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Hirudin interruption of heparin-resistant arterial thrombus formation in
baboons
AB Kelly, UM Marzec, W Krupski, A Bass, Y Cadroy, SR Hanson and LA Harker
Department of Medicine, Emory University School of Medicine, Atlanta, GA.
To determine the role of thrombin in high blood flow, platelet- dependent
thrombotic and hemostatic processes we measured the relative antithrombotic
and antihemostatic effects in baboons of hirudin, a highly potent and
specific antithrombin, and compared the effects of heparin, an antithrombin
III-dependent inhibitor of thrombin. Thrombus formation was determined in
vivo using three relevant models (homologous endarterectomized aorta,
collagen-coated tubing, and Dacron vascular graft) by measuring: (1)
platelet deposition, using gamma camera imaging of 111In-platelets; (2)
fibrin deposition, as assessed by the incorporation of circulating
125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of
1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin)
maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3
+/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin
deposition in a dose-dependent manner that was profound at the highest dose
for all three thrombogenic surfaces and significant at the lowest dose for
thrombus formation on endarterectomized aorta. Thrombotic occlusion was
prevented by all doses studied. In contrast, heparin did not inhibit either
platelet or fibrin deposition when administered at a dose that maximally
prolonged clotting times (100 U/kg) (P greater than .1), and only
intermediate effects were produced at 10-fold that dose (1,000 U/kg).
Moreover, heparin did not prevent occlusion of the test segments. Hirudin
inhibited platelet hemostatic function in concert with its antithrombotic
effects (bleeding times were prolonged by the intermediate and higher
doses). By comparison, intravenous heparin failed to affect the bleeding
time at the 100 U/kg dose (P greater than .5), and only minimally prolonged
the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude
that platelet-dependent thrombotic and hemostatic processes are
thrombin-mediated and that the biologic antithrombin hirudin produces a
potent, dose-dependent inhibition of arterial thrombus formation that
greatly exceeds the minimal antithrombotic effects produced by heparin.
Volume 77,
Issue 5,
pp. 1006-1012,
03/01/1991
Copyright © 1991 by The American Society of Hematology
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