Role of EPCR in malaria. In malaria, Plasmodium-infected erythrocytes (IEs) express PfEMP1 on the membrane. PfEMP1 binds EPCR in the same region as protein C (PC) and APC; therefore, IEs expressing PfEMP1 compete with PC and APC for EPCR. Such competition reduces PC and APC binding to EPCR and leads to down-regulation of PC activation by the thrombin (T):TM complex and loss of EPCR-APC–induced cytoprotective signaling. This results in increased barrier disruption and proinflammatory responses. Furthermore, binding of IEs to the endothelium, either through PfEMP1-EPCR interaction or other adhesive mechanisms, activates endothelial cells, and the activated endothelial cells release proinflammatory cytokines (C), which induce shedding of EPCR and TM from the cell surface. Loss of EPCR and TM from the cell surface impairs the ability of the endothelium to generate the APC and APC-induced cytoprotective effect. Down-regulation of APC also leads to increased thrombin generation and thrombin-induced proinflammatory reactions.