The endogenous thrombin potential and high levels of coagulation factor VIII, factor IX and factor XI

SummaryThe gene encoding murine coagulation factor X (fX) was isolated and characterized from a λFIX II library generated from murine genomic DNA. The 20130 bp sequence contains 18049 nucleotides that extend from the initiating methionine to the polyadenylation site. 1056 nucleotides 5’ of the start codon were determined and contain putative start sites for the FX mRNA as well as sites for binding of putative transcription factors. The sequence extends 1024 3’ of the polyadenylattion site.The gene contains 8 exons and 7 introns which were determined by comparing the mouse FX cDNA and gene sequences. The exonic structure of the gene is similar to that of the other mammalian vitamin K-dependent serine proteases of the coagulation system. These include an exon encoding the prepropepetide, the gladomain, a short helical stack, two exons for the two EGF domains, the activation pepetide, and two exons encoding the serine protease domain. The 5’ sequence of the mouse FX gene overlaps with the 3’ region of the FVII gene indicating that the murine FVII and FX gene are arranged in a head to tail arrangement as they are in humans. Abbreviations: fVII, coagulation factor VII; fIX, coagulation factor IX; fX, coagulation factor X; PC, Protein C; fV, coagulation factor V; fVa, activated coagulation factor V; fVIII, coagulation factor VIII; fVIIIa, activated coagulation factor VIII.

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Summary of the WHO hearing on the development of product-specific reference materials for coagulation factor VIII and factor IX products

Biologicals ◽

10.1016/j.biologicals.2020.07.009 ◽

2020 ◽

Vol 67 ◽

pp. 88-93

Author(s):

Mikhail V. Ovanesov ◽

Stella C. Williams ◽

C.Micha Nübling ◽

Johannes Dodt ◽

Anneliese Hilger ◽

...

Keyword(s):

Factor Viii ◽

Reference Materials ◽

Coagulation Factor ◽

Factor Ix ◽

Coagulation Factor Viii ◽

Specific Reference

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Orphan designation: Adeno-associated viral vector serotype 5 containing a B-domain deleted variant of human coagulation factor VIII gene, Treatment of haemophilia A

Case Medical Research ◽

10.31525/cmr-3996ed ◽

2018 ◽

Author(s):

Keyword(s):

Factor Viii ◽

Viral Vector ◽

Coagulation Factor ◽

Coagulation Factor Viii ◽

Haemophilia A ◽

Factor Viii Gene ◽

Orphan Designation ◽

Gene Treatment ◽

Serotype 5

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Orphan designation: Recombinant human coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein, Treatment of haemophilia A

Case Medical Research ◽

10.31525/cmr-1f3d2fd ◽

2019 ◽

Author(s):

Keyword(s):

Fusion Protein ◽

Factor Viii ◽

Von Willebrand Factor ◽

Coagulation Factor ◽

Coagulation Factor Viii ◽

Haemophilia A ◽

Orphan Designation ◽

Von Willebrand ◽

Willebrand Factor ◽

Protein Treatment

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Generation of active coagulation factor VIII from isolated subunits.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)57273-8 ◽

1988 ◽

Vol 263 (3) ◽

pp. 1115-1118

Author(s):

O Nordfang ◽

M Ezban

Keyword(s):

Factor Viii ◽

Coagulation Factor ◽

Coagulation Factor Viii

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Gene Therapy in Hemophilia: Recent Advances

International Journal of Molecular Sciences ◽

10.3390/ijms22147647 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7647

Author(s):

E. Carlos Rodríguez-Merchán ◽

Juan Andres De Pablo-Moreno ◽

Antonio Liras

Keyword(s):

Gene Therapy ◽

Adverse Events ◽

Factor Viii ◽

Coagulation Factor ◽

Cost Savings ◽

Factor Ix ◽

Clotting Factors ◽

Advanced Therapies ◽

Potential Benefits

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

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