Dataset Information

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

ABSTRACT:

Background

Recombinant human soluble thrombomodulin (rTM) has been used for the treatment of disseminated intravascular coagulation in Japan, and an international phase III clinical trial for rTM is currently in progress. rTM mainly exerts its anticoagulant effects through an activated protein C (APC)-dependent mechanism, but the circulating APC levels after rTM treatment have not been clarified. This prospective observational study investigated plasma APC levels after rTM treatment.

Methods

Plasma levels of soluble thrombomodulin, thrombin-antithrombin complex (TAT), protein C, and APC were measured in eight septic patients treated with rTM. APC generation in vitro was assessed in the presence or absence of rTM.

Results

rTM significantly increased thrombin-mediated APC generation in vitro. In septic patients, soluble thrombomodulin levels were significantly increased during a 30-60-min period of rTM treatment and TAT levels were decreased. However, APC activity was not increased during the treatment period.

Conclusions

Plasma APC activity is not increased in septic patients treated with rTM. It is possible that APC acts locally and does not circulate systemically.

SUBMITTER: Arishima T

PROVIDER: S-EPMC6161343 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

Arishima Takuro T Ito Takashi T Yasuda Tomotsugu T Yashima Nozomi N Furubeppu Hiroaki H Kamikokuryo Chinatsu C Futatsuki Takahiro T Madokoro Yutaro Y Miyamoto Shotaro S Eguchi Tomohiro T Haraura Hiroyuki H Maruyama Ikuro I Kakihana Yasuyuki Y

Thrombosis journal 20180928

<h4>Background</h4>Recombinant human soluble thrombomodulin (rTM) has been used for the treatment of disseminated intravascular coagulation in Japan, and an international phase III clinical trial for rTM is currently in progress. rTM mainly exerts its anticoagulant effects through an activated protein C (APC)-dependent mechanism, but the circulating APC levels after rTM treatment have not been clarified. This prospective observational study investigated plasma APC levels after rTM treatment.<h4> ...[more]

PMID: 30275773

Similar Datasets

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:ObjectivesTo assess the effects of recombinant human soluble thrombomodulin treatment on 28-day all-cause mortality in subgroups categorized by baseline coagulation biomarker levels (prothrombin fragment 1.2, thrombin-antithrombin complex, D-dimer) in patients with sepsis-associated coagulopathy in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial (SCARLET) (NCT01598831).DesignPost hoc, subgroup analysis of a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study.SettingICUs at 159 sites in 26 countries.PatientsEight-hundred adults with sepsis-associated coagulopathy defined as international normalized ratio greater than 1.40 and platelet count between 30 × 10/L and 150 × 10/L or greater than 30% decrease within 24 hours with concomitant cardiovascular and/or respiratory failure.InterventionsPatients randomized and treated with recombinant human soluble thrombomodulin (0.06 mg/kg/d; n = 395) or equivalent placebo (n = 405) for 6 days.Measurements and main resultsRecombinant human soluble thrombomodulin did not significantly reduce 28-day all-cause mortality in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial: absolute risk reduction was 2.55% (p = 0.32) in patients with sepsis-associated coagulopathy. In this post hoc analysis, mortality steadily increased with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex levels in the placebo group; for those values exceeding the upper limit of normal, the mortality increases in the recombinant human soluble thrombomodulin group were lower or negligible with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex. Consequently, absolute risk reductions were greater in subgroups with higher baseline prothrombin fragment 1.2 or thrombin-antithrombin complex. Absolute risk reductions were also greater in subgroups with baseline coagulation biomarker levels at or above median of the entire study population, ranging from 4.2% (95% CI, -5.0% to 13.4%) to 5.5% (95% CI, -4.0% to 14.9%).ConclusionsCompared with patients receiving placebo, patients treated with recombinant human soluble thrombomodulin having higher baseline thrombin generation biomarker levels had lower mortality. Further research regarding the predictive role of coagulation biomarkers for recombinant human soluble thrombomodulin treatment response in sepsis-associated coagulopathy is warranted to evaluate clinical relevance.

Dataset Information

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

Background

Methods

Results

Conclusions

Publications

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

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