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Management of disseminated intravascular coagulation: current insights on antithrombin and thrombomodulin treatments.

ABSTRACT: Sepsis and septic shock are frequently complicated by disseminated intravascular coagulation (DIC), which decreases the survival rate of patients with sepsis. In the past, large international randomized controlled trials (RCTs) using physiological anticoagulants for sepsis-induced DIC were not performed; however, RCTs have been conducted for sepsis and/or septic shock. In these trials, physiological anticoagulants did not show any beneficial effects compared with placebo for the treatment of sepsis and/or septic shock. In Japan, DIC treatments using antithrombin (AT) and/or recombinant human soluble thrombomodulin (rhTM) are common for patients with sepsis-induced DIC. Recently, large propensity score analyses demonstrated that AT and rhTM improved survival in patients with sepsis-induced DIC. Furthermore, post hoc analyses and meta-analyses that selected patients with sepsis-induced DIC from the previous large international RCTs indicated that physiological anticoagulants improved survival without increasing the associated sepsis-induced DIC bleeding. DIC treatments, such as AT and rhTM, may demonstrate beneficial effects when they are targeted at patients with sepsis-induced DIC only.

SUBMITTER: Hayakawa M

PROVIDER: S-EPMC5749552 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Management of disseminated intravascular coagulation: current insights on antithrombin and thrombomodulin treatments.

Hayakawa Mineji M

Open access emergency medicine : OAEM 20171228

Sepsis and septic shock are frequently complicated by disseminated intravascular coagulation (DIC), which decreases the survival rate of patients with sepsis. In the past, large international randomized controlled trials (RCTs) using physiological anticoagulants for sepsis-induced DIC were not performed; however, RCTs have been conducted for sepsis and/or septic shock. In these trials, physiological anticoagulants did not show any beneficial effects compared with placebo for the treatment of sep ...[more]

PMID: 29343993

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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:BackgroundDisseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model.MethodWe searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study.ResultsWe analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I2 values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I2 value 55%).ConclusionsAlthough the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results.Trial registrationThis study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).

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Management of disseminated intravascular coagulation: current insights on antithrombin and thrombomodulin treatments.

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Management of disseminated intravascular coagulation: current insights on antithrombin and thrombomodulin treatments.

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