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薬理と治療
Abstract
Disseminated intravascular coagulation(DIC)is a serious clinical condition that is characterizedby considerable activation of coagulation in circulating blood leading to multipleorgan failure and bleeding tendency. Recently, thrombomodulin alfa(TM alfa), a recombinanthuman soluble thrombomodulin, was approved for the treatment of DIC in Japan. In thisstudy, to address the detailed mechanisms of action with TM alfa on DIC, we examined theeffects of TM alfa and gabexate mesilate(GM)on lipopolysaccharide(LPS)-induced DICmodel in rats. Male Sprague-Dawley rats were given a single intravenous injection of LPS(5mg/kg). They were maintained with or without the treatment with 30 minutes infusion ofTM alfa(1 and 3 mg/kg)before LPS injection or GM(10 and 30 mg/kg)from 30 minutesbefore to 6 hours after LPS injection. Six and nine hours after LPS injection, blood was collectedand platelet count and plasma level of several parameters including soluble intracellularadhesion molecule-1, plasminogen activator inhibitor-1, thrombin-antithrombin Ⅲ complex,high mobility group box-1(HMGB-1), aspartate aminotransferase and alanine aminitransferasewere measured. Furthermore, we also examined the effect of TM alfa on thedecrease of plasma antithrombin activity in the model. TM alfa improved the changes ofthese parameters by LPS injection. On the other hand, GM was not effective in this model.These results suggest that TM alfa is effective against LPS-induced DIC model through suppressionof endothelial dysfunction, fibrinolysis inhibition, coagulation activation and HMGB-1 elevation, resulting in preventing the decrease of antithrombin and liver injury.
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