Molecular Basis for the Resistance of Fibrin-Bound Thrombin to Inactivation by Heparin/Serpin Complexes

Despite advances in the treatment of venous thrombosis with the use of better heparin dosing regimens (Cruickshank et al., 1991), the treatment of arterial thrombosis remains problematic. Not only does heparin have limitations in patients with acute coronary syndromes, but also hirudin, a potent and specific inhibitor of α-thrombin (thrombin), is of limited efficacy in this patient group (GUSTO Investigators, 1996). Thus, when used alone or as adjuncts to thrombolytic therapy, heparin and hirudin are unable to fully block thrombus growth and there is evidence of reactivation of coagulation when treatment is stopped. It is likely that both the resistance of acute arterial thrombi to these anticoagulants and rebound activation of coagulation after stopping treatment reflect the inability of heparin or hirudin to pacify the intense procoagulant activity of the thrombus. At least two factors contribute to the procoagulant activity of thrombi (figure 1); thrombin bound to fibrin (Hogg and Jackson, 1989; Weitz et al., 1990) and factor Xa bound to platelets within the thrombus (Eisenberg et al., 1993). In this paper, we (a) highlight the limitations of heparin and hirudin in the setting of acute arterial thrombosis, (b) discuss the factors responsible for the prothrombotic activity of thrombi, (c) review the current understanding of the mechanism of thrombin’s interaction with fibrin, (d) discuss the consequences of the thrombin—fibrin interaction, and (e) outline the potential mechanisms by which thrombin bound to fibrin is protected from inactivation by heparin.