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Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway

The protein C pathway provides multiple important functions to maintain a regulated balance between hemostasis and host defense systems in response to vascular and inflammatory injury. The anticoagulant protein C pathway is designed to regulate coagulation, maintain the fluidity of blood within the vasculature, and prevent thrombosis, whereas the cytoprotective protein C pathway prevents vascular damage and stress. The cytoprotective activities of activated protein C (APC) include anti‐apoptotic activity, anti‐inflammatory activity, beneficial alterations of gene expression profiles, and endothelial barrier stabilization. These cytoprotective activities of APC, which require the endothelial protein C receptor (EPCR) and protease‐activated receptor‐1 (PAR1), have been a major research focus. Recent insights, such as non‐canonical activation of PAR1 at Arg46 by APC and biased PAR1 signaling, provided better understanding of the molecular mechanisms by which APC elicits cytoprotective signaling through cleavage of PAR1. The discovery and development of anticoagulant‐selective and cytoprotective‐selective APC mutants provided unique opportunities for preclinical research that has been and may continue to be translated to clinical research. New mechanisms for the regulation of EPCR functionality, such as modulation of EPCR‐bound lipids that affect APC's cytoprotective activities, may provide new research directions to improve the efficacy of APC to convey its cytoprotective activities to cells. Moreover, emerging novel functions for EPCR expand the roles of EPCR beyond mediating protein C activation and APC‐induced PAR1 cleavage. These discoveries increasingly develop our understanding of the protein C pathway, which will conceivably expand its physiological implications to many areas in the future.