THROMBIN GENERATION IN PATIENTS WITH ACUTE MYOCARDIAL-INFARCTION TREATED WITH FRONT-LOADED RT-PA AND RECOMBINANT HIRUDIN (HBW-023)

Thrombin contributes to the pathogenesis of acute myocardial infarctio n and reocclusion after thrombolysis. Thrombolytic therapy is known to induce a paradoxic increase in thrombin generation. Specific thrombin inhibition enhances thrombolytic therapy in experimental models. The aim of this study was to determine thrombin generation in patients wit h acute myocardial infarction treated with rt-PA and conjunctive thera py with the specific thrombin inhibitor, recombinant hirudin. Thrombin generation was determined in 17 patients with acute myocardial infarc tion treated with front-loaded rt-PA (100 mg/90 min) and conjunctive t herapy with recombinant hirudin (HBW 023 bolus 0.4 mg/kg, infusion of 0.15 mg/kg/h) over 48 hours. Mean free hirudin plasma levels of 1320-1 545 ng/mL produced a stable anticoagulation with mean aPTT values betw een 63 and 81 seconds throughout the treatment period. Thrombin genera tion increased during thrombolysis, indicated by a transient elevation of prothrombin fragment 1.2 levels, which were 3.0 nmol/L at baseline , 11.1 nmol/L after 30 minutes, 8.3 nmol/L after 60 minutes, 3.1 nmol/ L after 12 hours, and 1.5 nmol/L after 24 hours, respectively. In cont rast, thrombin-antithrombin IPI complex levels during and after thromb olysis did not exceed the baseline level of 21.8 ug/L. Thrombin-hirudi n complex levels increased constantly during the 48-hour treatment per iod from 3.1 ug/L at baseline to 64.2 ug/L. All patients had an open i nfarct vessel (TIMI 2/3 potency) after 36-48 hours. Thrombolysis with rt-PA is associated with a significant increase in thrombin generation , which is not blocked by r-hirudin, whereas circulating thrombin seem s to be effectively inhibited by r-hirudin.