A 4-HOUR INFUSION OF RECOMBINANT HIRUDIN RESULTS IN LONG-TERM INHIBITION OF ARTERIAL-TYPE THROMBOSIS IN BABOONS

Intravenous recombinant (r)-hirudin has a potent antithrombotic effect in aspirin- and heparin-resistant platelet-dependent thrombus formation in baboon models, However, these thrombi reform when therapy is stopped after 60 minutes, To determine if 4 hours of therapy can produce a lasting antithrombotic effect, we investigated the extent of deposition of In-111-labeled platelets onto 0.5-cm(2) segments of Dacron Vascular grafts for 53 hours. These grafts had been incorporated into exteriorized permanent femoral arteriovenous shunts in baboons. Platelet deposition in eight untreated animals was generally sigmiodal. Maximum platelet deposition, 1.7% +/- 0.9% of injected labeled platelets, was reached after approximately 4 hours, Deposition then gradually decreased to 0.4% +/- 0.2% of injected labeled platelets after 53 hours, After a thrombus was allowed to form for 15 minutes in six animals, intravenous treatment with r-hirudin at a dose of 20 nmol (0.14 mg)/kg-min(-1) (aPTT > 300 seconds) was started and maintained for 4 hours, Platelet deposition was interrupted during treatment, After infusion was stopped, platelets accumulated again, but not as much as in the untreated animals, Maximum platelet deposition, 0.7% +/- 0.2% of injected labeled platelets, was significantly less (P < .01), and was reached after approximately 23 hours, Thereafter, deposition decreased to 0.4% +/- 0.2% at 53 hours, The shunts in all of the untreated animals occluded at some stage during the study, while only one shunt occluded in the treated animals, We conclude that 4 hours of treatment of a freshly formed thrombus with a full antithrombotic dose of r-hirudin markedly reduced the maximum thrombus size and the rate of initial platelet deposition after treatment was stopped, This approach could produce lasting benefits in certain clinical settings. (C) 1995 by The American Society of Hematology.