In the present study, we investigated mortality and DIC resolution in patients with sepsis-induced DIC who were treated with rTM. Comparisons between survivors and nonsurvivors showed that mortality was significantly associated with the APCHE II as well as SOFA score and PT-INR values before treatment with rTM, whereas it was not associated with the DIC score, the platelet count, or levels of FDP and CRP. After treatment with rTM, the DIC score and CRP levels significantly decreased in the total cohort, and not only in survivors but also in non-survivors. However, decreases in the DIC score and CRP levels were significantly less in nonsurvivors. Further, although the platelet count, PT-INR values, and FDP levels improved significantly after treatment with rTM in the total cohort, and also in survivors, they did not improve significantly in nonsurvivors. The DIC resolution rate was significantly higher in survivors than in nonsurvivors (78.6 % vs. 40.0 %). Comparisons between patients attaining and not attaining DIC resolution showed that DIC resolution was significantly associated with APACH II, SOFA, and DIC scores, the platelet count, and PT-INR values before treatment with rTM, but not with FDP or CRP levels. The mortality was significantly lower in patients attaining than not attaining DIC resolution (11.5 % vs. 41.7 %).
Reportedly, endothelial expressions of TM and protein C receptors were significantly reduced in patients with sepsis . Accordingly, replacement with rTM is expected to compensate for such downregulations of the endothelial thrombomodulin-protein C receptor pathway in septic patients. Although the primary anticoagulant effect of rTM is mediated by activated protein C, plasma activated protein C levels did not increase after administration of rTM in septic patients with DIC . These results suggest that activated protein C acts only locally and does not circulate systemically in response to rTM administration. Accordingly, the risk of bleeding associated with rTM could be significantly lower, compared with heparin . Indeed, we did not experience any significant adverse events related to rTM, including bleeding, in the present study.
TM, which is localized in the vascular endothelium, integrates biological pathways related to coagulation, innate immunity, and inflammation, and TM thus has anti-inflammatory as well as anticoagulation effects [5–8, 10]. In particular, the N-terminal lectin-like domain of rTM attenuates inflammation through inhibition of leukocyte adhesion to endothelial cells, inhibition of complement pathways, and degradation of HMGB 1 [8, 9]. The recombinant lectin-like domain of rTM binds to Gram-negative bacteria and lipopolysaccharides, enhances their elimination from the body, and protects the host by suppressing inflammatory responses . In the present study, CRP, which is one of the most commonly used biomarkers of infection and inflammation , significantly decreased after treatment with rTM not only in survivors and but also in nonsurvivors. These results suggested that rTM, in addition to antibiotics, played important roles in ameliorating inflammation.
In the present study, severity of sepsis indicated by APACHE II and SOFA scores before treatment with rTM was more significantly associated with mortality, compared with severity of coagulopathy indicated by the DIC score. Among coagulation-related variables examined before rTM, only PT-INR values were only marginally associated with mortality. After treatment with rTM, however, all coagulation-related variables improved significantly in survivors, but not in nonsurvivors. These results suggested that not only favorable responses of sepsis to therapies with antibiotics and rTM, but also favorable responses of DIC to them were crucial for improving the patients’ outcome.
Since the background of sepsis is highly heterogeneous, it is impossible to find one treatment to fit all situations. Therefore, clinicians have to select appropriate patients who are well suited to any supportive therapy including rTM. Using transcriptomics, a previous study classified bacterial sepsis into three subtypes, including “Inflammopathic”, “Adaptive”, and “Coagulopathic” subtypes, among which the “Coagulopathic” subtype with more significant coagulopathy was associated with higher mortality, suggesting that the early development of hypercoagulability in sepsis is associated with higher mortality . Reportedly, rTM could effectively suppress hypercoagulability indicated by increased levels of prothrombin fragment 1.2 and thrombin-antithrombin complex, compared with a placebo . Further, rTM-treated patients who had higher baseline levels of prothrombin fragment 1.2 and thrombin-antithrombin complex had lower mortality than placebo-treated patients, suggesting that rTM is effective in reducing mortality in patients with hypercoagulability . On the other hand, because the anticoagulant effects of rTM are dependent on thrombin activity in circulation, the ability of rTM to activate protein C and thus, the anticoagulant effect of rTM are expected to be reduced after thrombin depletion [5, 6]. The present study showed that patients with milder sepsis and milder coagulopathy before treatment with rTM were significantly more likely to attain DIC resolution, and patients who attained DIC resolution were associated with significantly less mortality. In this regard, diagnosing DIC in early phases of sepsis and starting treatment of DIC with rTM before depletion of coagulation factors might be crucial for inducing DIC resolution and reducing mortality in patients with sepsis-induced DIC.
This study had several limitations. First, only a small number of patients were included because of the study conducted at a single institute. Second, the data were retrospectively collected. Third, there was no control group. Because rTM therapy has been recognized as a standard treatment for sepsis-induced DIC in Japan, ethics consideration prevented us from allocating patients to a group without rTM. Alternatively, we compared coagulation- and inflammation-related variables before and after treatment with rTM. Further, we compared these variables between survivors and nonsurvivors, and between patients attaining and not attaining DIC resolution. Clearly, further studies are required to verify the efficacy of rTM in patients with sepsis-induced DIC.