Preventing Platelet Thrombosis with a PAR1 Pepducin
Platelet-mediated arterial thrombosis, such as occurs following atherosclerotic plaque rupture, erosion, or percutaneous coronary interventions (PCI), is the underlying cause for most myocardial infarctions and many ischemic strokes1. 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 peri-procedural complications due to thrombin-dependent platelet activation2,3. Human platelets possess two main thrombin G-protein coupled receptors (GPCR), protease activated receptor (PAR) 1 and 4 (Figure 1), which when cleaved by thrombin, trigger a host of intracellular signaling events resulting in secretion of granule contents including ADP, production of thromboxane A2 (TXA2), 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 TXA2 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 ~15-17% of lethal cardiovascular events with a ceiling effect4,5. 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. (SELECT FULL TEXT TO CONTINUE)
- Received June 2, 2012.
- Accepted June 4, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited