The two adverse events in the control group were gastrointestinal bleeding and respiratory tract bleeding, with both patients requiring massive blood transfusion.DiscussionThe results of this study provide www.selleckchem.com/products/SB-203580.html evidence that rhTM may have a beneficial effect on organ dysfunction in patients with sepsis-induced DIC. We have demonstrated a significant decrease in SOFA score in the rhTM group compared to the control group. In addition, Cox regression analysis indicated that 28-day mortality was significantly lower in the patients treated with rhTM than in control patients treated without rhTM.A few clinical investigations on the effects of rhTM have been reported. Saito et al. [15] showed the results of a multicenter, randomized controlled trial that examined the effects of rhTM on DIC patients.

However, there were several issues in that trial. First, there was no limitation as to the underlying disease causing the DIC in the study patients. Accordingly, DIC resulted from a hematologic malignancy in half of the patients and from sepsis in the other half. Second, the control group was treated not with a placebo, but with unfractionated heparin. Third, the primary end point was defined as DIC resolution rate, not mortality. Although these investigators demonstrated a significant improvement in the rate of DIC resolution in the rhTM group compared with the heparin group, the effects of rhTM on mortality were not significantly different in the patients with sepsis. There has been no other report in which the effects of rhTM on mortality in patients with sepsis-induced DIC were assessed.

Several animal studies have demonstrated a reduction in mortality in a severe sepsis model with the administration of rhTM. Nagato et al. [17] reported that rhTM inhibits the production of inflammatory cytokines, decreases plasma HMGB1 levels and reduces mortality in experimental endotoxemia in rats. Iba et al. [18] showed that the changes in coagulation abnormalities were reduced and that mortality was decreased by the concomitant administration of rhTM and AT in rats in which sepsis was induced by lipopolysaccharide infusion. These results suggest that rhTM plays a central role in regulating not only coagulation but also inflammation in sepsis, but the clinical mechanism of action responsible for these effects of rhTM was not fully elucidated.

Two different mechanisms have been described for the anticoagulative effects of rhTM [10,19]. One is a pathway through the production of APC, and the other is by direct binding of rhTM to thrombin to disrupt it, thus producing an anti-thrombin effect. TM is a transmembrane protein on the endothelial cell surface, and the thrombin-TM complex activates protein C to Brefeldin_A produce APC. In the presence of protein S, APC inactivates factors VIIIa and Va, thereby inhibiting further thrombin formation.