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Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting
Y Takahashi1, Y Hosaka, K Imada
1Fuji Central Research Laboratory, Mochida Pharmaceutical Co. Ltd., Gotemba, Japan.
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.
Insights
Human urinary soluble thrombomodulin (MR-33) shows potent antithrombotic effects in rats, comparable to low molecular weight heparin (LMW-heparin). MR-33 demonstrates a significantly better benefit-risk ratio, indicating a reduced risk of hemorrhage during treatment for disseminated intravascular coagulation (DIC).
Area of Science:
- Pharmacology
- Hematology
- Biochemistry
Background:
- Disseminated intravascular coagulation (DIC) is a life-threatening condition characterized by abnormal blood clotting.
- Heparins are commonly used antithrombotic agents but carry a risk of hemorrhage.
- Soluble thrombomodulin is a naturally occurring anticoagulant protein.
Purpose of the Study:
- To compare the antithrombotic and hemorrhagic effects of human urinary soluble thrombomodulin (MR-33) with low molecular weight heparin (LMW-heparin) in rat models.
- To evaluate the safety profile of MR-33 in terms of bleeding risk during anticoagulation therapy.
Main Methods:
- In vitro experiments measuring activated partial thromboplastin time (APTT) prolongation.
- In vivo studies using endotoxin- or thromboplastin-induced DIC models in rats.
- Assessment of antithrombotic efficacy (Benefit: ED50) and hemorrhagic risk (Risk: bleeding time prolongation).
Main Results:
- MR-33 prolonged APTT similarly to LMW-heparin in vitro.
- MR-33 effectively treated DIC in rats without excessive APTT prolongation.
- MR-33 exhibited a superior Benefit-Risk ratio (1:27) compared to LMW-heparin (1:3) in a DIC model.
Conclusions:
- MR-33 demonstrates potent antithrombotic activity with a favorable safety profile.
- MR-33 may offer a reduced risk of hemorrhage compared to LMW-heparin for DIC treatment.
- Soluble thrombomodulin presents a promising therapeutic option for managing thrombotic disorders.