factor IX

File:Coagulation full.svg pathway.|left]]

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.{{cite journal | vauthors = Di Scipio RG, Kurachi K, Davie EW | title = Activation of human factor IX (Christmas factor) | journal = The Journal of Clinical Investigation | volume = 61 | issue = 6 | pages = 1528–38 | date = Jun 1978 | pmid = 659613 | pmc = 372679 | doi = 10.1172/JCI109073 }}{{cite journal | vauthors = Taran LD | title = Factor IX of the blood coagulation system: a review | journal = Biochemistry. Biokhimiia | volume = 62 | issue = 7 | pages = 685–93 | date = Jul 1997 | pmid = 9331959 }} 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.{{cite journal | vauthors = Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P | title = Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice | journal = Blood | volume = 86 | issue = 6 | pages = 2198–205 | date = Sep 1995 | pmid = 7662969 | doi = 10.1182/blood.V86.6.2198.bloodjournal8662198 | doi-access = free }}

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.{{cite journal | vauthors = Zhong D, Bajaj MS, Schmidt AE, Bajaj SP | title = The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 5 | pages = 3622–31 | date = Feb 2002 | pmid = 11723140 | doi = 10.1074/jbc.M111202200 | doi-access = free }} 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.

Image:Factor IX.png

The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor. 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.{{cite journal | vauthors = Wilkinson FH, Ahmad SS, Walsh PN | title = The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 5734–41 | date = Feb 2002 | pmid = 11714704 | doi = 10.1074/jbc.M107753200 | doi-access = free }}

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.{{cite journal | vauthors = Brandstetter H, Bauer M, Huber R, Lollar P, Bode W | title = X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9796–800 | date = Oct 1995 | pmid = 7568220 | pmc = 40889 | doi = 10.1073/pnas.92.21.9796 | bibcode = 1995PNAS...92.9796B | doi-access = free }} The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.{{cite journal | vauthors = Freedman SJ, Furie BC, Furie B, Baleja JD | title = Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX | journal = Biochemistry | volume = 34 | issue = 38 | pages = 12126–37 | date = Sep 1995 | pmid = 7547952 | doi = 10.1021/bi00038a005 }}

Several structures of 'super active' mutants have been solved,{{cite journal | vauthors = Zögg T, Brandstetter H | title = Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa | journal = Structure | volume = 17 | issue = 12 | pages = 1669–78 | date = Dec 2009 | pmid = 20004170 | doi = 10.1016/j.str.2009.10.011 | doi-access = free }} which reveal the nature of factor IX activation by other proteins in the clotting cascade.

File:F9 gene location.png at position q27.1.]]

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.{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }} The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.{{cite journal | vauthors = Kurachi K, Davie EW | title = Isolation and characterization of a cDNA coding for human factor IX | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 21 | pages = 6461–4 | date = Nov 1982 | pmid = 6959130 | pmc = 347146 | doi = 10.1073/pnas.79.21.6461 | bibcode = 1982PNAS...79.6461K | doi-access = free }}

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.{{cite book |author=Nicholl D. |title=An Introduction to Genetic Engineering Second Edition | publisher=Cambridge University Press |page=257 |year=2002}}

{{See also|Prothrombin complex concentrate}}

{{anchor|nonacog alfa}}{{anchor|nonacog gamma}}{{anchor|albutrepenonacog alfa}}{{anchor|eftrenonacog alfa}}{{anchor|nonacog beta pegol}}{{anchor|coagulation factor IX}}

{{Infobox drug

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{{Infobox drug

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{{Infobox drug

| INN = albutrepenonacog alfa

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{{Infobox drug

| INN = eftrenonacog alfa

| image =

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| tradename = Alprolix

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{{Infobox drug

| INN = nonacog beta pegol

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Deficiency of factor IX causes Christmas disease (hemophilia B). Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;{{Cite journal | doi=10.1111/jth.12958|title = Hemophilia B: Molecular pathogenesis and mutation analysis|year = 2015|last1 = Goodeve|first1 = A. C.|journal = Journal of Thrombosis and Haemostasis|volume = 13|issue = 7|pages = 1184–1195|pmid = 25851415|pmc = 4496316}} 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.{{cite journal | vauthors = Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP | title = Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis | journal = Thrombosis and Haemostasis | volume = 67 | issue = 1 | pages = 63–5 | date = Jan 1992 | pmid = 1615485 | doi = 10.1055/s-0038-1648381 | s2cid = 25251813 }}

Recombinant factor IX is used to treat Christmas disease. Formulations include:

• nonacog alfa (brand name Benefix){{cite web | title=Benefix EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/benefix | access-date=17 June 2020 | archive-date=17 June 2020 | archive-url=https://web.archive.org/web/20200617185142/https://www.ema.europa.eu/en/medicines/human/EPAR/benefix | url-status=live }}
• nonacog gamma (brand name Rixubis)
• albutrepenonacog alfa (brand name Idelvion){{cite web | title=Idelvion EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/idelvion | access-date=17 June 2020 | archive-date=17 June 2020 | archive-url=https://web.archive.org/web/20200617185347/https://www.ema.europa.eu/en/medicines/human/EPAR/idelvion | url-status=live }}
• eftrenonacog alfa (brand name Alprolix){{cite web | title=Alprolix EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/alprolix | access-date=17 June 2020 | archive-date=11 August 2020 | archive-url=https://web.archive.org/web/20200811013858/https://www.ema.europa.eu/en/medicines/human/EPAR/alprolix | url-status=live }}
• nonacog beta pegol (brand name Refixia){{cite web | title=Refixia EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/refixia | access-date=17 June 2020 | archive-date=18 June 2020 | archive-url=https://web.archive.org/web/20200618123853/https://www.ema.europa.eu/en/medicines/human/EPAR/refixia | url-status=live }}
• coagulation factor IX [recombinant] (Benefix){{cite web | title=Benefix (coagulation factor ix- recombinant kit | website=DailyMed | date=1 March 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=85faa5bc-cee5-4ef1-8d80-bdbcb7eba1e4 | access-date=23 March 2024 | archive-date=29 January 2023 | archive-url=https://web.archive.org/web/20230129101744/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=85faa5bc-cee5-4ef1-8d80-bdbcb7eba1e4 | url-status=live }}
• coagulation factor IX [recombinant] (Idelvion){{cite web | title=Idelvion- coagulation factor ix recombinant human kit | website=DailyMed | date=30 June 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f74301bf-95e2-44ab-a8b6-98aa07b04683 | access-date=23 March 2024 | archive-date=27 January 2023 | archive-url=https://web.archive.org/web/20230127043907/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f74301bf-95e2-44ab-a8b6-98aa07b04683 | url-status=live }}
• coagulation factor IX (recombinant), Fc fusion protein (Alprolix){{cite web | title=Alprolix (coagulation factor ix- recombinant, fc fusion protein kit | website=DailyMed | date=25 May 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2fb3fb92-379d-4683-80d6-b06c0a7dc063 | access-date=23 March 2024 | archive-date=7 February 2023 | archive-url=https://web.archive.org/web/20230207041747/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2fb3fb92-379d-4683-80d6-b06c0a7dc063 | url-status=live }}
• coagulation factor IX [recombinant] (Ixinity){{cite web | title=Ixinity (coagulation factor ix- recombinant kit | website=DailyMed | date=23 February 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9521898c-61aa-44ab-8ab8-84274ca19943 | access-date=23 March 2024 | archive-date=28 September 2023 | archive-url=https://web.archive.org/web/20230928022338/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9521898c-61aa-44ab-8ab8-84274ca19943 | url-status=live }}{{cite web | title=Ixinity (coagulation factor ix- recombinant kit | website=DailyMed | date=9 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26bc221d-c9bc-4aba-92f3-6c21acaaf194 | access-date=23 March 2024 | archive-date=3 December 2022 | archive-url=https://web.archive.org/web/20221203225735/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26bc221d-c9bc-4aba-92f3-6c21acaaf194 | url-status=live }}
• coagulation factor IX [recombinant] (Rebinyn){{cite web | title=Rebinyn ((coagulation factor ix- recombinant, glycopegylated kit | website=DailyMed | date=11 August 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ea37235-35fd-410d-b8c4-40ba15fe1294 | access-date=23 March 2024 | archive-date=29 November 2022 | archive-url=https://web.archive.org/web/20221129210522/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ea37235-35fd-410d-b8c4-40ba15fe1294 | url-status=live }}
• coagulation factor IX [recombinant] (Rixubis){{cite web | title=Rixubis (coagulation factor ix- recombinant kit | website=DailyMed | date=22 March 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5070a92-96b8-476a-a2dc-18b22d95e5e0 | access-date=23 March 2024 | archive-date=2 July 2022 | archive-url=https://web.archive.org/web/20220702231401/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5070a92-96b8-476a-a2dc-18b22d95e5e0 | url-status=live }}
• coagulation factor IX (human) (Alphanine SD){{cite web | title=Alphanine SD (coagulation factor ix- human kit | website=DailyMed | date=18 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e99052d-4442-4283-8915-c9a796c77008 | access-date=23 March 2024 | archive-date=18 February 2024 | archive-url=https://web.archive.org/web/20240218105505/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e99052d-4442-4283-8915-c9a796c77008 | url-status=live }}

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.{{cite journal | vauthors = Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR | title = X-linked thrombophilia with a mutant factor IX (factor IX Padua) | journal = The New England Journal of Medicine | volume = 361 | issue = 17 | pages = 1671–5 | date = Oct 2009 | pmid = 19846852 | doi = 10.1056/NEJMoa0904377 | doi-access = free | hdl = 11577/2438365 | hdl-access = free }}

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.{{cite journal | vauthors = Rossi M, Jayaram R, Sayeed R | title = Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes? | journal = Interactive Cardiovascular and Thoracic Surgery | volume = 13 | issue = 3 | pages = 320–31 | date = Sep 2011 | pmid = 21712351 | doi = 10.1510/icvts.2011.272401 | doi-access = free }}

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.{{cite web |url=https://f9-db.eahad.org/ |title=Home: EAHAD Factor 9 Gene Variant Database |access-date=2020-10-23 |archive-date=2020-10-28 |archive-url=https://web.archive.org/web/20201028103237/https://f9-db.eahad.org/ |url-status=live }}

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

{{reflist}}

{{refbegin|33em}}

• {{cite journal | vauthors = Davie EW, Fujikawa K | title = Basic mechanisms in blood coagulation | journal = Annual Review of Biochemistry | volume = 44 | pages = 799–829 | year = 1975 | pmid = 237463 | doi = 10.1146/annurev.bi.44.070175.004055 }}
• {{cite journal | vauthors = Sommer SS | title = Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene | journal = FASEB Journal | volume = 6 | issue = 10 | pages = 2767–74 | date = Jul 1992 | pmid = 1634040 | doi = 10.1096/fasebj.6.10.1634040| doi-access = free | s2cid = 15211597 }}
• {{cite journal | vauthors = Lenting PJ, van Mourik JA, Mertens K | title = The life cycle of coagulation factor VIII in view of its structure and function | journal = Blood | volume = 92 | issue = 11 | pages = 3983–96 | date = Dec 1998 | pmid = 9834200 | doi = 10.1182/blood.V92.11.3983}}
• {{cite journal | vauthors = Lowe GD | title = Factor IX and thrombosis | journal = British Journal of Haematology | volume = 115 | issue = 3 | pages = 507–13 | date = Dec 2001 | pmid = 11736930 | doi = 10.1046/j.1365-2141.2001.03186.x | s2cid = 44650866 | url = http://eprints.gla.ac.uk/650/1/Br_Jour_Haem_115_507-513%5B1%5D.pdf | doi-access = free | access-date = 2019-12-11 | archive-date = 2021-06-19 | archive-url = https://web.archive.org/web/20210619100443/https://eprints.gla.ac.uk/650/1/Br_Jour_Haem_115_507-513%5B1%5D.pdf | url-status = live }}
• {{cite journal | vauthors = O'Connell NM | title = Factor XI deficiency--from molecular genetics to clinical management | journal = Blood Coagulation & Fibrinolysis | volume = 14 | pages = S59-64 | date = Jun 2003 | issue = Suppl 1 | pmid = 14567539 | doi = 10.1097/00001721-200306001-00014 }}
• {{cite journal | vauthors = Du X | title = Signaling and regulation of the platelet glycoprotein Ib-IX-V complex | journal = Current Opinion in Hematology | volume = 14 | issue = 3 | pages = 262–9 | date = May 2007 | pmid = 17414217 | doi = 10.1097/MOH.0b013e3280dce51a | s2cid = 39904506 }}

{{refend}}

• {{PDBe-KB2|P00740|Coagulation factor IX}}
• [https://www.ncbi.nlm.nih.gov/books/NBK1495/ GeneReviews/NCBI/NIH/UW entry on Hemophilia B]
• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.214 S01.214] {{Webarchive|url=https://web.archive.org/web/20050505032245/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.214 |date=2005-05-05 }}

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Category:Coagulation system

Category:EC 3.4.21

Category:Peripheral membrane proteins

Category:Drugs developed by Pfizer

Category:Zymogens

Category:Sanofi

Category:World Health Organization essential medicines