In vivo roles of factor XII

Abstract

Coagulation factor XII (FXII, Hageman factor, EC = 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by "contact" to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII(-/-) mice have a normal hemostatic capacity. However, thrombus formation in FXII(-/-) mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.

Figures

Figure 1

The FXII-driven contact system. Contact with negatively charged surfaces activates coagulation FXII on endothelial cells, leukocytes, bacteria, and thrombocytes and initiates procoagulant and proinflammatory proteolytic reactions. Activated FXII triggers fibrin formation through the FXI-mediated intrinsic pathway of coagulation. Simultaneously, activation of prekallikrein by FXIIa leads to generation of the vasoactive peptide BK by PK-mediated cleavage of HK.

Figure 2

The role of polyP/FXII in thrombosis. (A) Initially, the TF/FVIIa-driven “extrinsic” coagulation pathway triggers fibrin formation at sites of injury. FXII has no function during this stage. Tissue factor pathway inhibitor (TFPI) is released from endothelial cells and adherent platelets and blocks TF activity. (B) In the developing thrombus, activated platelet–released polyP triggers fibrin production via activation of FXII that drives the “intrinsic” coagulation cascade. polyP/FXII-driven fibrin formation operates distant from the injured vessel wall and, hence, does not contribute to hemostasis.

Figure 3

Model of zymogen FXII signaling pathway. FXII binds to domain 2 of uPAR and induces uPAR to communicate intracellularly through β1 integrins. Monoclonal antibody 6S6 to β1 integrin blocks this pathway. Cell stimulation through uPAR and integrin requires an interaction with 1 or more of the ErbB receptor kinases because the tyrosine inhibitors AG1478 or PP3 block FXII signaling. The MEK inhibitor PD98059 blocks FXII-induced ERK1/2 phosphorylation. LY294002, a PI3 kinase inhibitor, blocks FXII-induced Akt phosphorylation. Crosstalk between pERK1/2 and pAkt systems also occurs. Cleaved forms of HK (HKa) block binding of FXII to endothelial cells. Inhibition of any step of the FXII signaling pathways blocks cell proliferation and angiogenesis in HUVEC and aortic segments, respectively. Modified from Falati et al with permission.