Pleiotropic effects of the hemostatic system.

Atherothrombosis is characterized by the inflammatory process of atherosclerosis combined with a hypercoagulable state leading to superimposed thrombus formation. In atherosclerotic plaques, cell signaling can occur via protease-activated receptors (PARs), four of which have been identified so far (PAR1-PAR4). Proteases that are able to activate PARs can be produced systemically, but also at the sites of lesions, and they include thrombin and activated factor X. After PAR activation, downstream signaling can lead to both proinflammatory effects and a hypercoagulable state. Which specific effect occurs depends on the type of protease and activated PAR, and the site of activation. Hypercoagulable effects are mainly exerted through PAR1 and PAR4, whereas proinflammatory responses are mostly seen after PAR1 and PAR2 activation. PAR signaling pathways contribute to atherothrombosis, suggesting that inhibition of these pathways possibly prevents cardiovascular events based on this pathophysiological mechanism. In this review, we highlight the pathways by which PAR activation leads to proinflammatory responses and a hypercoagulable state. Furthermore, we give an overview of potential pharmacological treatment targets that promote vascular protection.