Protein C activation and expression of APC’s multiple activities. Activation of the EPCR-bound protein C (PC) zymogen (bottom left) is accomplished by thrombomodulin (TM)-bound thrombin (IIa). Anticoagulant activity (upper right) is based on limited proteolysis, causing irreversible inactivation (i) of the activated clotting factors (f)Va and fVIIIa for which various lipids and protein cofactors play essential roles, as shown for this reaction on platelet membranes. Cytoprotective actions of APC (bottom right) include its antiapoptotic and anti-inflammatory activities, its ability to stabilize endothelial barriers to prevent vascular leakage, and its ability to alter gene expression profiles for many genes. APC’s various cytoprotective activities and regenerative effects generally require EPCR and PAR1. Not depicted here is the fact that APC’s cytoprotective or regenerative actions sometimes require PAR3 and/or other receptors, depending on the biological context, cell type, and organ. Inactivation of circulating APC by plasma serine protease inhibitors (SERPINs; upper left) is a major mechanism for clearance of APC. Coloring of molecules is as follows: protein C zymogen and active protease, APC (yellow); IIa (green); TM (red); EPCR (blue); and SERPINs (purple).