Iatrogenic Immunization with Bovine Thrombin: A Mechanism for Prolonged Thrombin Times after Surgery

Abstract

Unexplained very-prolonged thrombin times (> 300 s) were found in plasma from four patients. Other coagulation variables were normal, and there was no history of coagulopathy. Mixing studies suggested the presence of thrombin inhibitors in patient plasma. Substitution of human thrombin for bovine thrombin in performing the thrombin time test resulted in normal clotting times, indicating that the inhibitory activity was directed primarily against bovine thrombin. Each patient had been treated with topical bovine thrombin during previous surgery. In the one patient with a preoperative thrombin time, the initial value was normal and prolongation began 16 days after surgery. An enzyme-linked immunoassay showed elevated levels of IgM or IgG antibodies to bovine thrombin in each patient tested. Affinity-purified antibodies to bovine thrombin from patient serum prolonged the thrombin time of normal plasma. These results suggest that iatrogenic immunization by intraoperative exposure to bovine thrombin is responsible for antibodies to bovine thrombin, which accounts for the prolonged thrombin times found in some patients after surgery.