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 formati on in baboon models, However, these thrombi reform when therapy is sto pped after 60 minutes, To determine if 4 hours of therapy can produce a lasting antithrombotic effect, we investigated the extent of deposit ion of In-111-labeled platelets onto 0.5-cm(2) segments of Dacron Vasc ular grafts for 53 hours. These grafts had been incorporated into exte riorized permanent femoral arteriovenous shunts in baboons. Platelet d eposition 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 decreas ed to 0.4% +/- 0.2% of injected labeled platelets after 53 hours, Afte r a thrombus was allowed to form for 15 minutes in six animals, intrav enous 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, Platel et deposition was interrupted during treatment, After infusion was sto pped, platelets accumulated again, but not as much as in the untreated animals, Maximum platelet deposition, 0.7% +/- 0.2% of injected label ed 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 a t some stage during the study, while only one shunt occluded in the tr eated animals, We conclude that 4 hours of treatment of a freshly form ed thrombus with a full antithrombotic dose of r-hirudin markedly redu ced the maximum thrombus size and the rate of initial platelet deposit ion after treatment was stopped, This approach could produce lasting b enefits in certain clinical settings. (C) 1995 by The American Society of Hematology.