Effects of P. falciparum infection on the protein C system. (A) A normal functional protein C system is depicted in which protein C is activated by thrombin (IIa) bound to TM on the EC membrane. Generation of activated protein C (APC) is enhanced by recruitment of protein C to the cell membrane by binding to EPCR. After activation, APC conveys anticoagulant and cytoprotective responses. APC’s anticoagulant activities involve dissociation from EPCR and binding of APC to negatively charged phospholipid membranes such as those on activated platelets where APC proteolytically inactivates factors Va and VIIIa (not shown). Binding of APC to EPCR facilitates APC-mediated activation of protease-activated receptor 1 (PAR-1) and induction of protective PAR-1 signaling, which contributes to maintaining a quiescent state of the endothelium. (B) During P. falciparum infection, IEs (expressing PfEMP1 variants containing DC8 and/or DC13) bind to EPCR and promote EC activation. Activated ECs release proinflammatory cytokines, which, in turn, induce shedding of TM and EPCR from the cell surface and release of the ectodomains soluble TM and soluble EPCR (sEPCR) in the circulation. In addition, PfEMP1 binding to EPCR inhibits the function of the receptor. Collectively, these changes severely impair the ability of the endothelium to generate APC, setting up a vicious cycle of procoagulant and proinflammatory reactions leading to further endothelial dysfunction augmented by proinflammatory PAR-1 signaling by thrombin.