Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates

Abstract

Introduction Pharmacological enhancement of coagulation using activated prothrombin complex concentrate (APCC) or activated factor VII (FVIIa) might be useful hemostatic approaches to bleeding emergencies during anticoagulant therapy. However, any such intervention should not increase thrombotic risk. We therefore investigated their hemostatic and prothrombotic potential during propagation of large arterial-type thrombin in anticoagulated baboons. Materials and methods High dose melagatran, a competitive inhibitor of thrombin (0.6 mg/kg/h), or inactivated FVIIa (FVIIai), a competitive inhibitor of FVIIa (2 mg/kg) were used for anticoagulation. APCC or FVIIa were administered to melagatran-anticoagulated animals only. Primary hemostasis was assessed as template bleeding time (BT). Thrombus formation was quantified as fibrin deposition (FD) and platelet deposition (PLD) in synthetic vascular grafts that were deployed for 40 min into arteriovenous shunts. Results Melagatran ( n = 11) prolonged BT to 279% (95% CI ± 140%; P < 0.019), reduced FD to 33% [± 8%; P < 0.001]; and PLD to 39% [± 11%; P < 0.001] of untreated controls. FVIIai ( n = 3) prolonged BT (222% [± 51%; P < 0.010]) without inhibiting thrombus propagation. APCC ( n = 10) reduced the antithrombotic effect of melagatran (FD 52% [± 9%; P < 0.002], PLD 61% [± 17%; P = 0.028] versus melagatran alone) at a dose (250 U/kg) that had no effect on the BT (327% [± 150%; P = 0.607]. Meanwhile, FVIIa ( n = 12) normalized the BT to 115% (± 32%; P < 0.05) at a dose (270 μg/kg) that was not yet prothrombotic (FD 26% [± 4%; P < 0.001], PLD 39% [± 9%; P = 0.970]). Conclusion Administration of FVIIa during antithrombotic treatment with direct thrombin inhibitors might support hemostasis before promoting the intraluminal expansion of thrombi.