title: Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting bleeding time in rats: comparison with low molecular weight heparin.
abstract: We compared the antithrombotic and hemorrhagic effects of naturally existing human urinary soluble thrombomodulin (MR-33) with those of low molecular weight heparin (LMW-heparin) in rats. In in vitro experiments, MR-33 prolonged APTT in a dose-dependent fashion; its effect in this respect was as potent as that of LMW-heparin, but it was less potent than unfractionated heparin (UF-heparin). MR-33 was effective on endotoxin- or thromboplastin-induced disseminated intravascular coagulation (DIC) in rats. In both DIC models, infusion of MR-33 improved hematological abnormalities compatible with DIC in a dose-dependent, fashion without excessive prolongation effect on APTT. Although LMW-heparin and UF-heparin also improved both DIC models, excessive prolongation of APTT was observed at high doses. It is well-known that the excessive prolongation of APTT with antithrombotic drugs like heparins is an index for hemorrhage, which is a major side effect in the treatment of DIC. We therefore further compared the antithrombotic (Benefit: dose required for 50% inhibition of fibrinogen decrease: ED50) and hemorrhagic (Risk: minimum dose required for significant prolongation of bleeding time) effects of MR-33 and LMW-heparin in the thromboplastin-induced DIC model. As a result, Benefit-Risk ratio was 1:27 for MR-33 and 1:3 for LMW-heparin. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage compared with LMW-heparin.
authors.affiliation: Fuji Central Research Laboratory, Mochida Pharmaceutical Co. Ltd., Gotemba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Hosaka
authors.forename: K
authors.initials: K
authors.lastname: Imada
authors.forename: T
authors.initials: T
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Niina
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D001760:Bleeding Time; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced*; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008070:Lipopolysaccharides; D010314:Partial Thromboplastin Time; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology; D018570:Risk Assessment; D012995:Solubility; D018180:Thrombomodulin / Q000502:physiology*
chemical_list: D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D018180:Thrombomodulin