Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor

Melagatran is the active form of the oral, direct thrombin inhibitor H 376/ 95. In several animal models of thrombosis, the antithrombotic properties o f melagatran have been demonstrated, without any increase in experimental b leeding. However, as with all anticoagulants, in emergency situations, reve rsal of the anticoagulation may be necessary. In this study, increasing dos es of activated prothrombin complex concentrate (APCC, Feiba) or recombinan t factor VIIa (r-F VIIa, NovoSeven) were superimposed on high doses of mela gatran, or saline, in anaesthetised rats. The haemostatic effect was evalua ted in two bleeding time models and a potential prothrombotic effect was ev aluated in an arterial thrombosis model. Compared with melagatran alone (0. 5 mu mol/kg/h), Feiba in doses of greater than or equal to 25 U/kg signific antly shortened the prolonged bleeding time and reduced blood loss. In addi tion, Feiba greater than or equal to 50 U/kg when added to melagatran (2 mu mol/kg/h), significantly reduced bleeding time. No potentiation of thrombu s formation was observed when Feiba was added to melagatran, compared with controls. NovoSeven at high doses (2-10 mg/kg) produced a nonsignificant tr end in reduction of blood loss and with the highest dose (10 mg/kg) produci ng only a mild nonsignificant reduction in bleeding time. The prolonged pro thrombin time (PT) and the ecarin clotting time (ECT) were more effectively shortened by Feiba than by NovoSeven. In contrast, whole blood clotting ti me (WBCT) was more effectively shortened by NovoSeven than by Feiba. Activa ted partial thromboplastin time (APTT) was shortened by NovoSeven but was p rolonged by Feiba. Thrombin-antithrombin (TAT) complex formation was increa sed in a dose-dependent fashion more effectively by Feiba than by NovoSeven . Conclusion: Feiba (APCC) reversed prolonged bleeding time and blood loss in rats treated with high doses of melagatran and compared with the control group thrombus formation was not potentiated. NovoSeven (r-F VIIa) at high doses had less pronounced effects on blood loss and bleeding times compare d with Feiba. (C) 2001 Elsevier Science Ltd. All rights reserved.