Abstract

Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y₁₂ and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl₃-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y₁₂(−/−) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y₁₂. Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y₁₂(−/−) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y₁₂ activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y₁₂-independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.