Schematic models of PC activation and APC activities. Protein C (PC) activation occurs on the endothelial cell membrane and requires thrombomodulin (TM) (A). Thrombin (IIa) bound to thrombomodulin activates protein C. Binding of protein C to its endothelial receptor, EPCR, provides for the most efficient activation of protein C. Protein C and APC have a similar affinity for EPCR. Dissociation of APC from EPCR allows expression of APC's anticoagulant activity (B), whereas retention of APC bound to EPCR allows APC to express multiple direct cellular activities (C). APC conveys its anticoagulant activity (B) when bound to cell membrane surfaces, various microparticles, or lipoproteins (eg, HDL). As an anticoagulant, APC cleaves the activated cofactors Va (fV_a) and VIIIa (fVIII_a) to yield the inactivated cofactors fV_i and fVIII_i. Inactivation of factors Va and VIIIa by APC is enhanced by a number of different protein cofactors (eg, protein S, factor V) and various lipids cofactors (eg, phosphatidylserine, cardiolipin, glucosylceramide, HDL). Beneficial activities of APC that involve direct effects of APC on cells require the cellular receptors EPCR and PAR-1 (C). These activities include APC-mediated alteration of gene expression, anti-inflammatory activities, antiapoptotic activities, and protection of endothelial barrier functions. Collectively, these activities are referred to as APC's cytoprotective activities.