Repurposing of Fibrinogen Concentrate as a Cost-Effective and Safe Hemostatic Agent in Infants Undergoing Cardiac Surgery on Cardiopulmonary Bypass
Phase: PHASE4
Conditions: Congenital Heart Disease
Sponsor: Stanford University

Repurposing of Fibrinogen Concentrate as a Cost-Effective and Safe 
Hemostatic Agent in Infants Undergoing Cardiac Surgery on 
Cardiopulmonary Bypass 
Study Protocol 
NCT03014700 
February 3, 2017 
 
Laura A Downey, Principal Investigator 
Emory University 
 
Glyn David Williams, Principal Investigator 
Stanford University 

LDowney 
Page 1 of 9 
Version 02.03.2017 
Study Title:  Repurposing of Fibrinogen Concentrate as an Efficacious and Safe 
Hemostatic Agent in Infants undergoing cardiac surgery on cardiopulmonary 
bypass 
 
Principal Investigator: Laura A Downey, MD 
 
Abstract 
 
Neonates and infants undergoing cardiac surgery are at high risk for perioperative 
bleeding and massive transfusion due to immature coagulation systems, cardiopulmonary 
bypass effects, hemodilution, and the complexity of surgeries.  The current treatment for 
post-bypass bleeding includes transfusion of multiple rounds of blood products, which 
increases the risk of volume overload, immunologic burden, morbidity, and mortality.   
The average number of donor exposures for a neonate undergoing cardiac surgery 
requiring CBP at Children’s Healthcare of Atlanta is nine exposures. Targeting 
transfusion strategies and alternative hemostatic agents that would reduce bleeding and 
transfusions would be a significant benefit to these patients.  
 
The most common hemostatic derangement after CPB is an acute acquired 
hypofibrinogenemia, which compromises fibrin clot generation and platelet aggregation, 
resulting in increased bleeding and need for allogenic blood product transfusions.  
Currently, management of this acquired hypofibrinogenemia is replaced with a blood 
product, cryoprecipitate. Fibrinogen concentrate, RiaSTAP (CSL Bering), is a 
commercially available product that is being used off-label in cardiac and pediatric 
surgery to reduce bleeding and transfusions.  However, a study specifically targeting 
neonates undergoing open-heart surgery with CPB has not been done to determine the 
efficacy of RiaSTAP in this population.  
 
In this study, we plan to complete a multi-center randomized, control trial comparing 
cryoprecipitate to fibrinogen concentrate in reducing allogenic blood transfusions in 
infants undergoing cardiac surgery with CPB.  Secondary outcomes will evaluate 
perioperative laboratory values, length of mechanical ventilation, length of ICU and 
hospital stays, as well as adverse events. Overall, we hope to use the results of this study 
to develop alternative transfusion strategies to treat post-CPB bleeding in infants.  
 
Introduction and Background 
 
In patients undergoing open-heart surgery (OHS), transfusion of allogenic blood products 
is independently associated with increased morbidity and mortality (1,2). In response to 
this, research in adult cardiac anesthesia has focused on blood product usage and 
developing algorithms to limit blood product exposure. Due to the smaller population, 
considerable variability in patient characteristics, and wide range of procedures 
performed in pediatric cardiac patients, the literature regarding blood conservation 
strategies for pediatric cardiac patients is limited. In children undergoing OHS, there are 
no published algorithms even though product exposure, particularly in neonates, is 
significant. The National Heart, Lung and Blood Institute (NHLBI) has determined 
pediatric transfusion medicine (PTM) to be a high priority for clinical and translational 

LDowney 
Page 2 of 9 
Version 02.03.2017 
research, specifically targeting transfusion strategies that could reduce short and long 
term morbidity and mortality (3).  
 
Approximately 10,000 babies born with congenital heart disease require OHS during the 
first year of life. Excessive bleeding after CPB is an independent predictor of increased 
adverse events and massive transfusions in neonates (4).  Higher perioperative 
transfusions of allogenic blood products during pediatric cardiac surgery are associated 
with increased mortality, increased pulmonary complications, prolonged mechanical 
ventilation, prolonged hospital stays, increased risk of hospital acquired infections and 
other adverse events (5,6). Many children with failed single-ventricle surgical palliation 
become higher-risk heart transplantation candidates because of the allo-sensitization after 
donor blood exposure. Finally, exposure to blood borne infections is a potential 
complication from receiving human derived blood products. Therefore, developing 
strategies to reduce bleeding and standardize blood transfusions for pediatric patients 
during CPB is an urgent need with a potential to reduce short and long-term morbidity 
and mortality.  
 
Neonates and infants undergoing cardiac surgery are at high risk for perioperative 
bleeding and massive transfusion due to immature coagulation systems, cardiopulmonary 
bypass (CPB) effects (deep hypothermia, extreme hemodilution, large non-
endothelialized surfaces) and complexity of surgery.  The most common hemostatic 
derangement after CPB is an acute acquired hypofibrinogenemia, which compromises 
fibrin clot generation and platelet aggregation, resulting in increased bleeding and need 
for allogenic blood product transfusions. Recent studies suggest that qualitative and 
quantitative fibrinogen deficiencies may contribute to impaired hemostasis in neonates 
and infants (7). Using confocal microscopy, Brown et al demonstrated neonatal clot 
formation before and after cardiopulmonary bypass is more porous and less dense than 
clots from adults.  However, the addition of adult fibrinogen was able to establish more 
effective clot formation in neonates (7).  In conjunction with the decreased function of 
neonatal fibrinogen, the acute acquired hypofibrinogenemia after OHS contributes to 
impaired fibrin clot generation and platelet aggregation. Currently, fresh frozen plasma 
and cryoprecipitate are used to supplement fibrinogen in pediatric cardiac patients, thus 
increasing the allogenic transfusion exposures.  
 
RiaSTAP (fibrinogen concentrate (FC)), an FDA-approved medication for congenital 
hypofibrinogenemia, is being used off-label for treatment of acute acquired 
hypofibrinogenemia associated with massive bleeding and CPB in adult and pediatric 
patients (8-10). Fibrinogen concentrate has many potential advantages for pediatric 
patients including 1) smaller volume to achieve target levels of fibrinogen, 2) decreased 
exposure to allogenic blood products, 3) decreased risk of infectious transmission, 
immunologic or allergic reactions, and 4) no required cross-matching or thawing process 
that makes it rapidly available for all patients. Recent studies found that FC was as 
effective as cryoprecipitate in reducing bleeding and transfusions for pediatric patients 
undergoing craniofacial and open-heart surgery (9,10).  However, these studies did not 
specifically examine the neonatal and infant population, who are most vulnerable to the 
affects of hypofibrinogenemia, excessive bleeding and large transfusions associated with 

LDowney 
Page 3 of 9 
Version 02.03.2017 
OHS.  We propose that FC poses many advantages over current options, but there is a 
clear need for a randomized, prospective study in this population.  After communication 
with the Center for Biologic Evaluation and Research (CBER) and the Office of Blood 
Research and Review (OBRR) at the FDA, an IND exemption was granted for this study. 
A grant from The Child Health Research Institute at Stanford University and SPARK has 
supported the initial work on this study and will help support the center at Children’s 
Healthcare of Atlanta.  
 
Significance: 
 
Specific Aim #1: 
Demonstrate that fibrinogen concentrate can reduce allogenic donor exposures when 
compared with cryoprecipitate in infants undergoing cardiac surgery with CPB.   The 
most common cause of post-bypass coagulopathy in infants after bypass surgery is from 
an acquired hypofibrinogenemia due to hemodilution from the bypass circuit. Secondly, 
immature neonatal fibrinogen does not function as well as adult fibrinogen in forming 
stable clots.  This acquired hypofibrinogenemia is currently treated with cryoprecipitate, 
a human derived blood product, which requires blood type matching and time to obtain 
from the blood bank. The FDA has approved fibrinogen concentrate, a lyophilized 
protein with minimal side effects, for use in pediatric and adult patients with congenital 
hypofibrinogenemia. Fibrinogen concentrate is being used off-label for treatment of acute 
acquired hypofibrinogenemia associated with massive bleeding and CPB in pediatric 
patients. No studies have been done specifically in cardiac surgery patients <12 months, 
who are most at risk for hypofibrinogenemia due to their small circulating blood 
volumes, immature coagulation systems, and potential long-term effects of transfusion 
related risks. Therefore, we have received an IND exemption from the FDA to conduct 
this randomized, control trial comparing fibrinogen concentrate to cryoprecipitate in 
hemostatic management of post-bypass coagulopathy in patients <12 months. We 
propose that replacing cryoprecipitate with reconstituted fibrinogen concentrate will be as 
effective as cryoprecipitate in treating post-CPB bleeding and decrease total donor 
exposures by 20%.   
 
Specific Aim #2: 
Comparison of fibrinogen concentrate to cryoprecipitate as a safe and effective 
hemostatic agent:  
By evaluating the laboratory values, transfusion requirements, and outcomes, we will 
examine the effectiveness of FC in reducing transfusion related risks, such as 1) length of 
mechanical ventilation time, 2) length of ICU stay, 3) length of hospital stay, 4) adverse 
events within seven days of surgery, 5) preoperative and post-operative coagulation 
laboratory values.  
 
 
 
 
 
 
 

LDowney 
Page 4 of 9 
Version 02.03.2017 
Experimental Design and Methods 
 
Design: 
 
This study will be a multi-center prospective, randomized control trial.  After informed 
and written parental consent, a total of 60 neonates and infants (<12 months) will be 
enrolled at Children’s Healthcare of Atlanta or Lucile Packard Children’s Hospital  at 
Stanford  Hospital. 
 
Study Population: 
 
The following criteria will be used to determine patient eligibility: 
Inclusion Criteria: 
• Full term neonates (32-42 weeks gestational age) 
• weight > to 3 kg at time of surgery 
• Infants less than 12 months of age 
• Infants and Neonates undergoing elective cardiac surgery requiring CPB at 
Children’s Healthcare of Atlanta or Lucile Packard Children’s Hospital at 
Stanford Hospital 
• No known patient or family history of coagulation defect or coagulopathy 
• Parents willing to participate and able to understand and sign the provided 
informed consent 
 
Exclusion Criteria: 
• Preterm neonates (less than 32 weeks gestation) 
• Patients less than 3 kg at time of surgery 
• Patients >12 months of age 
• Patients undergoing emergent procedure 
• Patients undergoing cardiac surgery not requiring CPB 
• Patients with known coagulation defect or coagulopathy  
• Family history of coagulation defect or coagulopathy 
• Parents unwilling to participate or unable to understand and sign the provided 
informed consent 
 
Enrollment/Consent Process: 
 
The Institutional Review Board will approve informed consent documents prior to 
commencement of the study. Only those patients who meet the entry criteria will be 
considered as possible study candidates.  Patients will be enrolled consecutively and 
randomized per protocol as they present to Children’s Healthcare of Atlanta.   
 
The parent(s) or legal guardian of the neonate will be approached on a day prior to 
surgery by the principal investigator, or a member of the IRB approved study team to 
discuss the goals, benefits and risks of the project.  A thorough discussion between the 
parent(s) or legal guardian and the IRB approved study team will occur during the study 
consent process.  Written informed consent will be obtained following this discussion.  

LDowney 
Page 5 of 9 
Version 02.03.2017 
For the occasions when parent(s) or legal guardian does not arrive at the hospital until the 
day of surgery, they will be approached only if there is sufficient time to allow for their 
full consideration.  No study related procedure will occur prior to obtaining appropriate 
informed consent.   
 
Patients undergoing emergent/urgent procedures or when there is insufficient time for the 
parent(s) or legal guardian to fully consider  the goals, benefits and risks of this project 
will not be approached for enrollment. 
 
Study Description: 
 
This study is a prospective, randomized trial designed to evaluate the role of fibrinogen 
concentrate versus cryoprecipitate in reducing allogenic donor exposures in infants 
undergoing cardiac surgery with CPB.  Prior to surgery, we will randomize infants 
undergoing cardiac surgery to receive cryoprecipitate (standard of care) or fibrinogen 
concentrate (study arm) as part of a post-bypass transfusion algorithm.  
For patients enrolled in the study, we will follow our standard anesthetic management, 
cardiopulmonary bypass protocol, and transfusion thresholds in the operating room and 
ICU.   
 
In each patient, results from our standard of care labs will be obtained at seven different 
time points:  
1) Preoperative labs (for outpatients, preoperative baseline labs are obtained in the 
preoperative clinic; for inpatients, baseline labs are obtained in the hospital the 
day before surgery) (CBC, Coagulation tests, Fibrinogen, Chemistry),  
2) After induction of anesthesia but prior to surgical incision (ABG, TEG),  
3) 10min after initiation of CPB (TEG, Fibrinogen, ABG),  
4) After termination of CPB, protamine reversal and first cryoprecipitate/FC 
administration (ABG, TEG, fibrinogen),  
5) After chest closure or placement of silastic patch if chest remains open (ABG, 
TEG),  
6) Coagulation labs on immediate arrival to the ICU as per ICU protocol (ABG, 
Fibrinogen, Coagulation studies, CBC, Chemistry), and  
7) On the morning of the first post-operative day in the ICU as per ICU protocol 
(fibrinogen, ABG, coagulation studies, chemistry, CBC).   
Blood samples drawn prior to surgery (i.e time number 1) will be done either by our 
clinical laboratory for outpatients or by hospital protocol for inpatients. For all other time 
points, blood samples will be drawn from an indwelling line placed for the surgery.  
 
After separation from bypass, patients will receive either cryoprecipitate or FC, 
depending on their randomization group.  For patients randomized to the study arm, the 
fibrinogen level measured on bypass will be used to calculate the appropriate dose of 
fibrinogen concentrate to achieve a level of 300mg/dL after separation from bypass.  In 
these patients, FC will replace cryoprecipitate in our post-bypass transfusion algorithm 

LDowney 
Page 6 of 9 
Version 02.03.2017 
for the first dose only. If a patient in either arm continues to have post-bypass bleeding, 
the anesthesiologist will use point of care testing and the transfusion algorithm to 
determine appropriate products for transfusion.  Patients on the study arm will only 
receive the initial dose of FC; cryoprecipitate should be used for subsequent low 
fibrinogen levels.  
 
Data regarding patient demographics, CPB variables, intraoperative and post-operative 
laboratory values, intraoperative and post-operative transfusion requirements, chest tube 
output, adverse events, length of ventilation time, ICU and hospital length of stay will be 
recorded and maintained in a HIPPA secure database.  
 
Fibrinogen Concentrate (RiaSTAP) Dose: 
  
Hypofibrinogenemia is one of the main reasons for the perioperative coagulopathy in 
major pediatric surgeries. This hemostatic derangement is amplified in the pediatric 
population undergoing cardiac surgery due to the hemodilutional effects of the 
cardiopulmonary bypass machine.  Therefore, post-bypass transfusion guidelines often 
include cryoprecipitate to maintain an adequate fibrinogen level.   
 
Haas et al (10) found that maintaining a higher fibrinogen concentration level (FIBTEM 
<13mm vs <8mm) significantly decreased bleeding and transfusion requirements for 
patients undergoing craniosynostosis (median age 10months), but not scoliosis patients 
(mean age 12 years). Brown et al (7) recently demonstrated that clots formed with 
neonatal fibrinogen are more porous and less dense than adult clots.  The addition of 
adult fibrinogen to neonatal fibrinogen in higher concentrations creates a more three-
dimensional structure than neonatal fibrinogen alone. Using these studies and our 
historical data that neonates undergoing cardiac surgery had a median post-operative 
fibrinogen level of 345mg/dL (258-469) (unpublished data), we chose to target a post-
transfusion fibrinogen level of 300mg/dL. 
 
Fibrinogen Concentrate (RiaSTAP)    
 
Fibrinogen concentrate can be dosed two ways.  For unknown fibrinogen levels, the 
RiaSTAP dose is 70mg/kg.  However, the dose of FC can be calculated to reach a target 
fibrinogen level.   
 
Dose = (Target Level-Measured Level)/1.7 x weight (kg) 
 
As we have chosen a target fibrinogen level of 300mg/dL, we will use the above equation 
to calculate the RiaSTAP dose for each patient in the study arm.  In order to account for 
the hemodilutional effects of the bypass prime on fibrinogen levels, the “measured level” 
will be the fibrinogen level measured after 10min on the CPB machine, time point #2.  
 
Specific Aim #1: 
 

LDowney 
Page 7 of 9 
Version 02.03.2017 
Rational: The goal of Aim #1 is to determine if fibrinogen concentrate can decrease 
overall allogenic donor exposure in infants undergoing CPB surgery.  By targeting a 
higher level of fibrinogen, we hope to mitigate the effects of the acquired 
hypofibrinogenemia in post-bypass coagulopathy, while also decreasing the 
hemodilutional effects of additional blood products during post-bypass transfusion.  As 
massive transfusion in infants is associated with worse outcomes, we hope that reducing 
transfusions will reduce the short and long term risks associated with allogenic donor 
exposures.  
 
Specific Aim #2: 
By evaluating the laboratory values, transfusion requirements, and short-term outcomes, 
we will examine the effectiveness of FC in post-bypass hemostasis.  We will evaluate 
hematocrits, fibrinogen levels, and thrombelastogram values to determine if FC is at least 
as effective as the standard of care in post-bypass transfusion management.  Secondly, we 
will evaluate secondary outcomes to determine if FC can decrease transfusion related 
risks such as increased mechanical ventilation, prolonged ICU/hospital stays, infection 
risks, and thrombosis.  
 
Sample Size/Statistical Analysis 
 
The primary aim of this study is to determine if fibrinogen concentrate can decrease 
allogenic donor transfusions in infants undergoing cardiac surgery with cardiopulmonary 
bypass in patients when compared with the current standard of care, cryoprecipitate.   
Therefore, we analyzed our blood product transfusion data from CHOA in infants 
requiring CPB. We counted the number of units of packed red blood cells (PRBCs), fresh 
frozen plasma (FFP), cryoprecipitate, and platelets the patient received.  Each unit was 
counted as one donor exposure. On average, the patients had nine donor exposures. We 
propose replacing two units of cryoprecipitate with fibrinogen concentrate will result in a 
20% reduction in donor exposures. In order to achieve a power of 0.9, we plan to enroll 
15 patients in each arm, for 30 patients at this institution. 
 
The Quantitative Statistical Unit at Stanford University will provide assistance with data 
management, conducting data analyses, and interpreting statistical results.  Continuous 
variables will be compared by analysis of variance and will be presented as mean + 
standard variation if normally distributed or by median (IQ range) if non-normally 
distributed.  Nominal variables will be compared by chi-squared analysis or Fisher’s 
exact test. Significance will be defined as a p-value less than or equal to 0.05. 
 
Adverse Events Reporting 
 
Monitoring of Adverse Events (AEs) and Serious Adverse Events (SAEs) is an important 
aspect of data collection. The study subjects will be reviewed on a case-by-case basis. 
The principal investigator will determine the seriousness of each adverse event and 
whether or not the event was related to the study.  
 

LDowney 
Page 8 of 9 
Version 02.03.2017 
After enrollment, the principal investigator or designee will collect the adverse 
experiences from the medical record. Serious adverse Events (life-threatening, requiring 
intervention) will be reported to the IRB within the guidelines set by the IRB.  
 
The risk of Fibrinogen concentrate administration is low, but adverse events include 
headache, fever, chills, allergic reaction, or thrombosis.   The risks are comparable to the 
administration of cryoprecipitate.  
 
Data Safety Monitoring Plan 
 
A potential risk of this study is related to drug reactions including fever, chills, headache, 
allergic reactions, or thrombosis.  This medication has been used extensively in Europe 
and as part of transfusion algorithms around the United States.  Based on this data and the 
need to minimized transfusions in the infant population undergoing cardiac surgery with 
CPB, the FDA has granted an IND exemption for use of this medication in this 
randomized, control trial.  
 
The study subjects will be reviewed on a case-by-case basis by the PIs at each institution 
and quarterly at a committee of experienced cardiac anesthesiologists not involved in the 
study for review of each study subject for potential adverse events and whether or not the 
event was related to the study.  
 
A second risk of this study is patient confidentiality since protected health information is 
included in the study data. This risk will be minimized by only recording information 
absolutely necessary to fulfill the study’s objectives. Information directly identifying 
patients will be excluded (names, addresses, telephone numbers, social security numbers, 
email addresses, and account numbers). A unique study number will identify the study 
subjects. The study information will be collected and stored in a password-protected 
database. Consents, along with the code linking a subject’s identity to an assigned 
number, will be locked in the office of the principal investigator or designee.  
 
References 
 
1. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased 
mortality, postoperative morbidity, and cost after red blood cell transfusion in 
patients having cardiac surgery. Circulation 2007; 116: 2544-52. 
2. Iyengar A, Scipione CN, Sheth P, Ohye RG, Riegger L, Bove EL, Devaney EJ and 
Hirsch-Romano JC. Association of Complications With Blood Transfusions in 
Pediatric Cardiac Surgery Patients. Ann Thorac Surg 2013; 96:910–6. 
3. Josephson CD, Mondoro TH, Ambruso DR, Sanchez R, Sloan SR, Luban NLC and 
Widness JA.  One Size Will Never Fit All: Clinical and Translational Research 
Gaps in Pediatric Transfusion Medicine. Pediatr Res. 2014 Nov;76(5):425-31.  
4. Guzzetta NA, Allen NN, Wilson EC, Foster GS, Ehrlich AC, and Miller BE. 
Excessive Postoperative Bleeding and Outcomes in Neonates Undergoing 
Cardiopulmonary Bypass. Anesth & Anal. February 2015: 120 (2): 405-410. 

LDowney 
Page 9 of 9 
Version 02.03.2017 
5. Kipps AK, Wypij D, Thiagarajan RR, Bacha EA, and Newburger JW. Blood 
transfusion is associated with prolonged duration of mechanical ventilation in 
infants undergoing reparative cardiac surgery. Pediatr Crit Care Med 2011 Vol. 12, 
No. 1: 52-56.  
6. Salvin JW, Scheurer MA, Laussen PC, Wypij D, Polito A, Bacha EA, Pigula FA, 
McGowan FX, Costello JM and Thiagarajan RR. Blood Transfusion After Pediatric 
Cardiac Surgery Is Associated With Prolonged Hospital Stay. Ann Thorac Surg 
2011;91:204 –11. 
7. Brown AC, Hannan RH, Timmons LH, Fernandez JD, Barker, TH, Guzzetta, NA. 
Fibrin Network Changes in Neonates after Cardiopulmonary Bypass. 
Anesthesiology 2016; 124:1021-31.  
8. Ranucci M, Baryshnikova E, Crapelli GB, Rahe-Meyer N, Menicanti L, Frigiola A. 
Randomized, Double-Blinded, Placebo-Controlled Trial of Fibrinogen Concentrate 
Supplementation After Complex Cardiac Surgery. J Am Heart Assoc. 
2015;4:e002066. 
9. Galas FR, de Almeida JP, Fukushima JT, Vincent JL, Osawa EA, Zeferino S, 
Camara L, Guimar~aes VA, Jatene MB, and Hajjar LA. Hemostatic effects of 
fibrinogen concentrate compared with cryoprecipitate in children after cardiac 
surgery: A randomized pilot trial. The Journal of Thoracic and Cardiovascular 
Surgery Volume 148, Number 4: 1647-1655. 
10. Haas T, Speilmann N, Restin T, Seirfert B, Henze G, Obwegeser J, Min K, 
Jeszenszky D, Weiss M, Schmugge M. Higher fibrinogen concentrations for 
reduction of transfusion requirements during major paediatric surgery: A 
prospective randomized controlled trial. British Journal of Anesthesia 2015; 115 (2): 
234-43. 
11. Tao GZ, Liu B, Zhang R, Liu G, Abdulla F, Harris MC, Brandt ML, Ehrenkranz 
RA, Bowers C, Martin CR, Moss RL, Sylvester KG. Impaired Activity of Blood 
Coagulant Factor XIII in Patients with Necrotizing Enterocolitis. Scientific Reports 
2015 Aug 17;5:13119