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Antithrombotic properties of a dermatan sulfate hexadecasaccharide
fractionated by affinity for heparin cofactor II
P Sie, D Dupouy, C Caranobe, M Petitou and B Boneu
Laboratoire d'Hemostase, Centre de Transfusion Sanguine CHU Purpan,
Toulouse, France.
The relationship between the antithrombotic activity of dermatan sulfate
(DS) in vivo and its catalytic effect on the inhibition of thrombin by
heparin cofactor II (HC II) in vitro was investigated. DS was depolymerized
by Smith degradation and the fragments obtained were separated by gel
filtration. The fragment of minimal size with full catalytic activity was a
hexadecasaccharide, which was further fractionated by affinity for
immobilized HC II. Only a small proportion by weight (6.7%) was recovered
in the high-affinity fraction, which had about 10 times more catalytic
activity than the unfractionated oligosaccharide; the change in activity
was primarily caused by the removal of inert materials, recovered in the
low-affinity fraction. 1H- NMR spectra indicated strengthening of the
signal given by Ido A (2S04) in the high-affinity fraction compared with
that of the low-affinity fraction. The anticoagulant activity of the
high-affinity fraction was exclusively HC II-dependent. The antithrombotic
potency was evaluated in rabbits using the Wessler-thromboplastin model.
Half-maximal prevention of thrombosis was obtained after injection of 250
micrograms/kg DS, of 500 micrograms/kg hexadecasaccharide, or of 60
micrograms/kg of its high-affinity fraction. The low-affinity fraction was
ineffective at the highest dose tested (1,200 micrograms/kg) and did not
potentiate the effect of the high-affinity fraction. These results show
that the antithrombotic effect of DS is essentially dependent on HC II
binding and activation and that HC II is therefore a suitable target for
antithrombotic drugs.
Volume 81,
Issue 7,
pp. 1771-1777,
04/01/1993
Copyright © 1993 by The American Society of Hematology
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