Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis

Abstract

Factor XII (FXII) is a coagulation protein that is essential for surface-activated blood coagulation tests but whose deficiency is not associated with bleeding. For over forty years, investigators in hemostasis have not considered FXII important because its deficiency is not associated with bleeding. It is because there is a dichotomy between abnormal laboratory assay findings due to FXII deficiency and clinical hemostasis that investigators sought explanations for physiologic hemostasis independent of FXII. FXII is a multidomain protein that contains two fibronectin binding consensual sequences, two epidermal growth factor regions, a kringle region, a proline-rich domain, and a catalytic domain that when proteolyzed turns into a plasma serine protease. Recent investigations with FXII deleted mice that are protected from thrombosis indicate that it contributes to the extent of developing thrombus in the intravascular compartment. These findings suggest that it has a role in thrombus formation without influencing hemostasis. Last, FXII has been newly appreciated to be a growth factor that may influence tissue injury repair and angiogenesis. These combined studies suggest that FXII may become a pharmacologic target to reduce arterial thrombosis risk and promote cell repair after injury, without influencing hemostasis.

Figure 1

Structural Basis of FXII Function: FXII is divided into several domains. Top structure: amino acid sequence; bottom structure, linear diagram color coding each of the regions on the protein. Amino acids -19-1: leader peptide, 1–88: fibronectin type II domain, 94–131: EGF-like domain, 133–173: fibronectin type I domain, 174–210: EGF-like domain, 215–295: kringle domain, 296–349: proline-rich region, 354–596: catalytic domain or light chain. Amino acids 1–353 are the so-called heavy chain. Each of these areas is highlighted in the same color as the linear cartoon below it. This figure is adapted from Cool and MacGillivray [5].