Bleeding time prolongation and bleeding during infusion of recombinant tissue-type plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin

Cardiac Division, Massachusetts General Hospital, Boston 02114.

Thrombolytic therapy is associated with a bleeding tendency that may be exacerbated by adjunctive antiplatelet agents. The effect of recombinant tissue-type plasminogen activator (rt-PA) alone or in combination with aspirin on serial measurements of template bleeding time, ex vivo platelet aggregation and coagulation factors and the frequency of bleeding was studied in dogs. During infusion of rt-PA (15, 30 or 60 micrograms/kg per min for 90 min), a dose-related increase in bleeding time was observed. In a randomized blinded study of 25 dogs, the baseline bleeding time (mean +/- SD) was 3.5 +/- 1 min in control animals and 4 +/- 2 min after oral aspirin (15 mg/kg body weight). Infusion of rt-PA (15 micrograms/kg per min for 90 min) prolonged the bleeding time to a maximum of 15 +/- 12 min. In contrast, combined aspirin and rt-PA therapy produced an increase to greater than 30 min during infusion, reverting to 13 +/- 10 min within 2 h after cessation of infusion. Recurrent continuous bleeding from incision sites occurred in one of six dogs given aspirin alone, two of seven given rt-PA alone and all six dogs given both aspirin and rt-PA (p = 0.02). Bleeding time greater than 9 min correlated significantly with bleeding frequency (p less than 0.0001), with a sensitivity of 100% and a specificity of 87%. Intravenous bolus injection of aprotinin (20,000 kallikrein inhibitor units/kg body weight) in six dogs given both rt-PA and aspirin produced a decrease in bleeding time from greater than 30 min to 9.5 +/- 9 min and resulted in cessation of bleeding. Thus, bleeding and bleeding time prolongation in this canine model are potentiated by a marked interactive effect of rt-PA and aspirin that is rapidly reversible. Template bleeding times may provide a useful quantitative index for monitoring the bleeding tendency associated with thrombolytic therapy.

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