Coagulation factor Xa is the sole
enzyme responsible for activating the
zymogen prothrombin to
thrombin, resulting in
fibrin generation, platelet activation, and subsequent
thrombus formation. Our objective was to evaluate the antithrombotic efficacy of the novel
factor Xa inhibitor, 2-(3-carbamimidoyl-benzyl)-3-[(3', 4'dimethoxy-
biphenyl-4-carbonyl)-amino]-
butyric acid methyl
ester-
trifluoroacetate (
RPR208566), in a well-established rat model of arterial
thrombosis, and to compare the results with those obtained with
argatroban and
heparin, direct and indirect inhibitors of
thrombin, respectively.
Thrombus formation was initiated by placing a filter paper saturated with FeCl(2) on the adventia of the carotid artery for 10 min. Time-to-occlusion was measured from initiation of injury until blood flow reached zero. Formed thrombi were removed and weighed 60 min after the placement of the filter paper.
RPR208566,
heparin, and
argatroban dose-dependently increased time-to-occlusion and reduced
thrombus mass. When administered at 500 microgram/kg+50 microgram/kg/min,
RPR208566 prolonged time-to-occlusion to 56+/-4 min (vs. 18+/-2 min for vehicle) and reduced
thrombus mass to 3.0+/-0.7 mg (vs. 7.3+/-0.6 mg for vehicle). The highest doses of
argatroban (500 microgram/kg+50 microgram/kg/min) and
heparin (300 U/kg+10 U/kg/min) increased time-to-occlusion to the maximum of 60 min and decreased
thrombus mass to 5.5+/-0.8 and 2.6+/-0.3, respectively. The antithrombotic effects of
heparin and
argatroban at these doses were associated with increases in activated partial thromboplastin time of 5.6+/-0.9- and 2.9+/-0.3-fold over baseline, respectively. However, the highest dose of
RPR208566 produced a modest 1.3+/-0.1-fold increase in activated partial thromboplastin time. These results indicate that
factor Xa inhibition with compounds such as
RPR208566 may be an attractive mechanism for novel antithrombotic
drug therapy.