The relationship of polyP to factor XII (FXII) activation and C1s inhibition. Zymogen FXII auto-activates to FXIIa in the presence of polyP. FXIIa is converted to a fluid-phase activator βFXIIa by plasma kallikrein (Kal). βFXIIa has the ability to convert the macromolecular complex of C1(qrs) to its enzymatically active form C1(qrs). C1s produces C3 convertase (C4bC2a) from C4, C2. C1-INH in the presence of polyP inhibits C1s. C1-INH also is known to inhibit FXIIa, βFXIIa, and Kal. Plasma kallikrein is produced by FXIIa-activating plasma prekallikrein (PK). Plasma kallikrein also has the ability to convert FXII into FXIIa by reciprocal activation on polyP (not shown). These reactions may occur in the fluid phase of the intravascular compartment, but both platelets and endothelium contain polyP and C1-INH. FXII/FXIIa also has a multiprotein receptor on endothelial cells consisting of urokinase plasminogen activator receptor (uPAR), gC1qR, and cytokeratin 1 (CK1) that could localize these reactions. These studies show the novel finding that polyP activates FXII leading to complement activation and potentiates the inhibition of C1s by C1-INH.