Role of EPCR in cerebral malaria. (A) During normal homeostasis, excessive thrombin is bound by thrombomodulin expressed by endothelial cells. The thrombomodulin-thrombin complex activates protein C to APC, a process that is strongly accelerated by EPCR. APC exerts anticoagulant effects when it becomes detached from EPCR by inactivating clotting factor Va and VIIIa. In addition, APC bound to EPCR has cytoprotective properties by activating PAR1. (B) (Upper) In malaria, parasite-infected erythrocytes induce the loss of EPCR and thrombomodulin from the endothelial cell surface at least in part by shedding of these receptors. As a consequence, the capacity to produce APC is greatly impaired, resulting in enhanced coagulation. The resulting high thrombin levels can induce proinflammatory barrier disruptive effects on blood vessels via PAR1. (Lower) Plasmodium-infected erythrocytes transport PfEMP1 to their membrane, which can bind EPCR in the same region as APC. As a result, APC is less capable of inducing cytoprotective effects via PAR1.