title: An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery.
abstract: BACKGROUND
  Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest.
  
  
  METHODS
  Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment.
  
  
  RESULTS
  Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median [interquartile range], 650 mL [325-1075] vs 277 mL [175-608], P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number [percent], 44 [80%] vs 34 [76%], P = 0.594) or in the number of units of red blood cells transfused (median [interquartile range], 2 [1-4] vs 3 [1-5] units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio [OR] 2.39, 95% confidence interval [CI] 0.51-11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03-3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14-3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50-1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59-1.40, P = 0.66).
  
  
  CONCLUSIONS
  This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted.
authors.affiliation: From the Departments of Anaesthesia and Intensive Care and Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals Foundation Trust, Cambridge, United Kingdom; and MRC Biostatistics Unit, Cambridge, United Kingdom.
authors.forename: Erik
authors.initials: E
authors.lastname: Ortmann
authors.forename: Martin W
authors.initials: MW
authors.lastname: Besser
authors.forename: Linda D
authors.initials: LD
authors.lastname: Sharples
authors.forename: Caroline
authors.initials: C
authors.lastname: Gerrard
authors.forename: Marius
authors.initials: M
authors.lastname: Berman
authors.forename: David P
authors.initials: DP
authors.lastname: Jenkins
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Klein
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D050792:Circulatory Arrest, Deep Hypothermia Induced; D003029:Coagulants / Q000009:adverse effects / Q000627:therapeutic use*; D004691:Endarterectomy / Q000009:adverse effects* / Q000401:mortality; D017707:Erythrocyte Transfusion; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010314:Partial Thromboplastin Time; D010949:Plasma; D010976:Platelet Count; D019106:Postoperative Hemorrhage / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000628:therapy*; D057216:Propensity Score; D016016:Proportional Hazards Models; D011651:Pulmonary Artery / Q000601:surgery*; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001779:Blood Coagulation Factors; D003029:Coagulants; C025667:prothrombin complex concentrates
references.citation: Besser MW, Klein AA. The coagulopathy of cardiopulmonary bypass. Crit Rev Clin Lab Sci. 2010;47:197–212
references.citation: Biancari F, Myllylä M, Lepojärvi S, Kuttila K, Porela P, Laitio T, Ylitalo A, Jokinen V, Luokkala A, Airaksinen KE. Preoperative warfarin treatment and outcome of coronary artery bypass graft surgery. Ann Thorac Surg. 2010;89:1139–45
references.citation: Dietrich W, Dilthey G, Spannagl M, Richter JA. Warfarin pretreatment does not lead to increased bleeding tendency during cardiac surgery. J Cardiothorac Vasc Anesth. 1995;9:250–4
references.citation: Airaksinen KE, Biancari F, Karjalainen P, Mikkola R, Kuttila K, Porela P, Laitio T, Lip GY. Safety of coronary artery bypass surgery during therapeutic oral anticoagulation. Thromb Res. 2011;128:435–9
references.citation: Sniecinski RM, Levy JH. Bleeding and management of coagulopathy. J Thorac Cardiovasc Surg. 2011;142:662–7
references.citation: Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology. 2008;109:918–26
references.citation: Tanaka KA, Szlam F, Dickneite G, Levy JH. Effects of prothrombin complex concentrate and recombinant activated factor VII on vitamin K antagonist induced anticoagulation. Thromb Res. 2008;122:117–23
references.citation: Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates–evaluation of safety and thrombogenicity. Crit Care. 2011;15:201
references.citation: Chowdary P, Chowdhury P, Saayman AG, Paulus U, Findlay GP, Collins PW. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol. 2004;125:69–73
references.citation: Vuylsteke A, Sharples L, Charman G, Kneeshaw J, Tsui S, Dunning J, Wheaton E, Klein A, Arrowsmith J, Hall R, Jenkins D. Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): a randomised controlled trial. Lancet. 2011;378:1379–87
references.citation: Godier A, Susen S, Samama CM. Treatment of massive bleeding with prothrombin complex concentrate: argument against. J Thromb Haemost. 2010;8:2592–5
references.citation: Tanaka KA, Szlam F. Treatment of massive bleeding with prothrombin complex concentrate: argument for. J Thromb Haemost. 2010;8:2589–91
references.citation: Banks DA, Pretorius GV, Kerr KM, Manecke GR. Pulmonary endarterectomy: part II. Operation, anesthetic management, and postoperative care. Semin Cardiothorac Vasc Anesth. 2014;18:331–40
references.citation: Berman M, Cardone D, Sharples L, Vuylsteke A, Klein A, Gerrard C, Dunning J, Tsui S, Jenkins D. Safety and efficacy of aprotinin and tranexamic acid in pulmonary endarterectomy surgery with hypothermia: review of 200 patients. Ann Thorac Surg. 2010;90:1432–6
references.citation: D’Agostino RB Jr.. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265–81
references.citation: Papachristofi O, Mackay JH, Powell SJ, Nashef SA, Sharples L. Impact of the anesthesiologist and surgeon on cardiac surgical outcomes. J Cardiothorac Vasc Anesth. 2014;28:103–9
references.citation: Thistlethwaite PA, Mo M, Madani MM, Deutsch R, Blanchard D, Kapelanski DP, Jamieson SW. Operative classification of thromboembolic disease determines outcome after pulmonary endarterectomy. J Thorac Cardiovasc Surg. 2002;124:1203–11
references.citation: Johansson PI, Stensballe J. Effect of Haemostatic Control Resuscitation on mortality in massively bleeding patients: a before and after study. Vox Sang. 2009;96:111–8
references.citation: Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet. 2007;370:439–48
references.citation: Grottke O, Braunschweig T, Spronk HM, Esch S, Rieg AD, van Oerle R, ten Cate H, Fitzner C, Tolba R, Rossaint R. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–51
references.citation: Majeed A, Eelde A, Agren A, Schulman S, Holmström M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res. 2012;129:146–51
references.citation: Hanke AA, Joch C, Görlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth. 2013;110:764–72
references.citation: Görlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, Jakob H, Peters J. 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;115:1179–91
references.citation: 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
references.citation: Arnékian V, Camous J, Fattal S, Rézaiguia-Delclaux S, Nottin R, Stéphan F. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg. 2012;15:382–9
references.citation: Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251–60
references.citation: Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12:R105
references.citation: 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
references.citation: Schick KS, Fertmann JM, Jauch KW, Hoffmann JN. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care. 2009;13:R191
references.citation: Samama CM. Prothrombin complex concentrates: a brief review. Eur J Anaesthesiol. 2008;25:784–9
references.citation: Köhler M, Hellstern P, Lechler E, Uberfuhr P, Müller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998;80:399–402
references.citation: Warren O, Simon B. Massive, fatal, intracardiac thrombosis associated with prothrombin complex concentrate. Ann Emerg Med. 2009;53:758–61
references.citation: Koster A, Meyer-Jark T, Schirmer U, Sandica E. Fulminant intraoperative right heart and pulmonary artery thrombosis following prothrombin complex concentrate infusion after complex open heart surgery with cardiopulmonary bypass. A&A Case Rep. 2014;2:89–91
references.citation: Nascimento B, Al Mahoos M, Callum J, Capone A, Pacher J, Tien H, Rizoli S. Vitamin K-dependent coagulation factor deficiency in trauma: a comparative analysis between international normalized ratio and thromboelastography. Transfusion. 2012;52:7–13
references.citation: Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res. 2007;121:9–16