THROMBIN BINDS TO SOLUBLE FIBRIN DEGRADATION PRODUCTS WHERE IT IS PROTECTED FROM INHIBITION BY HEPARIN-ANTITHROMBIN BUT SUSCEPTIBLE TO INACTIVATION BY ANTITHROMBIN-INDEPENDENT INHIBITORS

Background-Thrombolytic therapy induces a procoagulant state character ized by elevated plasma levels of fibrinopeptide A (FPA), but the resp onsible mechanism is uncertain, Methods and Results-Washed plasma clot s were incubated in citrated plasma in the presence or absence of tiss ue plasminogen activator (t-PA), and FPA generation was monitored as a n index of unopposed thrombin activity. FPA levels are almost twofold higher in the presence of t-PA than in its absence. This primarily ref lects the action of thrombin bound to soluble fibrin degradation produ cts because (a) there is progressive FPA generation even after clots a re removed from t-PA-containing plasma, and (b) clot lysates produce c oncentration-dependent FPA generation when incubated in citrated plasm a. Using thrombin-agarose affinity chromatography, (DD)E and fragment E but not D-dimer were identified as the thrombin-binding fibrin fragm ents, indicating that the thrombin-binding site is located within the E domain, Heparin inhibits thrombin bound to fibrin degradation produc ts less effectively than free thrombin. In contrast, D-Phe-ProArgCH(2) Cl, hirudin and hirugen inhibit free thrombin and thrombin bound to fi brin degradation products equally well. Conclusions-Thrombin bound to soluble fibrin degradation products is primarily responsible for the i ncrease in FPA levels that occurs when a clot undergoes t-PA-induced l ysis. Like clot-bound thrombin, thrombin bound to fibrin derivatives i s protected from inhibition by heparin but susceptible to inactivation by direct thrombin inhibitors, These findings help to explain the sup eriority of direct thrombin inhibitors over heparin as adjuncts to thr ombolytic therapy.