Drugs targeting protease-activated receptor-4 improve the antithrombotic therapeutic window

Antiplatelet agents are the main pharmacotherapy for arterial thrombosis prevention and are central in the management of cardiovascular conditions such as myocardial infarction, transient ischaemic attack, and coronary and peripheral artery diseases. Yet despite their long history and extensive clinical use, antiplatelet agents appear to have reached a disappointingly low therapeutic ceiling-predominantly due to the narrow therapeutic window afforded by strategies targeting platelet function. Platelets are critical for normal hemostasis as well as pathological thrombosis. Inhibiting platelet function for protective benefit without causing unwanted bleeding limits the efficacy of current antiplatelet drugs. Aspirin and the thienopyridine class of drugs (e.g., clopidogrel, prasugrel, ticagrelor) are by far the most commonly prescribed antiplatelet agents, yet prevent just 15 and 17% of lethal cardiovascular events respectively (1,2). Combination therapy provides a marginal increase in efficacy (~7%), but also increases the risk of bleeding (2). More potent antiplatelet drugs, such as the glycoprotein α_IIbβ₃ inhibitors, carry even more bleeding risk and are thereby limited to acute use settings such as periprocedural percutaneous coronary intervention (3,4). Therefore, the search to identify antiplatelet drugs that increase the therapeutic window of antithrombotic therapy continues. A recent study by Wong et al. (5) provides compelling evidence that targeting the platelet thrombin receptor, PAR4, may achieve this goal.