Thrombin (EC184.108.40.206, α-thrombin) is the product of proteolytic activation of the zymogen prothrombin. Human thrombin is a two-chain serine protease with a mass of 37 kDa. The active site is located within the heavy chain. Thrombin has a high specificity for certain arginine bonds in protein substrates. The primary substrate is fibrinogen which thrombin converts to fibrin through the cleavage of four arginyl-glycyl peptide bonds. Thrombin is also an important activator of platelets, factor XIII, Protein C and TAFI (Plasma procarboxypeptidase B). In a positive feedback mechanism, thrombin increases the rate of its own production by activation of factors VIII and V. The rate of thrombin production is subsequently limited indirectly through the activation of Protein C by thrombin, which then inactivates the activated cofactors VIII and V. The binding of thrombin to thrombomodulin on the cell surface dramatically alters thrombin’s specificity, increasing it’s activity toward Protein C and TAFI, and decreasing it’s activity toward fibrinogen and activating cofactors VIII and V. In plasma, thrombin activity is inhibited primarily by antithrombin and to a lesser extent heparin cofactor II. The rate of inhibition by both of these inhibitors is profoundly increased in the presence of optimal concentrations of heparin. Other physiological inhibitors of thrombin in the absence of heparin include α2-macroglobulin and α1-antitrypsin1-4.