Mechanisms by which polyP regulates complement activation. Upon activation, polyP and C1-INH can colocalize, after which they are secreted. PolyP triggers a conformational change in FXII, resulting in generation of FXIIa, which can activate prekallikrein and/or FXI to FXIa. Kallikrein or plasmin (not shown) can further cleave FXIIa to generate βFXIIa, which may activate C1r and thus promote complement activation. C1-INH dampens that pathway by inhibiting FXIIa, βFXIIa, and kallikrein. C1s cleaves C4 and C2 to generate the C4b2a C3 convertase, which ultimately leads to formation of the C5b,6 complex, and assembly of the C5b-9 MAC. PolyP or heparin potentiate the inhibitory function of C1-INH via direct interactions with C1-INH and the target protease, C1s. PolyP also destabilizes C5b,6, thereby dampening the formation of the MAC. The over-riding effect of polyP in a serum-based endothelial cell culture system is to suppress complement activation. K, kallikrein; MAC, membrane attack complex; PK, prekallikrein.