Preventing Platelet Thrombosis With a PAR1 Pepducin

Platelet-mediated arterial thrombosis, such as occurs after atherosclerotic plaque rupture, erosion, or percutaneous coronary interventions (PCI), is the underlying cause for most myocardial infarctions and many ischemic strokes.1 Platelets adhere to damaged blood vessels, aggregate with one another, and facilitate the generation of thrombin, which in turn makes fibrin. Thrombin is also a highly potent stimulator of platelets, and shear stress in settings such as PCI may lead to periprocedural complications due to thrombin-dependent platelet activation.2,3 Human platelets possess 2 main thrombin G-protein–coupled receptors, protease-activated receptor (PAR) 1 and 4 (Figure), which, when cleaved by thrombin, trigger a host of intracellular signaling events resulting in secretion of granule contents including ADP, production of thromboxane A2, and activation of the platelet fibrinogen receptor integrin αIIbβ3 (GPIIb/IIIa). In the setting of acute coronary syndrome and PCI, antiplatelet therapy for secondary prevention of vascular events consists of aspirin to reduce thromboxane A2 production, P2Y12 antagonists to block the effects of ADP, and GPIIb/IIIa inhibitors. However, despite the use of these therapies, the rate of ischemic events remains high. Furthermore, this approach is estimated to prevent only ≈15% to 17% of lethal cardiovascular events with a ceiling effect.4,5 The ability of thrombin to activate platelets in the presence of aspirin and P2Y12 antagonists may explain some of the residual risk. Thus, strategies that target thrombin signaling in platelets have been the focus of considerable attention.Figure. Platelet activation pathways, the role of thrombin receptors. In humans, protease-activated receptors (PAR)-1 and PAR-4 …