Factor VIII
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Location (UCSC) | Chr X: 154.84 – 155.03 Mb | Chr X: 74.22 – 74.43 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Factor VIII (FVIII) is an essential
Factor VIII participates in
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
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 (F8A1) 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
In the blood, it mainly circulates in a stable noncovalent complex with
The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor. [20]
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.[21][22]
Medical use
FVIII concentrated from donated blood plasma, or alternatively
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.[23]
Immunostain target
Factor VIII related antigen is used as a target for immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.[24]
Contamination scandal
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.[25] 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).[25]
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, Frances Rotblat and coworkers led to the molecular identification of the protein.[26][27]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000185010 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031196 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 4313575.
- PMID 3935400.
- S2CID 23435953.
- ^ a b "NIH: F8 – coagulation factor VIII". National Institutes of Health.
- ^ "Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)".
- PMID 22530883.
- PMID 8602593.
- ^ "19th WHO Model List of Essential Medicines" (PDF). WHO. April 2015. Retrieved May 10, 2015.
- S2CID 4358041.
- PMID 2110545.
- PMID 9655335.
- S2CID 4393638.
- PMID 9632668.
- ISBN 978-0-8089-2450-0.
- ^ ISBN 978-0-07-162151-9.
- PMID 19707594.
- S2CID 20091477.
- ISBN 1-889325-04-X.
- ^ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. Archived from the original on 2008-12-16. Retrieved 2009-01-07.
- ^ Nat Pernick, M.D. "Stains & CD markers - Factor VIII related antigen". Pathology Outlines. Topic Completed: 1 July 2012. Minor changes: 25 June 2021
- ^ PMID 12812170. Retrieved 2009-01-07.
- PMID 366050.)
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: CS1 maint: multiple names: authors list (link - ^ "Frances Rotblat obituary". The Times. 12 June 2021. Retrieved 12 June 2021.
Further reading
- Gitschier J (1991). "The molecular basis of hemophilia A". Annals of the New York Academy of Sciences. 614 (1 Process in Va): 89–96. S2CID 26493612.
- White GC, Shoemaker CB (January 1989). "Factor VIII gene and hemophilia A". Blood. 73 (1): 1–12. PMID 2491949.
- Antonarakis SE, Kazazian HH, Tuddenham EG (1995). "Molecular etiology of factor VIII deficiency in hemophilia A". Human Mutation. 5 (1): 1–22. S2CID 2346510.
- Lenting PJ, van Mourik JA, Mertens K (December 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96. PMID 9834200.
- Saenko EL, Ananyeva N, Kouiavskaia D, Schwinn H, Josic D, Shima M, Hauser CA, Pipe S (August 2002). "Molecular defects in coagulation Factor VIII and their impact on Factor VIII function" (PDF). Vox Sanguinis. 83 (2): 89–96. PMID 12201837.
- Lollar P (August 2002). "Molecular characterization of the immune response to factor VIII". Vox Sanguinis. 83. 83 (Suppl 1): 403–08. S2CID 26050729.
- Fay PJ (March 2004). "Activation of factor VIII and mechanisms of cofactor action". Blood Reviews. 18 (1): 1–15. PMID 14684146.
- Lavigne-Lissalde G, Schved JF, Granier C, Villard S (October 2005). "Anti-factor VIII antibodies: a 2005 update". Thrombosis and Haemostasis. 94 (4): 760–69. S2CID 38533008.
- Fang H, Wang L, Wang H (2007). "The protein structure and effect of factor VIII". Thrombosis Research. 119 (1): 1–13. PMID 16487577.
External links
- GeneReviews/NCBI/NIH/UW entry on Hemophilia A
- The Coagulation Factor VIII Protein
- Factor+VIII at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P00451 (Human Factor VIII) at the PDBe-KB.