In healthy individuals, cleavage of a single peptide bond converts factor XII (FXII, F12, Hageman factor) to activated FXII (FXIIa) (Fujikawa and McMullen 1983; McMullen and Fujikawa 1985). FXII undergoes autoactivation to FXIIa either by endogenous activator (nucleic acids RNA/DNA, neutrophil extracellular traps (NETs), polyphosphate and heparin) or artificial surfaces. FXIIa then activates four different pathways: 1) The inflammation kallikrein-kinin pathway by converting plasma pre-kallikrein (PK) into active plasma kallikrein, which cleaves both FXII into FXIIa and high molecular weight kininogen (HK) to bradykinin (BK). The latter binds to kinin receptors (B2 and B1 receptors) and triggers inflammation. 2) The complement system by activation of the C1qrs complex subunits C1r and C1s leading formation of the membrane attack complex by the classical complement pathway. 3) The fibrinolytic system by activation of pro-urokinase into urokinase that in turn cleaves plasminogen into plasmin, an enzyme that degrades fibrin clots. 4) The intrinsic coagulation pathway by FXI activation into FXIa leading to thrombin activation and fibrin generation. The contact system is controlled mainly by C1 inhibitor (C1-Inh or SERPING1) that inhibits both FXIIa and kallikrein.
Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Angioedema initiated by bradykinin is usually associated with SERPING1 deficiency. More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). The substitution of threonine 328 by either a lysine or an arginine residue (T328K or T328R) in the FXII proline-rich region have been identified in several families with HAE and normal SEPING1. FXII T328K or T328R variants change protein glycosylation and introduce a new site that is sensitive to enzymatic cleavage by fibrinolytic and coagulation proteases such as plasmin, thrombin or FXIa (de Maat S et al. 2016; Ivanov I et al. 2019). FXII T328K or T328R variants are cleaved after residue 328 by proteases, removing the protein’s noncatalytic heavy chain (HC) region. Truncation of the pathological FXII T309K by plasmin exposes R372 for subsequent cleavage by plasma kallikrein in solution (de Maat S et al. 2016, 2019). The intrinsic capacity of the truncated form of FXII (329-615) to convert PK to kallikrein is greater than that of activated FXII leading to more kallikrein generated early during reciprocal activation (Ivanov I et al. 2019). Second, the truncated form of FXII (329-615) is a better kallikrein substrate than is FXII (Ivanov I et al. 2019). Further, the accelerated PK/FXII activation in HAE patients carrying FXII variants appears to overwhelm the regulatory function of SERPING1 at normal plasma levels leading to uncontrolled bradykinin formation in a surface-independent manner (de Maat S et al. 2016; Ivanov I et al. 2019).