Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg–1 h–1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables. In contrast, hirudin, hirulog, and PPACK significantly (p <0.01) increased the percentage of the time that the vessel remained patent from 63.9 ± 7.7 to 90.7 ± 2.2, 94.0 ± 0.9, and 94.7 ± 1.0%, respectively by significantly (p <0.01) decreasing the number of reocclusions. The superiority of the antithrombin III-independent inhibitors over heparin supports the hypothesis that the limited effectiveness of heparin in this setting reflects its inability to inactivate clot-bound thrombin. Compared to saline, hirulog and PPACK also significantly (p <0.02) accelerated the time to thrombolysis from 10.5 ± 2.3 to 4.4 ± 0.6, and 4.2 ± 0.8 min, respectively, whereas heparin and hirudin did not. The ability of the lower molecular weight inhibitors of thrombin to accelerate lysis may reflect their greater accessibility to clot-bound thrombin. These findings raise the possibility that the antithrombin III-independent inhibitors of thrombin may not be equally effective as adjuncts to thrombolytic therapy with t-PA.