Abstract 19905: Comparative and Synergistic Effects of an Inhibitor of Integrin Outside-in Signaling With Clopidogrel and Aspirin in Inhibiting Arterial Thrombosis, and Their Different Effects on Hemostasis

Abstract

Due to shared mechanisms of thrombosis and hemostasis, all current anti-thrombotic drugs in clinical use, including anti-coagulant and anti-platelet drugs, are associated with increased bleeding risks, which can be life-threatening. Thus, there is a need for developing new anti-thrombotics that minimally cause excessive bleeding. We have recently shown that integrin outside-in signaling, which plays an important role in occlusive thrombosis but is not required for primary platelet thrombus formation, is mediated via the interaction between integrin [[Unsupported Character - Symbol Font ]]3 subunit and heterotrimeric G protein, G[[Unsupported Character - Symbol Font ]]13. We have developed a novel inhibitor of integrin-G[[Unsupported Character - Symbol Font ]]13 interaction, mP6, which inhibits thrombosis without causing excessive bleeding in mouse models. In this study, we have directly compared effects of an improved formulation of mP6, M2mP6, with current anti-platelet drugs clopidogrel and aspirin on arterial thrombosis and hemostasis. We demonstrate that retroorbital injection of M2mP6 exerted potent anti-thrombotic effect within 5 min compared reported effects of clopidogrel of more than 1 hour. One time injection of M2mP6 (15 min, 5 μmol/kg, retro-orbital) is significantly superior to one-time ingestion of clopidogrel (2 hours, 2 mg/kg, oral) and superior to high concentrations of aspirin in inhibiting occlusive thrombosis using FeCl3-induced mouse carotid artery thrombosis model. Importantly, both clopidogrel and aspirin caused significantly prolonged tail bleeding time. In contrast, M2mP6 injection is not statistically different from control mice in tail bleeding time analysis. Furthermore, M2mP6, when used together with clopidogrel or clopidogrel and aspirin, showed synergistic effect in inhibiting occlusive thrombosis. These data demonstrates M2mP6 can potentially be a fast-acting and potent anti-thrombotic drug that does not cause adverse effect of bleeding.