Effect of thrombin inhibition on the dynamics of thrombolysis and on platelet function during thrombolytic therapy

To evaluate the effect of thrombin on the dynamics of thrombolysis, we infused rabbits with heparin or hirudin alone or in conjunction with tissue-type plasminogen activator (t-PA) and monitored the kinetics of fibrinolysis and changes in ex vivo platelet aggregation responses over time. Both heparin and hirudin enhanced total fibrinolysis in an ex vivo arteriovenous shunt preparation: 82±2% and 79±2%, respectively, compared with 51±8% for t-PA alone (p<0.05) and 50±4% for t-PA plus aspirin (p<0.05). Heparin coadministered with t-PA significantly reduced the half-time for clot lysis compared with t-PA alone (p<0.05), whereas hirudin coadministered with t-PA significantly reduced the half-time for clot lysis compared with that for t-PA alone, t-PA plus aspirin, and t-PA plus heparin (5.5±0.6 versus 12.1±2.0 versus 12.6±2.2 versus 10.0±0.8 minutes, respectively; p<0.05). Both heparin and hirudin prevented the increase in ADP-induced platelet aggregation normally seen with t-PA alone (p<0.01 by t test; p<0.05 by two-way analysis of variance). These data demonstrate that selective, antithrombin III-independent thrombin inhibitors can enhance the efficacy of thrombolysis by modulating the dynamics of the process and preventing platelet activation associated with plasminogen activator therapy.