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The accompanying paper (Nagashima, H. (2002) J. Biol. Chem. 277, 50439 -50444) has demonstrated that argatroban can yield a stronger inhibitory effect on thrombin generation than DX-9065a during extrinsic pathway-stimulated human plasma coagulation, while these anticoagulant compounds have comparable abilities to prolong clot time. Since thrombin generation is known to be an important determinant for fibrinolytic resistance of clots formed during coagulation, the two compounds are compared by tissue plasminogen activator-induced clot lysis assays. The results demonstrated that, in the presence of thrombomodulin, argatroban dose dependently accelerated fibrinolysis of the clots, whereas DX-9065a did not. The activation of thrombin activatable fibrinolysis inhibitor (TAFI) determined in separate assays reflected the differential influence on thrombin generation by these compounds. Moreover, TAFI activation correlated closely with the fibrinolytic resistance observed during tissue plasminogen activator-induced clot lysis. This study demonstrates the differential effects of DX-9065a and argatroban on thrombin generation, which in turn results in a differential acceleration of fibrinolysis as well as TAFI activation in the clots formed under the influence of these compounds. The data implicate a possible difference in the antifibrinolytic properties of clots formed during treatment with these compounds.Thrombin plays a central role in thrombosis and hemostasis. While only a small amount of prothrombin is activated at the moment of clotting, the remaining prothrombin is activated predominantly after clot formation (1). These observations are consistent with the recently proposed notion (2) that activation of the extrinsic pathway is responsible for the rapid generation of a small amount of thrombin, which is sufficient for clot formation; however, activation of the intrinsic pathway is responsible for a massive production of thrombin mostly after clot formation, which effectively augments the antifibrinolytic properties of the clot. Such an intrinsic pathway-mediated thrombin burst is critically dependent on a feedback activation mechanism mediated by thrombin-catalyzed activation of factor XI (3, 4). TAFI1 is a zymogen that plays a key role in the regulation of fibrinolysis. During coagulation, TAFI is proteolytically activated by thrombin in a TM-dependent manner to its active form, TAFIa, which inhibits fibrinolysis by removing the carboxyl-terminal lysine and arginine residues from partially degraded fibrin (5, 6). As activation of TAFI requires exposure to relatively high concentrations of thrombin, the intrinsic pathway-mediated thrombin generation plays a pivotal role in the regulation of fibrinolysis (7).The accompanying paper (8) demonstrates the differential actions on thrombin generation by two different anticoagulant protease inhibitors DX-9065a (9) and argatroban (10). Both theoretical and experimental approaches (8) revealed that the thrombin inhibitor, argatroban, yielded a stronger inhibitory effect on...

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