Pro-Con Debate

Fibrinogen Concentrate or Cryoprecipitate for Treatment of Acquired Hypofibrinogenemia in Cardiac Surgical Patients

Nadia B. Hensley, MD; Michael A. Mazzeffi, MD, MPH, MSc, FASA

Anesth Analg. 2021;133(1):19-28.

Evidence for Fibrinogen Replacement in Cardiac Surgical Patients With Acquired Hypofibrinogenemia

Lyophilized, pooled fibrinogen concentrate has emerged as an alternative source of fibrinogen for the cardiac surgical patients with acquired hypofibrinogenemia. Fibrinogen concentrate has several potential advantages over cryoprecipitate, but there are also potential disadvantages. Given the increased emphasis that has been placed on reducing allogeneic transfusion in the cardiac surgical patients, the advantages and disadvantages of using fibrinogen concentrate or cryoprecipitate to treat acquired hypofibrinogenemia in the cardiac surgical patients must be considered.

In vitro and observational studies have demonstrated the importance of fibrinogen replacement for adequate hemostasis, yet randomized controlled trials of fibrinogen treatment compared to placebo have not shown a mortality benefit.^[19] Cushing and Haas^[20] examined these clinical trials and determined that fibrinogen's inconsistent efficacy may be related to design flaws in the trials themselves, including variable definitions for hypofibrinogenemia, inclusion of patients with insignificant bleeding, and off-protocol interventions.

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Table 1. Comparison of Fibrinogen Concentrate Versus Cryoprecipitate
Attribute	Fibrinogen concentrate	Cryoprecipitate
Fibrinogen concentration	Standard concentration of ~1 g per vial, after reconstitution becomes 1 g per 50 mL	Variable concentration of ~120–796 mg per 15 mL in each individual single donor unit
Viral screening and/or inactivation	Nucleic acid testing for HIV, hepatitis A, B, and C, and human parvovirus in donor plasma units Additional viral inactivation through precipitation/adsorption/pasteurization processes	Nucleic acid testing for HIV, hepatitis B and C, and other viruses^a
Factor content	Purified fibrinogen	Fibrinogen and other coagulation factors including VWF, FVIII, FXIII, fibronectin, and platelet microparticles
Aspect of hemostasis that is treated	Secondary hemostasis by increasing substrate for thrombin	Primary hemostasis by increasing VWF and platelet microparticles
Aspect of hemostasis that is treated	Secondary hemostasis by increasing substrate for thrombin	Secondary hemostasis by increasing substrate for thrombin and FVIII activity (intrinsic tenase activity)
Acquisition time	Rapid reconstitution in minutes can be rapidly administered to the patient after reconstitution	Kept frozen at −20 °C and requires 30–45 min to thaw, once available can be rapidly administered to the patient
Shelf life after reconstitution or thawing	Shelf life is up to 24 h after reconstitution	Limited shelf life after thawing of 4–6 h; FVIII activity degrades relatively quickly, fibrinogen is more stable
Risk for transfusion adverse events	Negligible risk of alloimmunization, TACO, TRALI	Low, but present risk of allergic transfusion reactions, alloimmunization, and other transfusion adverse events (TACO or TRALI)
Total volume	50 mL diluent volume per 1 g vial	70–120 mL volume for 10 unit pool
Thrombotic risk in FIBRES study²⁴	7.0% overall incidence	9.6% overall incidence
Thrombotic risk in FIBRES study²⁴	4.6% stroke or TIA incidence	5.0% stroke or TIA incidence
Acquisition cost	Acquisition cost of ~$1000 per 1 g in the United States, lower acquisition cost in Europe and Canada of ~$400–$500 per 1 g	Acquisition cost of ~$300–$400 per 5–6 unit pool in the United States Additional "hidden" costs include blood bank processing (~45 min to 1 h) and wastage, which increase the total cost

Abbreviations: FIBRES, FIBrinogen REplenishment in Surgery; HIV, human immunodeficiency virus; TACO, transfusion-associated circulatory overload; TIA, transient ischemic attack; TRALI, transfusion-related acute lung injury; VWF, von Willebrand factor.
^aZika and West Nile virus may be tested by pooling samples of multiple blood donations but with triggering individual donors if there is an outbreak.

Table 2. Randomized Controlled Trials Examining Fibrinogen Concentrate in Cardiac Surgery
References	n	Surgery	Timing of administration	Dosing	Comparator	Primary end points	Findings
Karlsson et al³⁵	20	Elective CABG	Preincision	2 g	Placebo	Clinical adverse events^a and graft occlusion by CT 3–4 d postsurgery	No detectable adverse events; 1 vein graft occlusion in the FC group; LIMA grafts patient in both groups
Rahe-Meyer et al³⁶	15	Elective AVR and ascending aorta replacement	Postbypass with signs of clinical bleeding	Dose based on the MCF on FIBTEM; mean, 5.7 ± 0.7 g	Placebo	Transfusion of allogeneic blood products after CPB in 24 h postop	Significantly fewer RBC, FFP, and platelet transfusions in the FC group
Sadeghi et al³⁷	60	Elective CABG	Preincision	1 g	Placebo	Chest tube output in first 12 h	Significantly lower chest tube output in the FC group
Tanaka et al³⁸	20	Elective valve replacement/repair, double valve, or valve + CABG	Postbypass with signs of clinical bleeding	4 g	1 unit platelet apheresis	Hemostatic conditions in the field^b after intervention and 24 h usage of allogeneic blood products	Hemostatic scores similar between groups; no differences in RBC, FFP, cryo transfusions between groups; less platelets in the FC group
Ranucci et al³⁹	116	Elective complex surgery with >90 min CPB and at least 1 risk factor^c	Postbypass with signs of clinical bleeding	Dose based on MCF on FIBTEM for target = 22 mm	Placebo	Avoidance of any allogeneic blood products up to 30 d postop	67.2% in the FC group and 44.8% in the control group avoided any allogeneic blood products (OR, 0.40; 0.19–0.84); P < .015
Jeppsson et al⁴⁰	48	Elective CABG	Preincision	2 g	Placebo	Mediastinal drainage loss during first 24 h postop	No significant differences between the FC group and the control group
Rahe-Meyer et al⁴¹	152	Elective open aortic surgery (TAAA repair, TAA with prox. arch, TAA without prox. arch)	Postbypass with signs of clinical bleeding	Dose based on MCF on FIBTEM for target = 22 mm	Placebo	Number of allogeneic blood product units (RBC, FFP, and platelets) in 24 h after FC	Median total of 5.0 (IQR, 2.0–11.0) units of allogeneic blood products in the FC group compared with 3.0 (IQR, 0.0–7.0) units in the placebo group
Bilecen et al⁴²	120	Elective high-risk^d cardiac surgery	Postbypass with signs of clinical bleeding	Dose based on plasma fibrinogen levels^e to target 2.5 g/L	Placebo	Intraoperative blood loss (mL) measured between intervention and chest closure	No significant differences in blood loss measured between the time of FC administration and chest closure. FC group 50 mL (29–100) versus placebo 70 mL (33–145)
Callum et al²⁴	735	Cardiac surgery with CPB and fibrinogen replacement necessary	Postbypass with plasma fibrinogen level <2.0 g/L^e or MCF on FIBTEM <10 mm	4 g	10 units of cryoprecipitate	Cumulative allogeneic blood product units (RBC, FFP, platelets)	Noninferiority criteria met; mean 24 h postbypass cumulative transfusions 16.3 (95% CI, 14.9–17.8) vs 17.0 (95% CI, 15.6–18.6)

Abbreviations: AVR, aortic valve replacement; CABG, coronary artery bypass grafting; CI, confidence interval; CPB, cardiopulmonary bypass; cryo, cryoprecipitate; CT, computed tomography; FC, fibrinogen concentrate; FFP, fresh frozen plasma; FIBTEM, fibrin-based thromboelastometry test extrinsically activated with tissue factor and containing the platelet inhibitor cytochalasin D; IQR, interquartile range; LIMA, left internal mammary artery; MCF, maximum clot firmness; OR, odds ratio; postop, postoperative; prox, proximal; RBC, red blood cell; TAA, thoracic aortic aneurysm; TAAA, thoracoabdominal aneurysm.
^aDefined as clinical signs of central or peripheral thromboembolism, respiratory or circulatory failure, or allergic reactions during hospital stay.
^bAssessment of surgical bleeding by senior surgical staff using scale ranging from: 0 = excellent hemostasis; 1 = mild bleeding (oozing); 2 = moderate bleeding (controllable with applied pressure); 3 = severe bleeding (multiple diffuse bleeding sites).
^cRisk factors defined as age >65 years, nonelective, creatinine > 1.36 mg/dL, and redo-sternotomy.
^dHigh risk defined as CABG + valve replacement/repair; multiple valve replacements; aortic root reconstruction or reconstruction of ascending aorta or aortic arch.
^eMeasured by the Clauss method (turbidometric).