Abstract 13849: Enhancing Anti-thrombotic Efficacy but Reducing Hemorrhage: Comparison and Combination Use of a Novel Integrin Outside-in Signaling Inhibitor With Current Anti-platelet Drugs

Abstract

Introduction and Hypothesis: Current anti-platelets drugs cause excessive bleeding. We have developed a novel anti-platelet drug, M3mP6, which selectively inhibits integrin outside-in signaling but not ligand binding to integrin αIIbβ3. Here we test the hypothesis that M3mP6 may synergistically enhance anti-thrombotic effects of current anti-platelet drugs but reduce risk of hemorrhage. Methods and Results: One time bolus injection of M3mP6 (10 uMol/kg,15 min) has superior anti-thrombotic effect compared to high doses of clopidogrel (4 mg/kg, oral, 2 hours), and very high doses of aspirin (36 mg/kg, i.p., 1 hour), using a FeCl 3 -induced occlusive carotid artery thrombosis model in mice. However, unlike the high doses of clopidogrel and aspirin, M3mP6 did not affect bleeding using a tail bleeding time model. We found that M3mP6 was comparable with the loading doses of ticagrelor (3 mg/kg) and cangrelor (30 μg/kg) in anti-thrombotic efficacy. However, ticagrelor or cangrelor cause dramatically increased hemorrhage, which is in contrast to M3mP6’s lack of bleeding side effect. To mimic hemorrhage during intravascular/surgical procedures, we designed a carotid artery puncture model of surgical hemorrhage. Cangrelor caused dramatically excessive bleeding even treated with a hemostatic pad. In contrast, M3mP6-treated mice are not different from control. Importantly, M3mP6 exerts synergistic anti-thrombotic effects when used together with current anti-platelets drugs, without further increases in bleeding. Furthermore, when M3mP6 was used in combination with a reduced dose of cangrelor, the anti-thrombotic effect was significantly more potent than high dose cangrelor, but hemorrhage was greatly reduced. Conclusions: M3mP6 is potentially a superior new anti-platelet drug, ideal for patients with bleeding risk, and also for greatly enhancing anti-thrombotic effects of current anti-platelet drugs while reducing hemorrhage.