Medical Science Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8426, Japan.
End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
J Thromb Thrombolysis. 2019 Jul;48(1):103-110. doi: 10.1007/s11239-019-01851-8.
A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.
直接口服抗凝剂依度沙班在治疗静脉血栓栓塞症（VTE）方面与维生素 K 拮抗剂同样有效。然而，其治疗 VTE 的作用机制仍有待确定。本研究旨在评估依度沙班对人血浆中组织型纤溶酶原激活剂（t-PA）诱导的血栓溶解的影响，并确定纤溶酶和血栓调节蛋白激活的纤溶抑制物（TAFI）在依度沙班的促纤溶作用中的作用。将混合人正常血浆或 TAFI 缺乏血浆（含有 180ng/ml t-PA 和 0.1nM 血栓调节蛋白）与依度沙班或一种活化的 TAFI 抑制剂，土豆羧肽酶抑制剂（PCI）混合。通过添加组织因子和磷脂诱导血栓形成。测定血栓溶解时间和血浆纤溶酶-α2 抗纤溶酶复合物（PAP）浓度。用扫描电子显微镜对血栓结构进行成像。在正常血浆中，临床相关浓度（75、150 和 300ng/ml）的依度沙班和 PCI 显著缩短了血栓溶解时间。PCI 增加了 PAP 浓度，并观察到 PAP 浓度与血栓溶解百分比之间存在相关性。依度沙班也呈剂量依赖性地提高了 PAP 浓度。在 TAFI 缺乏的血浆中，与正常血浆相比，依度沙班和 PCI 对血栓溶解和 PAP 浓度的影响明显减弱。在依度沙班存在的情况下形成的血栓中的纤维蛋白纤维更细。总之，在临床相关浓度下，依度沙班通过增加人血浆中纤溶酶的产生加速 t-PA 诱导的纤溶。依度沙班的作用主要依赖于 TAFI。依度沙班的促纤溶作用可能有助于其治疗 VTE 的疗效。
