There are two pathways for FXII (Hageman factor) activation: autoactivation upon exposure to negatively charged surfaces and proteolytic activation on cell membranes. FXII autoactivates (K_m = 2.4 μM) on an artificial or biologic surface such as kaolin or a thrombus to activate FXII to α-FXIIa. α-FXIIa then activates FXI to FXIa to initiate hemostasis and activates PK to form plasma kallikrein (KAL). KAL cleaves HK to liberate bradykinin, which induces vasodilatation and vascular permeability. KAL also activates the complement system by directly activating complement components C3 and C5 and cleaving α-FXIIa to form β-FXIIa (a soluble light chain enzymatic form [Hageman factor fragment]), which then activates the macromolecular C1qr,s complex to enzymatically active C1r and C1s. The results of the study by Maas et al. in this issue of the JCI (10) suggest that a second FXII autoactivation mechanism occurs upon exposure of FXII to aggregates of misfolded proteins and that this activation results in PK activation without FXI activation — showing that the kallikrein-kinin system can be activated separately from the coagulation cascade by FXII. A second pathway for FXII activation occurs on endothelial cells. PK bound to HK on endothelial cells is activated to plasma KAL by the serine protease prolylcarboxypeptidase (PRCP) (K_m = 9 nM). KAL then activates FXII to α-FXIIa (K_m = 11 μM). FXII also binds to endothelial cells in the presence of zinc ions and when bound stimulates ERK1/2 phosphorylation. CK1, cytokeratin 1; gC1qR, gC1q receptor; uPAR, urokinase plasminogen activator receptor.