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

Disclosures

Anesth Analg. 2021;133(1):19-28. 

In This Article

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 al[40] 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 al[42] 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]

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