Abstract 414: Combined Tissue Factor/Factor VIIa Inhibitor and Acetylsalicylic Acid Show Increased Antithrombotic Potency Without Affecting Bleeding Time

Abstract

Since increased tissue factor (TF) in human atherosclerotic plaques is believed to trigger thrombotic events, TF/factor VIIa (FVIIa) inhibition might have prophylactic potential for atherothrombosis such as acute coronary syndrome (ACS). Although recent clinical observation by rivaroxaban provides a scientific rationale for the addition of anticoagulant to current antiplatelet treatment, these might have potential to increase bleeding. It is therefore important that emerging anticoagulants demonstrate additive antithrombotic effects with no concomitant increase in bleeding for ACS indication. We recently discovered ER-410660, a potent TF/FVIIa inhibitor. It suppressed venous thrombosis without affecting bleeding time and suggested that ER-410660 could act as a novel anticoagulant with a low bleeding risk. In the photochemically-induced thrombosis (PIT) model, the thrombus after vessel-wall injury has been developed by the deposition of TF, platelets, and fibrin. Therefore, we hypothesized that ER-410660 would be effective in the PIT model and could show enough margin against bleeding. The antithrombotic effects of ER-410660 and acetylsalicylic acid (ASA), both alone and in combination, was assessed using a rat PIT model. We also measured the bleeding time of ER-410660 in combination with ASA using a rat tail-transection model. Intravenous (iv) pretreatment with ER-410660 prolonged the time to occlusion (TTO) of the artery. The TTO was doubled at 0.99 mg/kg (95% CI, 0.51-1.9). Orally administered ASA also showed antithrombotic effect, and the TTO was doubled at approximately 12 mg/kg. Combined administration of 1 mg/kg ER-410660 (iv) and 10 mg/kg ASA (orally) showed an additive antithrombotic effect, with no cessation of blood flow during the 30-min observation period. Intravenous administration of ER-410660 (0.6, 2, and 6 mg/kg) to rats treated with ASA (10 mg/kg) did not significantly increased when compared with ASA alone, even at the highest dose. In conclusion, a TF/FVIIa inhibitor suppressed arterial thrombosis without affecting the bleeding time associated with ASA. Owing to these favorable characteristics, anticoagulation via TF/FVIIa inhibition may be a superior approach to the prophylaxis of atherothrombotic diseases.