Prevention of experimental arterial thrombosis by topical administration of active site-inactivated factor VIIa.

Abstract

In vivo, the coagulation pathway is triggered by formation of a high-affinity complex between the tissue factor of the injured vascular wall and the activated form of blood coagulation factor VII (VIIa). We used a rabbit model of arterial thrombosis to examine the antithrombotic effect of topically administered active site-inactivated recombinant human factor VIIa (VIIai), which binds to tissue factor but is unable to initiate coagulation. Segments of both central arteries of rabbits' ears were isolated between vascular clamps, followed by arteriotomies and deep-vessel wall trauma. In each rabbit, the injured vessel segments were superfused with either VIIai (0.5 mg in 200 microliters vehicle) or vehicle alone in a blinded random manner (n = 20). The vessels were then closed with running sutures and reperfused. The effect of intravenously infused VIIai (4 mg/kg) or vehicle was studied in a separate series. The administration of VIIai increased patency rates from 40% and 30% in the vehicle group at 30 and 120 minutes after reperfusion, respectively, to 85% and 75% in the VIIai group (p = 0.008 and p = 0.004). No antihemostatic side effects occurred: median arteriotomy bleeding times were 2 minutes in the vehicle group and 1 1/2 minutes in the VIIai group (p = 1). By contrast, intravenous infusion of VIIai produced no antithrombotic effect. We have shown that topical administration of VIIai at arterial trauma sites produces an antithrombotic effect without the expense of a hemostatic defect. This mode of treatment seems to be highly attractive in the prevention of thrombotic complications in surgery on blood vessels.