Effects of thrombomodulin alfa on hemostatic parameters in disseminated intravascular coagulation: Post hoc analysis of a phase 3 randomized controlled trial

Background: The efficacy and safety of thrombomodulin alfa (TM-alpha), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-alpha is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). Objective: To investigate the basis for the efficacy of TM-alpha in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters. Patients/Methods: The 227 patients of the full analysis set population described in the original phase 3 trial in Japan were included in this analysis. Changes in parameters between before and after TM-alpha or heparin administration in each of the two patient groups, with underlying diseases of either hematologic malignancy or infection, were studied separately and results were compared between TM-alpha and heparin treatment groups in a post hoc manner. Results: TM-alpha administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-alpha administration reduced consumption of endogenous anticoagulants such as antithrombin and protein C by DIC, compared with the heparin group. DIC scores were decreased in both TM-alpha and heparin groups during the 6-day treatment. Conclusion: TM-alpha can alleviate intravascular coagulation and consumption of anticoagulants without extending coagulation times. This may be associated with the relatively low risk of bleeding during TM-alpha treatment.