Interrelationship of Thrombin and Platelets: The Protease Activated Receptor-1

The leading cause of death world-wide continues to be ischemic heart disease despite invasive and pharmacologic therapy advances, and the central role of platelets in atherothrombosis is an area of ongoing research. A number of platelet receptors, including receptors for thromboxane A2, adenosine diphosphate, and fibrinogen, have been targeted using a variety of pharmacologic strategies in order to affect platelet-mediated thrombosis. However, residual morbidity and mortality still exist despite the use of pharmacologic agents directed at these pathways. One challenge is the achievement of a more favorable balance between the reduction in ischemic events and minimization of bleeding events. Thrombin, the most potent stimulant of platelet-mediated thrombosis, acts on the platelet through a family of receptors known as the protease-activated receptors (PARs). Platelet activation through thrombin's interaction with, specifically, the PAR-1 receptor gives rise to an early and intense response leading to platelet activation and aggregation. Because of the pivotal role PAR-1 has and its abundance on the surface of platelets, it is a potentially desirable target for therapy. Two PAR-1 antagonists, atopaxar and vorapaxar, have been tested in clinical trials and results have been recently published. Generally, the results have been mixed with a reduction in some ischemic event rates but an increase in some bleeding event rates. This chapter summarizes the current understanding of PAR's structure and function on platelets, as well as the clinical applications of the PAR-1 inhibitors and aprotinin. Lastly, we will cover the role of PAR in vascular remodeling.