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Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation.

ABSTRACT: BACKGROUND:Anticoagulant therapy has been evaluated with respect to its potential usefulness in reducing the high mortality rates associated with severe sepsis, including sepsis-induced disseminated intravascular coagulation (DIC) after intestinal perforation. We examined the hypothesis that recombinant human soluble thrombomodulin (rhTM) is effective in the treatment of patients with septic shock with sepsis-induced DIC after laparotomy for intestinal perforation. METHODS:We performed propensity-score and instrumental variable analyses of the Japanese Diagnosis Procedure Combination in-patient database, a nationwide administrative database. The main outcome was 28-day in-hospital all-cause mortality. RESULTS:We categorized eligible patients (n?=?2202) from 622 hospitals into the rhTM group (n?=?726) and control group (n?=?1476). Propensity-score matching created 621 matched pairs of patients with and without rhTM. There was neither significant difference in 28-day mortality between the two groups in the unmatched analysis (rhTM vs. control, 25.3 vs. 23.4%, respectively; difference, 1.9%; 95% CI, -1.9 to 5.7) nor in the propensity-score-matched analysis (rhTM vs. control, 26.1 vs. 24.8%, respectively; difference, 1.3%; 95% CI, -3.6 to 6.1). The logistic analysis showed no significant association between the use of rhTM and the mortality in propensity-score-matched patients (OR, 1.1; 95% CI, 0.82-1.4). The instrumental variable analyses, using the hospital rhTM-prescribing proportion as the variable, found that receipt of rhTM was not associated with the reduction in the mortality (risk difference, -6.7%; 95% CI, -16.4 to 3.0). CONCLUSION:We found no association between administration of rhTM and 28-day mortality in mechanically ventilated patients with septic shock and concurrent DIC after intestinal perforation.

SUBMITTER: Tagami T

PROVIDER: S-EPMC4341430 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation.

Tagami Takashi T Matsui Hiroki H Fushimi Kiyohide K Yasunaga Hideo H

Frontiers in medicine 20150226

<h4>Background</h4>Anticoagulant therapy has been evaluated with respect to its potential usefulness in reducing the high mortality rates associated with severe sepsis, including sepsis-induced disseminated intravascular coagulation (DIC) after intestinal perforation. We examined the hypothesis that recombinant human soluble thrombomodulin (rhTM) is effective in the treatment of patients with septic shock with sepsis-induced DIC after laparotomy for intestinal perforation.<h4>Methods</h4>We perf ...[more]

PMID: 25767801

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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.

Dataset Information

Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation.

Publications

Use of recombinant human soluble thrombomodulin in patients with sepsis-induced disseminated intravascular coagulation after intestinal perforation.

Similar Datasets

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