There are concerns that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. We have shown that low-dose administration of a direct thrombin inhibitor, melagatran, significantly worsens the coagulation status induced by tissue factor injection in rats. We compared the effect of inhibition of thrombin and factor Xa for their potential to aggravate tissue factor-induced coagulation in rats. Hypercoagulation was induced by the injection of 2.8 U/kg tissue factor after administration of melagatran, heparin and edoxaban in rats. Blood samples were collected 10min after tissue factor injection. Platelet numbers, thrombin-antithrombin complex concentrations and plasma compound concentrations were measured. Though a high dose of melagatran (1mg/kg, i.v.) suppressed platelet consumption and thrombin-antithrombin complex generation induced by tissue factor, lower doses of melagatran (0.01, 0.03 and 0.1mg/kg, i.v.) significantly enhanced platelet consumption and thrombin-antithrombin complex generation. In addition, although melagatran (3mg/kg, i.v.) improved coagulation status when tissue factor was given 5min after the drug administration, and 2, 4 and 8h after melagatran dosing, it deteriorated coagulation status. These results were well explained by the plasma melagatran concentration. Low concentrations (15-234ng/ml) of melagatran aggravated coagulation status whereas it was mended by high concentrations (1190ng/ml or more) of the compound. In contrast, edoxaban and heparin did not show any exacerbation under these examination conditions. These results show that subtherapeutic concentrations of melagatran are associated with coagulation pathway activation, whereas factor Xa inhibition with edoxaban has a low risk of paradoxical hypercoagulation.

译文

:有人担心在某些情况下某些抗凝剂会反常增加血栓形成。我们已经显示,直接凝血酶抑制剂美拉加群的低剂量给药显着恶化了大鼠组织因子注射诱导的凝血状态。我们比较了凝血酶和凝血因子Xa抑制其加重组织因子诱导的大鼠凝血的作用的效果。在大鼠中施用美拉加群,肝素和依多沙班后,通过注射2.8 U / kg组织因子诱导高凝。组织因子注射后10分钟收集血样。测量血小板数,凝血酶-抗凝血酶复合物浓度和血浆化合物浓度。尽管高剂量的美拉加群(1mg / kg,iv)抑制了组织因子诱导的血小板消耗和凝血酶-抗凝血酶复合物的产生,但低剂量的美拉加群(0.01、0.03和0.1mg / kg,iv)显着增加了血小板的消耗和凝血酶-抗凝血酶复合物的产生。另外,尽管在药物给药后5分钟,给药后2、4和8小时给予组织因子,美拉加群(3mg / kg,i.v。)改善了凝血状态,但是其恶化了凝血状态。血浆三聚氰胺浓度很好地解释了这些结果。低浓度(15-234ng / ml)的美拉加群加剧了凝血状态,而高浓度(1190ng / ml或更高)的化合物改善了凝血状态。相反,依多沙班和肝素在这些检查条件下未显示出任何恶化。这些结果表明美拉加群的亚治疗浓度与凝血途径激活有关,而用edoxaban抑制因子Xa具有较低的矛盾性高凝风险。

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