Figure 1. Factor XIIa pathways. The intrinsic pathway of coagulation and the kallikrein-kinin system are both activated downstream of factor XII (FXII).

(I) In the intrinsic pathway, activated FXII (FXIIa) initiates an activation cascade of serine protease enzymes, including factor XIa (FXIa), factor IXa (FIXa), factor Xa (FXa) and thrombin (factor IIa; F2). Thrombin cleaves fibrinogen to form soluble fibrin, which aggregates or polymerizes to form a clot or thrombus.

(II) In the kallikrein-kinin system, FXIIa cleaves high-molecular weight (HMW) kininogen to form bradykinin. Bradykinin is degraded, and the degradation products activate bradykinin B2 receptor (BDKRB2; B2R), leading to edema.

A number of companies are developing inhibitors of the components of these two systems (see "Targeting the intrinsic pathway of coagulation and the kallikrein-kinin system). Reports in Science Translational Medicine and Blood provide evidence that FXII and FXIIa can be targeted to prevent clot formation without risk of bleeding.1,2