients. 
 
 
Anticoagulation as an adjunct in the treatment of ACS has not been studied. We propose a single-
center, randomized controlled, open-label, pilot study to determine the feasibility of performing a larger 
multicenter phase III trial to assess the effects of UFH in ACS. Specific feasibility criteria include the ability to 
enroll potential study participants, which entails the timely notification of all hospitalized patients diagnosed 
with ACS, the capacity to consent eligible individuals, and the ability to appropriately randomize screened 
patients within 24 hours of diagnosis. Additional feasibility objectives involve ensuring appropriate inclusion 
and exclusion criteria, proper administration of the study drug, and the ability to completely and accurately 
collect clinical data of interest. The final aim of our pilot study is to provide preliminary data, with respect to 
treatment effect and variance, for future sample size calculations given the lack of existing data to help guide 
this process. We hypothesize that the use of UFH in ACS will result in a decrease in the duration of 
hospitalization and improve other clinical outcomes, such as the duration of hypoxemia and duration of 
moderate to severe pain. 
 
2.2 Significance 
ACS is common complication of SCD that will affect a large percentage of individuals at some point in 
their lifetime.4 Furthermore, ACS is the leading cause of death in SCD and repeated episodes can lead to early 
death.4 Clinically, ACS can be unpredictable, and it is difficult to identify which patients will have an 
uncomplicated course versus those that will develop severe disease with refractory hypoxemia and respiratory 
failure. Despite the above, the optimal treatment of ACS remains undefined. Currently, standard of care 
involves a combination of the following: intravenous fluids, supplemental oxygen, pain medication, antibiotics 
tailored to treat community acquired pathogens involved in the development of pneumonia, red blood cell 
and/or exchange transfusions, and respiratory therapies, such as incentive spirometry and nebulizers if a 
reactive airway disease component is felt to be present. Given the high morbidity and mortality, better 
therapies are needed to improve the clinical course and outcomes in ACS.  
 
Given the increasingly recognized role of the thrombophilic state associated with SCD, anticoagulation 
is an attractive therapeutic modality in the treatment of VOC and ACS. Moreover, the use of anticoagulation in 
SCD, appears to be an interesting option because it has been shown that UFH decreases sickle cell adhesion 
to the endothelium under static conditions as well as P-selectin mediated flow adherence of sickle cells to 
thrombin treated human vascular endothelial cells.4 At this time, there is limited data available regarding the 
use of anticoagulation in VOC with only one randomized controlled trial in the literature and another 
randomized controlled trial actively enrolling patients.12,13 To our knowledge, the use of anticoagulation in the 
treatment of ACS has not been evaluated.  
 

Given the continued morbidity and mortality associated with ACS in SCD and no optimally defined 
therapy, it is imperative that other treatments be evaluated in well-designed clinical trials to provide high quality 
evidence of efficacy. UFH is potential treatment, for reasons outlined above, that we hypothesize will decrease 
the duration of hospitalization and improve other clinical outcomes, such as the duration of hypoxemia and 
duration of moderate to severe pain. Other indirect benefits related to decreased length of hospital stay include 
limiting the risk for potential iatrogenic complications, such as venous thromboembolism (VTE), if not already 
present, pneumonia, if not already present, central venous catheter related infections, delirium, and adverse 
affects of medications among others. Additionally, decreased duration of hospitalization will result in healthcare 
related cost savings.   
 
3.0 Research Design and Methods 
3.1 Drug Information 
 
Heparin is an anionic, highly sulfated, mucopolysaccharide that binds to antithrombin III via a unique 
pentasaccharide sequence.14 The heparin/antithrombin III complex catalyzes antithrombin III mediated 
inactivation of factors IIa, IXa, Xa, XIa, and XIIa.14 Heparin therapy is indicated for the treatment and 
prevention of arterial and venous thromboses in a wide variety of clinical circumstances, including DVT, PE, 
atrial fibrillation, myocardial infarction, etc. 
 
Patients receiving UFH will do so intravenously via a peripheral intravenous catheter, or central venous 
access device if already present, per treating physician preference. Peripheral intravenous catheter, if needed, 
will be inserted by the inpatient nursing staff. UFH will be obtained from the University of Pittsburgh Medical 
Center (UPMC) inpatient hospital pharmacy. UFH will be ordered by a member of the research staff via the 
electronic medical record system. 25,000 units of UFH in 250 milliliters dextrose 5% in water, 100 units per 1 
milliliter, will be infused according to institutional guidelines.15 An initial dose will be given as an 80 unit per 
kilogram bolus rounded to the nearest 100 units not exceeding 10,000 units (regardless of weight). 
Subsequently, a continuous infusion will begin at 18 units per kilogram per hour rounded to the nearest tenth 
but not exceeding 1600 units per hour (regardless of weight). An anti-Xa UFH level will be obtained 6 hours 
after the start of the heparin infusion with adjustments as follows: 
 
• 
If the anti-Xa UFH level is less than 0.2 units per milliliter, an 80 unit per kilogram bolus (maximum 
10,000 units) will be given followed by an increase in the rate of the infusion by 4 units per kilogram per 
hour. A repeat anti-Xa UFH level will be checked 6 hours after the change in the infusion rate.  
• 
If the anti-Xa UFH level is 0.21 to 0.29 units per milliliter, a 40 unit per kilogram bolus (maximum 10,000 
units) will be given followed by an increase in the rate of the infusion by 2 units per kilogram per hour. A 
repeat anti-Xa UFH level will be checked 6 hours after the change in the infusion rate.  
• 
If the anti-Xa UFH level is 0.30 to 0.70 units per milliliter, or therapeutic, no changes are necessary. 
Once a therapeutic anti-Xa UFH level is obtained, an anti-Xa UFH level will be repeated every 6 hours 
until two consecutive therapeutic results are achieved at which time the anti-Xa UFH level can be 
checked daily. 
• 
If the anti-Xa UFH level is 0.71 to 0.80 units per milliliter, the rate of the infusion will be decreased by 2 
units per kilogram per hour. A repeat anti-Xa UFH level will be checked 6 hours after the change in the 
infusion rate.  
• 
If the anti-Xa UFH level is 0.81 to 1.00 units per milliliter, the infusion will be held for 1 hour then 
restarted after decreasing the rate of infusion by 3 units per kilogram per hour followed by a repeat anti-
Xa UFH level in 2 hours.  
• 
If the anti-Xa UFH level greater than 1.00 units per milliliter, the infusion will be held for 2 hours then 
restarted after decreasing the rate of infusion by 4 units per kilogram per hour followed by a repeat anti-
Xa UFH level in 2 hours. 
 
In the event of major bleeding, the anticoagulation effects of heparin will be reversed with protamine 
sulfate, a cationic protein that binds to heparin forming an ionic complex that neutralizes the anticoagulant 
effects of heparin.14 Protamine will be administered according to institutional guidelines15. The maximum 
protamine dose is not to exceed 50 mg and no more than 50 mg is to be given over 10 minutes. Protamine will 
be given by slow intravenous infusion via a peripheral intravenous catheter, or central venous access device if 
already present, per treating physician preference, over 10 minutes to minimize the risk of hypotension, 
bradycardia, dyspnea, flushing, feeling of warmth, nausea, vomiting, or rarely anaphylaxis.14 If a heparin bolus 

was given within 2 hours of bleeding, protamine 1 mg per 100 units of heparin bolus will be administered. If no 
heparin bolus was given in the preceding 2 hours then the following protocol will be followed: 
  
• 
If the heparin infusion, prior to bleeding, was less than 600 units per hours then 10 mg of protamine will 
be given.  
• 
If the heparin infusion was 600 to 800 units per hour then 15 mg of protamine will be given.  
• 
If the heparin infusion was 801 to 1100 units per hour then 20 mg of protamine will be given.  
• 
If the heparin infusion was 1101 to 1400 units per hour then 25 mg of protamine will be given.  
• 
If the heparin infusion was 1401 to 1700 units per hour then 30 mg of protamine will be given.  
• 
If the heparin infusion was 1701 to 2000 units per hour then 35 mg of protamine will be given.  
• 
If the heparin infusion was 2001 to 2300 units per hour prior then 40 mg of protamine will be given.  
• 
If the heparin infusion was 2301 to 2600 units per hour then 45 mg of protamine will be given.  
• 
If the heparin infusion was greater than 2600 units per hour then 50 mg of protamine will be given.  
 
 
Adherence will be measured in hours UFH is not being infused (unless infusion is stopped per 
institutional guidelines, such as a supratherapeutic anti-Xa UFH level) according to the inpatient electronic 
medical record.  
 
3.2 Study Design  
This is a single-center, randomized controlled, open-label, pilot study to determine the feasibility of 
performing a larger multicenter phase III trial to assess the effects of UFH in ACS. Adult patients with SCD 
(HbSS, SC, or Sβ0) aged 18 years or older admitted to UPMC (Presbyterian, Montefiore, Magee, Shadyside) 
hospitals with a diagnosis of ACS will be eligible for screening to participate in the trial. Subjects meeting 
inclusion and exclusion criteria and consenting to study will be randomized within 24 hours of diagnosis to one 
of two treatment arms, Arm A, anticoagulation and standard of care, or Arm B, no anticoagulation and standard 
of care. Weight-adjusted UFH will be given at doses of 80 units per kilogram followed by 18 units per kilogram 
per hour intravenously for 7 days, or until discharge, if discharge is shorter than 7 days. UFH will be monitored 
by standard protocol to maintain the anti-Xa UFH level in the therapeutic range per institutional guidelines.15 
During the study period, if therapeutic anticoagulation is indicated for non-research purposes, it will be given at 
the discretion of the treating physician.  
 
Standard of care, per the treating physician, will include the following:  
 
• 
Intravenous fluids, preferably hypotonic saline, will be given to maintain adequate hydration. The 
specific rate, subsequent changes in rate, and duration will be per the treating physician’s discretion. 
• 
Antibiotics will be given to treat pathogens that are responsible for community acquired pneumonia, 
such as “atypicals” or, if necessary, to provide a broader spectrum of coverage against antimicrobial 
organisms as the treating physician sees fit.  
• 
Supplemental oxygen will be provided to maintain the arterial oxygen saturation, as recorded by pulse 
oximetry, greater than or equal to 90%.  
• 
Incentive spirometry will be provided with recommendations to take 10 breaths every 2 hours while 
awake.  
• 
Pain management will consist of acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), or 
opioids as needed to maintain adequate analgesia. Specifics regarding pain management will be 
individualized according to each patient’s established plan of care as dictated by his or her outpatient 
hematologist.  
• 
Red blood cell transfusions will be given routinely as standard clinical practice in acute chest syndrome 
with the goal of preventing progression to acute respiratory failure. 
• 
Exchange transfusions will be performed if extensive bilateral pulmonary disease is present, hypoxemia 
is not corrected with supplemental oxygen, or rapid clinical deterioration occurs with a goal HgbS less 
than or equal to 30%. 
 
Following completion of the study, primary care or another accountable physician will assume patient 
care responsibilities. 
 

3.3 Data Collection and Statistical Considerations 
Data collection is summarized in Table 1. Body temperature and pulse oximetry will be checked by the 
inpatient nursing staff at least three times daily, beginning with randomization and ending with resolution of 
fever and hypoxemia, respectively, or study completion. Body temperature and pulse oximetry orders will be 
entered into the electronic medical record by a member of the research staff if not already ordered as part of 
standard of care. Documentation will be entered into the electronic medical record in the form of a research 
progress note informing the treating physician of vital signs ordered for research purposes to avoid duplication 
of tasks. The visual analog scale (VAS) for pain will be assessed once daily beginning with randomization and 
ending with resolution of moderate to severe pain or study completion. Laboratory evaluation will include a 
complete blood count (white blood cell count, hemoglobin and hematocrit, and platelet count). Complete blood 
count (white blood cell count) will be obtained daily beginning with randomization and ending with resolution of 
leukocytosis or study completion. Complete blood count (hemoglobin, hematocrit, and platelet count) will be 
obtained daily beginning with randomization and ending with study completion in subjects receiving UFH. Anti-
Xa UFH level will be ordered according to the heparin infusion protocol as detailed earlier in subjects receiving 
UFH. Complete blood count will be entered into the electronic medical record by a member of the research 
staff if not already ordered as part of standard of care. Documentation will be entered into the electronic 
medical record in the form of a research progress note informing the treating physician of laboratory studies 
ordered for research purposes to avoid repeat blood draws. All blood samples will be collected by the inpatient 
phlebotomy team or nursing staff and sent to the inpatient laboratory for analysis.  
 
Further data collected will include information regarding standard of care therapy (collected daily during 
duration of study), demographics (collected following study enrollment and screening), and medical information 
(collected following study enrollment and screening). Regarding standard of care therapy, data collected will 
consist of whether or not intravenous fluids were given; whether or not antibiotics were administered, number 
of antibiotics received, and class of antibiotics given (penicillin, cephalosporin, macrolide, fluoroquinolone, 
vancomycin, other); whether or not supplemental oxygen was received with documentation of need for 
noninvasive positive pressure ventilation or mechanical ventilation; whether or not pain medication was 
provided, including type of pain medication (opioid, NSAIDs, acetaminophen, other); number of red blood cell 
transfusions given; and whether or not exchange transfusion was necessary. Demographics include age, race, 
and sex. SCD related medical information includes number of previous episodes of ACS, current 
administration of outpatient hydroxyurea, and prior DVT or PE. General medical information includes history of 
myocardial infarction; chronic lung disease, defined as a documented baseline arterial oxygen saturation less 
than 90% and/or home supplemental oxygen requirement; previous stroke; and current or former smoker. 
 
Prespecified feasibility criteria are as follows: the ability to enroll potential study participants, which 
includes the timely notification of hospitalized patients with ACS, the capacity to consent eligible individuals, 
and the ability to appropriately randomize screened patients within 24 hours of diagnosis, all of which should 
occur at a frequency greater than or equal to 80%; inclusion and exclusion criteria that does not exclude 
potential study participants at a frequency greater than or equal to 20%; the proper administration of the study 
drug at a frequency greater than or equal to 90%; and the ability to completely and accurately collect clinical 
data of interest at frequency greater than or equal to 90%. The final aim of our pilot study is to provide 
preliminary data, with respect to treatment effect and variance, for future sample size calculations given the 
lack of existing data to help guide this process. 
 
 
The primary clinical outcome is duration of hospitalization. Secondary clinical outcomes include the 
duration of hypoxemia, duration of fever, duration of leukocytosis, duration of moderate to severe pain, total 
dose of opioids, and the number of red blood cell transfusions administered. Additional clinical outcomes will 
include the rate of transfer to the ICU, requirement for mechanical ventilation, and development of MODS.  
 
Duration of hospitalization will be defined as beginning with randomization and measured in hours. 
Conclusion of hospitalization will be defined as the time of order entry into the inpatient electronic medical 
record system stating the patient is appropriate for medical discharge, per the discretion of the treating 
physician. Duration of hypoxemia will be defined as beginning with randomization and measured in hours. 
Hypoxemia will be defined as arterial oxygen saturation less than 90% according to pulse oximetry and/or the 
continued need for supplemental oxygen. If the patient’s baseline arterial oxygen saturation is less than 90%, 
hypoxemia will be defined as a decrease in arterial oxygen saturation below the patient’s baseline. Similarly, if 

the patient has a baseline supplemental oxygen requirement, hypoxemia will be defined as an increase in 
supplemental oxygen requirement above the patient’s baseline. If the patient does not meet criteria for 
hypoxemia following the initial 3 nursing vital signs assessments after randomization, hypoxemia will be 
considered absent and no further assessments will occur. Resolution of hypoxemia will be defined as failure to 
meet the criteria for hypoxemia on 3 consecutive nursing vital signs assessments. Duration of fever will be 
defined as beginning with randomization and measured in hours. Fever will be defined as a body temperature 
greater than or equal to 38.0 degrees Celsius measured by a thermometer orally. If the patient does not meet 
criteria for fever following the initial 3 nursing vital signs assessments after randomization, fever will be 
considered absent and no further assessments will occur. Resolution of fever will be defined as failure to meet 
the criteria for fever on 3 consecutive nursing vital signs assessments. Duration of leukocytosis will be defined 
as beginning with randomization and measured in hours. Leukocytosis will be defined as a white blood cell 
count greater than 10,000 per liter. If the patient does not meet criteria for leukocytosis following the initial 2 
complete blood counts after randomization, leukocytosis will be considered absent and no further assessments 
will occur. Resolution of leukocytosis will be defined as failure to meet the criteria for leukocytosis on 2 
consecutive complete blood counts. Duration of moderate to severe pain will be defined as beginning with 
randomization and measured in hours. If the patient does not report a score of 4 or greater on the VAS for pain 
following the initial 2 assessments after randomization, moderate to severe pain will be considered absent and 
no further assessments will occur. The end of the duration of moderate to severe pain will be defined as 2 
consecutive scores of less than 4 on the VAS for pain. Total dose of opioids will be defined as beginning with 
randomization, ending with study completion, and measured in milligrams of oral morphine equivalents. Red 
blood cell transfusions will be given routinely as standard clinical practice in acute chest syndrome with the 
goal of preventing progression to acute respiratory failure. Number of red blood cells transfused will be defined 
as beginning with randomization, ending with study completion, and measured in units of packed red blood 
cells received. Red blood cell transfusions given for suspected or proven hemorrhage secondary to UFH will 
not be included in the outcome as defined above. Rate of transfer to the ICU, requirement for mechanical 
ventilation, and development of MODS will be defined as beginning with randomization, ending with study 
completion, and categorized as present or absent. Further, MODS will be defined as the acute development of 
2 or more organs or organ systems unable to maintain homeostasis in a critically ill individual. 
 
Potential adverse events include heparin-associated risks, such as allergic reaction, major bleeding, 
minor bleeding, thrombocytopenia, and heparin induced thrombocytopenia (HIT), or any other adverse reaction 
suspected secondary to drug administration. All subjects enrolled in the study and received any UFH will be 
included in the safety evaluation. 
 
A member of the research staff will collect the study data. All data required by the study protocol will be 
documented in the inpatient electronic medical record system. De-identified subject information will be written 
on Case Report Forms (CRFs) and all data collected will be stored in locked files at the Hemophilia Center of 
Western Pennsylvania (HCWP). Additionally, data will be entered into research electronic capture (REDCap) 
and compared to ensure consistency. No personal identifiers will be associated with the data. The Institutional 
Review Board (IRB) may inspect records at any time. 
 
A sample size of 20 subjects for the pilot study is based on clinical rather than statistical considerations 
and should provide a preliminary estimate of primary and secondary clinical outcomes and assess prespecified 
feasibility criteria as detailed above. Based on 75,000 to 100,000 African Americans with SCD in the United 
States who develop ACS at a frequency of 8.8 per 100 patient years, with 50% developing ACS at some point 
during his or her lifetime, and given the fact that approximately 30 patients are admitted annually at UPMC 
hospitals (Presbyterian, Montefiore, Magee, Shadyside) with ACS, we estimate that at least 80%, or 24 
patients per year, will meet inclusion and exclusion criteria, and expect to enroll 10 patients, or slightly less 
than 50% per year, which should meet the n=20 subjects required for the pilot study.3,4 This is a pilot feasibility 
study, so comparisons will be descriptive, including frequencies and percentages for categorical variables and 
mean, median, range, and standard deviation for continuous variables.  
 
Demographics and medical information will be summarized with descriptive statistics as well. Adverse 
events will be summarized by frequency, relatedness, and severity.  
 
4.0 Human Subjects  

4.1 General Characteristics – Minority Inclusion and Non-Discriminatory Statements 
Adult patients with SCD (HbSS, SC, or Sβ0) aged 18 years or older admitted to UPMC (Presbyterian, 
Montefiore, Magee, Shadyside) hospitals with a diagnosis of ACS will be eligible for screening to participate in 
the trial. Children and pregnant females will not be enrolled in the study. Any patient with a predisposition 
towards thrombosis, other than SCD, and bleeding, as detailed in the inclusion and exclusion criteria, will 
excluded from study participation. Specifically, moyamoya disease has a 20% incidence of intracranial 
hemorrhage in adults in the United States.16 The incidence of the disease is 1 in 1 million in the United States; 
therefore, even with an increased association between moyamoya disease and SCD, it is unlikely to affect 
patient recruitment.16 Additionally, proliferative retinopathy predisposes towards vitreous hemorrhages with 
visual loss; however, the incidence of the disease is 0.5 per 100 patients, which, again, will be unlikely to affect 
patient recruitment.17 
 
As SCD is an autosomal recessive disorder that predominantly affects individuals of African descent, it 
is anticipated that the study population will be comprised largely of African Americans, and the percentage of 
male and female participants will be similar in number. There will be no discrimination based on gender, race, 
or ethnicity. The gender, racial, and ethnic characteristics of the proposed study population will reflect the 
demographics of the disease, the city of Pittsburgh and surrounding areas, and UPMC. Written informed 
consent will be obtained from all subjects prior to enrollment in the study.  
 
4.2 Recruitment Procedures 
Patients with SCD will be given a flyer presenting the study during SCD clinic visits to produce study 
awareness and increase the liklihood of future study participation. All subjects will be enrolled at UPMC 
(Presbyterian, Montefiore, Magee, Shadyside) hospitals. The SCD inpatient service, including Drs. Novelli and 
Kato, two of the study co-investigators, is consulted to assist in the management of all hospitalized patients 
with SCD. Individuals approached for participation in this study will be subjects age 18 years or older admitted 
to one of the aforementioned hospitals with a diagnosis of ACS. A member of the research staff will meet with 
prospective subjects during inpatient admission and determine the patient’s interest in study participation, and 
if interested, discuss the study in further detail. Informed consent will be obtained by Dr. Seaman, and include 
the purpose of the study, protocol specifics as they relate to the patient, potential adverse effects, and risks 
and benefit of the study. Each potential subject will be encouraged to ask all questions that he or she feels are 
necessary to enable him or her to make an informed decision regarding participation in the study. Each 
potential subject will be encouraged to take the time needed for thoughtful consideration whether or not to 
participate in the study; however, due to the design of the trial, which requires randomization within 24 hours of 
the diagnosis of ACS, there will be some time constraints with respect to the decision regarding study 
participation. Subjects who read the consent form are free to refuse enrollment. No experimental interventions 
will occur until after informed consent is obtained.  
 
Subjects will be considered enrolled in the study after informed consent is obtained. Each study 
participant will receive a unique subject identification number. Afterwards, screening assessment will be 
completed by a member of the research staff. All individuals will have any reason for study exclusion 
documented. Following enrollment and screening, patients will undergo randomization. Prior to beginning the 
study, an independent statistician will perform a 1:1 randomization using randomization software ensuring 10 
patients are placed in each arm of the study. A card will be labeled heparin or standard of care, placed in a 
sealed envelope numbered 1 to 20, and stored in locked files at HCWP. Following enrollment and screening, a 
member of the research staff will access the appropriate numbered envelope to ascertain patient assignment.  
 
Study participants will be free to withdraw at any time by notifying a member of the research staff. Any 
data collected prior to the time of withdrawal will continue to be used, but no additional information will be 
collected. Processed blood sample results will continue to be used; however, remaining samples will be 
destroyed or used as indicated by the subject. The reason and date of study withdrawal for all subjects will be 
recorded.  
 
4.3 Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
 

1. Diagnosis of ACS defined as a new pulmonary infiltrate involving at least one segment of the lung on a chest 
x-ray or chest CT scan with 2 or more of the following: chest pain, tachypnea (defined as a respiratory rate 
greater than 20 breaths per minute), dyspnea, cough, hypoxemia (see 3.3 Data Collection and Statistical 
Considerations for definition of hypoxemia), or body temperature greater than or equal to 38.0 degrees 
Celsius.  
 
2. Hemoglobin electrophoresis confirming (HbSS, SC, or Sβ0) (historical records sufficient). 
 
3. Age greater than or equal to 18. 
 
Exclusion Criteria: 
 
1. Any absolute contraindication to heparin, including known bleeding diathesis, history of HIT, or history of an 
allergic reaction. 
 
2. Platelet count less than 50 per microliter (current admission). 
 
3. Historical diagnosis of moyamoya disease as documented in medical records. 
 
4. Historical diagnosis of proliferative retinopathy as documented in medical records. 
 
5.  Current participation in a chronic exchange transfusion program. 
 
6. Underlying hypercoagulable disorder other than SCD. 
 
7. Currently receiving therapeutic anticoagulation. 
 
8. Currently receiving antiplatelet agents. 
 
9. Currently receiving estrogen containing oral contraceptives. 
 
10. Chest CT scan documented PE performed as standard of care prior to study enrollment (current 
admission). 
 
4.4 Risk/Benefit Ratio 
 
Risk of blood drawing  
There may be discomfort with drawing blood, which may include pain, lightheadedness, dizziness, syncope, 
ecchymosis, bleeding, or infection in the tissue surrounding the vein.  Appropriate medical intervention may 
consist of applying pressure to resolve bleeding or antibiotics in the setting of infection. 
 
Risk of peripheral intravenous catheter placement 
There may be discomfort with peripheral intravenous catheter placement, which may include pain, ecchymosis, 
bleeding, thrombophlebitis, or infection in the tissue surrounding the vein. Appropriate medical intervention 
may consist of applying pressure to resolve bleeding or antibiotics in the setting of infection. 
 
Heparin associated risks 
1. Allergic reaction 
Allergic reactions are rarely reported with the use of intravenous UFH.18 Because of this, the exact incidence is 
unknown, but expected to be rare.18 Adverse events will be classified using the Common Terminology Criteria 
for Adverse Events (CTCAE) system, volume 4.03, 2010.19 Allergic type symptoms may include fever, chills, 
pruritis, rash, urticaria, paresthesias, chest pain, dyspnea, wheezing, nausea, vomiting, edema, tachycardia, 
hypotension, anaphylaxis, or death. Subjects will be monitored for the development of these symptoms. If 
these symptoms occur, and are felt to be the result of UFH, the infusion will be discontinued, and 
diphenhydramine, methylprednisolone, or other appropriate medical interventions will be administered. 
Anaphylaxis will result in the permanent discontinuation of UFH. The decision to permanently discontinue UFH 

in less severe, or minor, allergic reactions will be at the discretion of the investigator. A known history of an 
allergic reaction to heparin will result in exclusion from study participation.  
 
2. Bleeding 
Heparin therapy, like any other form of anticoagulation, increases the risk of bleeding. The risk of bleeding with 
UFH varies among clinical settings. The risk of bleeding with intravenous UFH in acute VTE is less than 3%.20 
Bleeding may be major, defined as a decrease in hemoglobin 2 grams per deciliter or more; transfusion of 2 or 
more units of red blood cells; or bleeding in a critical organ, such as intracranial, intraspinal, intraocular, 
pericardial, or retroperitoneal.21 The presence of major bleeding will result in the permanent discontinuation of 
UFH. If major bleeding occurs, protamine will be administered to reverse the anticoagulant effects of heparin. 
Protamine may result in hypotension, bradycardia, dyspnea, flushing, feeling of warmth, nausea, vomiting, or 
rarely anaphylaxis.14 Other medical interventions, such as intravenous fluids and red blood cell transfusions, 
will be administered as deemed appropriate. Minor bleeding is defined as all bleeding episodes that do not 
meet criteria for major bleeding. The treatment of minor bleeding may vary and will be determined by the 
specific clinical scenario. The decision to discontinue UFH in the setting of minor bleeding, permanently or only 
for a brief period of time, will be at the investigator’s discretion. A known history of a bleeding diathesis will 
result in exclusion from study participation. 
3. Thrombocytopenia 
The risk of non-immune related thrombocytopenia with heparin varies anywhere between 5 and 30%.22 
Thrombocytopenia will be defined as a platelet count less than 100,000 per microliter. UFH will be discontinued 
if the platelet count is less than 50,000 per microliter and may be resumed if the platelet count increases to 
greater than 50,000 per microliter during the study period. A baseline platelet count less than 50,000 per 
microliter will result in exclusion from study participation. 
 
4. HIT 
HIT is an immunologically mediated thrombotic state that occurs in 1-2% of patients receiving heparin 
therapy.23 Antibodies of the IgG class recognize large macromolecular complexes of platelet factor 4 bound to 
heparin.23 Subsequently, these antibodies produce strong activation of platelets by binding to platelet FcγIIa 
receptors.23 The ensuing thrombotic state may lead to arterial and venous thrombosis, skin necrosis, venous 
limb gangrene, stroke, and myocardial infarction. The diagnosis of HIT is a clinical-pathologic syndrome, which 
means the diagnosis requires a compatible clinical picture and laboratory evidence of platelet activating 
antibodies.23 The laboratory diagnosis of HIT will be made with the serotonin release assay (SRA) that has a 
sensitivity of greater than 95% and a specificity of approximately 90% for the detection of platelet activating 
antibodies.23 If HIT is suspected and/or confirmed, UFH will be discontinued for the duration of the study 
period, and an alternate non-heparin-based anticoagulant will be instituted at the discretion of the investigator. 
Subsequently, the SRA will be performed to confirm or exclude the diagnosis. The SRA will be collected by the 
inpatient phlebotomy team or nursing staff and sent to the inpatient laboratory for analysis.  A known history of 
HIT will result in exclusion from study participation. 
 
Risk of inadvertent disclosure 
Study participation and related data will be protected to maintain confidentiality. There is a possibility that the 
subject’s personal information could become generally known. This information could impact future insurability, 
employability, have a negative impact on family relationships, or result in stigmatization. In order to reduce 
risks of disclosure or breach of confidentiality, the research related documents, blood samples, and clinical 
information stored in the subject’s research file will be assigned an alphanumeric identifier, i.e. ACS001, which 
does not contain any personal identifying information. A linkage key for linking the assigned alphanumeric 
identifier with the subject’s name will be stored in locked files at HCWP. Any publication arising from this study 
will not contain names or other identifying information. 
 
Potential benefits 
UFH may result in a decrease in the duration of hospitalization, hypoxemia, fever, leukocytosis, moderate to 
severe pain, and the number of red blood cell transfusions administered; however, as this is a pilot study, 
specifically designed to evaluate predefined feasibility criteria for conducting a large scale clinical trial, there 
may be no benefit from participation in the study.  
 

4.5 Data Safety Monitoring Plan (DSMP) 
 
The Data Safety Monitoring Committee (DSMC) will meet at least weekly to review all aspects of the 
study. The DSMC is comprised of the research team at HCWP consisting of three physicians (Dr. Seaman, Dr. 
Ragni, and another hematologist), two research nurses, and one regulatory coordinator. Subjects will be 
closely monitored to ensure subject safety and to ensure that procedures are in place to maintain privacy and 
confidentiality, progress of study, integrity of the data, procedure reviews, and for discussion of pertinent 
scientific literature or events which could effect the benefit to risk ratio. All serious and unexpected adverse 
events and/or major breaches of confidentiality will be reported to the IRB according to regulations outlined in 
the IRB Reference Manual for the Use of Human Subjects. The DSMC will determine if the risk benefit ratio is 
sufficiently favorable that it is appropriate to continue the trial. The events are: 
 
• 
A subject develops major bleeding in association with UFH. 
• 
A subject develops HIT in association with UFH.  
• 
A subject develops a Grade 2 or greater allergic reaction in association with UFH, defined as follows 
using the CTCAE grading. 
o Grade 2 - Intervention or interruption of infusion necessary. Responds promptly to symptomatic 
treatment. Prophylactic medications indicated for less than or equal to 24 hours. 
o Grade 3 - Prolonged, or not rapidly responsive to symptomatic treatment and/or interruption of 
infusion. Recurrence of symptoms following initial improvement.  
o Grade 4 - Life-threatening consequences. Urgent intervention indicated. 
• 
A subject develops anaphylaxis in association with UFH, defined as follows using the CTCAE grading 
(all anaphylactic events are Grade 3 or higher). 
o Grade 3 - Symptomatic bronchospasm with or without urticaria. Allergy-related edema and/or 
angioedema. Hypotension. Parenteral intervention needed. 
o Grade 4 - Life-threatening consequences. Urgent intervention indicated. 
 
 
 
Such events will be handled as serious adverse events (SAEs) and reported in an expedited time frame 
to the IRB. The data concerning the event will be reviewed by the DSMC along with all other available data to 
determine appropriate follow-up, with a decision to continue enrollment and treatment of subjects at that time. 
Additionally, the following may also stop further subject enrollment and treatment.   
 
• 
The DSMC warrants temporary suspension of enrollment for further review of data generated to date. 
• 
The investigator determines that a medically important event warrants further evaluation by the DSMC. 
 
 
 
A report summarizing the above DSMP activities will be submitted to the IRB at the time of annual 
renewal. 
 
4.6 Adverse Event Reporting 
All adverse events (AE) experienced by study subjects are to be recorded on the CRF, regardless of 
the severity of the event or its relationship to study treatment. The AE reporting procedures are based on the 
CTCAE system, volume 4.03, 2010. Subjects will report any symptoms to the investigator, research staff, 
inpatient nursing staff, or treating physician. Dr. Seaman will determine if symptoms qualify as an AE or SAE 
with confirmation by Dr. Ragni. AEs will be classified as mild (does not interfere with routine activities), 
moderate (interferes somewhat with routine activities), or severe (impossible to perform routine activities). The 
following algorithm will be used to assess the causality of all AEs: 
 
• 
Not related: The event can readily be explained by factors not involving UFH, and a temporal 
relationship with UFH does not exist. 
• 
Possibly related: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of UFH but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
• 
Probably related: The temporal relationship between the administration of UFH is compelling, and the 
event cannot be explained by the subject’s medical condition or other therapies. 
• 
Related: The event follows a reasonable temporal sequence from the administration of UFH, follows a 
known or suspected response pattern to UFH, is confirmed by improvement upon stopping UFH, and 
reappears upon repeated exposure to UFH. 

 
The investigator will follow up all AEs, regardless of severity, until satisfactory resolution. All subjects 
experiencing AEs will be monitored until symptoms subside and any abnormal laboratory values have returned 
to baseline, or until there is a satisfactory explanation for the changes observed, or until death, in which case a 
full pathologist's report will be supplied, if possible. Withdrawal from the clinical study and therapeutic 
measures shall be at the discretion of the investigator. As required by the IRB, if there is a serious, unexpected 
or adverse event that is determined to be associated with UFH, it will be reported to the IRB within 24 hours. If 
the event is not serious, unexpected or related to UFH, it will be reported within 5 days. All events must be 
assessed to determine the following: 
 
• 
If the event meets the criteria for an SAE.   
• 
The relationship of the event to study treatment.   
• 
The severity of the event. 
 
An AE is any untoward medical occurrence in a subject in whom a pharmaceutical product is 
administered but does not necessarily have a causal relationship with the pharmaceutical product.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a pharmaceutical product, whether or not related to the 
pharmaceutical product.27 A SAE is any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
• 
In the view of the investigator, places the subject at immediate risk of death. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Results in a congenital anomaly/birth defect. 
 
An SAE may also be any other medically important event that, in the opinion of the investigator, may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.  
 
5.0 Costs and Payments 
5.1   Research Study Costs  
The subject will incur no costs for study participation. The Vascular Medicine Institute (VMI) of UPMC 
will provide compensation for research related costs as outlined in the budget proposal.  
 
5.2   Research Study Payments 
 
Subjects will receive compensation in the amount of $100.00 following randomization and at the 
completion of the study, using the WePay system, for a total compensation of $200.00. 
 
6.0 Appendices 
6.1 References 
1. 
Gregory SA, McCrae KR. (2010). American Society of Hematology Self-Assessment Program, 4th Edition. 
Washington, DC: American Society of Hematology. 
2. 
Gladwin MT, Kato GJ, Weiner D, et al. Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell 
Pain Crisis: A Randomized Controlled Trial. JAMA. 2011;305:893-902. 
3.  
Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4 
Suppl.):S512–21.  
4.  
Paul RN, Castro OL, Aggarwal A, et al. Acute chest syndrome: sickle cell disease. European Journal of 
Hematology. 2011;87:191-207. 
5.  
Vichinsky EP, Neumayr LD, Earles AN, et al. For the National Acute Chest Syndrome Study Group. 
Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med. 
2000;342:1855–65.  

6.  
Ataga KI, Key NS. Hypercoagulability in sickle cell disease: new approaches to an old problem. 
Hematology Am Soc Hematol Educ Program.2007:91-6.  
7.  
Naik RP, Streiff MB, Lanzkron, S. Sickle cell disease and venous thromboembolism: what the 
anticoagulation expert needs to know. Journal of Thrombosis and Thrombolysis. 2013;35:352-8. 
8.  
Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 
2008;359:2254–65. 
9.  
Novelli EM, Huynh C, Gladwin MT, et al. Pulmonary embolism in sickle cell disease: a case–control 
study. Journal of Thrombosis and Haemostasis. 2012;10:760–766. 
10.  
Dessap AM, Deux JF, Abidi N, et al. Pulmonary artery thrombosis during acute chest syndrome in 
sickle cell disease. Am J Respir Crit Care Med. 2011;184:1022–9.  
11.  
Graham JK, Mosunjac M, Hanzlick RL. Sickle cell lung disease and sudden death: a 
retrospective/prospective study of 21 autopsy cases and literature review. Am J Forensic Med Pathol. 
2007;28:168–172. 
12.  
Qari MH, Aljaouni SK, Alardawi MS, et al. Reduction of painful vaso-occlusive crisis of sickle cell 
anemia by tinzaparin in a double-blind randomized trial. Thromb Haemost. 2007;98:392–6. 
13.  
Shah N. Treatment of Sickle Cell Patients Hospitalized in Pain Crisis With Prophylactic Dose Low-
molecular weight Heparin Versus Placebo. In: ClinicaTrials.gov [Internet]. Bethesda (MD): National 
Library of Medicine (US). 2000-[July 11, 2013]. Available at: 
http://clinicaltrials.gov/ct2/show/NCT01419977.  
14.  
Garcia DA, Baglin TP, Weitz JI, et al. Parenteral Anticoagulants: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical 
practice guidelines. CHEST. 2012;141(2 Suppl.):e24S-43S. 
15.  
University of Pittsburgh Medical Center Pharmacy. Intravenous Heparin Nomogram. Electronic Medical 
Record. 20012.  
16.  
Smith ER, Scott RM. Moyamoya: Epidemiology, Presentation, and Diagnosis. Neurosurg Clin N Am. 
2010:21;543–551. 
17.  
Downes SM, Hambleton IR, Chuang EL, et al. Incidence and Natural History of Proliferative Sickle Cell 
Retinopathy: Observations from a Cohort Study. Ophthalmology. 2005:112;1869-1875. 
18.  
Berkun Y, Havivw YS, Schwartzz LB, et al. Heparin-induced recurrent anaphylaxis. Clin Exp Allergy. 
2004;34:1916–1918. 
19.  
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 
June 14 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
20.  
Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic 
treatment: 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. 
CHEST. 2008;133(6 Suppl):257S-298S. 
21.  
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis. 2005;3:692–694. 
22.  
Pravinkumar E, Webster NR. HIT/HITT and alternative anticoagulation: current concepts. British 
Journal of Anaesthesia. 2003;90:676-85. 
23.  
Warkentin TE. How I Diagnose and Manage HIT. Hematology Am Soc Hematol Educ 
Program.2007:91-6.  
24.  
Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others 
and Adverse Events, September 3, 2013. Available at: 
 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
Table 1. Schedule of Events 
Schedule of 
Events1 
 
Study Day 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Demographic  
information2 
 
X 
 
 
 
 
 
 
Medical 
information3 
 
X 
 
 
 
 
 
 
Body 
temperature 
and pulse 
oximetry 
 
X 
X 
X 
X 
X 
X 
X 
Visual analog 
scale for pain 
score 
 
X 
X 
X 
X 
X 
X 
X 
Complete 
blood count 
  
 
X 
X 
X 
X 
X 
X 
X 
Anti-Xa UFH 
level 
 
X 
X 
X 
X 
X 
X 
X 
Clinical data 
(standard of 
care4) 
 
X 
X 
X 
X 
X 
X 
X 
Primary and 
secondary 
outcomes5 
 
X 
X 
X 
X 
X 
X 
X 
Adverse 
events 
 
X 
X 
X 
X 
X 
X 
X 
Adherence 
 
X 
X 
X 
X 
X 
X 
X 
1All data will be obtained by a member of the research staff. 
 
2Demographics include age, race, and sex.  
 
3Medical information includes number of previous episodes of ACS, current administration of outpatient hydroxyurea, prior 
DVT or PE, history of myocardial infarction, chronic lung disease, previous stroke, and current or former smoker. 

4SOC data includes whether or not intravenous fluids were given; whether or not antibiotics were administered, number of 
antibiotics received, and class of antibiotics given (penicillin, cephalosporin, macrolide, fluoroquinolone, vancomycin, 
other); whether or not supplemental oxygen was received with documentation of need for noninvasive positive pressure 
ventilation or mechanical ventilation; whether or not pain medication was provided, including type of pain medication 
(opioid, NSAIDs, acetaminophen, other); number of red blood cell transfusions given; and whether or not exchange 
transfusion was necessary.  
 
5Primary clinical outcome is duration of hospitalization. Secondary clinical outcomes include duration of hypoxemia, fever, 
leukocytosis, and moderate to severe pain; total dose of opioids; number of red blood cell transfusions administered; rate 
of transfer to the ICU; requirement for mechanical ventilation; and development of MODS.