Active site-inactivated factor VIIa prevents thrombosis without increased surgical bleeding: Topical and intravenous administration in a rat model ofdeep arterial injury

Purpose: The primary event in the procoagulant response after vascular inte rventions is the tissue factor (TF)-factor VIIa complex formation, which oc curs when TF is exposed to the circulating blood by the inflicted trauma. H uman recombinant active site-inhibited coagulation factor VIIa (FFR-rFVIIa) binds well to TF but cannot initiate blood coagulation, and should thereby block thrombus formation. This hypothesis was tested with a rat model of a rterial thrombosis. Methods In a blinded randomized study, the antithrombotic and antihemostati c effects of FFR-rFVIIa and heparin were evaluated in a rat model of mechan ical deep arterial injury. In one arm of the study, FFR-rFVIIa (0.2 mg in 1 50 muL) or vehicle alone was applied topically at the site of vascular inju ry. In the other arm, FFR-rFVIIa (4 mg/kg), heparin (1 mg/kg), or vehicle a lone was injected intravenously. Results: FFR-rFVIIa produced a powerful antithrombotic effect after both to pical and intravenous administrations (P = .02 and P = .005, respectively) without increasing the surgical bleeding. Heparin prevented thrombosis equa lly well as FFR-rFVIIa (P = .0007), but doubled the surgical bleeding compa red with FFR-rFVIIa (P = .03) and controls (P = .008). In the topical study , the antithrombotic effect was achieved without altering parameters of pla sma anticoagulation (prothrombin time and activated partial thromboplastin time) or producing detectable levels of FFR-rFVIIa in plasma. Conclusion: In this model FFR-rFVIIa effectively inhibits thrombus formatio n without the expense of increased surgical bleeding, which indicates the p otential of FFR-rFVIIa as an effective and safe strategy for prevention of thrombosis in reconstructive vascular surgery and various forms of percutan eous revascularization.