The relative importance of
antithrombin and anti-
factor Xa activities of
heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard
heparin, an octasaccharide
heparin fraction (anti-
factor Xa activity only), and
dermatan sulfate (
antithrombin activity only) on the prevention of
thrombosis and related this to their
anticoagulant effects in vivo in rabbits.
Thrombosis was measured as the incorporation of 125I-fibrinogen into
tissue thromboplastin-induced thrombi using a Wessler-type model. Ex vivo changes in
thrombin clotting time (TCT) were used as an index of
antithrombin activity, and a chromogenic anti-
factor Xa assay was used to measure anti-
factor Xa activity. In addition, the ability of the three sulfated
polysaccharides to simultaneously inhibit the generation of
thrombin activity and to enhance the inactivation of the
factor Xa added to initiate
thrombin generation in plasma was determined. Standard
heparin, in a dose of 10 anti-
factor Xa U/kg, inhibited
thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-
factor Xa level of 0.32 U/mL. The octasaccharide
heparin fraction, in a dose of 10 anti-
factor Xa U/kg, inhibited
thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-
factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-
factor Xa levels but had no further effect on
thrombus formation.
Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited
thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting
factor Xa is limited and that better antithrombotic effects are achieved by
heparin or
heparin-like substances capable of influencing the inactivation and/or the generation of
thrombin.