FXII: The Cuckoo in the Nest
Authors: Roger E.G. Schutgens
Journal: HemaSphere (2018)

In 1955, Ratnoff and Colopy1 described 3 patients with deficiency of a previously unknown clotting factor, which he called “the Hageman factor” (later termed FXII), named after the first patient. It was the starting point for the waterfall sequence theory published by Davie and Ratnoff in 1964.2 Remarkably, these patients had no bleeding tendency, but demonstrated prolonged clotting times in vitro. Already in the sixties, it was thought that FXII played a role in thrombosis, fibrinolysis, inflammation, vascular permeability, and the contact system. Recent studies have improved our insights in the role of FXII in health and disease (Fig. 1)3 and the potential benefits of targeted interference.Figure 1: Thromboinflammatory activities of FXII in vivo (from Maas and Renné3).FXII in angioedema FXII is described as the linking pin for plasmin-mediated activation of the contact system (plasminflammation) in a recent review, which has substantial implications for patients with (hereditary) angioedema.4 Indeed, antibody-mediated blocking of FXIIa reduced edema formation in mice and prevented bradykinin formation following contact activation in plasma samples from patients with hereditary and acquired angioedema.5 FXII in thrombosis The intrinsic activation route of coagulation is initiated by FXII activation and is especially important in contact-mediated thrombotic events, such as those associated with venous catheters, extracorporal vascular systems and mechanic heart valves. Interfering with the FXII/FXI pathway by antibody or antisense therapies has been successful in preventing thrombosis in animal and human studies. In support of a role for the FXII-driven contact system in thrombosis, mice with deficiencies in prekallikrein or high-molecular-weight kininogen are also protected from thrombosis.3 FXII in wound healing Inflammatory processes and wound healing are closely connected. Chronic, nonhealing wounds are characterized by excessive neutrophil activity or the persistence of neutrophils at the site of the wound. Stavrou et al6 identified the FXII/uPAR/pAkt2 axis in neutrophils, which promotes cell activation and leads to impaired wound healing. FXII knockout mice exhibited decreased neutrophil recruitment in a model of sterile inflammation with increased wound healing. However, subsequent targeting of FXII production in the liver with a siRNA knockdown strategy unexpectedly did not affect neutrophil migration. In addition, reconstituting plasma of FXII knockout mice with FXII did not correct the neutrophil migration defect. They then found FXII mRNA in murine neutrophils and FXII protein in murine and human peripheral neutrophils, indicating 2 pools of FXII production sites (liver and neutrophils). Activities of neutrophil-derived FXII are distinct from the function of plasma-derived FXII (Fig. 2). Specifically, silencing FXII-mediated signaling in hematopoietic cells influences neutrophil adhesion, migration and chemotaxis and results in improved wound healing.Figure 2: Role of FXII in inflammation and wound healing (from Stavrou et al6).Altogether, these recent data emphasize that an important role of FXII has been overlooked. Clearly, FXII is critical for contact-mediated inflammation, thrombosis, and wound healing. Ongoing research in this field will further explore the clinical potential of inhibiting FXII in these medical conditions.