Medical Science Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8426, Japan.
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, 103-8426, Japan.
J Thromb Thrombolysis. 2021 Jul;52(1):9-17. doi: 10.1007/s11239-021-02381-y. Epub 2021 Feb 3.
Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
感染通过激活炎症和凝血增加血栓形成的风险。依度沙班是一种直接口服的 Xa 因子抑制剂，用于预防和治疗血栓性疾病。本研究旨在确定依度沙班对脂多糖（LPS）诱导的凝血功能障碍大鼠模型中小血管血栓形成的影响。大鼠静脉注射 7.5mg/kg LPS（大肠杆菌 055：B5）。LPS 注射后立即给予皮下注射依度沙班。在 LPS 注射后 2 和 6 小时，测量凝血和器官损伤的生物标志物以及炎症细胞因子。使用 I-纤维蛋白原（人）或通过病理分析评估器官中小血管血栓形成。在 LPS 注射后 24 小时检查死亡率。注射 LPS 后，D-二聚体和凝血酶抗凝血酶复合物增加，血小板数量减少，表明凝血激活。在肝脏中发现了微血栓。肝损伤标志物（天冬氨酸转氨酶和丙氨酸转氨酶）也增加。依度沙班治疗减轻了凝血标志物的变化和肝脏中的微血管血栓形成。依度沙班抑制了肝损伤标志物的增加，并降低了死亡率。依度沙班对炎症细胞因子水平没有影响。总之，依度沙班显著抑制了凝血的激活、肝脏中小血管血栓形成和肝损伤，并降低了 LPS 注射大鼠的死亡率。这些结果表明，依度沙班对 FXa 的抑制可能是治疗感染相关血栓形成的有益疗法。
