Sequestration-induced loss of protein C receptors links coagulation, inflammation, and endothelial permeability. PAR1 activation by thrombin acts as a molecular switch, inhibiting or promoting inflammation and leakage, depending on whether there is a modifying signal from the protein C pathway. Thrombin is produced by the interaction between circulating activated factor VII (VIIa) in the plasma and tissue factor on monocytes and from endothelial tissue factor induced by IE (step 1 in both A and B). (A) Thrombin/PAR1 signaling when the protein C system is intact; 2) thrombin initiates the TM/EPCR-facilitated activation of protein C, which inhibits thrombin production upstream; 3) aPC modifies the effect of PAR1 through EPCR; 4) aPC/EPCR-modified PAR1 signaling decreases endothelial permeability via S1P1 signaling (not shown) and production of S1P, which leads to enhancement of tight junctions; 5) in the presence of EPCR has pleotropic antiinflammatory and endothelial protective properties, including downregulation of Nuclear Factor κ-B (NFKB) and increased Angiopoetin-1 (Ang1) production. Ang1 decreases Weibel Palade body (WPB) exocytosis by occupancy of Tie2. (B) Thrombin/PAR1 signaling in a vessel with high level of sequestered malaria-IEs when there is complete loss of protein C receptors, such as in microvessels in the brain, and therefore no modification of PAR1 signaling. 2) IE sequestration is associated with loss of TM and EPCR; protein C is therefore not activated; 3) thrombin signals through PAR1 without modification by EPCR signaling; 4) unmodified PAR1 signaling inhibits S1P release with resultant loss of tight junctions, loss of endothelial barrier function, and localized vascular leak; and 5) thrombin signaling in the absence of modification by aPC/EPCR has strong proinflammatory effects, including upregulation of NFKB with increased tumor necrosis factor (TNF) and interleukin (IL)-6 production and reduction of Ang1 production, leading to increased Weibel Palade body (WPB) exocytosis with production of Von Willebrand Factor (vWF) and Ang2. Ang2 further increases WPB exocytosis by occupancy of Tie2 and also contributes to loss of endothelial barrier integrity and leak. 6) Thrombin and inflammatory cytokines cause activation of platelets, leading to the production of platelet microparticles. 7) In the absence of inhibition from aPC, thrombin triggers the production of fibrin from fibrinogen and fibrin and activated platelets coalesce to form thrombi. 8) Activated platelets adhere to vWF strings. Both thrombi and these platelet-vWF complexes impair cerebral circulation. Solid black arrows indicate stimulation of a pathway and dotted red lines indicate inhibition.
