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Acquired bleeding disorders

Bovine coagulation factor inhibitors

Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, M.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 17 August 2010, last major update August 2010
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● Antibodies that develop against bovine proteins after exposure to topical bovine thrombin preparations which can potentially cross-react with corresponding human coagulation factors
● Antibodies can form against bovine thrombin, factor V/Va, and fibrinogen, and less commonly against bovine factors VII and X
● Some fibrin glues contain bovine thrombin and cryoprecipitate (containing human fibrinogen)
● After use of bovine “fibrin glue” to achieve hemostasis, 1.7% develop a clinically significant inhibitor


● One study reported 10% of patients exposed to bovine thrombin developed bovine thrombin antibodies; the rate was 5% for those singly exposed and 39% for those with multiple exposures
● The incidence of serious bleeds in bovine thrombin exposed patients was 1.7%, compared to 17% for those with bovine thrombin antibodies (Arch Pathol Lab Med 1998;122:887)
● One review found that 40-66% of cardiac surgery patients and 20% of neurosurgery patients developed factor V antibodies after bovine thrombin exposure (Transfusion 2002;42:18)

Clinical features

● Elevated PT and PTT (see below) that does not normalize with vitamin K or fresh frozen plasma (FFP) administration
● Patients may not have bleeding, but mucocutaneous and surgical site bleeding, retroperitoneal hematoma, petechiae and hematuria have been reported
● Recent review articles have concluded that there is insufficient evidence for a definitive association between elevations in anti-bovine antibodies and the development of clinically significant adverse events in surgical patients (Patient Saf Surg 2008;2:5, Clin Ther 2009;31:679, Curr Med Res Opin 2008;24:2071)


● Prolonged PT and PTT that does not correct with mixing studies

Case reports

● Case reports of 2 children who developed anti-factor V antibodies following bovine thrombin exposure (Pediatr Blood Cancer 2007;49:1025)


● Steroids, cyclophosphamide, cyclosporine A, IV immunoglobulin
● Management of acute bleeding includes plasmapheresis, platelet-transfusions and immunoabsorption

Differential diagnosis

Disseminated invtravascular coagulation (DIC)

End of Coagulation > Acquired bleeding disorders > Bovine coagulation factor inhibitors

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