Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxin-induced disseminated intravascular coagulation in rats.
Thrombomodulin (TM) is an endothelial cell membrane glycoprotein which neutralizes thrombin procoagulant activity and accelerates the thrombin-catalyzed activation of protein C. We expressed recombinant human soluble TM (rhs-TM) in Chinese hamster ovary cells and compared the effects of rhs-TM and heparin on endotoxin-induced experimental disseminated intravascular coagulation (DIC) in rats. Experimental DIC was induced by a continuous intravenous infusion of endotoxin for four hours. rhs-TM or heparin was infused simultaneously with endotoxin. Treatment with rhs-TM significantly reversed the endotoxin-induced changes in significantly reversed the endotoxin-induced changes in following parameters: platelet count, fibrinogen level and fibrinogen and fibrin degradation products. Furthermore, glomerular fibrin deposits elevated by endotoxin treatment were reduced by the rhs-TM administration. Heparin showed the similar effects to rhs-TM. Activated partial thromboplastin time (APTT) in rats receiving rhs-TM were slightly longer than APTT in endotoxin-treated rats, but rats receiving heparin had much more prolonged APTT. From these results, we concluded that rhs-TM may be useful for the clinical treatment of DIC while having only minor adverse effects on APTT.
Gonda
Y
Y
Institute for Life Science Research, Asahi Chemical Industry, Shizuoka, Japan.
Hirata
S
S
Saitoh
K
K
Aoki
Y
Y
Mohri
M
M
Gomi
K
K
Sugihara
T
T
Kiyota
T
T
Yamamoto
S
S
Ishida
T
T
D000818:Animals; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D005337:Fibrin / Q000032:analysis; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007678:Kidney Glomerulus / Q000737:chemistry / Q000473:pathology; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D018180:Thrombomodulin
D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D018180:Thrombomodulin; C044101:endotoxin, Escherichia coli; D005337:Fibrin; D005340:Fibrinogen