ART‐123: Recombinant Human Soluble Thrombomodulin

Abstract

ART-123 is a soluble form of recombinant human thrombomodulin comprising all extracellular domains of thrombomodulin. Bound to thrombin, ART-123 inhibits its procoagulant activity and promotes activation of protein C. ART-123 inhibits thrombin generation by the activation of protein C and the subsequent inactivation of factor Va in the presence of protein S. ART-123 attenuates the extension of the clot by inhibiting further thrombin generation on clots, while other anticoagulants inhibit the initiation of clot formation. A higher concentration of ART-123 is needed to affect clotting time and platelet aggregation than thrombin generation. Intravenous administration of ART-123 is effective in animal models of disseminated intravascular coagulation (DIC), AV-shunt, and other models with a wider safety margin than conventional anticoagulants. The plasma half-life of ART-123 is long, especially on subcutaneous injection. Clinical studies have been performed or are planned to evaluate the efficacy of ART-123 in DIC and deep venous thrombosis (DVT). In clinical trials against DIC ART-123 was well tolerated and showed a good dose-response effect. These findings suggested that ART-123 is a promising drug for thrombotic diseases.

Antiinflammatory and Anticoagulant Effects of Transgenic Expression of Human Thrombomodulin in Mice

“…The antiinflammatory effect of TBM was apparent as a significant reduction in IVC wall leukocyte infiltration in the hTBM-Tg mice at 24 and 48 h. Given that the actual clot burden was not different at these times, a direct antiinflammatory effect of hTBM is implicated. This is consistent with the effect obtained using rhs-TBM in models of DIC (45). The antiinflammatory effect inherent to TBM was further substantiated in a model of LPS sepsis.…”

Non‐fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX

“…One likely possibility is that the high s-TM levels reflect endothelial damage, as has been described in, for example, sepsis [13], diabetes mellitus [14], and possibly also in patients experiencing a major bleeding complication. The second possibility is that the high s-TM levels facilitate the anticoagulant action of activated protein C at the site of vascular injury [15] that would potentiate the poor procoagulant state that results from VKA therapy, and thus increases bleeding risk. Obviously, the two mechanisms may also act simultaneously.…”

Effective Control of Relapsing Disseminated Intravascular Coagulation in a Patient with Decompensated Liver Cirrhosis by Recombinant Soluble Thrombomodulin

“…However, repeated treatments with rhsTM were effective, and antibodies against rhsTM were not detected, indicating that, regardless of the Child-Pugh score, rhsTM can be an effective and safe treatment for DIC in patients with liver cirrhosis. The anticoagulant effect of rhsTM is influenced by the plasma level of protein C (being especially effective when the level is >10% of the normal level) (11). The plasma level of protein C in this patient decreased to 19-32% before the initiation of the administration of rhsTM, and the administration of rhsTM improved the DIC without the need for additional administration of fresh-frozen plasma.…”

“…Patients with liver cirrhosis usually demonstrate prolonged PT-INR and decreased AT III. The anticoagulant effect of rhsTM is not influenced by the plasma level of AT III (11). This patient showed a prolonged PT-INR and decreased AT III (approximately 50% of normal), but rhsTM was effective without requiring the administration of fresh-frozen plasma and AT III concentrate.…”