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Pro-Con Debate: Fibrinogen Concentrate or Cryoprecipitate for Treatment of Acquired Hypofibrinogenemia in Cardiac Surgical Patients

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

Author Information
doi: 10.1213/ANE.0000000000005513

Abstract

See Article, p 16

Ten to 15% of the United States blood supply is transfused in cardiac surgical patients.1 Multiple factors including fibrinogen concentration impact bleeding and transfusion risk in cardiac surgical patients.2–4 About 15 years ago, most European countries removed cryoprecipitate from their markets and began to use fibrinogen concentrate for the treatment of acquired hypofibrinogenemia, mainly because of its superior safety profile. Although fibrinogen concentrate is now extensively used in Europe and Canada, there remains debate in the United States about whether a fibrinogen concentrate is superior when compared to a cryoprecipitate for treating acquired hypofibrinogenemia in the cardiac surgical patients. In this Pro-Con commentary article, we discuss the advantages and disadvantages of both products for treating acquired hypofibrinogenemia in the cardiac surgical patients.

ROLE OF FIBRINOGEN IN HEMOSTASIS DURING CARDIAC SURGERY

Fibrinogen, which is a plasma glycoprotein that is made in the liver (half-life of ~100 hours), is a critical substrate for thrombin. It catalyzes the conversion of fibrinogen to fibrin and also activates platelets through protease-activated receptors (PARs) 1 and 4 on platelet surfaces. Activation of PARs lead to the release of adenosine diphosphate (ADP) from dense granules and activation of the platelet surface glycoprotein IIb/IIIa receptor, which binds activated platelets to fibrinogen/fibrin.5,6

Clot strength is dependent on fibrinogen concentration, and multiple studies have shown that a fibrinogen concentration of >200 mg/dL is necessary for optimal hemostasis in cardiac surgical patients.3,7 The European guidelines recommend replacing fibrinogen when its concentration is <150 mg/dL in the noncardiac surgical patients.8 Clot firmness and plasma fibrinogen concentration predictably fall after cardiopulmonary bypass (CPB), mainly due to hemodilution and a lesser degree from consumption.2 Decreases in clotting factors of 30%–50% are common after CPB and depend on CPB priming volume, retrograde autologous priming (RAP), autologous whole blood collection before CPB, and the amount of cell salvage.4,9

CRYOPRECIPITATE HISTORY AND USE IN CARDIAC SURGICAL PATIENTS

Cryoprecipitate was serendipitously discovered by Judith Graham Pool in the 1960s at Stanford University.10,11 Dr Pool noted that when plasma was thawed, very little factor VIII was present in the supernatant, whereas abundant factor VIII was present in the unthawed material at the bottom of the container. This observation led to the use of cryoprecipitate for treating the patients with hemophilia A and von Willebrand disease (VWD). Currently, cryoprecipitate is rarely used to treat hemophilia A and VWD because concentrated, lyophilized, plasma-derived, and recombinant products are available for both diseases. Instead, cryoprecipitate is used to treat acquired hypofibrinogenemia in cardiac surgery, multitrauma, obstetrical hemorrhage, and other critical care settings.12 Until recently, cryoprecipitate was the only effective treatment for acquired hypofibrinogenemia in cardiac surgical patients.

CRYOPRECIPITATE PROCESSING

Cryoprecipitate is derived from fresh frozen plasma (FFP), which is frozen within 8 hours of collection. FFP can be thawed in a water bath or a refrigerator, and plasma supernatant is separated from precipitate using centrifugation.13 Plasma supernatant is discarded except for a small volume (10–15 mL), which is kept to suspend the cryoprecipitate.13 Multiple single donor units of cryoprecipitate (typically 5 or 6 units) are combined into a single pooled unit using sterile “welding.” Pooled cryoprecipitate is refrozen and stored at a temperature <−18 °C for 1 year. When frozen cryoprecipitate is thawed for transfusion, it must be used within 6 hours and cannot be refrozen. The main reason for this is that factor VIII activity decreases quickly at room temperature. Alternatively, fibrinogen content is stable up to 5 weeks.14

US FOOD AND DRUG ADMINISTRATION REQUIREMENTS FOR CRYOPRECIPITATE

US Food and Drug Administration (FDA) requirements for cryoprecipitate are outlined in the Code of Federal Regulations (CFR) Title 21, Section 640.5. In this document, the FDA describes the minimum factor VIII activity that is required for a single donor cryoprecipitate unit, which is 80 international units (IUs). When 5 single donor units are pooled together, this can be extrapolated to a minimum of 400 IU of factor VIII. The CFR further states that at least 4 cryoprecipitate units must be tested per month to determine the adequate factor VIII potency in any center that processes cryoprecipitate.

CRYOPRECIPITATE CONTENT

Cryoprecipitate contains factor VIII, von Willebrand factor (VWF), fibrinogen, factor XIII, and fibronectin. The exact content of an individual cryoprecipitate unit depends on the methods used for preparation. In particular, VWF and fibrinogen content can be affected by the amount of plasma that is left for suspension.15 Cryoprecipitate content is also affected by donor variability in factor activity and the type of freezer that is used for storage.16 Most single donor cryoprecipitate units contain at least 250 mg of fibrinogen, which translates to 1.25 g of fibrinogen for a 5 donor pool or 1.5 g of fibrinogen for a 6 donor pool.17 According to the American Red Cross, the mean factor VIII activity of a single donor cryoprecipitate unit is 136 IU and of a pool is 555 IU. The mean fibrinogen content of a single donor unit is 525 mg and of a pool is 2.5 g.18

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 Haas20 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.

FIBRINOGEN CONCENTRATE ADVANTAGE: DOSE PREDICTABILITY

FDA-approved fibrinogen concentrates contain a standardized concentration of fibrinogen (Table 1). The 2 fibrinogen concentrates approved for the treatment of congenital hypofibrinogenemia in the United States are RiaSTAP (CSL Behring, King of Prussia, PA), which has a fibrinogen concentration of 900–1300 mg/vial (~1000 mg); and FIBRYGA (Octapharma USA, Paramus, NJ), which has a fibrinogen concentration of 1000 mg/vial.21,22 Previous studies have demonstrated a significant variation in the fibrinogen content of cryoprecipitate, which ranges from 120 to 796 mg per individual unit.23–26 This variability may lead to an inconsistent hemostatic efficacy for cryoprecipitate. Alternatively, fibrinogen concentrate has a known fibrinogen content, leading to predictable effects. The following formula can be used to find the dose fibrinogen concentrate.

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 Nucleic acid testing for HIV, hepatitis B and C, and other virusesa
Additional viral inactivation through precipitation/adsorption/pasteurization processes
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
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
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.

Dose of fibrinogen concentrate (mg) = Target plasma concentration (mg/dL) − Measured plasma concentration (mg/dL)/1.7 × body weight (kg).

FIBRINOGEN CONCENTRATE ADVANTAGE: VIRAL INACTIVATION

Inactivation of viruses with solvents, detergents, pasteurization, and filtration methods is an important advantage of fibrinogen concentrate (Table 1).21,22,24 These processes significantly reduce the risk of viral transmission. Even though allogeneic blood products have been screened since 1985 with nucleic acid testing for viruses such as hepatitis C and human immunodeficiency virus (HIV), it is impractical to screen for all viruses or emerging infectious diseases. The World Federation of Hemophilia supports the use of fibrinogen concentrate, as opposed to cryoprecipitate, because of the potential to reduce infectious disease transmission.27

In December 2019, a novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China, where the first case of coronavirus disease 2019 (COVID-19) was described.28 AABB, formerly known as the American Association of Blood Banking, and the US FDA have stated that there are no reported cases of SARS-CoV-2 infection related to blood transfusion.29 Careful screening of blood donors through questionnaires and routine temperature checks, as well as volunteer reporting of COVID-19 symptoms within 48 hours of blood donation, have apparently kept the blood supply safe. No known transmission of other respiratory viruses (eg, severe acute respiratory syndrome or Middle East respiratory syndrome coronavirus) has occurred during the past 20 years through blood transfusion.

Cappy et al30 reported that between January 20 and May 29 of 2020, 311 blood donations to the French National Blood Service were investigated including 268 postdonation infections (PDIs) and 43 trace-back donations (patients who reported COVID-19 symptoms within 14 days of donation). Three of the 268 PDI donations (1.1%) tested positive for SARS-CoV-2 ribonucleic acid (RNA). Two of these donations were not utilized. One donor positive platelet unit was pathogen reduced and transfused 3 days after donation to a patient who remained asymptomatic, and a red blood cell (RBC) unit was given to a SARS-CoV-2–positive patient. Four immunocompromised recipients (aged 5–67 years) were involved in trace-back donations and received 2–25 blood products including 18 RBCs and 23 pathogen-reduced platelets. None of these 43 trace-back repository samples were positive for SARS-CoV-2 RNA. In conclusion, current evidence suggests that the risk of transmission of SARS-CoV-2 through the blood supply is exceedingly low. Nonetheless, viral inactivation of fibrinogen concentrate further reduces any risk of transmitting SARS-CoV-2.

FIBRINOGEN CONCENTRATE ADVANTAGE: RAPID RECONSTITUTION AND LONGER SHELF LIFE

Another advantage of fibrinogen concentrate is that it can be rapidly reconstituted and administered to patients. Fibrinogen concentrate can be stored at room temperature and is easily reconstituted in sterile water within 5–10 minutes. After reconstitution, fibrinogen concentrate can be used for up to 24 hours, reducing wastage.21,22 In contrast, cryoprecipitate is kept frozen, requires 30–45 minutes for thawing, and has a shelf life of only 6 hours after thawing. During massive hemorrhage, thawing time may be detrimental, leading to an additional hemodilution or consumptive coagulopathy, as the minimal fibrinogen is given in other allogeneic blood products. Due to plasma’s low fibrinogen content of 500–600 mg per 250 mL, plasma fibrinogen concentration is likely to remain low, while awaiting cryoprecipitate.31

FIBRINOGEN CONCENTRATE ADVANTAGE: REDUCED RISK OF TRANSFUSION ADVERSE EVENTS

With any allogeneic transfusion, including cryoprecipitate, there is a risk of alloimmunization and allergic transfusion reaction.32 Fibrinogen concentrate undergoes viral inactivation processing, which also removes blood and human leukocyte antigen (HLA) antibodies and antigens and significantly reduces the risk of immunological transfusion reaction.12 Transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and allergic transfusion reactions remain significant risks of allogeneic blood transfusion and are associated with increased health care cost, morbidity, and mortality.33,34

FIBRINOGEN CONCENTRATE ADVANTAGE: EVIDENCE OF SAFETY AND EFFICACY IN CARDIAC SURGICAL PATIENTS

There have been several randomized controlled trials of fibrinogen concentrate in cardiac surgical patients (Table 2).24,35–42 One of the first trials conducted by Karlsson et al35 randomized elective coronary artery bypass grafting (CABG) patients who had a preoperative plasma fibrinogen concentration of ≤380 mg/L. Randomized patients received an infusion of 2 g fibrinogen concentrate (n = 10) or no infusion (n = 10) immediately before surgery.35 Primary end points were clinically detectable adverse events and early graft occlusion by cardiac computed tomography (CT). There was 1 vein graft occlusion in the fibrinogen concentrate group, and no vein graft occlusions in the control group. All left internal mammary grafts were patent in both groups.

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 eventsa 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 fieldb 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 factorc 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-riskd cardiac surgery Postbypass with signs of clinical bleeding Dose based on plasma fibrinogen levelse 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/Le 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).

Rahe-Meyer et al36 conducted another small randomized trial in patients undergoing elective aortic valve and ascending aortic replacement surgery. In 1 group (n = 5), patients were treated with a transfusion algorithm based on the platelet count at cross-clamp removal and bleeding (defined by >60 g of blood weighed on surgical swabs), and in the other group (n = 10), patients were given fibrinogen concentrate before being transfused according to an algorithm. For the primary end point, the use of allogeneic blood products, the fibrinogen concentrate group was transfused fewer RBC units (0.5 ± 1.1 vs 2.4 ± 1.1), fewer FFP units (0.2 ± 0.6 vs 4.5 ± 2.1), and fewer platelet units (0.0 ± 0.0 vs 1.6 ± 1.7).36

Ranucci et al39 enrolled 116 cardiac surgical patients and randomized them to receive either fibrinogen concentrate or placebo after protamine was given. Fibrinogen concentrate was given based on the rotational thromboelastometry (ROTEM; TEM International, Munich, Germany) parameters.39 Fifteen minutes after fibrinogen concentrate was given, patients could receive prothrombin complex concentrate if ROTEM parameters remained abnormal. The authors found that 67.2% of patients in the treatment arm avoided any allogeneic transfusion (primary outcome) compared to 44.8% in the control group (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.19-0.84).

The largest randomized multicenter clinical trial of fibrinogen concentrate, the FIBrinogen REplenishment in Surgery (FIBRES) study, enrolled 725 patients at 11 centers in Canada (Table 2).24 This study included adult patients who had significant bleeding related to acquired hypofibrinogenemia after CPB, defined as fibrinogen <200 mg/dL by the Clauss method or the fibrin-based thromboelastometry test extrinsically activated with tissue factor and containing the platelet inhibitor cytochalasin D (FIBTEM) amplitude <10 mm at 10 minutes. Randomized patients received 4 g of fibrinogen concentrate or 10 units of cryoprecipitate. Mean 24-hour post-CPB cumulative allogeneic transfusions were 16.3 units (95% CI, 14.9-17.8) in the fibrinogen concentrate group and 17.0 units (95% CI, 15.6-18.6) in the cryoprecipitate group. These findings met the prespecified criteria for noninferiority. Noninferiority was also met for the secondary outcomes, including 24-hour and cumulative 7-day blood component transfusion and cumulative transfusion measured from product administration to 24 hours after CPB. The trial was stopped prematurely due to noninferiority being satisfied.24

FIBRINOGEN CONCENTRATE ADVANTAGE: LOWER THROMBOEMBOLIC RISK

Because cryoprecipitate is not a purified product and contains platelet microparticles, fibronectin, Factor VIII, and VWF, there may be an increased thromboembolic risk. Solomon et al’s43 pharmacovigilance evaluation of fibrinogen concentrate over a 27-year period specifically analyzed the risk of thromboembolism. In this study, the authors identified 28 possible cases of thromboembolism in >600,000 administered doses of fibrinogen concentrate. This extrapolates to ~1 thromboembolic event per 23,300 doses of 4 g of fibrinogen concentrate or an absolute risk of 0.004%. The FIBRES study reported a 2.6% higher thromboembolism rate in patients who received cryoprecipitate at 9.6% compared to 7.0% in patients who received fibrinogen concentrate (Table 1); however, this difference was not statistically different.24

Another randomized controlled trial, which included patients with pseudomyxoma peritonei and cytoreductive surgery, found a higher incidence of thromboembolic events in the cryoprecipitate group at 30.4% (7 of 23) compared to 0% (0 of 22) in the fibrinogen concentrate group.44 In a recent systematic review of randomized controlled trials examining fibrinogen concentrate, the authors concluded that the overall risk of thromboembolism is probably extremely low, and no studies reported a significantly increased risk of thromboembolism in patients receiving fibrinogen concentrate.20

FIBRINOGEN CONCENTRATE DISADVANTAGE: LOWER EFFICACY IN COMPLEX CASES WITH LONG CPB TIME BENEFITS OF CRYOPRECIPITATE OVER FIBRINOGEN CONCENTRATE IN CARDIAC SURGERY

Despite the findings of the FIBRES study, cryoprecipitate may be superior in some cardiac surgical patients.24 In the FIBRES study, the median CPB duration was 130–140 minutes, but the CPB duration is often longer in complex aortic surgery with deep hypothermic circulatory arrest or in the other combined cardiac surgery procedures. It remains unclear whether fibrinogen concentrate will have equal efficacy in these types of cases where CPB duration is 200–300 minutes.24

FIBRINOGEN CONCENTRATE DISADVANTAGE: HIGHER COST

Fibrinogen concentrate is very costly in the United States. Acquisition cost is approximately $1000 per 1 g. In comparison, a pooled cryoprecipitate unit (5 donor pool) costs around $300 to acquire, but there are also processing costs and significant costs related to wastage. In a recent economic analysis that accounted for cryoprecipitate wastage, it was estimated that the cost of fibrinogen concentrate would need to decrease by around 40% to be competitive with cryoprecipitate in the United States.45

FIBRINOGEN CONCENTRATE DISADVANTAGE: OFF-LABEL USE

Another important limitation of fibrinogen concentrate is that its use in acquired hypofibrinogenemia is off-label in the United States. Although this may seem trivial, off-label drug use is associated with a 1.5-fold higher incidence of serious adverse drug events.46 Furthermore, a significant amount of pharmacovigilance time may be needed to identify a pattern of increased thromboembolic risk. Recombinant activated factor VII is an excellent example of this phenomenon, where a clear pattern of increased thromboembolic risk was observed, as the drug was increasingly used off-label in the cardiac surgical patients.47,48

FIBRINOGEN CONCENTRATE DISADVANTAGE: SOME EVIDENCE OF A LACK OF EFFICACY IN CARDIAC SURGICAL PATIENTS

There are at least 4 randomized controlled studies of fibrinogen concentrate in the cardiac surgical patients who did not show benefits in terms of reduced RBC transfusion, reduced platelet transfusion, or reoperations for bleeding.38,40–42 Three of these studies utilized fibrinogen concentrate after CPB, and 1 utilized fibrinogen concentrate before CPB. The dose of fibrinogen concentrate that was administered in these studies (3–8 g) was relatively high, representing a significant cost to the patients.

A major criticism of these studies is that patients received fibrinogen concentrate without demonstrating low fibrinogen concentration, and in 1 trial, without clinically significant bleeding, because fibrinogen concentrate was given before surgery. Jeppsson et al40 randomized patients presenting for elective CABG surgery to receive either fibrinogen concentrate (2 g) before surgery or placebo and found that median postoperative blood loss at 12 hours was not significantly different between the 2 groups.

In the Randomized Evaluation of Fibrinogen Versus Placebo in Complex Cardiovascular Surgery (REPLACE) trial, 152 patients undergoing elective aortic replacement surgery were randomized to receive either fibrinogen concentrate or placebo, depending on whether there was a bleeding mass of 60–250 g on surgical packing post-CPB. Patients had to be normothermic, have an activated clotting time within 25% of their baseline value, and have a pH value of >7.3.41 The study found that there was a median of 5.0 (interquartile range [IQR], 2.0–11.0) units of allogeneic blood products administered in the fibrinogen concentrate group within 24 hours versus only 3.0 (IQR, 0.0–7.0) units in the placebo group (P = .026). However, 48 patients in the fibrinogen concentrate group were nonadherent to the transfusion algorithm, which may have confounded the study’s results.

Bilecen et al42 randomized patients (n = 120) having complex cardiac surgery (CABG + valve, multivalve, aortic root, ascending aorta, or arch repair) to receive fibrinogen concentrate or placebo if there was post-CPB bleeding >60 mL after attempts at surgical hemostasis. For the primary outcome of intraoperative bleeding, there was no difference between the fibrinogen concentrate group (median, 50 mL; IQR, 29–100 mL) and the control group (median, 70 mL; IQR, 33–145 mL; P = .19) with an absolute difference of 20 mL (95% CI, 13–35 mL). In a mixed-effects regression model for cumulative blood loss in the first 24 hours after surgery, the fibrinogen concentrate group was significantly lower with a median blood loss of 570 mL (IQR, 390–730 mL) compared to 690 mL (IQR, 400–1090 mL; P = .047). However, the small difference in a chest tube output observed in this study may not be clinically significant.42 The limitations of this small, single-center trial were that 6 patients (10%) in the control group were given fibrinogen concentrate postoperatively, confounding the study’s results, and the chest tube output is well known to have limitations as a surrogate for bleeding.

A recent meta-analysis of randomized controlled trials of fibrinogen concentrate in the cardiac surgical patients suggested that the fibrinogen concentrate decreases RBC transfusion (relative risk [RR] = 0.64; 95% CI, 0.49-0.83), but there was no reduction in other transfusions (eg, platelets and plasma), and there was no reduction in the reoperations for bleeding.49 Taken together, the current evidence supporting the routine use of fibrinogen concentrate in the cardiac surgical patients is not particularly strong, even when the treatment is based on the whole blood viscoelastic coagulation testing.

Cryoprecipitate Advantage: Hemostatic Benefits of VWF, Factor XIII, and Fibronectin

Patients with aortic stenosis have loss of large VWF multimers due to high shear stress, which is referred to as Heyde syndrome.50 The Heyde syndrome is similar to type 2a VWD, where there is a loss of VWF function and poor platelet adhesion to collagen. When Heyde syndrome patients develop post-CPB–acquired hypofibrinogenemia, they may be better served by the treatment with cryoprecipitate, which contains large VWF multimers. The treatment with fibrinogen concentrate will not replace VWF multimers, and poor platelet adhesion may persist despite normalization of fibrinogen. In cases with long CPB duration, particularly in complex congenital heart surgery, acquired von Willebrand syndrome (VWS) is common, and cryoprecipitate may be a superior option for replacing both fibrinogen and large VWF multimers.51 Finally, patients on extracorporeal membrane oxygenation (ECMO) and patients with ventricular assist devices (VADs) are well known to have acquired VWS and may benefit from the treatment with cryoprecipitate compared to fibrinogen concentrate.52–54

Factor XIII, also known as fibrin stabilization factor, is contained in cryoprecipitate and its presence may add to cryoprecipitate’s superiority over fibrinogen concentrate in patients having complex cardiac surgery. Low levels of factor XIII are associated with increased postoperative bleeding and reoperation for bleeding in the cardiac surgery.55 Factor XIII administration was previously found to reduce blood loss in the CABG patients, when given at a dose of 1250 or 2500 IU.56 Unfortunately, these results were not replicated in a larger study of cardiac surgical patients, where 17.5 and 35 IU/kg doses were administered, and there was no reduction in allogeneic transfusion or reoperation.57 Nevertheless, in patients with excessive hemodilution or in those with major blood loss, the additional factor XIII activity that is present in the cryoprecipitate may be beneficial in achieving hemostasis.

Fibronectin is the least appreciated factor in cryoprecipitate and only recently has its role in hemostasis been elucidated. Fibronectin promotes platelet adhesion, increases the diameter of fibrin fibers, and strengthens thrombi.58,59 Alternatively, fibronectin inhibits thrombus formation in the absence of fibrin, helping to maintain normal vascular integrity.60 Fibronectin may be particularly important in patients with hypofibrinogenemia because it helps to solidify and strengthen fibrin mesh.58,60

CRYOPRECIPITATE DISADVANTAGE: INFERIOR SAFETY PROFILE COMPARED TO FIBRINOGEN CONCENTRATE

The risk of pathogen transmission is one of the primary reasons that cryoprecipitate was removed from European markets. Similar to other allogeneic blood products, cryoprecipitate undergoes nucleic acid testing for HIV, hepatitis B, and hepatitis C. Yet, it does not undergo viral inactivation, as it occurs with fibrinogen concentrate. Over 10,000 men with hemophilia were infected with HIV through blood transfusion in the United States before universal HIV screening began. Although the direct acquisition cost for fibrinogen concentrate is higher in the United States, this type of analysis does not take into account the cost associated with pathogen transmission.45 It is important to note that as Europe withdrew cryoprecipitate from its markets 15 years ago, it has not reversed course based on the new information. After the FIBRES study, Health Canada also approved fibrinogen concentrate to treat acquired hypofibrinogenemia.

CRYOPRECIPITATE DISADVANTAGE: LONGER ACQUISITION TIME AND SHELF LIFE

The acquisition time for cryoprecipitate (30–40 minutes) is considerably longer compared to fibrinogen concentrate because of the need to thaw cryoprecipitate. In the cases of severe hypofibrinogenemia, as occurs in massive transfusion, delayed treatment can be quite detrimental due to dilutional coagulopathy with a fixed-ratio RBC, FFP, and platelet transfusion.

The shelf life is also much longer for fibrinogen concentrate (3 years) compared to cryoprecipitate (1 year), which may be important in smaller, rural hospitals that have a less frequent need for fibrinogen therapy.61 There is also a longer shelf life after reconstitution because fibrinogen concentrate is able to be used for 24 hours after reconstitution versus 6 hours after cryoprecipitate thaws.

CONCLUSIONS

Whether to use fibrinogen concentrate or cryoprecipitate as a first-line therapy for the treatment of acquired hypofibrinogenemia in the cardiac surgical patients continues to be a subject of intense debate in the United States. Fibrinogen concentrate has many potential advantages including a rapid administration, the predictability of dose response, and a lower risk for viral transmission, which aligns well with the FDA’s recommendation to use pathogen-reduced blood products when feasible.62 However, fibrinogen concentrate’s lack of VWF, factor VIII, factor XIII, and fibronectin may reduce its hemostatic efficacy, particularly in cases with long CPB duration, in aortic stenosis patients, and in ECMO and left ventricular assist device (LVAD) patients. Fibrinogen concentrate’s higher cost and lack of regulatory approval for treating acquired hypofibrinogenemia continue to be significant impediments to more widespread use in the United States despite widespread use in Canada and Europe. Furthermore, evidence supporting the routine or prophylactic use of fibrinogen concentrate in the cardiac surgical patients is not robust, and larger studies are needed to confirm its value compared to cryoprecipitate, which has been the gold standard for treating acquired hypofibrinogenemia for almost 50 years.

DISCLOSURES

Name: Nadia B. Hensley, MD.

Contribution: This author helped conceive and design the pro/con manuscript, analyze and interpret the data, and write the manuscript.

Conflicts of Interest: N. B. Hensley has served on the scientific advisory board for Octapharma USA (Paramus, NJ) and received royalties from Wolters Kluwer for uptodate.com contributions.

Name: Michael A. Mazzeffi, MD, MPH, MSc, FASA.

Contribution: This author helped conceive and design the pro/con manuscript, analyze and interpret the data, and write the manuscript.

Conflicts of Interest: None.

This manuscript was handled by: Susan Goobie, MD, FRCPC.

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