Th particular attention to bleeding. 2) LMWH Only dalteparin is approv…

Th particular attention to bleeding. 2) LMWH Only dalteparin is approved for DIC in Japan. A multicenter double-blind study on 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one DIC reported that dalteparin reduced the occurrence of organ failure, alleviated bleeding symptoms, and showed higher safety PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14960617 compared with UFH [267]. 3) DS A multicenter randomized study demonstrated that DS showed no significant differences in both effects and safety in DIC as compared with UFH [268]. 4) Antithrombin The 2008 SSCG recommended that antithrombin should not be used in the treatment of severe sepsisOda et al. Journal of Intensive Care 2014, 2:55 http://www.jintensivecare.com/content/2/1/Page 21 ofand septic shock. As an evidence for this statement, the guidelines referred to a large-scale prospective RCT on high-dose antithrombin (KyberSept study) in adult patients with severe sepsis and septic shock, which reported in 2001 that antithrombin did not bring beneficial effects on all-cause 28-day mortality and that concomitant use of heparin increased the risk of bleeding [266]. However, a subgroup analysis in 2006 reported that antithrombin reduced the 90-day mortality in septic patients without a concomitant use of heparin [269]. Furthermore, in severe sepsis patients complicated with DIC, antithrombin was reported to improve the 90-day outcome [270]. In Japan, according to expert consensus opinion in light of the above reports [269,270], the use of antithrombin alone (without concomitant heparin) is 4-Bromo-5-nitro-1H-indazole recommended, although weakly, in septic patients complicated with DIC [264]. However, the dose of antithrombin in the KyberSept study is extremely high compared with those used in Japan; therefore, care must be taken in interpreting the results even in subgroup analysis. 5) Thrombomodulin Thrombomodulin activates protein C through the generation of the thrombin-thrombomodulin complex and exert the effect of activated protein C (APC) in vivo [271]. rhTM is an agent developed as a soluble protein containing extracellular domain that is required for the expression of the PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/13485127 function of thrombomodulin. rhTM reversibly binds with thrombin to form a complex that activates protein C. Furthermore, APC in combination with protein S inactivates coagulation factor Va and factor VIIIa, resulting in the suppression of further production of thrombin [265,271]. In addition to its anticoagulatory effect, thrombomodulin has antifibrolytic effects through the activation of the thrombin-activatable fibrinolysis inhibitor [272]. Furthermore, rhTM is reported to adsorb HMGB-1, neutralize and degrade the adsorbed HMGB-1, and suppress HMGB-1-mediated inflammatory responses through receptor for advanced glycation end products (RAGE). Furthermore, rhTM was reported to bind lipopolysaccharide; thus, rhTM has expedient pharmacologic properties as a therapeutic drug for septic DIC [273]. A multicenter double-blind RCT comparing rhTM and heparin groups was conducted in 234 patients with DIC. As a result, the improvement rate of DIC was 66.1 in the rhTM group and 49.9 in the heparin group. Also, this trial reported that the rhTM group showed improvement in the clinical manifestation of bleeding and DIC as compared with the heparin group ijms17122034 [265]. In addition, it has been reported thatthe 28-day mortality was significantly lower in the rhTM group than in historical controls in mechanically ventilated septic patients complicated with DIC [274]. CQ5: Are protease inhibitors effective for septic DIC? A5: Synthetic protease inhibitors (SPIs).