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

ABSTRACT: Background:The efficacy and safety of thrombomodulin alfa (TM-?), 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-? is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC). Objective:To investigate the basis for the efficacy of TM-? 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-? 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-? and heparin treatment groups in a post hoc manner. Results:TM-? administration did not prolong activated partial thromboplastin time but significantly decreased thrombin-antithrombin complex levels compared with heparin treatment. TM-? 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-? and heparin groups during the 6-day treatment. Conclusion:TM-? 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-? treatment.

SUBMITTER: Ito T

PROVIDER: S-EPMC7590306 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Ito Takashi T Maruyama Ikuro I Shimazaki Shuji S Yamamoto Yasuhiro Y Aikawa Naoki N Hirayama Akio A Honda Goichi G Saito Hidehiko H

Research and practice in thrombosis and haemostasis 20200811 7

<h4>Background</h4>The efficacy and safety of thrombomodulin alfa (TM-α), 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-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC).<h4>Objective</h4>To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of ...[more]

PMID: 33134780

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Project description:The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti-inflammatory and cytoprotective activities in septic DIC patients.

Project description:IntroductionSince disseminated intravascular coagulation (DIC) was first described, it has been considered a serious disease of the coagulation system and a major challenge to clinicians. Currently, several important knowledge gaps remain. The DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study will aim to answer questions regarding the incidence and mortality of patients with DIC including time trends. The study will also identify prognostic factors that may guide personalised prevention and treatment. Furthermore, the study will describe treatment patterns and the safety and effectiveness of various treatment modalities.Methods and analysisWe will establish the DANDIC Cohort using data collected in daily clinical practice from the Central Denmark Region, which covers approximately 1.3 million residents. The study period will encompass 1 January 2011 through 1 July 2021. Potential DIC cases will be identified from the hospital laboratory database, based on coagulation biomarkers, and diagnoses will be adjudicated by medical experts. The dataset will be enriched with detailed clinical data from electronic medical charts on aetiologies, bleeding, microthrombus formation, organ failure, thrombosis, treatments and comorbidities. The dataset will also take advantage of in-hospital data with longitudinal information on laboratory records, transfusions, microbiology and treatments. It will be possible to merge this dataset with other unique Danish health registries with more than 10 years of virtually complete follow-up. The project will use state-of-the-art epidemiological and biostatistical methods.Ethics and disseminationThe project has been approved by the Danish Patient Safety Authority (31-1521-452), the Central Denmark Region (1-45-70-83-21), the Danish Data Protection Agency (1-16-02-258-21) and all the hospital chairs. Register-based studies require no ethical approval in Denmark. The results will be disseminated in international peer-reviewed journals.

Dataset Information

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

Publications

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

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