DiaPharma Group, Inc.

Factor XII (FXII, Hageman factor) is a 76 kDa, single chain glycoprotein produced in the liver. In plasma, FXII circulates as a protease zymogen at a concentration of approximately 30 micrograms/milliliters (400 nM). Upon vascular injury FXII binds to negatively charged extravascular surfaces such as cartilage and skin, which facilitate activation of the zymogen to the active serine protease. Cleavage of FXII by kallikrein after residue Arg³⁵³produces the enzyme alpha-FXIIa, consisting of a 28 kDa light chain containing the protease domain, and a 52 kDa heavy chain containing the anionic surface-binding domain. Substrates for surface bound FXIIa include the zymogens prekallikrein (PK) and factor XI (FXI) as well as the procofactor highmolecular weight kininogen (HK). The activation of these substrates results in positive feedback activation of FXII. Further cleavage of alpha-FXIIa by kallikrein produces the 28 kDa fragment Beta-FXIIa (Hageman factor fragment). Beta-FXIIa has reduced procoagulant activity as it lacks the anionic surface-binding domain, but is capable of fluid-phase activation of PK, factor VII and complement C1. The activity of FXIIa in plasma is regulated predominantly by C1-Inhibitor, with relatively minor contributions by alpha2-antiplasmin, alpha2-macroglobulin and antithrombin, even in the presence of therapeutic levels of heparin.