Factor IX explained

Factor IX, also known as Christmas factor, is one of the serine proteases involved in coagulation; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B.

It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.[1] Coagulation factor IX is on the World Health Organization's List of Essential Medicines.[2]

Physiology

Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form, where the chains are linked by a disulfide bridge.[3] [4] When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.

Factor IX is inhibited by antithrombin.

Factor IX expression increases with age in humans and mice. In mouse models, mutations within the promoter region of factor IX have an age-dependent phenotype.[5]

Domain architecture

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[6] The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.

The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor.[6] Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.[7]

The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein.[8] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[9]

Several structures of 'super active' mutants have been solved,[10] which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics

Because the gene for factor IX is located on the X chromosome (Xq27.1-q27.2), loss-of-function mutations thereof are X-linked recessive: males experience the disease phenotype much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered.[11] The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.[12]

Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.[13]

Role in disease

See also: Prothrombin complex concentrate.

Inn:nonacog alfa
Tradename:Benefix
Dailymedid:Coagulation Factor IX
Atc Prefix:None
Legal Au:S4
Inn:nonacog gamma
Tradename:Rixubis
Routes Of Administration:Intravenous
Atc Prefix:None
Legal Eu:Rx-only
Legal Eu Comment:[14]
Inn:albutrepenonacog alfa
Tradename:Idelvion
Dailymedid:Coagulation Factor IX
Atc Prefix:None
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:[15]
Inn:eftrenonacog alfa
Tradename:Alprolix
Dailymedid:Coagulation Factor IX
Atc Prefix:None
Legal Au:S4
Legal Eu:Rx-only
Legal Eu Comment:[16]
Inn:nonacog beta pegol
Tradename:Refixia
Atc Prefix:None
Legal Au:S4

Deficiency of factor IX causes Christmas disease (hemophilia B). Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;[17] some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine.[18] Recombinant factor IX is used to treat Christmas disease. Formulations include:

Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis. This gain of function mutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia.[31]

Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.[32]

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.[33]

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.

Further reading

External links

Notes and References

  1. Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR . Christmas disease: a condition previously mistaken for haemophilia . British Medical Journal . 2 . 4799 . 1378–82 . Dec 1952 . 12997790 . 2022306 . 10.1136/bmj.2.4799.1378 .
  2. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  3. Di Scipio RG, Kurachi K, Davie EW . Activation of human factor IX (Christmas factor) . The Journal of Clinical Investigation . 61 . 6 . 1528–38 . Jun 1978 . 659613 . 372679 . 10.1172/JCI109073 .
  4. Taran LD . Factor IX of the blood coagulation system: a review . Biochemistry. Biokhimiia . 62 . 7 . 685–93 . Jul 1997 . 9331959 .
  5. Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P . Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice . Blood . 86 . 6 . 2198–205 . Sep 1995 . 7662969 . 10.1182/blood.V86.6.2198.bloodjournal8662198 . free .
  6. Zhong D, Bajaj MS, Schmidt AE, Bajaj SP . The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor . The Journal of Biological Chemistry . 277 . 5 . 3622–31 . Feb 2002 . 11723140 . 10.1074/jbc.M111202200 . free .
  7. Wilkinson FH, Ahmad SS, Walsh PN . The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex . The Journal of Biological Chemistry . 277 . 8 . 5734–41 . Feb 2002 . 11714704 . 10.1074/jbc.M107753200 . free .
  8. Brandstetter H, Bauer M, Huber R, Lollar P, Bode W . X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B . Proceedings of the National Academy of Sciences of the United States of America . 92 . 21 . 9796–800 . Oct 1995 . 7568220 . 40889 . 10.1073/pnas.92.21.9796 . 1995PNAS...92.9796B . free .
  9. Freedman SJ, Furie BC, Furie B, Baleja JD . Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX . Biochemistry . 34 . 38 . 12126–37 . Sep 1995 . 7547952 . 10.1021/bi00038a005 .
  10. Zögg T, Brandstetter H . Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa . Structure . 17 . 12 . 1669–78 . Dec 2009 . 20004170 . 10.1016/j.str.2009.10.011 . free .
  11. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
  12. Kurachi K, Davie EW . Isolation and characterization of a cDNA coding for human factor IX . Proceedings of the National Academy of Sciences of the United States of America . 79 . 21 . 6461–4 . Nov 1982 . 6959130 . 347146 . 10.1073/pnas.79.21.6461 . 1982PNAS...79.6461K . free .
  13. Book: Nicholl D. . An Introduction to Genetic Engineering Second Edition . Cambridge University Press . 257 . 2002.
  14. Web site: Rixubis EPAR . European Medicines Agency (EMA) . 19 December 2014 . 1 June 2024.
  15. Web site: Health Canada New Drug Authorizations: 2016 Highlights . . 14 March 2017 . 7 April 2024.
  16. Web site: Alprolix EPAR . European Medicines Agency (EMA) . 8 June 2007 . 7 June 2024.
  17. 10.1111/jth.12958. Hemophilia B: Molecular pathogenesis and mutation analysis. 2015. Goodeve. A. C.. Journal of Thrombosis and Haemostasis. 13. 7. 1184–1195. 25851415. 4496316.
  18. Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP . Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis . Thrombosis and Haemostasis . 67 . 1 . 63–5 . Jan 1992 . 1615485 . 10.1055/s-0038-1648381 . 25251813 .
  19. Web site: Benefix EPAR . European Medicines Agency (EMA) . 17 September 2018 . 17 June 2020 . 17 June 2020 . https://web.archive.org/web/20200617185142/https://www.ema.europa.eu/en/medicines/human/EPAR/benefix . live .
  20. Web site: Idelvion EPAR . European Medicines Agency (EMA) . 17 September 2018 . 17 June 2020 . 17 June 2020 . https://web.archive.org/web/20200617185347/https://www.ema.europa.eu/en/medicines/human/EPAR/idelvion . live .
  21. Web site: Alprolix EPAR . European Medicines Agency (EMA) . 17 September 2018 . 17 June 2020 . 11 August 2020 . https://web.archive.org/web/20200811013858/https://www.ema.europa.eu/en/medicines/human/EPAR/alprolix . live .
  22. Web site: Refixia EPAR . European Medicines Agency (EMA) . 17 September 2018 . 17 June 2020 . 18 June 2020 . https://web.archive.org/web/20200618123853/https://www.ema.europa.eu/en/medicines/human/EPAR/refixia . live .
  23. Web site: Benefix (coagulation factor ix- recombinant kit . DailyMed . 1 March 2023 . 23 March 2024 . 29 January 2023 . https://web.archive.org/web/20230129101744/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=85faa5bc-cee5-4ef1-8d80-bdbcb7eba1e4 . live .
  24. Web site: Idelvion- coagulation factor ix recombinant human kit . DailyMed . 30 June 2023 . 23 March 2024 . 27 January 2023 . https://web.archive.org/web/20230127043907/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f74301bf-95e2-44ab-a8b6-98aa07b04683 . live .
  25. Web site: Alprolix (coagulation factor ix- recombinant, fc fusion protein kit . DailyMed . 25 May 2023 . 23 March 2024 . 7 February 2023 . https://web.archive.org/web/20230207041747/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2fb3fb92-379d-4683-80d6-b06c0a7dc063 . live .
  26. Web site: Ixinity (coagulation factor ix- recombinant kit . DailyMed . 23 February 2021 . 23 March 2024 . 28 September 2023 . https://web.archive.org/web/20230928022338/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9521898c-61aa-44ab-8ab8-84274ca19943 . live .
  27. Web site: Ixinity (coagulation factor ix- recombinant kit . DailyMed . 9 January 2024 . 23 March 2024 . 3 December 2022 . https://web.archive.org/web/20221203225735/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26bc221d-c9bc-4aba-92f3-6c21acaaf194 . live .
  28. Web site: Rebinyn ((coagulation factor ix- recombinant, glycopegylated kit . DailyMed . 11 August 2022 . 23 March 2024 . 29 November 2022 . https://web.archive.org/web/20221129210522/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ea37235-35fd-410d-b8c4-40ba15fe1294 . live .
  29. Web site: Rixubis (coagulation factor ix- recombinant kit . DailyMed . 22 March 2023 . 23 March 2024 . 2 July 2022 . https://web.archive.org/web/20220702231401/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5070a92-96b8-476a-a2dc-18b22d95e5e0 . live .
  30. Web site: Alphanine SD (coagulation factor ix- human kit . DailyMed . 18 January 2024 . 23 March 2024 . 18 February 2024 . https://web.archive.org/web/20240218105505/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e99052d-4442-4283-8915-c9a796c77008 . live .
  31. Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR . X-linked thrombophilia with a mutant factor IX (factor IX Padua) . The New England Journal of Medicine . 361 . 17 . 1671–5 . Oct 2009 . 19846852 . 10.1056/NEJMoa0904377 . free . 11577/2438365 . free .
  32. Rossi M, Jayaram R, Sayeed R . Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes? . Interactive Cardiovascular and Thoracic Surgery . 13 . 3 . 320–31 . Sep 2011 . 21712351 . 10.1510/icvts.2011.272401 . free .
  33. Web site: Home: EAHAD Factor 9 Gene Variant Database . 2020-10-23 . 2020-10-28 . https://web.archive.org/web/20201028103237/https://f9-db.eahad.org/ . live .

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