A Novel Recombinant Soluble Human Thrombomodulin, ART‐123, Activates the Protein C Pathway in Healthy Male Volunteers

Abstract

The effect of a novel recombinant soluble human thrombomodulin, ART-123, on protein C activation was investigated by measuring plasma prothrombinase activity in four healthy male volunteers. ART-123 at a dose of 0.3 mg was administered as a bolus intravenous injection for 1 minute. Plasma ART-123 concentration and prothrombinase activity were determined before and immediately, 24, and 48 hours after injection, and thromboelastography was recorded before and immediately and 24 hours after injection. The mean elimination half-life was 19.82 +/- 2.10 hours. Compared with pretreatment levels, ART-123 reduced prothrombinase activity by 44.2 +/- 11.7%, 52.1 +/- 10.8%, and 61.0 +/- 14.7%, respectively, immediately, 24, and 48 hours after injection, suggesting that ART-123 activated the protein C pathway. ART-123 did not affect thromboelastography values. There were no abnormal findings for objective signs or laboratory tests, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, coagulation and hemostatic parameters, blood chemistry, and urinalysis. Based on these observations, ART-123 at a dose of 0.3 mg can activate the protein C pathway in healthy volunteers.

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

“…To reduce the problem of increased bleeding risk with activated protein C, soluble thrombomodulin is being developed as adjunctive therapy. Recomodulin (ART-123; Asahi Kasei, Japan) is a recombinant human-soluble thrombomodulin-␣, which retains its ability to bind thrombin and activate protein C, albeit at a slower rate than its endogenous membrane-bound counterpart (262). It was successful in an industry sponsored multicenter, randomized phase III trial of 231 DIC adult patients (JMHW criteria) with malignancy or infection (338).…”

Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects

“…Approved in 2008 for human therapy in Japan, ART-123 (thrombomodulin alpha, Recomodulin) is a recombinant human soluble TM comprising extracellular domains 1-3, which are essential for the antiinflammatory and anticoagulant actions of the molecule. ART-123 has been reported to be extremely effective in the rapid resolution of DIC (69,76,115), proving safer and more effective as an inhibitor of the propagation of coagulation than traditional low-dose heparin therapy (109). ART-123 has also been used to successfully treat microangiopathies stemming from transplantation-associated sepsis (133) and Lupus-induced thrombosis (150), as well reversing the capillary leakage that accompanies "inflammatory engraftment syndrome" in individuals undergoing hematopoietic stem cell therapy (63).…”

ART‐123: Recombinant Human Soluble Thrombomodulin

“…18 thought to be affected by the level of protein C and protein S. An alternative is needed to monitor the activity of ART-123. The prothrombinase assay to detect abnormalities in the protein C anticoagulant pathway using human thrombomodulin (37) was used to measure the anticoagulant activity in plasma from volunteers administered ART-123 (32). Prothrombinase assay is sensitive to the plasma concentration of ART-123 as well as the plasma concentration of proteins C and S (32).…”