Platelet biology and implications for antiplatelet therapy in atherothrombotic disease

Platelet activation is crucial for wound healing at sites of endothelial cell injury and involves multiple factors that mediate platelet recruitment, adherence, and aggregation. Platelet activation in response to atherosclerotic plaque rupture or endothelial cell detachment can result in pathologic thrombus formation and acute ischemic events. Current oral antiplatelet agents, aspirin and adenosine diphosphate (ADP) receptor antagonists, are effective but associated with bleeding as they target activation pathways critical for protective hemostasis and pathologic thrombosis. Each inhibits a single platelet activation pathway and does not impact activation by thrombin. The lack of complete inhibition of platelet function allows continued thrombus formation and recurrent thrombotic events. Inhibition of the protease-activated receptor 1 (PAR-1) stimulated by thrombin offers a rational strategy to achieve more comprehensive platelet inhibition when used in combination with standard-of-care, dual antiplatelet therapy. We expect that this new approach may mitigate bleeding risk, because PAR-1 is not essential for hemostasis.