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Depolymerized holothurian glycosaminoglycan with novel anticoagulant
actions: antithrombin III- and heparin cofactor II-independent inhibition
of factor X activation by factor IXa-factor VIIIa complex and heparin
cofactor II-dependent inhibition of thrombin
H Nagase, K Enjyoji, K Minamiguchi, KT Kitazato, K Kitazato, H Saito and H Kato
Taiho Pharmaceutical Co Ltd, Tokushima, Japan.
The inhibition mechanism of a polysaccharide anticoagulant, depolymerized
holothurian glycosaminoglycan (DHG), was examined by analyzing its effects
on the clotting time of human plasma depleted of antithrombin III (ATIII),
of heparin cofactor II (HCII), or of both heparin cofactors. The effect
exerted by this agent on the activation of prothrombin and factor X in
purified human components were also examined and all effects were compared
with those of other glycosaminoglycans (GAGs). The capacity of DHG to
prolong activated partial thromboplastin time was not reduced in
ATIII-depleted, HCII- depleted, HCII-depleted, or ATIII- and HCII-depleted
plasma, whereas its capacity to prolong prothrombin time and thrombin
clotting time was reduced in HCII-depleted plasma. DHG inhibited the
amidolytic activity of thrombin in the presence of HCII with a second order
rate constant of 1.2 x 10(8) (mol/L)-1 min-1. These results indicated that
DHG has two different inhibitory activities, one being an HCII-dependent
thrombin inhibition and the other an ATIII- and HCII-independent inhibition
of the coagulation cascade. The heparin cofactors- independent inhibitory
activity of DHG was investigated in the activation of prothrombin by factor
Xa and in the activation of factor X by tissue factor-factor VIIa complex
or by factor IXa. DHG significantly inhibited the activation of factor X by
factor IXa in the presence of factor VIIIa, but not in the absence of
factor VIIIa. The interaction between DHG and factors IXa, VIIIa, and X was
investigated with a DHG-cellulofine column, on which DHG had strong
affinity for factors IXa and VIIIa. These findings show that the heparin
cofactors- independent inhibition exhibited by DHG was caused by inhibition
of the interaction of factor X with the intrinsic factor Xase complex,
probably by binding to the factor IXa-factor VIIIa complex.
Volume 85,
Issue 6,
pp. 1527-1534,
03/15/1995
Copyright © 1995 by The American Society of Hematology
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