Prothrombin Complex Concentrates in Cardiac Surgery – Is it Time to Call Pharmacy Instead of Blood Bank?

Published:March 15, 2023DOI:
      Perioperative coagulopathy and bleeding in patients undergoing cardiac surgery is common, particularly among those undergoing complex operations. The etiology of microvascular bleeding that ensues in some patients is complex and related to blood exposure to cardiopulmonary bypass (CPB) components, surgical and/or patient specific factors. Treatment of clinically significant microvascular bleeding requires laboratory evaluation to help guide targeted therapy. When a coagulation factor deficiency associated bleeding is the culprit, historic therapy has been with allogenic plasma transfusion. This treatment is less than ideal for several reasons: (1) The risk of transfusion associated complications (e.g. transfusion associated lung injury (TRALI), transfusion associated circulatory overload (TACO), infection, etc.), (2) The degree of hemodilution seen with modest plasma transfusion volumes can lead to further red blood cell transfusions simply to restore the pre-transfusion hematocrit levels, and (3) The amount of coagulation factor activity increase per mL of plasma transfused is small, hence large transfusion volumes are often required to “normalize” the defect which can be particularly problematic to patients with ventricular dysfunction.
      In the past decade or more the off-label use of factor concentrates and particularly prothrombin complex concentrates (PCCs) for the treatment of non-warfarin related perioperative coagulopathy in cardiac surgical patients has increased. Inactive four-factor PCCs contain factors II, VII, IX, and X along with Proteins C &S. Prothrombin complex concentrates have appeal in that the infusion volume is small (often 50 mL or less), lack blood bank compatibility concerns, and have a negligible risk of most transfusion related complications (e.g., infection, TRALI, TACO). Despite early and more routine use in Europe, there remained a relative paucity of data on this topic. Given the fear of thromboembolic complications with PCCs, widespread use and adoption in the United States was appropriately cautious. However, what was initially seen and used as a last resort salvage therapy in ongoing refractory coagulopathy and bleeding scenarios, has in recent years become a more targeted first line agent in certain settings. The increase in use of PCCs in this patient population has been driven largely by small retrospective studies and growing societal guidelines.1 A 2019 metanalysis by Roman et al. which is the largest to date (861 patients from 4 studies) noted that patients receiving PCCs had a significant reduction in the risk for RBC transfusion (OR, 2.22; 95% confidence interval [CI], 1.45 to 3.40) and units of RBC received (OR, 1.34; 95% CI, 0.78 to 1.90) without an increased risk for thromboembolic complications.2 The authors acknowledge the limitations being the small number of studies, lack of prospective randomized controlled trails (RCTs), and lack of consistent algorithm guided transfusion practices in all included studies. In 2020-21, 2 randomized pilot studies were published demonstrating feasibility of recruitment without increased risk for thromboembolic complications.3; 4 In a post hoc observational substudy of FIBRES randomized trial, the authors analyzed patients not meeting criteria to receive fibrinogen concentrate or cryoprecipitate but did receive either PCC (n=72) or plasma (n =343) and found that PCC use was associated with significantly fewer RBC and platelet transfusions, with similar adverse event rates.5
      We recently published the article Prothrombin Complex Concentrate vs Plasma for Post-Cardiopulmonary Bypass Coagulopathy and Bleeding: A Randomized Clinical Trial; JAMA Surg. 2022 Sep 1;157(9):757-764. 6 This study represents the first published prospective RCT evaluating the use of PCCs compared to plasma for treatment of non-warfarin associated CPB coagulopathy and bleeding. Patients in this study were randomized to receive either 4-factor PCC 15 IU/kg or plasma 10-15 mL/kg if clinically significant microvascular bleeding AND laboratory-based evaluation suggesting coagulation factor abnormality were present. There was no difference in the primary outcome of bleeding defined as chest tube drainage (median [IQR], 1022 [799-1575] mL vs 937 [708-1443] mL). Patients receiving PCC compared to plasma had a greater improvement in prothrombin time (effect estimate, -1.37 seconds [95% CI, -1.91 to -0.84]; P < .001) and international normalized ratio (effect estimate, -0.12 [95% CI, -0.16 to -0.07]; P < .001). Also, fewer patients in the PCC group required intraoperative RBC transfusion after treatment (7 of 51 patients [13.7%] vs 15 of 49 patients [30.6%]; P = .04). Interestingly 13.7% of patients in the PCC group avoided ANY allogenic transfusion exposure in comparison to all patients receiving plasma being exposed. There were NO significant differences in adverse events between groups.
      The results of this trial are important for several reason. Historical fears of PCCs causing an increased risk for thromboembolic complications were not evident. This is further supported as previously mentioned by other recent studies. It should be noted that the exclusion criteria included any patients with prior history of hypercoagulable conditions OR any recent thromboembolic complications. These factors should go into the decision-making process when considering administration of PCCs. Additionally, the dosing strategy used in the referenced study was ∼15 units/kg6, which is similar to dosing seen in other recent published reports3; 4, but lower than the ∼25 units/kg dose reported in earlier studies.2; 7 Prior studies have discussed the correlation between reduced coagulation factor levels and thrombin generation potential with excessive post operative bleeding.5; 8 In an ex vivo study, 25 units/kg of PCC restored peak thrombin-generation parameters to greater than pre-bypass levels, however, lower doses were not tested.9 It is unclear yet unlikely that restoration of “normal” or “supranormal” prebypass coagulation status is necessary to sufficiently treat post-CPB microvascular bleeding. Regardless, it is important to provide data demonstrating that a lower PCC dose provided important clinical outcome data that was non-inferior in some respects and superior in others to that of historical 10-15 mL/kg plasma dosing. Data related to changes in coagulation factor levels and thrombin generation from our study cohort are forthcoming. These should provide further insight into dosing strategies for future studies.
      With regards to the off-label use of PCCs in the setting of cardiopulmonary bypass induced coagulopathy and bleeding, it seems that clinical use has outpaced high quality research on the topic. While this has provided some retrospective data, additional prospective studies are needed to further support use and define best practice initiatives with regards to patient selection and dosing. When considering the use of PCCs in cardiac surgery, it is important to discuss what is the rationale for use in each patient. Factors that go into the decision-making process should include the degree of coagulopathy and intravascular volume physiologic goals. In patients with markedly deranged coagulopathy, and/or those in whom excessive intravascular volume could be detrimental, the use of PCC may be a better option. However, in patients with a mild coagulopathy and/or those needing ongoing aggressive intravascular resuscitation perhaps the benefits of PCCs are not as evident. Additionally, while we exercised extreme caution in excluding patients at risk for or with recent thromboembolic complications in our study, to what degree is this necessary in clinical practice? This is where further prospective research is needed to better define the WHOM, WHEN and HOW PCCs should be incorporated into perioperative patient blood management algorithms.
      In conclusion there are several informative takeaways from this study that clinicians can use to make individualized transfusion decisions for cardiac surgical patients. The use of PCCs in patients undergoing complex cardiac surgery appears similarly safe and effective when compared to plasma transfusion practices. Avoiding the hemodilutional impact of large volume plasma transfusion with PCCs has the potential to reduce intraoperative RBC transfusions. There is insufficient evidence currently to say PCC administration should replace all plasma transfusions, and there are situations for which the latter may still be preferred as previously mentioned. Questions remain regarding ideal patient selection and proper administration dosage.


      • 1
        Tibi P, McClure RS, Huang J, et al. STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management. 2021;35:2569-2591.
      • 2
        Roman M, Biancari F, Ahmed AB, et al. Prothrombin Complex Concentrate in Cardiac Surgery: A Systematic Review and Meta-Analysis. 2019;107:1275-1283.
      • 3
        Green L, Roberts N, Platton S, et al. Impact of prothrombin complex concentrate and fresh frozen plasma on correction of haemostatic abnormalities in bleeding patients undergoing cardiac surgery (PROPHESY trial results). 2021;
      • 4
        Karkouti K, Bartoszko J, Grewal D, et al. Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery: A Randomized Pilot Trial. 2021;4:e213936.
      • 5
        Bartoszko J, Callum J, Karkouti K, et al. The association of prothrombin complex concentrates with postoperative outcomes in cardiac surgery: an observational substudy of the FIBRES randomized controlled trial. 2021;68:1789-1801.
      • 6
        Smith MM, Schroeder DR, Nelson JA, et al. Prothrombin Complex Concentrate vs Plasma for Post-Cardiopulmonary Bypass Coagulopathy and Bleeding: A Randomized Clinical Trial. 2022;157:757-764.
      • 7
        Gorlinger K, Dirkmann D, Hanke AA, et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology 2011;115:1179-1191.
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        Coakley M, Hall JE, Evans C, et al. Assessment of thrombin generation measured before and after cardiopulmonary bypass surgery and its association with postoperative bleeding. 2011;9:282-292.
      • 9
        Percy CL, Hartmann R, Jones RM, et al. Correcting thrombin generation ex vivo using different haemostatic agents following cardiac surgery requiring the use of cardiopulmonary bypass. 2015;26:357-367.