Summary
A previous study in this laboratory showed that depolymerized holothurian glycosaminoglycan
(DHG) has two different antithrombin III (ATIII)-independent inhibitory effects on
the in vitro blood coagulation system: heparin cofactor II (HCII)-dependent inhibition
of thrombin, and ATIII- and HCII-independent inhibition of factor X activation by
factor IXa-factor Villa complex (Nagase et al. Blood 85, 1527-1534, 1995). In the
present study, we compared the antithrombotic effects of DHG in normal and in ATIII-deficient
mice with those of unfractionated heparin (UFH) and low molecular weight heparin (LMWH).
DHG, unlike UFH and LMWH, exerted an in vivo antithrombotic effect even in mice with
decreased plasma ATIII activity (about 30% of normal). We then compared the anticoagulant
and antithrombotic effects of DHG in mice with those of high molecular weight (HMW)-DHG,
low molecular weight (LMW)-DHG, and dermatan sulfate (DS). In terms of in vitro anticoagulant
activity assessed by use of purified human components, DHGs (DHG, HMW-DHG, and LMW-DHG)
had different anti-thrombin activity in the presence of HCII and anti-factor Xase
activities, which differences were dependent on the molecular weight. With respect
to in vivo antithrombotic activity, DHG, HMW-DHG, and LMW-DHG showed almost the same
inhibitory effect on acute thromboembolism in mice (minimum effective dose [MED]:
>0.3 mg/kg). Since the antithrombotic activities of DHGs were not correlated with
the anticoagulant-specific activities, the contribution of the two anticoagulant activities
to the in vivo antithrombotic effect of DHGs remains unknown. However, DHG was more
effective against acute thromboembolism in mice than DS (MED >1 or >3 mg/kg), which
showed no inhibitory activity toward factor Xase. Therefore, it seems that factor
Xase inhibition contributes greatly to the antithrombotic effect of DHG and that DHG
exerts this effect in mice mainly by inhibiting factor Xase.
