Effect of Activated Prothrombin Complex Concentrate or Recombinant Factor VIIa on the Bleeding Time and Thrombus Formation During Anticoagulation with a Direct Thrombin Inhibitor

Abstract

Melagatran is the active form of the oral, direct thrombin inhibitor H 376/95. In several animal models of thrombosis, the antithrombotic properties of melagatran have been demonstrated, without any increase in experimental bleeding. However, as with all anticoagulants, in emergency situations, reversal of the anticoagulation may be necessary. In this study, increasing doses of activated prothrombin complex concentrate (APCC, Feiba) or recombinant factor VIIa (r-F VIIa, NovoSeven) were superimposed on high doses of melagatran, or saline, in anaesthetised rats. The haemostatic effect was evaluated in two bleeding time models and a potential prothrombotic effect was evaluated in an arterial thrombosis model. Compared with melagatran alone (0.5 μmol/kg/h), Feiba in doses of ≥25 U/kg significantly shortened the prolonged bleeding time and reduced blood loss. In addition, Feiba ≥50 U/kg when added to melagatran (2 μmol/kg/h), significantly reduced bleeding time. No potentiation of thrombus formation was observed when Feiba was added to melagatran, compared with controls. NovoSeven at high doses (2–10 mg/kg) produced a nonsignificant trend in reduction of blood loss and with the highest dose (10 mg/kg) producing only a mild nonsignificant reduction in bleeding time. The prolonged prothrombin time (PT) and the ecarin clotting time (ECT) were more effectively shortened by Feiba than by NovoSeven. In contrast, whole blood clotting time (WBCT) was more effectively shortened by NovoSeven than by Feiba. Activated partial thromboplastin time (APTT) was shortened by NovoSeven but was prolonged by Feiba. Thrombin–antithrombin (TAT) complex formation was increased 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 compared with Feiba.