Thrombomodulin (TM), a membrane-bound receptor for
thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the
anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of
thrombin, but also the
thrombin generation via accelerating the
thrombin-catalyzed
protein C activation. In rat
disseminated intravascular coagulation (
DIC) models,
intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of
fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the
anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on
heparin-resistant
DIC models with low AT III level in rats.
Intravenous injection of MR-33 prevented the
endotoxin-induced increases in TAT,
TNF-alpha and
IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful
antithrombotic agent with reduced risk for
hemorrhage, and this
drug also has anti-inflammatory effects. Clinical trials of MR-33 for the treatment of
DIC are now in progress in Japan.