The antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys (Macaca fascicularis)

Authors:
  • YGY. Gonda
    Y. Gonda
  • MOM. Oka
    M. Oka
  • YAY. Aoki
    Y. Aoki
  • KGK. Gomi
    K. Gomi
  • TKT. Kiyota
    T. Kiyota
  • TST. Sugihara
    T. Sugihara
  • SYS. Yamamoto
    S. Yamamoto
  • TLT. Lshida
    T. Lshida
  • IMI. Maruyama
    I. Maruyama
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Abstract
We evaluated the antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) in plasma and in a monkey model. rhsTM dose-dependently prolonged activated partial thromboplastin time (APTT) in the following order: humans > monkeys > rats ≫ rabbits. The prolongation of APTT by rhsTM was also observed in protein C-deficient plasma. rhsTM activated protein C and inactivated factor Va in human and monkey plasma, but not in rat plasma. These findings suggest that the antithrombotic activities of rhsTM are fully expressed in human and monkey. Therefore, to evaluate the whole activity of rhsTM in a clinical model, tissue factor (TF) was intravenously infused into crab-eating monkeys to induce disseminated intravascular coagulation (DIC). Pretreatment with rhsTM reduced fall in fibrinogen with a biphasic and moderate dose-dependency curve, and reduced thrombin-antithrombin III (TAT) levels with a flat linear dose-dependency, while heparin prevented fall in fibrinogen with a steep linear dose-dependency curve without reducing TAT levels. Further evidence suggesting that rhsTM activates protein C in vivo was also obtained. Taken together, the data indicate that rhsTM fully expresses its antithrombotic activities in human and monkey but not in rat and rabbit, and rhsTM prevents TF-induced DIC in monkeys by suppressing thrombin generation.