P falciparum infection causes coagulation activation through multiple different mechanisms. Procoagulant effects: P falciparum infection causes early EC activation and platelet activation. Furthermore, IEs induce TF expression on EC surfaces and on monocytes. This aberrant intravascular TF expression in combination with FVIIa results in initiation of the extrinsic coagulation pathway. In addition, P falciparum infection leads to expression of negatively charged PS on the red cell surface. This PS enables the assembly of the intrinsic tenase and prothrombinase complexes, thereby enhancing coagulation amplification. Activated clotting factor proteases (notably FXa and thrombin) generated through P falciparum–induced coagulation activation interact with specific EC surface including protease-activated receptor (PAR) 1 and thereby initiate downstream intracellular signaling, which ultimately results in enhanced EC activation, damage, and apoptosis. Attenuation of normal anticoagulant effects: In addition to the specific procoagulant effects described previously, P falciparum infection further promotes coagulation activation by downregulating normal endogenous anticoagulant pathways. EC surface expression of TM and the EPCR are both reduced, likely because of cytokine-enhanced shedding. Moreover, plasma levels of soluble TM and soluble EPCR (sEPCR) are both increased. Together, these effects combine to lead to a significant reduction in generation of anti-inflammatory and cytoprotective activated protein C (APC) on the EC surface. Finally, release of HRPII following spontaneous IE lysis significantly inhibits the anticoagulant effects of antithrombin (AT).