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Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is [[homology (biology)|homologous]] to [[factor V]].
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is [[homology (biology)|homologous]] to [[factor V]].


The A domains are [[homology (biology)|homologous]] to the A domains of the copper-binding protein [[ceruloplasmin]].<ref>{{cite journal | vauthors = Villoutreix BO, Dahlbäck B | title = Structural investigation of the A domains of human blood coagulation factor V by molecular modeling | journal = Protein Science | volume = 7 | issue = 6 | pages = 1317–25 | date = June 1998 | pmid = 9655335 | pmc = 2144041 | doi = 10.1002/pro.5560070607 }}</ref> The C domains belong to the [[phospholipid]]-binding [[discoidin domain]] family, and the C2 domain mediate membrane binding.<ref>{{cite journal | vauthors = Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P | title = Crystal structures of the membrane-binding C2 domain of human coagulation factor V | journal = Nature | volume = 402 | issue = 6760 | pages = 434–9 | date = November 1999 | pmid = 10586886 | doi = 10.1038/46594 | bibcode = 1999Natur.402..434M }}</ref>
The A domains are [[homology (biology)|homologous]] to the A domains of the copper-binding protein [[ceruloplasmin]].<ref>{{cite journal | vauthors = Villoutreix BO, Dahlbäck B | title = Structural investigation of the A domains of human blood coagulation factor V by molecular modeling | journal = Protein Science | volume = 7 | issue = 6 | pages = 1317–25 | date = June 1998 | pmid = 9655335 | pmc = 2144041 | doi = 10.1002/pro.5560070607 }}</ref> The C domains belong to the [[phospholipid]]-binding [[discoidin domain]] family, and the C2 domain mediate membrane binding.<ref>{{cite journal | vauthors = Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P | title = Crystal structures of the membrane-binding C2 domain of human coagulation factor V | journal = Nature | volume = 402 | issue = 6760 | pages = 434–39 | date = November 1999 | pmid = 10586886 | doi = 10.1038/46594 | bibcode = 1999Natur.402..434M }}</ref>


Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.<ref name = "Thorelli1998">{{cite journal | vauthors = Thorelli E, Kaufman RJ, Dahlbäck B | title = The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V | journal = The Journal of Biological Chemistry | volume = 273 | issue = 26 | pages = 16140–5 | date = June 1998 | pmid = 9632668 | doi = 10.1074/jbc.273.26.16140 }}</ref>
Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.<ref name = "Thorelli1998">{{cite journal | vauthors = Thorelli E, Kaufman RJ, Dahlbäck B | title = The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V | journal = The Journal of Biological Chemistry | volume = 273 | issue = 26 | pages = 16140–45 | date = June 1998 | pmid = 9632668 | doi = 10.1074/jbc.273.26.16140 }}</ref>


==Physiology==
==Physiology==

Revision as of 02:39, 23 March 2020

This article is about the protein. For the drug, see Factor VIII (medication). For the documentary, see Factor 8: The Arkansas Prison Blood Scandal.
F8
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesF8, AHF, DXS1253E, F8B, F8C, FVIII, HEMA, coagulation factor VIII, THPH13
External IDsOMIM: 300841; MGI: 88383; HomoloGene: 49153; GeneCards: F8; OMA:F8 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2157

14069

Ensembl

ENSG00000185010

ENSMUSG00000031196

UniProt

P00451

Q06194

RefSeq (mRNA)

NM_000132
NM_019863

NM_001161373
NM_001161374
NM_007977

RefSeq (protein)

NP_000123
NP_063916

NP_001154845
NP_001154846
NP_032003

Location (UCSC)Chr X: 154.84 – 155.03 MbChr X: 74.22 – 74.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene.[5][6] Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder.[7] Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs.[8] In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.[8]

Factor VIII participates in blood coagulation; it is a cofactor for factor IXa, which, in the presence of Ca2+ and phospholipids, forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.[9]

People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism.[10] Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.[11]

There is a formulation as a medication that is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[12]

Genetics

In human, the F8 gene is located on the X chromosome at position q28.

Factor VIII was first characterized in 1984 by scientists at Genentech.[13] The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene is embedded in one of its introns.[14]

Structure

Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.

The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin.[15] The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.[16]

Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.[17]

Physiology

FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver.[18] Hemophilia A has been corrected by liver transplantation.[19] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.[19]

In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor. Upon activation by thrombin (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot.

No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.

Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.[20][21]

Medical use

Main article: Factor VIII (medication)

FVIII concentrated from donated blood plasma, or alternatively recombinant FVIIa can be given to hemophiliacs to restore hemostasis.

Antibody formation to factor VIII can also be a major concern for patients receiving therapy against bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII product itself.[22]

Contamination scandal

Main article: Contaminated haemophilia blood products

In the 1980s, some pharmaceutical companies such as Baxter International and Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.[23] Under FDA pressure, unheated product was pulled from US markets, but was sold to Asian, Latin American, and some European countries. The product was tainted with HIV, a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA).[23]

In the early 1990s, pharmaceutical companies began to produce recombinant synthesized factor products, which now prevent nearly all forms of disease transmission during replacement therapy.

History

Factor VIII was first discovered in 1937, but it was not until 1979 that its purification by Edward Tuddenham and coworkers led to the molecular identification of the protein.[24]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000185010 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031196 – 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. ^ Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC (1984). "Molecular cloning of a cDNA encoding human antihaemophilic factor". Nature. 312 (5992): 342–47. Bibcode:1984Natur.312..342T. doi:10.1038/312342a0. PMID 6438528.
  6. ^ Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, Hartog K, Kuo CH, Masiarz FR, Merryweather JP (October 1985). "Characterization of the polypeptide composition of human factor VIII:C and the nucleotide sequence and expression of the human kidney cDNA". DNA. 4 (5): 333–49. doi:10.1089/dna.1985.4.333. PMID 3935400.
  7. ^ Antonarakis SE (July 1995). "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thrombosis and Haemostasis. 74 (1): 322–28. PMID 8578479.
  8. ^ a b "NIH: F8 – coagulation factor VIII". National Institutes of Health.
  9. ^ "Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)".
  10. ^ Jenkins PV, Rawley O, Smith OP, O'Donnell JS (June 2012). "Elevated factor VIII levels and risk of venous thrombosis". British Journal of Haematology. 157 (6): 653–63. doi:10.1111/j.1365-2141.2012.09134.x. PMID 22530883.
  11. ^ Milne DB, Nielsen FH (March 1996). "Effects of a diet low in copper on copper-status indicators in postmenopausal women". The American Journal of Clinical Nutrition. 63 (3): 358–64. doi:10.1093/ajcn/63.3.358. PMID 8602593.
  12. ^ "19th WHO Model List of Essential Medicines" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  13. ^ Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM (November 1984). "Characterization of the human factor VIII gene". Nature. 312 (5992): 326–30. Bibcode:1984Natur.312..326G. doi:10.1038/312326a0. PMID 6438525.
  14. ^ Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J (May 1990). "A transcribed gene in an intron of the human factor VIII gene". Genomics. 7 (1): 1–11. doi:10.1016/0888-7543(90)90512-S. PMID 2110545.
  15. ^ Villoutreix BO, Dahlbäck B (June 1998). "Structural investigation of the A domains of human blood coagulation factor V by molecular modeling". Protein Science. 7 (6): 1317–25. doi:10.1002/pro.5560070607. PMC 2144041. PMID 9655335.
  16. ^ Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P (November 1999). "Crystal structures of the membrane-binding C2 domain of human coagulation factor V". Nature. 402 (6760): 434–39. Bibcode:1999Natur.402..434M. doi:10.1038/46594. PMID 10586886.
  17. ^ Thorelli E, Kaufman RJ, Dahlbäck B (June 1998). "The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V". The Journal of Biological Chemistry. 273 (26): 16140–45. doi:10.1074/jbc.273.26.16140. PMID 9632668.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Kumar V, Abbas A, Aster J (2005). Robbins and Cotran Pathologic Basis of Disease (9th ed.). Pennsylvania: Elsevier. p. 655. ISBN 978-0-8089-2450-0.
  19. ^ a b Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U (2010). Williams Hematology (8th ed.). McGraw-Hill. ISBN 978-0-07-162151-9.
  20. ^ Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA (February 2004). "Factor VIII expression in liver disease". Thrombosis and Haemostasis. 91 (2): 267–75. doi:10.1160/th03-05-0310. PMID 14961153.
  21. ^ Rubin R, Leopold L (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. ISBN 1-889325-04-X.
  22. ^ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. Archived from the original on 2008-12-16. Retrieved 2009-01-07.
  23. ^ a b Bogdanich W, Koli E (2003-05-22). "2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas". The New York Times. Retrieved 2009-01-07.
  24. ^ Tuddenham EG, Trabold NC, Collins JA, Hoyer LW (1979). "The properties of factor VIII coagulant activity prepared by immunoadsorbent chromatography". J Lab Clin Med. 93: 40–53.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading


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