What is the Safest and Most Effective Source of Fibrinogen Replacement in Neonates Undergoing Open Heart Surgery: Cryoprecipitate or Fibrinogen Concentrate?

Susan Nicolson, James DiNardo, Lindsey Loveland, Viviane Nasr

Original article

Downey LA, Moiseiwitsch N, Nellenbach K, Xiang Y, Brown AC, Guzzetta NA. Effect of In Vivo Administration of Fibrinogen Concentrate Versus Cryoprecipitate on Ex Vivo Clot Degradation in Neonates Undergoing Cardiac Surgery. Anesth Analg. 2024 Aug 8. doi: 10.1213/ANE.0000000000007123. Epub ahead of print. PMID: 39116012.

Editorial

Faraoni D, DiNardo JA.  Fibrinogen supplementation in neonates undergoing cardiac surgery: looking beyond concentration alone.  Anesth Analg

Neonates undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk for post-bypass bleeding due to the impact of hemodilution from the pump prime on an immature coagulation system and complex procedures, many with suture lines in high pressure vessels.  Neonates are also at increased risk for postoperative thrombotic complications which carries morbidity and in some, mortality.  The perioperative management of coagulopathy to achieve hemostasis requires balancing the benefit of administering allogenic blood products and coagulation factor concentrates with the increased risk of thrombotic complications while minimizing donor exposure. 

Low fibrinogen is associated with increased post-CPB bleeding in pediatric and adult cardiac surgery patients.  The risk of hypofibrinogenemia is more prevalent in neonates due to disproportionate CPB-induced hemodilution particularly when insufficient fresh frozen plasma is incorporated in the pump prime.  Treating low fibrinogen early after termination of bypass is an important component of any algorithm-based transfusion protocol.  In the United States, cryoprecipitate (cryo) remains the first-line treatment for hypofibrinogenemia in neonates.  Cryo contains factors VIII and XIII, von Willebrand factor and fibronectin in addition to fibrinogen.  The role of the components of cryo in treating post-CPB bleeding has not been elucidated.  Because these other factors may or may not be deficient at the time of transfusion of cryo, some have suggested that administration of cryo could increase the risk of thrombotic complications in neonates.  Transfusion of cryo in the presence of an immature antifibrinolytic system may also increase the likelihood of postoperative thrombosis in neonates. 

Both adult and pediatric studies suggest that fibrinogen concentrate (FC) might be an acceptable alternative to cryo to treat hypofibinogenemia^1-3 resulting in its being used off-label with increasing frequency.  FC has several desirable properties for use in neonates: immediate availability, small volume of administration, accurate dosing and decreased immunologic and infectious risks.

Although fibrinogen levels in neonatal and adult plasma are comparable, neonatal fibrinogen has been shown to be dysfunctional and exist in a fetal form until 1 year of age.  The differences between fetal and adult forms of fibrinogen may contribute to the bleeding propensity in neonates undergoing open heart surgery.  Transfusion of cryo will replace neonatal fibrinogen with adult fibrinogen which could impact the density and stability of the fibrin network formed.  Brown and colleagues tested that hypothesis using blood samples collected from neonates before and after bypass and after transfusion with cryo.⁴  They found a decrease in the fibrin network density after bypass and that the addition of adult fibrinogen from cryo to neonatal blood led to less homogenous clots than clots formed with either exclusively neonatal or adult fibrinogen.  Clot formed with neonatal and adult fibrinogen had slower degradation than clot formed with neonatal fibrinogen alone which could potentially promote postoperative thrombosis. 

Downey and colleagues⁵ hypothesized that FC may restore hemostasis after CPB with a reduced risk of thrombosis due to the lack of clot stabilizing factors.  To test this hypothesis they performed an investigator-initiated randomized trial comparing the effect of in vivo administration of cryo versus FC as part of a post-CPB transfusion algorithm (see chart below) on ex vivo clot degradation in neonates undergoing open heart surgery.  Thirty six neonates were enrolled with the intent to treat, 13 patients in the cryo group and 17 patients in the FC group completed the study per protocol.  Blood samples were drawn at 4 times: T1- pre-surgery, T-2 - after treatment, T-3 - on arrival to the ICU and T-4 -24 hours post-surgery. 

The primary endpoint was percentage change in ex vivo clot degradation from baseline at 24 hours after surgery between the 2 groups.  Ex vivo clot degradation was estimated by measuring the supernatant fibrin degradation products concentration at the beginning of and after completion of clot degradation at each time point. Secondary outcomes were intraoperative blood transfusions, coagulation factor levels and adverse events. The authors used a CPB protocol and transfusion algorithm as outlined here:

CPB Management and Transfusion Algorithm

·       Bypass Circuit – non-heparin coated system, 250-300 priming volume – PRBCs < 14 days of age to achieve/maintain hct of 30%, 50 cc of FFP to the prime and another 50cc on re-warming with zero-balance ultrafiltration performed throughout CPB

·       Anticoagulation with heparin 500 units/kg to achieve ACT > 480 throughout CPB

·       Protamine 5 mg/kg to reverse heparin

·       TXA 100 mg/kg bolus prebypass and in pump prime, infusion of 10 mg/kg/hr until end of surgery

·       Transfusion:

-          15-20 ml/kg of platelets

-          Either 2 units of cryoprecipitate or FC to achieve a post treatment fibrinogen of 300 mg/dl

IF further post-CPB bleeding after using the above algorithm, TEG, point of care testing, and clinical judgement determined additional blood products for transfusion. 

After normalizing to the patient’s own baseline (T1), no significant differences were observed in clot degradation at T2 or T3, patients in the FC group had greater degradation when compared to those in the cryo group at 24 hours post surgery (T4).  Neonates who received FC received significantly less median post-CPB transfusions than neonates given cryo (27.2 ml/kg [19.0-36.9] vs 41.6 ml/kg [29.2-52.4]) and did not have increased bleeding or thrombotic complications.  The authors concluded that their data suggests that FC adequately restores hemostasis and reduces transfusions in neonates after bypass without increased bleeding or thrombosis risk.   

The conclusions of Downey et al. need to be interpreted taking into considerations the limitations of the study.  The sample size is small, conducted at a single center. The study design exposed all neonates to FFP in the pump prime resulting in blood samples taken after institution of CPB and post-transfusion containing a combination of 4 different sources of fibrinogen: neonatal fibrinogen, adult fibrinogen from FFP and cyro and FC.  Clot degradation was measured in the presence of an antifibrinolytic in all neonates.  It could be argued that clot degradation cannot be properly assessed until several hours after termination of tranexamic acid administration.  Neonates who received FC received fewer transfusions expressed as ml/kg but the study did not address donor exposures.   Although the study showed no difference in thrombotic or bleeding complications, it was not powered to assess safety.   

This study serves to emphasize the complex interaction between neonatal fibrinogen and the two forms of fibrinogen replacement to treat hypofibrinogenemia in neonates.  The combination of neonatal and adult fibrinogen (cryo) does not form a strong fibrin network and undergoes slower degradation which may be problematic in achieving hemostasia and may promote thrombosis. Addition of FC to neonatal blood both ex vivo and in vivo leads to a clot structure like that seen with cryo replacement, but degradation at 24 hours is faster.

This study by Downey et al supports the need for further investigation of the genesis and treatment of CPB related coagulopathy in neonates.  This review also raises the question – is it time to re-examine the efficacy of fresh whole blood both in the pump prime and post-bypass in preventing and/or treating coagulopathy in neonates.  Whole blood in the pump prime will minimize the reduction in fibrinogen on CPB and use both on and after bypass has the potential to reduce donor exposures.

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References

1.           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;322(20):1966-1976. (In eng). DOI: 10.1001/jama.2019.17312.

2.           Galas FR, de Almeida JP, Fukushima JT, et al. Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: a randomized pilot trial. The Journal of thoracic and cardiovascular surgery 2014;148(4):1647-55. (In eng). DOI: 10.1016/j.jtcvs.2014.04.029.

3.           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. Anesthesia and analgesia 2020;130(3):740-751. (In eng). DOI: 10.1213/ane.0000000000004384.

4.           Brown AC, Hannan RT, Timmins LH, Fernandez JD, Barker TH, Guzzetta NA. Fibrin Network Changes in Neonates after Cardiopulmonary Bypass. Anesthesiology 2016;124(5):1021-31. (In eng). DOI: 10.1097/aln.0000000000001058.

5.           Downey LA, Moiseiwitsch N, Nellenbach K, Xiang Y, Brown AC, Guzzetta NA. Effect of In Vivo Administration of Fibrinogen Concentrate Versus Cryoprecipitate on Ex Vivo Clot Degradation in Neonates Undergoing Cardiac Surgery. Anesthesia and analgesia 2024 (In eng). DOI: 10.1213/ane.0000000000007123.