Editing Factor VIII

{{short description|Blood-clotting protein}}
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{{About|the protein|the drug|Factor VIII (medication)|the documentary|Factor 8: The Arkansas Prison Blood Scandal}}
{{Infobox_gene}}

'''Coagulation factor VIII''' ('''Factor VIII''', '''FVIII''', also known as '''anti-hemophilic factor''' ('''AHF''')) is an essential [[blood clotting]] [[protein]]. In humans, it is encoded by ''F8'' [[gene]].<ref name="pmid6438528">{{cite journal | vauthors = Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC | title = Molecular cloning of a cDNA encoding human antihaemophilic factor | journal = Nature | volume = 312 | issue = 5992 | pages = 342–347 | year = 1984 | pmid = 6438528 | doi = 10.1038/312342a0 | s2cid = 4313575 | bibcode = 1984Natur.312..342T }}</ref><ref name="pmid3935400">{{cite journal | vauthors = Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, Hartog K, Kuo CH, Masiarz FR, Merryweather JP | title = Characterization of the polypeptide composition of human factor VIII:C and the nucleotide sequence and expression of the human kidney cDNA | journal = DNA | volume = 4 | issue = 5 | pages = 333–349 | date = October 1985 | pmid = 3935400 | doi = 10.1089/dna.1985.4.333 }}</ref> Defects in this gene result in [[hemophilia A]], an X-linked [[bleeding disorder]].<ref name="pmid8578479">{{cite journal | vauthors = Antonarakis SE | title = Molecular genetics of coagulation factor VIII gene and hemophilia A | journal = Thrombosis and Haemostasis | volume = 74 | issue = 1 | pages = 322–328 | date = July 1995 | pmid = 8578479 | doi = 10.1055/s-0038-1642697 | s2cid = 23435953 }}</ref> 

Factor VIII is produced in the [[liver]]'s [[liver sinusoid|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 vessel]]s occurs.<ref name="NIH: F8 - coagulation factor VIII">{{cite web|title=NIH: F8 – coagulation factor VIII|url=http://ghr.nlm.nih.gov/gene/F8|publisher=National Institutes of Health}}</ref> 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.<ref name="NIH: F8 - coagulation factor VIII"/>

Factor VIII participates in [[blood coagulation]]; it is a cofactor for [[factor IX]]a, which, in the presence of Ca<sup>2+</sup> and [[phospholipid]]s, 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.<ref name = "entrez">{{cite web | title = Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)| url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2157}}</ref>

People with high levels of factor VIII are at increased risk for [[deep vein thrombosis]] and [[pulmonary embolism]].<ref name="Jenkins">{{cite journal | vauthors = Jenkins PV, Rawley O, Smith OP, O'Donnell JS | title = Elevated factor VIII levels and risk of venous thrombosis | journal = British Journal of Haematology | volume = 157 | issue = 6 | pages = 653–663 | date = June 2012 | pmid = 22530883 | doi = 10.1111/j.1365-2141.2012.09134.x | doi-access = free }}</ref> Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.<ref name="Milne">{{cite journal | vauthors = Milne DB, Nielsen FH | title = Effects of a diet low in copper on copper-status indicators in postmenopausal women | journal = The American Journal of Clinical Nutrition | volume = 63 | issue = 3 | pages = 358–364 | date = March 1996 | pmid = 8602593 | doi = 10.1093/ajcn/63.3.358 | doi-access = free }}</ref>

<!-- History, society and culture -->
[[Factor VIII (medication)|Factor VIII]] is available as a medication that is on the [[WHO Model List of Essential Medicines]], the most important medications needed in a basic [[health system]].<ref name=WHO2015E>{{cite web |url=https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |title=19th WHO Model List of Essential Medicines |date=April 2015 |access-date=May 10, 2015 |publisher=WHO }}</ref>

==Genetics==
[[File:F8 gene location.png|thumb|left|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.<ref>{{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 }}</ref> 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 [[intron]]s.<ref>{{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 }}</ref>

== Structure ==
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 = 1317–1325 | 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 = 434–439 | date = November 1999 | pmid = 10586886 | doi = 10.1038/46594 | s2cid = 4393638 | 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 = 16140–16145 | date = June 1998 | pmid = 9632668 | doi = 10.1074/jbc.273.26.16140 | doi-access = free }}</ref>

==Physiology==
FVIII is a [[glycoprotein]] pro[[Cofactor (biochemistry)|cofactor]].  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 [[Sinusoid (blood vessel)|sinusoidal cells]] of the [[liver]].<ref>{{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 }}</ref> [[Hemophilia A]] has been corrected by liver [[organ transplant|transplantation]].<ref name="Williams2010-8">{{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 }}</ref> Transplanting [[hepatocyte]]s was ineffective, but liver endothelial cells were effective.<ref name="Williams2010-8"/>

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 IX]]a in the [[coagulation cascade]]. It is a cofactor to [[factor IX]]a in the activation of [[factor X]], which, in turn, with its cofactor [[factor V]]a, activates more thrombin. Thrombin cleaves [[fibrin]]ogen into [[fibrin]] which [[polymer]]izes 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]].<ref>{{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 }}</ref>

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

Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.<ref>{{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 }}</ref><ref>{{cite book | vauthors = Rubin R, Leopold L |title=Hematologic Pathophysiology |publisher=Fence Creek Publishing |location=Madison, Conn |year=1998 |isbn=1-889325-04-X }}</ref>

==Medical use==
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{{main|Factor VIII (medication)}}
FVIII concentrated from donated blood plasma, or recombinant FVIII can be given to [[hemophiliac]]s 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.<ref name="urlOverview of Factor VIII Inhibitors">{{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 }}</ref>

==Immunostain target==
Factor VIII related antigen is used as a target for [[immunohistochemistry]], where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.<ref>{{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</ref>

==Contamination scandal==
{{Main|Contaminated haemophilia blood products}}In the 1980s, some pharmaceutical companies such as [[Baxter International]] and [[Bayer]] sparked controversy by continuing to sell [[Contaminated haemophilia blood products|contaminated factor VIII]] after new heat-treated versions were available.<ref name="NYT2003">{{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 }}</ref> 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).<ref name="NYT2003"/>

In the early 1990s, pharmaceutical companies began to produce [[Recombinant DNA|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.<ref>{{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 }}</ref><ref name=timesobit>{{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}}</ref>

== See also ==
* [[Ralph Kekwick]]
* [[Frances Rotblat]]
* [[Edward Shanbrom]]
* [[Edward Tuddenham]]
* [[Ryan White]]

== References ==
{{Reflist}}

== Further reading ==
{{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}}

== External links ==
* [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}}

{{PDB Gallery|geneid=2157}}
{{Coagulation}}

[[Category:Acute-phase proteins]]
[[Category:Recombinant proteins]]
[[Category:Coagulation system]]
[[Category:Drugs developed by Wyeth]]
[[Category:Drugs developed by Pfizer]]
[[Category:Cofactors]]