Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON, Canada.
Department of Biochemistry, Room 4245A Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street North, London, ON, N6A 5B7, Canada.
J Thromb Thrombolysis. 2023 Aug;56(2):283-290. doi: 10.1007/s11239-023-02837-3. Epub 2023 Jun 13.
Rivaroxaban is a direct factor Xa inhibitor, recently implemented as a favorable alternative to warfarin in anticoagulation therapy. Rivaroxaban effectively reduces thrombin generation, which plays a major role in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) to TAFIa. Based on the antifibrinolytic role of TAFIa, we hypothesized that rivaroxaban would consequently induce more rapid clot lysis. In vitro clot lysis assays were used to explore this hypothesis and additionally determine the effects of varying TAFI levels and a stabilizing Thr325Ile polymorphism (rs1926447) in the TAFI protein on the effects of rivaroxaban. Rivaroxaban was shown to decrease thrombin generation, resulting in less TAFI activation, thus enhancing lysis. These effects were also shown to be less substantial in the presence of greater TAFI levels or the more stable Ile325 enzyme. These findings suggest a role for TAFI levels and the Thr325Ile polymorphism in the pharmacodynamics and pharmacogenomics of rivaroxaban.
利伐沙班是一种直接的 Xa 因子抑制剂，最近被用作抗凝治疗中优于华法林的替代药物。利伐沙班能有效减少凝血酶生成，而凝血酶生成在凝血酶激活的纤溶抑制物（TAFI）转化为 TAFIa 中起着主要作用。基于 TAFIa 的抗纤溶作用，我们假设利伐沙班会导致更快的血栓溶解。体外血栓溶解试验用于探索这一假设，并进一步确定 TAFI 水平的变化以及 TAFI 蛋白中稳定的 Thr325Ile 多态性（rs1926447）对利伐沙班的影响。结果表明，利伐沙班可降低凝血酶生成，导致 TAFI 激活减少，从而增强溶解。在 TAFI 水平较高或更稳定的 Ile325 酶存在下，这些作用也不太明显。这些发现表明 TAFI 水平和 Thr325Ile 多态性在利伐沙班的药效学和药物基因组学中起作用。
