Article ; Online: A mutated factor X activatable by thrombin corrects bleedings in vivo in a rabbit model of antibody-induced hemophilia A.
2020 Volume 105, Issue 9, Page(s) 2335–2340
Abstract: Rendering coagulation factor X sensitive to thrombin was proposed as a strategy that can bypass the need for factor VIII. In this paper, this non-replacement strategy was evaluated in vitro and in vivo in its ability to correct factor VIII but also ... ...
| Abstract | Rendering coagulation factor X sensitive to thrombin was proposed as a strategy that can bypass the need for factor VIII. In this paper, this non-replacement strategy was evaluated in vitro and in vivo in 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 keeps its ability to be activated by RVV-X, factor VIIa/tissue factor, factor VIIIa/factor IXa and acquires the ability to be activated by thrombin. The potency of the molecule was evaluated in respective deficient plasmas or hemophilia A plasmas, for some with inhibitors. Actiten corrects dose dependently all the assayed deficient plasmas. It is able to normalize the thrombin generation at 20 μg/mL showing however an increased lagtime. It was then assayed in a rabbit antibody-induced model of hemophilia A where, in contrast to recombinant factor X wild-type, 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 performed coagulation assays. This data indicates that Actiten may be considered as a possible non replacement factor to treat hemophilia's with the advantage of being a zymogen correcting bleedings only when needed. |
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| MeSH term(s) | Animals ; Factor IX ; Factor VIII/genetics ; Factor VIIa ; Factor X/genetics ; Hemophilia A/drug therapy ; Hemophilia A/genetics ; Rabbits ; Thrombin |
| Chemical Substances | Factor VIII (9001-27-8) ; Factor IX (9001-28-9) ; Factor X (9001-29-0) ; Factor VIIa (EC 3.4.21.21) ; Thrombin (EC 3.4.21.5) |
| Language | English |
| Publishing date | 2020-09-01 |
| Publishing country | Italy |
| Document type | Journal Article |
| ZDB-ID | 2333-4 |
| ISSN | 1592-8721 ; 0017-6567 ; 0390-6078 |
| ISSN (online) | 1592-8721 |
| ISSN | 0017-6567 ; 0390-6078 |
| DOI | 10.3324/haematol.2019.219865 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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