Accordingly, after controlling thrombin generation by rhTM administration, rhTM does not work in excess and generation of further rhAPC decreases. Although the clinical data on rhTM are Trichostatin A clinical limited, rhTM appears to result in fewer bleeding complications than rhAPC. In the phase III trial of rhTM in Japan, the incidence of bleeding complications was lower in the rhTM group than in the heparin group (P = 0.0487) [15]. In the present study, there was no increase of adverse events related to bleeding in the rhTM group compared with the control group. In the one patient in the rhTM group with cerebral hemorrhage, the cause-and-effect relationship between administration of rhTM and hemorrhage was not clear. Because of the small sample size of this study, future investigation into bleeding complications of patients treated with rhTM is required.

We acknowledge several limitations of our observational study design. First, this study was not a randomized controlled trial, and we compared the rhTM treatment group with a historical control group. Multiple unmeasured variables might account for the outcome differences observed in this study. Second, a small number of patients were included in this study. Third, this study was carried out in a single institution. Further multicenter, prospective, randomized trials are needed to thoroughly evaluate the effects of rhTM on the treatment of sepsis-induced DIC.ConclusionsIn conclusion, we found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC, as demonstrated by the significant reduction in SOFA score.

Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.Key messages? rhTM administration may improve organ dysfunction due to severe sepsis as demonstrated by the significant reduction in SOFA score.? Additional well-designed intervention studies are urgently needed to prove the clinical effectiveness and safety of rhTM.AbbreviationsANOVA: analysis of variance; APACHE: Acute Physiology and Chronic Health Evaluation; APC: activated protein C; AT: antithrombin; CRP: C-reactive protein; DIC: disseminated intravascular coagulation; FDP: fibrinogen degradation products; HMGB1: high-mobility group box 1 protein; ICU: intensive care unit; IL: interleukin; LOCF: last observation carried forward; PROWESS: Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; rhAPC: recombinant human activated protein C; rhTM: recombinant human soluble thrombomodulin; SOFA: Sequential Organ Failure Assessment; TM: thrombomodulin.

Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsKY participated in study design and data collection and interpretation, performed the statistical analysis and drafted the manuscript. SF conceived the study and its design Entinostat and helped to draft the manuscript.