Secondary Logo

Journal Logo

Factor Concentrates for Perioperative Bleeding

Old Drugs with New Approaches

Welsby, Ian J. BSc, MBBS, FRCA (Eng); Levy, Jerrold H. MD, FAHA, FCCM

doi: 10.1213/ANE.0000000000000806
Editorials: Editorial

From the Department of Anesthesiology and Critical Care, Duke University School of Medicine, Durham, North Carolina.

Accepted for publication March 25, 2015.

Funding: NIH R01 HL121232-01 (IJW).

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Jerrold H. Levy, MD, FAHA, FCCM, Department of Anesthesiology and Critical Care, Duke University Medical Center, 2301 Erwin Rd., 5691H HAFS, Box 3094, Durham, NC 27710. Address e-mail to

Bleeding and coagulopathy are major concerns for clinicians in the perioperative and trauma setting. Although blood product transfusions are the mainstay of therapy, they are clearly associated with multiple risks and require crossmatching, blood bank storage, and inventory management that is labor-intensive and complicated by potential availability and delay in delivery. Factor concentrates such as fibrinogen or prothrombin complex concentrates (PCCs) are increasingly evolving as a replacement for allogeneic blood products.1–3 Literature and guidelines describe the perioperative use of PCCs for the urgent reversal of vitamin K antagonist anticoagulants (i.e., warfarin).2,4 A growing body of literature also reports the off-label application of PCCs for reversing direct oral anticoagulants, apixaban, dabigatran, rivaroxaban, and edoxaban.5–7 PCCs can be rapidly deployed, do not require crossmatching, and are highly purified to prevent infectious disease transmission.

In the current edition of Anesthesia & Analgesia, Ortmann et al.8 present a retrospective series of patients undergoing pulmonary thromboendarterectomy treated with either PCCs or fresh-frozen plasma (FFP), comparing postoperative blood loss and clinical outcomes. The PCC group bled significantly less than the FFP group, despite the inclusion of more surgically complex patients and those with more pronounced pretreatment coagulopathy (higher baseline international normalized ratio, lower postcardiopulmonary bypass platelet counts, and higher partial thromboplastin times). Despite this, there were no differences in clinical outcomes reported (intensive care unit or hospital length of stay or other complications) between the PCC and the FFP groups either before or after adjustment for treatment group selection bias using a propensity score constructed from pretreatment laboratory values. Transfusions of platelets and cryoprecipitate were still required for both the FFP and the PCC groups, an expected finding considering the complex coagulopathy after circulatory arrest and the absence of platelets or fibrinogen in PCC preparations.

This study illustrates some important considerations regarding the potential perioperative use of PCCs in cardiac surgery. The current U.S. Food and Drug Administration indication for the 4-component PCC indication for Kcentra® (CSL Behring, Marburg, Germany) is the urgent reversal of warfarin anticoagulation for acute major bleeding or the need for an urgent surgery/invasive procedure. There are other 3-component PCC products available that have high levels of factor IX and were previously approved for the treatment of patients with hemophilia B. An increasing number of reports in the literature described the use of these agents off-label for bleeding in high-risk patients including for patients undergoing cardiac surgery. Regardless, the correction of warfarin anticoagulation is faster and more efficient with PCCs than FFP.9 We could also postulate a benefit from more rapid restoration of hemostasis in high-risk patients who are bleeding in a perioperative setting. An additional advantage of PCCs is in the setting of right ventricular failure, as the volume of PCCs required to rapidly restore adequate clotting factor levels is far less than the volume of FFP.

The purpose of administering PCCs or FFP was to restore clotting factor levels and, therefore, thrombin generation. The low incidence of postoperative thromboembolism in the current study is encouraging and consistent with the findings of Sarode et al.,9 but further studies are needed to determine the prothrombotic safety of PCCs in this setting. The levels of prothrombin/factor II are linearly related to thrombin generation and are reduced to approximately 50% after separation from cardiopulmonary bypass after major cardiac surgery.10 Although thought to be sufficiently hemostatic, subsequent blood loss or hemodilution may critically reduce factor II levels to approximately 25%–30%, a level expected with a therapeutic international normalized ratio of 2.5–3. Regarding dosing, 1 unit of PCC/kg of ideal body weight increases factor levels by approximately 1%. Therefore, the dose of PCC used in the current study and the 20–30 units/kg in previous reports11 seem reasonable and unlikely to overcorrect hemostatic factor levels and lead to a prothrombotic state,11 which is thought to result from an excess of factor II.

In summary, perioperative PCCs may present an alternative to plasma/FFP in some patients with bleeding after complex cardiac surgery or trauma, with possible advantages that need to be determined by prospective studies. All transfusion factors and factor concentrates pose potential risks, and their administration should be determined by risk versus benefit consideration. We believe that factor concentrates represent important therapies for major bleeding, and our current work is exploring their use in clinical settings. However, additional randomized and controlled studies are needed to better define their application in the complex milieu of perioperative bleeding.

Back to Top | Article Outline


Name: Ian J. Welsby BSc, MBBS, FRCA (Eng),

Contribution: The author helped write the manuscript.

Attestation: Ian J. Welsby approved the final manuscript.

Conflicts of Interest: Ian J. Welsby has received grant support from CSL Behring and Terumo BCT for investigator initiated trials.

Name: Jerrold H. Levy, MD, FAHA, FCCM.

Contribution: The author helped write the manuscript.

Attestation: Jerrold H. Levy approved the final manuscript.

Conflicts of Interest: Jerrold H. Levy serves on steering committees for CSL Behring, Grifols, and Janssen.

This manuscript was handled by: Charles W. Hogue, Jr., MD.

Back to Top | Article Outline


1. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion. 2014;54:1389–405
2. Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology. 2015;122:923–31
3. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood. 2015;125:1387–93
4. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology. 2008;109:918–26
5. Levi M, Moore KT, Castillejos CF, Kubitza D, Berkowitz SD, Goldhaber SZ, Raghoebar M, Patel MR, Weitz JI, Levy JH. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12:1428–36
6. Levy JH, Spyropoulos AC, Samama CM, Douketis J. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv. 2014;7:1333–51
7. Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, Lomeli B, Feussner A, Feng W, He L, Grosso MA, Lanz HJ, Antman EM. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131:82–90
8. Ortmann E, Besser MW, Sharples LD, Gerrard C, Berman M, Jenkins DP, Klein AA. An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. Anesth Analg. 2015;121:26–33
9. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–43
10. Solomon C, Rahe-Meyer N, Sørensen B. Fibrin formation is more impaired than thrombin generation and platelets immediately following cardiac surgery. Thromb Res. 2011;128:277–82
11. Weber CF, Görlinger K, Meininger D, Herrmann E, Bingold T, Moritz A, Cohn LH, Zacharowski K. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology. 2012;117:531–47
© 2015 International Anesthesia Research Society