A four-hour infusion of recombinant hirudin results in long-term inhibition of arterial-type thrombosis in baboons

Abstract

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 111In-labeled platelets onto 0.5-cm2 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 sigmoidal. 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Transient Interruption of Arterial Thrombosis by Inhibition of Factor Xa Results in Long-term Antithrombotic Effects in Baboons

“…The mechanism through which this was achieved is unclear, especially in view of the fact that thrombin generation reached a maximum at 3 1 h and remained elevated until the end of the study (Table 2). Similar results were reported when direct thrombin inhibitors were used (10,23) which suggests that both thrombin and factor Xa are equally important in thrombus growth.…”

“…It has been shown that its use in vivo prevents arterial-type platelet-rich thrombus formation (5), maintains coronary artery patency following thrombolysis (8), and prevents venous thrombosis (9). However, it is not known if the antithrombotic effect exerts itself only during infusion, or, if r-TAP has an effect after treatment is stopped, similar to r-hirudin (10).…”