In vivo effects of unfractionted heparin (UFH), MD-805 (argatroban, factor IIa inhibitor), DX-9065a (synthetic Xa inhibitor) were evaluated in a highly thrombogenic venous graft model.
A woven Dacron tube graft (3 cm long, 3 mm inner diameter) was interposed in the inferior vena cava of rabbits. All the grafts were completely occluded within five hours after a bolus injection of heparin (50U/kg) given just prior to the grafting
The
following agents were continuously given during 2 hours after the bolus injection of heparin ot the three groups respectively, i.e. UFH group (50 U/kg/hr, heparin), DX group (0.05mg/kg/hr, DX-9065a yielding a comparable anti-Xa activity with UFH
group),
MD group (32μg/kg/hr, MD-805, argatroban, yielding a comparable anti-IIa activity with UFH group). Five hours after the bolus injection of heparin, the patency was examined and the grafts were harvested for histological evaluation. During the 5
hour
observation period, the anti-Xa activities in blood were not significantly different betweer. the UFH and MD groups. The rates of graft patency in the DX group (4/4) and the MD group (4/4) were significantly better than that in the UFH group
(3/10).
Ultrastructural analysis of the luminal surface of the harvested graft by scanning electron microscopy revealed a reduced formation of fibrin networks entrapping erythrocytes in the DX group and MD group in comparison with the patient UFH group.
In conclusion, factor IIa inhibitor and ractor Xa ihbibitor exerted more potent in vivo antithrombotic effect than UFH. Their superior antithrombotic effects over heparin may be due to their smaller molecular size, which allows it better access
to
the
sites of local thrombin generation.
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