Factor XII (FXII) converts plasma prekallikrein (KLKB1(20–638)) to its active form, plasma kallikrein, a heterodimer consisting of a light chain (KLKB1(391–638)) and a heavy chain (KLKB1(20–390)). This conversion occurs within the prekallikrein:kininogen:FXII complexes bound to cell surface receptor complexes, including the gC1qR (C1QBP) homotrimer, gC1qR:CK1 (C1QBP:KRT1), or uPAR:CK1 (PLAUR:KRT1) (Joseph K et al., 2001; Mahdi F et al., 2002, 2003; Pixley RA et al., 2011; Kaira BG et al., 2020). Although these receptors are expressed on surfaces of various cell types, including activated platelets (Peerschke EIB et al., 2003; Khan MM et al., 2006; reviewed by Schmaier AH, 2016), activation of prekallikrein has been demonstrated only on endothelial cell surfaces (Lin Y et al., 1997; Motta G et al., 1998; Joseph K et al., 2001; Mahdi F et al., 2002, 2003; Pixley RA et al., 2011).
Activation of plasma prekallikrein (PK) to plasma kallikrein can be mediated by two mechanisms: (1) in the absence of FXII, endothelial cell–associated prolylcarboxypeptidase (PRCP) activates prekallikrein bound to kininogen (HK) in a Zn²⁺-dependent manner (Motta G et al., 1998, Shariat-Madar Z et al., 2002, Merkulova AA et al., 2023), and (2) by surface-bound single-chain FXII, which exhibits catalytic activity toward both itself and prekallikrein, even without being fully converted to its active form, FXIIa, as shown in this Reactome event (Engel R et al., 2014; Ivanov I et al., 2017, Merkulova AA, 2023). A natural variant of FXII, FXII-R372P, which is resistant to cleavage at R372 and is not converted to active FXIIa, retains the ability to convert prekallikrein to kallikrein (Mohammed BM et al., 2018). Additionally, a small-molecule FXIIa inhibitor effectively blocks the FXII-induced, kallikrein-catalyzed cleavage of high-molecular-weight kininogen (HK) in FXII-deficient mouse plasma supplemented with cleavage-resistant single-chain FXII variants and stimulated by a polyanionic surface, further confirming the catalytic function of single-chain FXII (Clermont AC et al., 2023).
In plasma, FXII circulates in its zymogen or "closed" conformation, which resists activation due to interactions between its fibronectin type 2, kringle, and catalytic domains. Upon surface binding, FXII undergoes a conformational change from the "closed" to an "open" form, facilitating its catalytic function (de Maat S et al., 2019; Clark CC et al., 2020; Shamanaev A et al., 2022, 2023, 2025). Mutations affecting the structure of FXII can result in abnormal FXII-driven contact activation, as observed in carriers of the FXII W287R variant (Hofman ZLM et al., 2020; Scheffel J et al., 2020). Although the enzymatic activity of FXII is significantly lower than that of FXIIa, it still has the capacity to efficiently cleave prekallikrein (Ivanov I et al., 2017).
Once activated, kallikrein amplifies the system by cleaving single-chain FXII into its two-chain active form, FXIIa, creating a positive feedback loop. The resulting pools of FXIIa and kallikrein induce bradykinin-mediated inflammatory responses and contribute to the coagulation cascade.
