Editing Factor IX

{{cs1 config|name-list-style=vanc}}
{{Short description|Protein involved in coagulation}}
{{Infobox_gene}}

'''Factor IX''' ({{EC number|3.4.21.22}}), also known as '''Christmas factor''', is one of the [[serine protease]]s involved in [[coagulation]]; it belongs to peptidase family S1. Deficiency of this protein causes [[haemophilia B]].

<!-- History, society and culture -->
It was discovered in 1952 after a young boy named [[Stephen Christmas]] was found to be lacking this exact factor, leading to [[haemophilia]].<ref name="PMD12997790">{{cite journal | vauthors = Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR | title = Christmas disease: a condition previously mistaken for haemophilia | journal = British Medical Journal | volume = 2 | issue = 4799 | pages = 1378–82 | date = Dec 1952 | pmid = 12997790 | pmc = 2022306 | doi = 10.1136/bmj.2.4799.1378 }}</ref> Coagulation factor IX is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>

== Physiology ==

[[File:Coagulation full.svg|thumb|The blood coagulation and [[Protein C]] pathway.|left]]

Factor IX is produced as a [[zymogen]], an inactive precursor.  It is processed to remove the [[signal peptide]], [[Glycosylation|glycosylated]] and then cleaved by [[factor XI]]a (of the contact pathway) or [[factor VII]]a (of the tissue factor pathway) to produce a two-chain form, where the chains are linked by a [[disulfide bridge]].<ref name="pmid659613">{{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 }}</ref><ref name="pmid9331959">{{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 }}</ref>  When activated into '''factor IXa''', in the presence of Ca<sup>2+</sup>, 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]].<ref name="pmid659613" />

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.<ref name="pmid7662969">{{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 }}</ref>

== Domain architecture ==

[[Factor VII|Factors VII]], IX, and [[Factor X|X]] all play key roles in [[blood coagulation]] and also share a common domain architecture.<ref name="pmid11723140">{{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 }}</ref> The factor IX protein is composed of four [[protein domain]]s: the [[Gla domain]], two tandem copies of the [[EGF-like domain|EGF domain]] and a C-terminal [[trypsin]]-like peptidase domain which carries out the catalytic cleavage.

[[Image:Factor IX.png|thumb|Human factor IX protein domain architecture, where each protein domain is represented by a coloured box|400px|left]]

The N-terminal EGF domain has been shown to at least in part be responsible for binding [[tissue factor]].<ref name="pmid11723140"/> 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.<ref name="pmid11714704">{{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 }}</ref>

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.<ref name="pmid7568220">{{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 }}</ref> The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by [[NMR]].<ref name="pmid7547952">{{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 }}</ref>

Several structures of 'super active' mutants have been solved,<ref name="pmid20004170">{{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 }}</ref> which reveal the nature of factor IX activation by other proteins in the clotting cascade.

== Genetics ==
[[File:F9 gene location.png|thumb|In human, the F9 gene is located on the [[X chromosome]] 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.<ref name = "Šimčíková_2019 - supplementary table S7">{{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 }}</ref> The F9 gene was first cloned in 1982 by Kotoku Kurachi and [[Earl Davie]].<ref>{{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 }}</ref>

[[Polly and Molly|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.<ref>{{cite book |author=Nicholl D. |title=An Introduction to Genetic Engineering Second Edition | publisher=Cambridge University Press |page=257 |year=2002}}</ref>

== Role in disease ==
{{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}}

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{{Infobox drug
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{{Infobox drug
| INN               = albutrepenonacog alfa
| image             = 
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| tradename         = Idelvion
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{{Infobox drug
| INN               = eftrenonacog alfa
| image             = 
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{{Infobox drug
| INN               = nonacog beta pegol
| image             = 
| width             = 
| alt               = 
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| tradename         = Refixia
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| legal_AU_comment  = <ref>{{cite web | title=Refixia (Novo Nordisk Pharmaceuticals Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=13 September 2024 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/refixia-novo-nordisk-pharmaceuticals-pty-ltd-0 | access-date=15 September 2024}}</ref>
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}}

Deficiency of factor IX causes Christmas disease ([[hemophilia B]]).<ref name="PMD12997790" /> Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;<ref>{{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}}</ref> 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.<ref>{{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 }}</ref>
[[Recombinant DNA|Recombinant]] factor IX is used to treat Christmas disease. Formulations include:

* nonacog alfa (brand name Benefix)<ref>{{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 }}</ref>
* nonacog gamma (brand name Rixubis)<ref name="Rixubis EPAR" />
* albutrepenonacog alfa (brand name Idelvion)<ref>{{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 }}</ref>
* eftrenonacog alfa (brand name Alprolix)<ref>{{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 }}</ref>
* nonacog beta pegol (brand name Refixia)<ref>{{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 }}</ref>
* coagulation factor IX [recombinant] (Benefix)<ref>{{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 }}</ref>
* coagulation factor IX [recombinant] (Idelvion)<ref>{{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 }}</ref>
* coagulation factor IX (recombinant), Fc fusion protein (Alprolix)<ref>{{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 }}</ref>
* coagulation factor IX [recombinant] (Ixinity)<ref>{{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 }}</ref><ref>{{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 }}</ref>
* coagulation factor IX [recombinant] (Rebinyn)<ref>{{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 }}</ref>
* coagulation factor IX [recombinant] (Rixubis)<ref>{{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 }}</ref>
* coagulation factor IX (human) (Alphanine SD)<ref>{{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 }}</ref>

Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as [[deep vein thrombosis]]. This [[mutation|gain of function]] mutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia.<ref name="pmid19846852">{{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 }}</ref>

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.<ref name="pmid21712351">{{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 }}</ref>

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.<ref name="urlHome: EAHAD Factor 9 Gene Variant Database">{{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 }}</ref>

Coagulation factor IX is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st" />

== References ==
{{reflist}}

== Further reading ==
{{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}}

== External links ==
* {{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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{{DEFAULTSORT:Factor Ix}}
[[Category:Coagulation system]]
[[Category:EC 3.4.21]]
[[Category:Peripheral membrane proteins]]
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