Functions of aPC in humoral and cellular innate immunity. After activation of PC, a portion of aPC dissociates from EPCR and binds to phospholipid membranes, probably in lipid rafts, where it exerts anticoagulant effects directly via inactivation of FVa and FVIIIa. By down-regulating thrombin levels, aPC enhances fibrinolysis through down-regulation of activated TAFI, as well as by inactivating the fibrinolytic inhibitor PAI-1. PS is a cofactor for these humoral processes. aPC also binds to cellular receptors, depending on the cell type, for example, EPCR in endothelial cells, various integrins in macrophages and neutrophils, and LRP8 in platelets and monocytes; this complex activates PAR-1, which in turn can cross-activate S1P1, probably via intracellular up-regulation of SphK1 and outward migration of S1P. These steps cause a variety of cytoprotective cellular processes indicated in the box below the schematic.