Factor IX

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PDB 1pfx EBI.jpg
Available structures
PDBOrtholog search: PDBe RCSB
AliasesF9, F9 p22, FIX, HEMB, P19, PTC, THPH8, coagulation factor IX, Blood coagulation factor IX, Christmas Factor
External IDsOMIM: 300746 MGI: 88384 HomoloGene: 106 GeneCards: F9
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr X: 139.53 – 139.56 MbChr X: 59.04 – 59.08 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Factor IX (or Christmas factor) (EC is one of the serine proteases of the coagulation system; 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.[5]

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.[6]


The blood coagulation and Protein C pathway.

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.[7][8] 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.[7]

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.[9]

Domain architecture[edit]

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[10] 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.

Human factor IX protein domain architecture, where each protein domain is represented by a coloured box

The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor.[10] 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.[11]

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.[12] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[13]

Several structures of 'super active' mutants have been solved,[14] which reveal the nature of factor IX activation by other proteins in the clotting cascade.


In human, the F9 gene is located on the X chromosome at position q27.1.

The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered.[15] The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.[16]

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.[17]

Role in disease[edit]

Deficiency of factor IX causes Christmas disease (hemophilia B).[5] Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;[18] 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.[19] Recombinant factor IX is used to treat Christmas disease. Formulations include:

  • nonacog alfa (brand name BeneFix)[20]
  • albutrepenonacog alfa (brand name Idelvion)[21]
  • eftrenonacog alfa (brand name Alprolix)[22]
  • nonacog beta pegol (brand name Refixia)[23]

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.[24]

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.[25]

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.[26]

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.[6]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000101981 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031138 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR (Dec 1952). "Christmas disease: a condition previously mistaken for haemophilia". British Medical Journal. 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790.
  6. ^ a b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ a b Di Scipio RG, Kurachi K, Davie EW (Jun 1978). "Activation of human factor IX (Christmas factor)". The Journal of Clinical Investigation. 61 (6): 1528–38. doi:10.1172/JCI109073. PMC 372679. PMID 659613.
  8. ^ Taran LD (Jul 1997). "Factor IX of the blood coagulation system: a review". Biochemistry. Biokhimiia. 62 (7): 685–93. PMID 9331959.
  9. ^ Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (Sep 1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood. 86 (6): 2198–205. doi:10.1182/blood.V86.6.2198.bloodjournal8662198. PMID 7662969.
  10. ^ a b Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (Feb 2002). "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. doi:10.1074/jbc.M111202200. PMID 11723140.
  11. ^ Wilkinson FH, Ahmad SS, Walsh PN (Feb 2002). "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. doi:10.1074/jbc.M107753200. PMID 11714704.
  12. ^ Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (Oct 1995). "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. Bibcode:1995PNAS...92.9796B. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220.
  13. ^ Freedman SJ, Furie BC, Furie B, Baleja JD (Sep 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry. 34 (38): 12126–37. doi:10.1021/bi00038a005. PMID 7547952.
  14. ^ Zögg T, Brandstetter H (Dec 2009). "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure. 17 (12): 1669–78. doi:10.1016/j.str.2009.10.011. PMID 20004170.
  15. ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
  16. ^ Kurachi K, Davie EW (Nov 1982). "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. Bibcode:1982PNAS...79.6461K. doi:10.1073/pnas.79.21.6461. PMC 347146. PMID 6959130.
  17. ^ Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. p. 257.
  18. ^ Goodeve, A. C. (2015). "Hemophilia B: Molecular pathogenesis and mutation analysis". Journal of Thrombosis and Haemostasis. 13 (7): 1184–1195. doi:10.1111/jth.12958. PMC 4496316. PMID 25851415.
  19. ^ Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP (Jan 1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis". Thrombosis and Haemostasis. 67 (1): 63–5. doi:10.1055/s-0038-1648381. PMID 1615485.
  20. ^ "BeneFIX EPAR". European Medicines Agency (EMA). Retrieved 17 June 2020.
  21. ^ "Idelvion EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 17 June 2020.
  22. ^ "Alprolix EPAR". European Medicines Agency (EMA). Retrieved 17 June 2020.
  23. ^ "Refixia EPAR". European Medicines Agency (EMA). Retrieved 17 June 2020.
  24. ^ Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (Oct 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852.
  25. ^ Rossi M, Jayaram R, Sayeed R (Sep 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery. 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351.
  26. ^ "Home: EAHAD Factor 9 Gene Variant Database".

Further reading[edit]

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