Comparison of Fibrinogen Concentrate and Cryoprecipitate in Pediatric Cardiac Surgery Patients
Phase: PHASE4
Conditions: Pediatric HD, Bleeding
Sponsor: University of Virginia

Title: Comparison of Fibrinogen Concentrate and Cryoprecipitate in Pediatric 
Cardiac Surgery Patients
NCT04376762 
Document Date: 8/5/2020

IRB-HSR# 180028: Comparison of fibrinogen concentrate and cryoprecipitate in pediatric 
cardiac surgery patients  
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PROTOCOL 
Background 
1. Provide the scientific background, rationale and relevance of this project.
INSTRUCTIONS 
•
This should include a referenced systematic evidenced-based review when possible.
•
If this study involves qualitative research explain the major constructs of your study.
•
Do not state in this section what you plan to do in this study.  This information
should be entered later under “What will be done in this protocol?”
•
Do not include the bibliography in this section.
•
For studies submitted under the Expedited review criteria, this section need not be
more than a few paragraphs.
•
For those studies where data will be analyzed collaboratively by multiple sites doing
a similar study for which there is no common protocol (Collaborative Site Analysis
Study) include a description of the common scientific goals/ procedures/data points.
•
If this is a FIVE YEAR UPDATE make sure the information throughout the protocol
includes the most current information.
Answer/Response: Postoperative bleeding in children undergoing cardiac surgery 
is a common complication that is associated with increased morbidity and mortality. 
While life saving during acute bleeding, the transfusion of red blood cells (RBC) and other 
blood-derived coagulation factors may be associated with serious postoperative 
complications such as infections, acute kidney injury, thromboembolic events, 
immunomodulation, volume overload (transfusion-associated cardiovascular overload, 
TACO) and lung injury (transfusion-related acute lung injury, TRALI) that can result in 
significant morbidity and mortality. Therefore, a significant effort is being invested in 
patient blood management strategies that will incorporate point-of-care-based 
transfusion algorithms and the use of novel coagulation concentrates in an attempt to 
reduce postoperative bleeding and need for allogeneic blood product transfusions after 
cardiac surgery1. 
Acquired fibrinogen deficiency is believed to be one of the key factors contributing 
to coagulopathy after cardiopulmonary bypass (CPB). Fibrinogen is the most abundant 
clotting factor in the human circulation and it plays a crucial role in hemostasis by 
promoting platelet aggregation and clot polymerization. However, it is also the first factor 
to be depleted during cardiac surgery, as there is no extra-vascular storage of fibrinogen2. 
During cardiopulmonary bypass, fibrinogen levels may fall to 40-50% from baseline3 as a 
result of acute bleeding, hemodilution due to priming of the CPB circuit, consumption due 
to activation of the coagulation cascade and increased breakdown (hyperfibrinolysis). 
Thus, in post-CPB bleeding patients with low fibrinogen levels, replenishment of 
fibrinogen may be indicated to achieve adequate hemostasis4. 
Until recently, the only option for fibrinogen supplementation in the USA for 
patients with hypofibrinogenemia (either congenital or acquired) was the transfusion of 
cryoprecipitate. As such, the standard of care fibrinogen replenishment in bleeding 

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surgical patients with acquired fibrinogen deficiency is cryoprecipitate transfusion. 
Recently, however, the use of purified human fibrinogen concentrate (FC) has been 
approved in the USA and in Canada and its use in bleeding cardiac surgery patients has 
significantly increased5 and is recommended by transfusion guidelines in cardiac surgery 
patients 6,7.  As such, UVA Medical Center has recently approved the use of fibrinogen 
concentrate as an alternative to cryoprecipitate in bleeding adult and pediatric surgical 
patients (including cardiac surgery patients). 
FC is a lyophilized, nano-filtered and pathogen reduced and inactivated human 
fibrinogen concentrate with a constant content of 900-1300 mg/vial (final concentration 
20g/L). While cryoprecipitate is still in use in North America, it is not available in Europe 
(except for the UK) due to safety concerns, as it does not undergo pathogen reduction 
and inactivation. FC has several important potential advantages over cryoprecipitate 
including: standardized fibrinogen content, higher purity, faster preparation without 
need for blood bank processing or cross-matching (which also eliminates the risk of 
human-related transfusion errors), improved safety via pathogen reduction, avoidance of 
transfusion related acute lung injury (TRALI) and significantly decreased volume of 
transfusion (which may be particularly important in children with congenital heart 
diseases as they may be intolerant to excessive volume overload). Yet, cryoprecipitate 
may be a better hemostatic agent as it also contains factors VIII and XIII, fibronectin, von 
Willebrand factor and platelet microparticles, all of which are important for normal 
hemostasis in bleeding patients. Hence it is not known whether FC will provide hemostatic 
efficacy similar to cryoprecipitate in bleeding pediatric cardiac surgery patients. 
Initial studies evaluating the use of FC in cardiac surgery patients reported 
conflicting results8-11. Surprisingly, several studies failed to report a benefit with the use 
of FC mainly due to enrollment of patients who did not have low fibrinogen levels 8,12. A 
recent large randomized controlled study in adult cardiac surgery patients, however, 
demonstrated non-inferiority of FC compared to cryoprecipitate in bleeding cardiac 
surgery adult patients with low fibrinogen levels (and as a matter of fact FC was found to 
be superior over cryoprecipitate in regard to several outcome measures)5. Hence it seems 
that FC may be a better alternative for fibrinogen supplementation in bleeding cardiac 
surgery patients compared to cryoprecipitate. 
Despite the growing data about the potential advantages of the use of FC in adult 
cardiac surgery patients, it is not yet known, however, whether the use of FC in pediatric 
cardiac surgery patients may offer similar advantages. A recent prospective randomized 
study by Downey et al13 compared the use of FC to cryoprecipitate in pediatric patients 
undergoing cardiac surgery. Although there was no difference in postoperative bleeding 
between the study groups, children in the FC group received significantly less allogeneic 
blood products compared to patients who received cryoprecipitate. Some of the patients, 
however, also received prothrombin complex concentrate – a potent mixture of vitamin 
K–dependent clotting factors, which may complicate the interpretation of the results. 
Furthermore, the standard of care at the UVA Medical Center, as well as in other pediatric 
cardiac surgery institutions, is to prime the cardiopulmonary bypass pump only with RBCs 
without adding FFP (which is different than in the Downey paper). This results in a much 
more significant hemodilution that may lead to a higher risk of postoperative bleeding.  

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Taken together, there is a growing body of evidence supporting the use of 
fibrinogen concentrate as an alternative for cryoprecipitate in adult cardiac surgery 
patients, however, there is insufficient data in the literature to determine whether FC 
may be a comparable (or even a superior) alternative to cryoprecipitate for fibrinogen 
supplementation after pediatric cardiac surgery. Therefore, we propose a single-
institution, prospective randomized pilot study to compare the use of FC (Fibryga, 
Octapharma USA, Hoboken, NJ, USA) to cryoprecipitate in pediatric cardiac surgery 
patients with postoperative bleeding and low fibrinogen levels. If FC is found to offer 
similar hemostatic efficacy as cryoprecipitate it may be a much better alternative for 
fibrinogen supplementation in bleeding pediatric cardiac surgery patients given its higher 
safety profile. 
 
Objectives/Hypothesis  
INSTRUCTIONS:   
If this study involves biomedical research clearly state the objectives and hypotheses and 
clearly define the primary and any secondary outcome measures.  If this study involves 
qualitative research clearly state your research hypothesis or question.  
 
This section should not include information already included in other sections such as 
background information or information from the procedures section.  
Answer/Response: Our hypothesis is that fibrinogen concentrate will be as effective as 
cryoprecipitate in achieving adequate hemostasis after separation from CPB in pediatric cardiac 
surgery patients.  
 
Study Design: Biomedical 
1.  Will controls be used? 
Answer/Response:  Yes 
 
►IF YES, explain the kind of controls to be used. 
Answer/Response:  active comparator 
 
2. What is the study design?  
Example:  case series, case control study, cohort study, randomized control study, 
single-blind, double-blind, met-analysis, systematic reviews, other.  You may also view 
the IRB-HSR Learning Shot on this topic to help you answer this question.  
(http://www.virginia.edu/vpr/irb/learningshots/Writing_protocol_June09/player.html 
Answer/Response: this will be a single-center, prospective, randomized, active-control 
study in pediatric (age < 24 months) patients undergoing elective cardiac surgery with 
CPB in-whom fibrinogen supplementation after separation from CPB is indicated, based 
on the presence of clinically-significant bleeding and documentation of low fibrinogen 
level on viscoelastic point-of-care testing (MCF < 10 mm on the FIBTEM assay of ROTEM) 
 

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3. Does the study involve a placebo? 
Answer/Response:  No 
►IF YES, provide a justification for the use of a placebo 
Answer/Response: 
Human Participants 
Ages: __under 24 months of age__ 
Sex: 
__male or female__ 
Race: __any__ 
Subjects- see below 
INSTRUCTIONS: For question 1-4 below insert an exact #.  Ranges or OPEN is not 
allowed.  This # should be the maximum # you expect to need to enroll (i.e. sign 
consent) If you are only collecting specimens the number of participants should equate 
to the # of specimens you need.  If you are collecting only data from a chart review the 
number should designate the number of subjects whose medical records you plan to 
review.  Age/ Sex/Race criteria should designate the demographics of participants from 
whom you will obtain the specimen/data. 
1.  Provide target # of subjects (at all sites) needed to complete protocol. 
INSTRUCTIONS: If this is NOT a database protocol, this number should be the same as 
the number of subjects needed to obtain statistically significant results.    
Answer/Response: 30 total with 15 in each arm 
 
2.  Describe expected rate of screen failure/ dropouts/withdrawals from all sites.   
Answer/Response: 5% 
 
3.  How many subjects will be enrolled at all sites?    
INSTRUCTIONS: This number must be the same or higher than the # from question # 1 
in order to account for the # of screen failures, dropouts, withdrawals described in 
question # 2.  
Answer/Response: 32 
 
4.  How many subjects will sign a consent form under this UVa protocol?     
INSTRUCTIONS: If the protocol does not have a consent form- the number listed here 
should reflect such things as the number of subjects from whom specimens will be 
obtained, the number of charts to be reviewed etc.  
Answer/Response: 32 
Inclusion/Exclusion Criteria 
INSTRUCTIONS: 
• The inclusion and exclusion criteria should be written in bullet format. 
• This item applicable if the study will require consent (verbal or written).        Unless there 
is a scientific reason for not recruiting a certain type of vulnerable population(e.g. not 

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enrolling fetuses, neonates or children in a study regarding Alzheimer’s) list the 
following vulnerable populations under either Inclusion or Exclusion criteria below:  
pregnant women, fetuses, neonates, children, prisoners, cognitively impaired, 
educational or economically disadvantage, non- English speaking subjects . 
• If you will not enroll subjects who do not speak English because certain procedures 
cannot be carried out if the subject does not speak English (e.g. a survey is not validated 
in other languages) insert the following as an Inclusion Criteria:  Willingness and ability 
to comply with scheduled visits and study procedures.   
• If this is a collection of only retrospective* specimens or data, the inclusion criteria must 
include a start and stop date for when specimens/ data will be collected.   
• The stop date must be prior to the version date of this protocol. 
• *Retrospective:  all specimens are in a lab at the time this protocol is approved by the 
IRB.  All data exists in medical records or records from previous studies at the time this 
protocol is approved by the IRB.   
1.  List the criteria for inclusion  
Answer/Response: 
• pediatric (age < 24  months) patients undergoing elective cardiac surgery with CPB in-
whom fibrinogen supplementation after separation from CPB is indicated, based on the 
presence of clinically-significant bleeding and documentation of low fibrinogen level on 
viscoelastic point-of-care testing (MCF < 10 mm on the FIBTEM assay of ROTEM). 
 
2.  List the criteria for exclusion 
Answer/Response: 
• refusal to participate in the study, 
• known severe allergic reaction/anaphylaxis to fibrinogen concentrate, 
• administration of FC or cryoprecipitate in the 24 hours prior to surgery and 
• baseline fibrinogen level higher than 300 mg/dL (to avoid the risk of increasing the 
fibrinogen level above the normal upper level of 400 mg/dL) 
 
3.  List any restrictions on use of other drugs or treatments. 
Answer/Response: None  
 
Statistical Considerations 
1. 
Is stratification/randomization involved? 
Answer/Response:  Yes 
 
►IF YES, describe the stratification/ randomization scheme. 
INSTRUCTIONS: 
The stratification factors and/or the randomization plan should be identified. If there is 
no randomization component or important patient characteristics that will be used in 
treatment allocation or data analysis, a statement to this effect should be included. 
 

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Stratification factors: These are pretreatment patient characteristics which could be 
balanced across treatment arms by design or may be used to determine starting dose or 
treatment allocation. 
 
If randomization is going to be used, the details of the randomization plan should be 
described.  
 
The description should include: 
--the method and timing of randomization 
--the type of randomization scheme that will be used in the study 
--whether or not the randomization masked/blinded/if so, then to whom is it 
masked/blinded 
--who has access to the randomization scheme 
Answer/Response:  
• Once the need for fibrinogen supplementation is confirmed after separation 
from CPB, patients will be randomized into one of two treatment groups (n=15 in 
each group):  
1. Cryoprecipitate group (dose: 10 ml/kg; active control group) or  
2. Fibrinogen Concentrate group (dose: 70 mg/kg; intervention group).  
• 1:1 randomization unblinded using a computer generated randomization list 
 
►IF YES, who will generate the randomization scheme?  
_____ Sponsor 
_____ UVa Statistician.   Insert name Answer/Response: 
_____ UVa Investigational Drug Service (IDS) 
__x___ Other:  Specify   Answer/Response: computer generated by the CRC  
 
2.  What are the statistical considerations for the protocol?  
The objectives section and the statistical section should correspond, and any objective for 
which analysis is unfeasible should be deleted.  Also, the estimates and non-statistical 
assumptions of the statistical section should be supported by discussion in the background 
section. 
 
The answer to this question should include: 
--Study Design/Endpoints 
--Recap of study objectives and endpoint definitions. An assessment of how study objectives 
will be assessed by identifying & defining which endpoints will be used to assess each 
component of the study objectives. 
--The study design should include contingencies for early stopping, interim analyses, 
stratification factors (If applicable), and any characteristics to be incorporated in analyses.  
--The power/precision of the study to address the major study endpoint(s), the assumptions 
involved in the determination of power/precision. 

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--If statistical hypothesis testing is included then specify the null and alternative hypotheses, 
the test statistic, and the type I and II error rates 
--If precision of an estimate, then provide a definition for precision 
--If other, then specify  
Answer/Response: Baseline clinical and demographic characteristics, follow-up measures, and 
clinical outcomes will be compared on an intention-to-treat basis according to the randomized 
study group assignment. Continuous variables will be compared using the Student t test for 
normally distributed variables or the Mann-Whitney U test or Wilcoxon matched-pairs signed-
rank test for non-normally distributed variables. Categorical variables will be compared using 
the Pearson χ2 test or Fisher exact test as appropriate. We estimate that 30 patients would be 
needed (15 in each study arm) to determine that an exposure to 2 additional allogeneic blood 
products will be statistically significant (C.I. 95%) providing 80% power with a type I error 
probability α = 0.05 (including 20% dropouts/withdrawals from the study) 
 
3.  Provide a justification for the sample size used in this protocol.   
Include sample size calculations or statistical power estimation.  If not applicable, please 
provide explanation.   
Also include the anticipated accrual rate, the accrual goal for the study, including accrual goals 
by strata if appropriate, adjustments for drop-outs etc. and study duration. 
Answer/Response:  This is a pilot study and no power analysis was performed. We anticipate 
enrollment in 2 years. 
 
4.  What is your plan for primary variable analysis? 
Include primary outcome(s)/predictor variable(s), statistical methods/models/tests to be 
employed, or descriptive summaries as appropriate.  If not applicable, please provide 
explanation.   
Answer/Response: 
Outcomes: the primary outcome of the study will be any allogeneic blood transfusion within 
the first 24 hours after administration of the FC or cryoprecipitate.  
 
5.  What is your plan for secondary variable analysis?  
Include the following:  
--Secondary outcome(s)/predictor variables, statistical methods/models/tests to be employed, 
or descriptive summaries as appropriate.  If not applicable, please provide explanation.  
--For phase III studies, the power/precision of the study to address the secondary objective(s). 
Answer/Response: Secondary outcomes will include: administration of individual blood 
products (RBC, platelets, FFP, cryoprecipitate) over the initial postoperative 48 hours and up to 
7 days after surgery, bleeding over the first postoperative 48 hours (intraoperatively = cell saver 
volume; postoperatively = chest drain/s output), the need for surgical re-exploration for 
hemostasis over the first postoperative 48 hours, the use of recombinant factor VIIa as rescue 
for refractory bleeding in the first 48 postoperative hours, length of ICU stay, hospital length of 
stay, thromboembolic complications over the first seven postoperative days and a 30-day 
composite of AKI, stroke, severe myocardial dysfunction or myocardial infarction, sepsis and 

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mortality (or until discharge whichever is earlier). 
 
6. Have you been working with a statistician in designing this protocol? 
Consultation with a professional statistician is highly recommended to ensure good science of 
the study and facilitate the review process.  
 
Answer/Response:  Yes 
 
IF YES, what is their name?   
Answer/Response: Jennie Z Ma 
 
7.  Will data from multiple sites be combined during analysis?   
Answer/Response:  No 
INSTRUCTIONS:  IF YES, answer the following questions 
7(a).  Does the study involve randomization?   
Answer/Response: 
IF YES, will randomization be done at each site or among sites?   
Answer/Response: 
7(b).  Has the sample size calculation considered the variation among sites?  
Answer/Response: 
7(c).  When combining the data from multiple sites to assess the study results, is the 
effect of the treatment to be tested (or the association to be tested) assumed to be the 
same across sites or vary among sites? What is the modelling strategy? 
Answer/Response: 
7(d). Is there a common protocol used in all sites?  
Answer/Response: 
IF NO, how will differences among sites, such as those related to the 
implementation, inclusion criteria, patient characteristics, or other sites 
characteristics, be considered to assess the study results? 
Answer/Response: 
Study Procedures-Biomedical Research 
1.  What will be done in this protocol?    
INSTRUCTIONS:  
This should include everything that will be done as part of this protocol. Do not repeat 
information that is included in other sections such as Background or Hypothesis 
sections.  
This section should include an indication of which research interventions if any offer a 
prospect for direct benefit and which interventions (invasive measurements, collection 
of blood, tissue, data, surveys, etc.) are being done solely to answer a research question 
and generate generalizable knowledge. If the interventions done solely for research 
purposes are associated with greater than minimal risk they need to be justified. 

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Describe and justify any control and experimental arm and include method, dose, and 
duration of drug administration. Reference any claim of clinical equipoise if applicable.   
 
If you are obtaining specimens or data, provide information regarding the type of 
specimen/data, amount of specimen needed and how the specimen/data will be 
obtained and what analysis will be done with the specimen/data. 
 
Special note for studies with waiver of consent/waiver of documentation of consent:  
Include a statement regarding how subjects will be recruited. For other studies this 
information is captured in Recruitment does not need to be duplicated in this section. 
Answer/Response:   
The parent/ legal guardian will be consented at a clinic or hospital visit prior to surgery 
by study staff and will include the Peds Cardiac NP they are familiar with when possible. 
Subjects will be monitored for 48 hours for the need for fibrinogen supplementation 
 
Once the need for fibrinogen supplementation is confirmed in the OR or PICU, subjects 
will be randomized into one of two treatment groups (n=15 in each group):  
 
1. Cryoprecipitate group (dose: 10 ml/kg; active control group) or  
2. Fibrinogen Concentrate group (dose: 70 mg/kg; intervention group) single dose.  
 
Administration of the study drug is via transfusion. 
 
There will be no placebo group since withholding treatment is neither consistent with 
standard of care nor acceptable ethically. 
 
No other aspects of care will be modified.  
 
In the event that a second round of fibrinogen supplementation is required (bleeding 
with documented hypofibrinogenemia) participants will receive either FC or 
cryoprecipitate based on their initial randomization. If any additional fibrinogen 
supplementation is then needed (after the first 2 supplementation doses), 
cryoprecipitate will be administered to all subjects per standard of care (including those 
who received FC).  
 
Data to be obtained: 
1. Demographic/preoperative data: collected from the medical record 
- age in days/months (all patients to be younger than 24  months) 
- gender 
- weight 
- preoperative diagnosis 
- surgery type & date (Norwood, arterial switch, truncus arteriosus, Glenn, Fontan, 
TAPVR, AV canal, tetralogy of Fallot, etc) 
- preoperative standard of care labs PT/aPTT/INR/hgb level/ hematocrit/ platelet count/ 

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fibrinogen level (if exists)/ creatinine  
 
2. Intra-operative Data: collected from the medical record 
- CPB time & aortic cross clamp time 
- use of hypothermic circulatory arrest (ice packs placed on the head) 
- was post-CPB ultrafiltration performed? 
- Platelet count prior to separation from CPB 
- was ATIII administered? (thrombate) 
- Transfusion requirements: PRBC/Cell Saver/FFP/PLT/ cryo - to be collected as number 
of units per each product, not volume. (for PLT - was it pooled PLT or single donor 
apheresis, if possible) 
- was rFVIIa given (factor seven, novoseven). Please pay attention - the fact that rFVIIa 
was ordered DOES NOT mean that was actually administered as we order factor VII for 
ALL big cases (to have available in the OR) but not necessarily administer it 
- Need for ECMO 
- Was the chest left open? (always in ECMO, but open chest does not necessarily mean 
ECMO) 
 
ROTEM (clotting labs) will be drawn for research purposes after admission and after 
administration of the study treatment: Extem (CT/A10/A20/MCF); Fibtem 
(A10/A20/MCF) and fibrinogen.  The blood drawn for this will be obtained through an 
existing line, put into place as part of the subject’s usual care.  
 
3. Postoperative Data (PICU, up to 48 hours after surgery) collected from the medical 
record  
- admission PT/aPTT/INR/platelet count/ fibrinogen level/ hgb level/HCT level (could be 
obtained from initial ABG) 
- Bleeding (Chest drain/s output) 
- Need for additional transfusion (PRBC/cell saver/FFP/platelets/cryoprecipitate). Will 
need to know, if possible, whether transfused from same unit that was already exposed 
to in the OR or new unit (= new exposure) 
- Factor VIIa administration 
- re-exploration? (= starting ECMO in the PICU) 
- delayed chest closure? (will answer whether went to PICU with chest open) 
 
2. If this protocol involves study treatment, explain how a subject will be transitioned from 
study treatment when they have completed their participation in the study.   
Example:  If the subject will be taking an investigational drug, will they need to be put 
back on an approved drug when they have completed the study?  If yes, explain how 
this will be accomplished and who will cover the cost.  If the subject has a device 
implanted will it be removed?  Again- who will cover the cost of the removal?   
Instructions: Answer NA if this study does not involve a study treatment.   
Answer/Response: There is no transition from study treatment. 
 

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Subject Compliance with Study Procedures 
1.  Explain how the study team will monitor the subject for compliance with the study 
procedures. 
 (e.g. study team will administer study drug/ study interventions, study drug inventory 
of dispensed and returned drug, diary etc.) 
Answer/Response:  Study team/ anesthesiologist / PICU staff will administer study drug 
and document administration in EPIC 
 
2.  Describe criteria for when a subject is considered to be non-compliant with study 
procedures.   
(e.g. subject returns more than 20% of the study drug, subject misses 20%  of study 
visits) 
Answer/Response: Not applicable 
Bibliography 
INSTRUCTIONS:  Provide a current bibliography supporting the hypothesis, background and 
methodology including references to papers and abstracts that have resulted from previous 
work by the investigator and references to the work of others. 
 
1. 
Faraoni D, Meier J, New HV, Van der Linden PJ, Hunt BJ. Patient Blood 
Management for Neonates and Children Undergoing Cardiac Surgery: 2019 NATA 
Guidelines. J Cardiothorac Vasc Anesth 2019;33:3249-63. 
2. 
Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: 
a review of critical levels and replacement therapy. Transfusion 2014;54:1389-405. 
3. 
Edmunds LH, Jr. Managing fibrinolysis without aprotinin. Ann Thorac Surg 
2010;89:324-31. 
4. 
Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired 
bleeding. Blood 2015;125:1387-93. 
5. 
Callum J, Farkouh ME, Scales DC, et al. Effect of Fibrinogen Concentrate vs 
Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES 
Randomized Clinical Trial. JAMA 2019:1-11. 
6. 
Raphael J, Mazer CD, Subramani S, et al. Society of Cardiovascular 
Anesthesiologists Clinical Practice Improvement Advisory for Management of 
Perioperative Bleeding and Hemostasis in Cardiac Surgery Patients. Anesth Analg 
2019;129:1209-21. 
7. 
Erdoes G, Koster A, Meesters MI, et al. The role of fibrinogen and fibrinogen 
concentrate in cardiac surgery: an international consensus statement from the 
Haemostasis and Transfusion Scientific Subcommittee of the European Association of 
Cardiothoracic Anaesthesiology. Anaesthesia 2019;74:1589-600. 
8. 
Rahe-Meyer N, Levy JH, Mazer CD, et al. Randomized evaluation of fibrinogen vs 
placebo in complex cardiovascular surgery (REPLACE): a double-blind phase III study of 
haemostatic therapy. Br J Anaesth 2016;117:41-51. 

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9. 
Ranucci M, Baryshnikova E, Crapelli GB, et al. Randomized, double-blinded, 
placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac 
surgery. J Am Heart Assoc 2015;4:e002066. 
10. 
Rahe-Meyer N, Solomon C, Hanke A, et al. Effects of fibrinogen concentrate as 
first-line therapy during major aortic replacement surgery: a randomized, placebo-
controlled trial. Anesthesiology 2013;118:40-50. 
11. 
Rahe-Meyer N. Fibrinogen concentrate in the treatment of severe bleeding after 
aortic aneurysm graft surgery. Thromb Res 2011;128 Suppl 1:S17-9. 
12. 
Bilecen S, de Groot JA, Kalkman CJ, et al. Effect of Fibrinogen Concentrate on 
Intraoperative Blood Loss Among Patients With Intraoperative Bleeding During High-Risk 
Cardiac Surgery: A Randomized Clinical Trial. JAMA 2017;317:738-47. 
13. 
Downey LA, Andrews J, Hedlin H, et al. Fibrinogen Concentrate as an Alternative 
to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing 
Cardiac Surgery: A Prospective Randomized Controlled Trial. Anesth Analg 2020;130:740-
51.