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

Purpose: In vivo, the coagulation pathway is triggered by formation of a high-affinity complex between the tissue factor of the injured vascular mall 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. Methods: 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 mu l 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. Results: 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. Conclusions 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.