ATIII-independence of anticoagulant effect of human urinary soluble thrombomodulin.
We investigated antithrombin III (ATIII)-dependency of the anticoagulant effects of human urinary soluble thrombomodulin (UTM) both in vivo and in vitro, in comparison with those of heparins. For neutralization of rat plasma ATIII activity, we used F(ab')2 fragment of anti-rat ATIII antibody and could establish an appropriate in vivo model to evaluate the ATIII-dependency of antithrombotic agents. The efficacy of UTM on thromboplastin-induced disseminated intravascular coagulation produced in ATIII-decreased rats was almost the same as that in normal rats, whereas unfractionated (UF)-heparin remarkably diminished its effect in ATIII-decreased rats. The prolongation effect of UTM on activated partial thromboplastin time or prothrombin time in plasma in vitro was unchanged in both normal and ATIII-decreased rats, but the effect of UF-heparin remarkably diminished in ATIII-decreased rat plasma. Such ATIII-independence in the anticoagulant effect of UTM was also observed in human plasma. Thus, differing from heparins, since the anticoagulant effect of UTM does not depend on plasma ATIII activity, UTM is expected to be a useful antithrombotic agent for the treatment of thromboembolic diseases, even in the case with low plasma ATIII activity.
Imada
K
K
Research Center, Mochida Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan. kimada@mochida.co.jp
Takahashi
Y
Y
Hosaka
Y
Y
Adachi
T
T
Niina
H
H
Mochizuki
H
H
D000818:Animals; D000925:Anticoagulants / Q000276:immunology / Q000494:pharmacology; D000990:Antithrombin III / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001779:Blood Coagulation Factors / Q000187:drug effects; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D018180:Thrombomodulin / Q000378:metabolism*; D013925:Thromboplastin / Q000009:adverse effects; D014556:Urine / Q000737:chemistry*; D014914:Whole Blood Coagulation Time
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D007140:Immunoglobulin Fab Fragments; D018180:Thrombomodulin; D000990:Antithrombin III; D006493:Heparin; D013925:Thromboplastin