A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A.
A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A.
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DOI：
10.3324/haematol.2019.219865
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发表时间：
2020-09-01
期刊：
影响因子：
10.1
通讯作者：
Plantier JL
中科院分区：
文献类型：
--
作者：
Abache T;Fontayne A;Grenier D;Jacque E;Longue A;Dezetter AS;Souilliart B;Chevreux G;Bataille D;Chtourou S;Plantier JL
使凝血因子X对凝血酶敏感被认为是一种绕过对凝血因子VIII的需要的策略。在这项研究中，这一非替代策略在体外和体内被评估其纠正凝血因子VIII的能力，但也纠正了因子IX、X和XI的缺陷。在HEK293F细胞系中产生了一种新的修饰因子X，命名为肌动蛋白。该分子具有所需的翻译后修饰，部分维持其被RVV-X、因子VIIa/组织因子和因子VIIIa/因子IXa激活的能力，并获得被凝血酶激活的能力。在缺乏相应因子的血浆样本和血友病A患者的血浆样本中评估了该分子的效力，其中一些样本含有抑制剂。激活剂量依赖地纠正了所有被检测的缺陷血浆。在20μg/m L时，凝血酶的生成能够恢复正常，但滞后时间有所增加。然后在兔抗体诱导的血友病A模型中进行检测，在该模型中，与重组野生型因子X相比，它使出血时间和血红蛋白损失归一化。在所有的凝血试验中，没有观察到血栓形成的迹象，激活因子X的产生是由抗凝途径控制的。这些数据表明，肌动蛋白可能被认为是治疗血友病的一种可能的非替代因子，其优点是作为一种酶原，仅在需要时才能纠正出血。
Rendering coagulation factor X sensitive to thrombin was proposed as a strategy to bypass the need for factor VIII. In this study, this nonreplacement strategy was evaluated in vitro and in vivo for its ability to correct factor VIII but also factor IX, X and XI deficiencies. A novel modified factor X, named actiten, was generated and produced in the HEK293F cell line. The molecule possesses the required post-translational modifications, partially maintaining its ability to be activated by RVV-X, factor VIIa/tissue factor, and factor VIIIa/factor IXa and acquires the ability to be activated by thrombin. The potency of the molecule was evaluated in plasma samples with deficiencies of the respective factors and in plasma samples from patients with hemophilia A, some of which contained inhibitors. Actiten dose-dependently corrected all the deficient plasmas that were assayed. It was able to normalize the thrombin generation at 20 μg/mL although the lag time was increased. It was then assayed in a rabbit antibody-induced model of hemophilia A in which, in contrast to recombinant wild-type factor X, it normalized the bleeding time and the loss of hemoglobin. No sign of thrombogenicity was observed and the generation of activated factor X was controlled by the anticoagulation pathway in all the coagulation assays performed. These data indicate that actiten may be considered as a possible non-replacement factor to treat hemophilia, with the advantage of being a zymogen that corrects bleeding only when needed.