Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer

Summary

Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A₂) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A₂ (11.9,25,35 or 50 IU/kg) or placebo in a 4:1 ratio.Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5–7.The primary end-point was incidence and severity of adverse events.Thirty-five patients were randomised to rFXIII-A₂ and eight to placebo. Eighteen serious adverse events were reported.These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/ kg rFXIII-A₂ was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25–50 IU/kg rFXIII-A₂ restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A₂, in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For postoperative FXIII replenishment, 35 IU/kg of rFXIII-A₂ may be the most appropriate dose.

Keywords

Cardiac surgery - FXIII - pharmacokinetics - safety.

Footnote: Jerrold H. Levy, Ravi Gill, and Nancy A. Nussmeier serve as consultants to Novo Nordisk; Henning F. Andersen, Frank V. Booth, and Christian M. Jespersen are employees of Novo Nordisk.

• References

• 1 Karkouti K, O’Farrell R, Yau TM. Reducing Bleeding in Cardiac Surgery Research Group. et al Prediction of massive blood transfusion in cardiac surgery. Can J Anaesth 2006; 53: 781-794.
• 2 Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med 2004; 30: 1873-1881.
• 3 Despotis GJ, Goodnough LT. Management approaches to platelet-related microvascular bleeding in cardiothoracic surgery. Ann Thorac Surg 2000; 70 (Suppl. 02) S20-S32.
• 4 Hein OV, Birnbaum J, Wernecke KD. et al. Threeyear survival after four major post-cardiac operative complications. Crit Care Med 2006; 34: 2729-2737.
• 5 Gödje O, Gallmeier U, Schelian M. et al. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg 2006; 54: 26-33.
• 6 Gödje O, Haushofer M, Lamm P. et al. The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg 1998; 46: 263-267.
• 7 Chandler WL, Patel MA, Gravelle L. et al. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001; 12: 101-108.
• 8 Bishop PD, Teller DC, Smith RA. et al. Expression, purification, and characterization of human factor XIII in Saccharomyces cerevisiae . Biochemistry 1990; 29: 1861-1869.
• 9 Cohn LH, Edmunds LH. Cardiac surgery in the adults. 2nd ed.. New York: McGraw-Hill; 2003
• 10 Weiler JM, Gellhaus MA, Carter JG. et al. A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol 1990; 85: 713-719.
• 11 Wang S, Tang H, Wilkinson V. et al. Saphenous vein harvest with SaphLITE system versus conventional technique: a prospective, randomized study. Ann Thorac Surg 2005; 79: 2018-2023.
• 12 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res 1999; 94: 271-305.
• 13 Ofosu FA, Freedman J, Semple JW. Plasma-derived biological medicines used to promote haemostasis. Thromb Haemost 2008; 99: 851-862.
• 14 Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99: 840-850.
• 15 Lahav J, Karniel E, Bagoly Z. et al. Coagulation factor XIII serves as protein disulfide isomerase. Thromb Haemost 2009; 101: 840-844.
• 16 de la Red G, Tassies D, Espinosa G. et al. Factor XIII-A subunit Val34Leu polymorphism is associated with the risk of thrombosis in patients with antiphospholipid antibodies and high fibrinogen levels. Thromb Haemost 2009; 101: 312-316.
• 17 Rallidis LS, Politou M, Komporozos C. et al. Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years. Thromb Haemost 2008; 99: 1085-1089.