A synthetic pentasaccharide, representing the critical sequence required in
heparin for binding to
antithrombin III (AT III), produces strong anti-
factor Xa activity in vitro in the presence of AT III and is devoid of any activity directed towards
thrombin. This pentasaccharide provides a unique tool to study the question of whether an agent capable of inhibiting
factor Xa but devoid of anti-
factor IIa activity in vitro, has the capacity to produce an antithrombotic effect in vivo. We have previously demonstrated in a rabbit stasis
thrombosis model using a human serum challenge, a significant antithrombotic effect of the pentasaccharide. This finding and discrepancies with some earlier reports on the antithrombotic actions of other
oligosaccharide fragments, led us to extend these studies. Four modifications of the stasis
thrombosis model were developed using the following thrombogenic challenges selected for their specified induction sites of
thrombosis,
thromboplastin, an activated
prothrombin complex concentrate, a non-activated
prothrombin complex concentrate administered simultaneously with
Russell's viper venom, and
factor Xa. Dose-dependent antithrombotic responses were obtained in all four systems with ED50 values between 25-43 ug/kg for pentasaccharide as compared to 16-47 ug/kg for
heparin. Complete inhibition of induced
thrombosis was obtained in all four systems for pentasaccharide. Ex vivo analysis revealed expected anti-
factor Xa levels but no anti-
factor IIa activity. It is concluded that an
oligosaccharide with high anti-
factor Xa activity and devoid of anti-
factor IIa activity is capable of inhibiting
thrombosis induced in rabbit stasis models, but that higher dosages than
heparin are required for this effect.