Factor XII in Hemostasis and Thrombosis: Active Player or (Innocent) Bystander?

Coagulation factor XII (FXII), formerly known as Hageman factor, is a plasma glycoprotein which exerts a kaleidoscope of biological functions, including the initiation of the intrinsic pathway of blood coagulation, the activation of the kallikrein-kinin system, and the generation of bradykinin and angiotensin. The large body of evidence accumulated over the past decades and the revised cell-based model of hemostasis suggest that FXII may be somehow "redundant" for physiological hemostasis, drawing a potential interpretation of this protein as a possible "innocent" bystander of in vivo hemostasis. Although the contribution of FXII remains unproven in the pathogenesis of venous thromboembolism, perhaps reinforcing this perception of "redundancy," recent work identifies FXII as critical for initiation of thrombosis on artificial surfaces (e.g., polyurethanes or polytetrafluoroethylene catheters), or in patients with strong prothrombotic conditions such as vulnerable atherosclerotic plaques or severe bacterial infections. Important evidence has also emerged from recent investigations using innovative FXII inhibitors in ex vivo animal models, wherein targeted FXII-mediated inhibition of thrombin and fibrin generation may open new avenues for prevention or treatment of certain types of thrombosis. Thus, interest in FXII, waned in the recent past, is again re-emerging, and pointing to important but under-recognized contribution to in vivo hemostasis and thrombosis.