In vitro effect of melagatran and lepirudin on clot-bound thrombin

Thrombin converts fibrinogen into fibrin monomers by cleaving fibrinopeptides A and B from aminoterminal regions of Aa and Bh chains of fibrinogen, respectively [1]. During this reaction, thrombin is adsorbed to fibrin through the fibrin(ogen)-binding site located within the E domain [2,3]. The fibrin-bound thrombin retains its enzymatic activity and has the potential to induce thrombosis extension [4]. Given this central role of thrombin, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity [5–7]. In vitro studies have shown that fibrin-bound thrombin is relatively protected from inactivation by heparin-antithrombin and this inactivation requires ligation of both exosites 1 and 2 of thrombin [8,9]. These findings could explain why heparin is limited in its ability to inhibit the extension of venous thrombosis and to prevent rethrombosis after successful thrombolysis [3]. Thus, direct thrombin inhibitors may represent alternatives to the treatment with heparin. At present, most clinical benefits of recombinant (r)hirudin have been demonstrated in the management of patients with heparin-induced thrombocytopenia. For this reason, lepirudin (a form of r-hirudin) has recently been approved for anticoagulation in patients with heparin-induced thrombocytopenia and associated thromboembolic disease [10,11].