major histocompatibility complex (MHC)-class 1/CD1 family of molecules. 1 EPCR was isolated and cloned as an endothelial cell-specific, high selectivity and high affinity binding protein for protein C (PC) and activated PC (APC). 1 EPCR binds PC on the endothelial surface and presents it to the thrombin: thrombomodulin (TM) complex for activation (Figure 1). Thrombin bound to TM proteolytically activates PC and generates APC which exerts independent anticoagulant and cellular activities. 2 The APC anticoagulant pathway is mediated by proteolytic inactivation of blood coagulation Factors Va and VIIIa with the contribution of several cofactors, including protein S, high density lipoproteins, phosphatidylserine, cardiolipin, and glucosylceramide to name a few. The APC cellular pathway on endothelium requires EPCR and the protease activated receptor-1 (PAR-1) 3 which mediates APC’s cytoprotective effects, including alterations in gene expression profiles, antiapoptotic activity, antiinflammatory activity and protection of endothelial barriers4–10 (Figure 1). EPCR also regulates endogenous physiologic activation of PC by thrombin which is linked to PAR-1-dependent APC protective autocrine signaling in endothelium. 11

EPCR signaling can decrease inflammation. APC binding to EPCR rescues baboons from E. coli sepsis. 12 EPCR has also cardioprotective role in lipopolyscharide-induced endotoxemia in mice. 14 In addition to the cell-surface EPCR, soluble EPCR lacking the transmembrane helix of native EPCR interacts with the integrin CD11b/CD18 (Mac-1)(αMß2)(CR3) on leukocytes (Figure 1), suggesting that binding of soluble EPCR to Mac-1 might regulate leukocytes adhesion. 15 Proteinase-3 (PR3), a serine protease with elastase-like properties stored in granules of neutrophils, binds both Mac-1 and soluble EPCR which may be implicated in APC mediated signaling and activation of PC on leukocytes, because soluble EPCR: PR3 complexes bind both APC and PC. 15