Summary
Inhibition of the tissue factor/factor Vila (TF/F. Vila) complex attenuates thrombosis
in different animal models of arterial thrombosis. However, it remains unclear to
what extent the antithrombotic effects are associated with changes in hemostatic functions
and how this compares with inhibition of thrombin, an enzyme acting at a later stage
in the coagulation cascade. The antithrombotic and the antihemostatic effects of a
monoclonal anti-TF antibody (AP-1) were compared in a model of arterial thrombosis
to those of a direct thrombin inhibitor (napsagatran) and heparin. In anesthetized
rabbits transient arterial thrombi were induced by mechanical damage to the subendothelium
of a moderately stenosed carotid artery. Recurrent formation and dis lodgement of
thrombi resulted in cyclic flow variations (CFVs) which were monitored over 2 hours.
Rabbits received intravenously either a placebo (control), a monoclonal anti-rabbit
TF antibody (AP-1, 05 mg/kg as an i.v. bolus repeated every 15 min, a specific low
molecular weight thrombin inhibitor (napsagatran, 3 fxg/kg/min) or heparin (3 and
13 fig/kg/min). The effect of the inhibitors on the hemostatic system was studied
in a separate set of rabbits by measuring template bleeding times (BT) in the ear
arterioles, marginal ear vein and the nail cuticle of the foreleg. AP-1 and napsagatran
showed a similar antithrombotic activity (78% and 80% abolition of the CFVs, respectively),
whereas either low or high dose heparin was poorly effective (43 % and 40% inhibition
of CFVs, respectively). At these antithrombotic doses and even at 4-fold higher dosage,
AP-1 did not significantly alter the BT, whereas napsagatran and heparin prolonged
the ear vessels and cuticle BT in a dose-dependent manner. These results suggest that
in contrast to direct thrombin inhibition, the blockade of the TF/F. Vila function
did not result in a concomitant prolongation of the bleeding time. Thus, dissociation
of antithrombotic and antihemostatic effects indicates that inhibition of the coagulation
system at its initial stage represents a promising approach for the development of
new anticoagulants.
