Factor VIII

File:F8 gene location.png at position q28.]]

Factor VIII was first characterized in 1984 by scientists at Genentech.{{cite journal | vauthors = Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM | title = Characterization of the human factor VIII gene | journal = Nature | volume = 312 | issue = 5992 | pages = 326–330 | date = November 1984 | pmid = 6438525 | doi = 10.1038/312326a0 | s2cid = 4358041 | bibcode = 1984Natur.312..326G }} 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.{{cite journal | vauthors = Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J | title = A transcribed gene in an intron of the human factor VIII gene | journal = Genomics | volume = 7 | issue = 1 | pages = 1–11 | date = May 1990 | pmid = 2110545 | doi = 10.1016/0888-7543(90)90512-S }}

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.{{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 = 1317–1325 | date = June 1998 | pmid = 9655335 | pmc = 2144041 | doi = 10.1002/pro.5560070607 }} The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.{{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 = 434–439 | date = November 1999 | pmid = 10586886 | doi = 10.1038/46594 | s2cid = 4393638 | bibcode = 1999Natur.402..434M }}

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.{{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 = 16140–16145 | date = June 1998 | pmid = 9632668 | doi = 10.1074/jbc.273.26.16140 | doi-access = free }}

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.{{cite book | vauthors = Kumar V, Abbas A, Aster J |title=Robbins and Cotran Pathologic Basis of Disease |publisher=Elsevier |location=Pennsylvania |year=2005 |page=655 |isbn=978-0-8089-2450-0 | edition = 9th }} Hemophilia A has been corrected by liver transplantation.{{cite book | vauthors = Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U | date = 2010 | edition =8th | title = Williams Hematology | publisher = McGraw-Hill | isbn = 978-0-07-162151-9 }} Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.

In the blood, it mainly circulates in a stable [[Noncovalent bonding|

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.

The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor.{{cite journal | vauthors = Fischer K, Pendu R, van Schooten CJ, van Dijk K, Denis CV, van den Berg HM, Lenting PJ | title = Models for prediction of factor VIII half-life in severe haemophiliacs: distinct approaches for blood group O and non-O patients | journal = PLOS ONE | volume = 4 | issue = 8 | pages = e6745 | date = August 2009 | pmid = 19707594 | pmc = 2727052 | doi = 10.1371/journal.pone.0006745 | doi-access = free | bibcode = 2009PLoSO...4.6745F }}

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.{{cite journal | vauthors = Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA | title = Factor VIII expression in liver disease | journal = Thrombosis and Haemostasis | volume = 91 | issue = 2 | pages = 267–275 | date = February 2004 | pmid = 14961153 | doi = 10.1160/th03-05-0310 | s2cid = 20091477 }}{{cite book | vauthors = Rubin R, Leopold L |title=Hematologic Pathophysiology |publisher=Fence Creek Publishing |location=Madison, Conn |year=1998 |isbn=1-889325-04-X }}

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{{main|Factor VIII (medication)}}

FVIII concentrated from donated blood plasma, or recombinant FVIII can be given to hemophiliacs to restore hemostasis. Bypassing agents such as recombinant FVIIa can be used in acquired hemophilia.

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.{{cite web |url=http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php |title=Overview of Factor VIII Inhibitors | vauthors = Lozier J |year=2004 |publisher=CMEonHemophilia.com |archive-url=https://web.archive.org/web/20081216021020/http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php |archive-date=2008-12-16 |access-date=2009-01-07 |url-status=dead }}

Factor VIII related antigen is used as a target for immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.{{cite web|url=https://www.pathologyoutlines.com/topic/stainsfactorviii.html|title=Stains & CD markers - Factor VIII related antigen| vauthors = Pernick N |website=Pathology Outlines}} Topic Completed: 1 July 2012. Minor changes: 25 June 2021

{{Main|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.{{cite journal | vauthors = Bogdanich W, Koli E | title = 2 paths of Bayer drug in 80's: riskier one steered overseas | journal = The New York Times on the Web | pages = A1, C5 | date = May 2003 | pmid = 12812170 | url = https://query.nytimes.com/gst/fullpage.html?res=9A00E4DA1F3EF931A15756C0A9659C8B63&sec=&spon=&pagewanted=1=2157 | access-date = 2009-01-07 }} 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).

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.

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.{{cite journal | vauthors = Tuddenham EG, Trabold NC, Collins JA, Hoyer LW | title = The properties of factor VIII coagulant activity prepared by immunoadsorbent chromatography | journal = The Journal of Laboratory and Clinical Medicine | volume = 93 | issue = 1 | pages = 40–53 | date = January 1979 | pmid = 366050 }}{{cite news|newspaper=The Times|url=https://www.thetimes.com/article/frances-rotblat-obituary-q9nbkp07d|title=Frances Rotblat obituary|date=12 June 2021|access-date=12 June 2021}}

• Ralph Kekwick
• Frances Rotblat
• Edward Shanbrom
• Edward Tuddenham
• Ryan White

{{Reflist}}

{{Refbegin|32em}}

• {{cite journal | vauthors = Gitschier J | title = The molecular basis of hemophilia A | journal = Annals of the New York Academy of Sciences | volume = 614 | issue = 1 Process in Va | pages = 89–96 | year = 1991 | pmid = 1902642 | doi = 10.1111/j.1749-6632.1991.tb43694.x | s2cid = 26493612 | bibcode = 1991NYASA.614...89G }}
• {{cite journal | vauthors = White GC, Shoemaker CB | title = Factor VIII gene and hemophilia A | journal = Blood | volume = 73 | issue = 1 | pages = 1–12 | date = January 1989 | pmid = 2491949 }}
• {{cite journal | vauthors = Antonarakis SE, Kazazian HH, Tuddenham EG | title = Molecular etiology of factor VIII deficiency in hemophilia A | journal = Human Mutation | volume = 5 | issue = 1 | pages = 1–22 | year = 1995 | pmid = 7728145 | doi = 10.1002/humu.1380050102 | s2cid = 2346510 | doi-access = free }}
• {{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 = 3983–3996 | date = December 1998 | pmid = 9834200 | doi = 10.1182/blood.V92.11.3983 }}
• {{cite journal | vauthors = Saenko EL, Ananyeva N, Kouiavskaia D, Schwinn H, Josic D, Shima M, Hauser CA, Pipe S | title = Molecular defects in coagulation Factor VIII and their impact on Factor VIII function | journal = Vox Sanguinis | volume = 83 | issue = 2 | pages = 89–96 | date = August 2002 | pmid = 12201837 | doi = 10.1046/j.1423-0410.2002.00183.x | doi-access = free | hdl = 2027.42/74861 | hdl-access = free }}
• {{cite journal | vauthors = Lollar P | title = Molecular characterization of the immune response to factor VIII | journal = Vox Sanguinis | volume = 83 | issue = Suppl 1 | pages = 403–408 | date = August 2002 | pmid = 12617176 | doi = 10.1111/j.1423-0410.2002.tb05342.x | series = 83 | s2cid = 26050729 }}
• {{cite journal | vauthors = Fay PJ | title = Activation of factor VIII and mechanisms of cofactor action | journal = Blood Reviews | volume = 18 | issue = 1 | pages = 1–15 | date = March 2004 | pmid = 14684146 | doi = 10.1016/S0268-960X(03)00025-0 }}
• {{cite journal | vauthors = Lavigne-Lissalde G, Schved JF, Granier C, Villard S | title = Anti-factor VIII antibodies: a 2005 update | journal = Thrombosis and Haemostasis | volume = 94 | issue = 4 | pages = 760–769 | date = October 2005 | pmid = 16270627 | doi = 10.1160/TH05-02-0118 | s2cid = 38533008 }}
• {{cite journal | vauthors = Fang H, Wang L, Wang H | title = The protein structure and effect of factor VIII | journal = Thrombosis Research | volume = 119 | issue = 1 | pages = 1–13 | year = 2007 | pmid = 16487577 | doi = 10.1016/j.thromres.2005.12.015 }}

{{Refend}}

• [https://www.ncbi.nlm.nih.gov/books/NBK1404/ GeneReviews/NCBI/NIH/UW entry on Hemophilia A]
• {{usurped|1=[https://archive.today/20130128073617/http://macromoleculeinsights.com/coagulationfactorviii.php The Coagulation Factor VIII Protein]}}
• {{MeshName|Factor+VIII}}
• {{PDBe-KB2|P00451|Human Factor VIII}}

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{{Coagulation}}

Category:Acute-phase proteins

Category:Recombinant proteins

Category:Coagulation system

Category:Drugs developed by Wyeth

Category:Drugs developed by Pfizer

Category:Cofactors