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A role for thrombomodulin in the pathogenesis of thrombin-induced
thromboembolism in mice
T Kumada, WA Dittman and PW Majerus
Department of Internal Medicine, Washington University School of Medicine,
St Louis, MO 63110.
The antithrombotic action of thrombomodulin was studied in mice. Rat and
mouse thrombomodulin were isolated from lung acetone powders, and anti-rat
thrombomodulin antibodies were prepared in rabbits. The antibodies
neutralized both mouse (Kd approximately 150 nM) and rat thrombomodulin (Kd
approximately 50 nM). A role for thrombomodulin in vivo was shown in mice
injected intravenously (IV) with thrombin. All mice injected with 15 U
thrombin (bolus) died of thromboembolism (mean survival 55 minutes),
whereas those injected with a lower dosage survived. Prior injection with
anti-rat thrombomodulin (1.8 mg IgG/mouse) potentiated the lethal effects
of subsequent thrombin, whereas injection of thrombomodulin (isolated from
mouse lung) prior to thrombin prolonged survival in a thrombomodulin
concentration-dependent manner. The protective effect of thrombomodulin
persisted for 30 minutes but after one hour thrombin injection was as toxic
as in control animals. The half life (t1/2) for plasma clearance of 125I-
mouse lung thrombomodulin was nine minutes. The major site of clearance was
the liver, although thrombomodulin accumulated in several organs ten
minutes after injection. The mechanism by which antithrombomodulin
antibodies potentiated the lethal effects of thrombin was studied by
measuring the protein C activating cofactor activity on vena cava removed
from animals injected with antibodies. Protein C activation was inhibited
by antibodies, suggesting a role for activated protein C in prevention of
lethal thromboembolism. We found no effect of antibodies on the clearance
of thrombin from mouse plasma, suggesting that blockade of endothelial
endocytosis of thrombin does not play a significant role in the effects of
antibodies. These results indicate that thrombomodulin participates in the
defense against thrombosis in vivo.
Volume 71,
Issue 3,
pp. 728-733,
03/01/1988
Copyright © 1988 by The American Society of Hematology
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