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{{Hatnote|For the documentary, see [[Factor 8: The Arkansas Prison Blood Scandal]]}}
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{{Infobox_gene}}
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'''Factor VIII''' ('''FVIII''') is an essential [[thrombus|blood-clot]]ting [[protein]], also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''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 = 342–7 | year = 1984 | pmid = 6438528 | doi = 10.1038/312342a0 }}</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 = 333–49 | date = October 1985 | pmid = 3935400 | doi = 10.1089/dna.1985.4.333 }}</ref> Defects in this gene result in [[hemophilia A]], a [[Dominance (genetics)#Recessive trait|recessive]] X-linked coagulation 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 = 322–8 | date = July 1995 | pmid = 8578479 | doi =  }}</ref> 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.<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"/>
| update_protein_box = yes
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{{GNF_Protein_box
| image = PBB_Protein_F8_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1d7p.
| Name = Coagulation factor VIII, procoagulant component (hemophilia A)
| HGNCid = 3546
| Symbol = F8
| AltSymbols =; AHF; DXS1253E; F8 protein; F8B; F8C; FVIII; HEMA
| OMIM = 306700
| ECnumber =
| Homologene = 49153
| MGIid = 88383
| GeneAtlas_image1 = PBB_GE_F8_205756_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}}
| Process = {{GNF_GO|id=GO:0006953 |text = acute-phase response}} {{GNF_GO|id=GO:0007155 |text = cell adhesion}} {{GNF_GO|id=GO:0007596 |text = blood coagulation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2157
    | Hs_Ensembl = ENSG00000185010
    | Hs_RefseqProtein = NP_000123
    | Hs_RefseqmRNA = NM_000132
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = X
    | Hs_GenLoc_start = 153717263
    | Hs_GenLoc_end = 153904192
    | Hs_Uniprot = P00451
    | Mm_EntrezGene = 14069
    | Mm_Ensembl = ENSMUSG00000031196
    | Mm_RefseqmRNA = NM_007977
    | Mm_RefseqProtein = NP_032003
    | Mm_GenLoc_db =   
    | Mm_GenLoc_chr = X
    | Mm_GenLoc_start = 71425575
    | Mm_GenLoc_end = 71635036
    | Mm_Uniprot = Q684Q7
  }}
}}
{{SI}}
{{CMG}}


==Overview==
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| access-date = }}</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 = 653–63 | date = June 2012 | pmid = 22530883 | doi = 10.1111/j.1365-2141.2012.09134.x }}</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 = 358–64 | date = March 1996 | pmid = 8602593 }}</ref>
 
<!-- History, society and culture -->
There is a [[Factor VIII (medication)|formulation 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=http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |title=19th WHO Model List of Essential Medicines (April 2015) |date=April 2015 |access-date=May 10, 2015 |publisher=WHO }}</ref>


'''Factor VIII''' (FVIII) is an essential [[clot]]ting factor. The lack of normal FVIII causes [[Hemophilia A]], an inherited bleeding disorder.
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa.  This 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. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder.<ref>{{cite web | title = Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2157| accessdate = }}</ref>
}}
==Genetics==
==Genetics==
The gene for Factor VIII is located on the [[X chromosome]] (Xq28). The gene for factor VIII presents an interesting primary structure, as in one of its introns another gene is embedded.<ref>{{cite journal |author=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 |year=1990 |pmid=2110545 |doi=}}</ref>.
[[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 = 326–30 | date = November 1984 | pmid = 6438525 }}</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 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 = 1317–25 | 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 }}</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>


==Physiology==
==Physiology==
FVIII is a [[glycoprotein]] pro[[cofactor]] synthesized and released into the bloodstream by the [[endothelium]]. In the circulating blood, it is mainly bound to [[von Willebrand factor]] (vWF, also known as ''Factor VIII-related antigen'') to form a stable complex. Upon activation by [[thrombin]] or [[factor X]]a, it dissociates from the complex to interact with [[Factor IX]]a the [[coagulation#The_coagulation_cascade|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.
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 |author=Kumar |author2=Abbas |author3=Fausto |title=Robbins and Cotran Pathologic Basis of Disease |publisher=Elsevier |location=Pennsylvania |year=2005 |page=655 |isbn=1-889325-04-X |oclc= |doi=}}</ref> [[Hemophilia A]] has been corrected by liver [[organ transplant|transplantation]].<ref name="Williams2010-8">Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U. (2010; edition 8) ''Williams Hematology''. 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.
 
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 = 267–75 | date = February 2004 | pmid = 14961153 | doi = 10.1160/th03-05-0310 }}</ref><ref>{{cite book |author=R. Rubin |author2=L. Leopold |title=Hematologic Pathophysiology |publisher=Fence Creek Publishing |location=Madison, Conn |year=1998 |pages= |isbn=1-889325-04-X |oclc= |doi=}}</ref>
 
==Medical use==
{{anchor|concentrate}}
{{main|Factor VIII (medication)}}
FVIII concentrated from donated blood plasma, or alternatively [[recombinant FVIIa]] can be given to [[hemophiliac]]s 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.<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 |author=Lozier J |year=2004 |work= |publisher=CMEonHemophilia.com |pages= |language= |archiveurl=https://web.archive.org/web/20081216021020/http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php |archivedate=2008-12-16 |quote= |accessdate=2009-01-07 |deadurl=yes |df= }}</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.
==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 web | url = https://query.nytimes.com/gst/fullpage.html?res=9A00E4DA1F3EF931A15756C0A9659C8B63&sec=&spon=&pagewanted=1=2157 | title = 2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas | vauthors = Bogdanich W, Koli E | date = 2003-05-22 | work = | publisher = The New York Times | pages = | quote = | accessdate = 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"/>


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


==Therapeutic use==
== See also ==
FVIII concentrated from donated blood plasma ([[Aafact]]), or alternatively [[recombinant]] FVIII can be given to [[hemophiliac]]s to restore [[hemostasis]]. Thus, FVIII is also known as '''''Anti''-hemophilic factor'''.
* [[Ralph Kekwick]]
* [[Ryan White]]
* [[Edward Tuddenham]]
* [[Edward Shanbrom]]


The transfer of a [[Blood plasma|plasma]] byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as [[HIV]] and [[hepatitis B]] and [[hepatitis C|C]] before purification methods were improved.  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. In particular, some pharmaceutical companies such as [[Bayer]] sparked controversy by continuing to sell [[Contaminated haemophilia blood products|contaminated factor VIII]] after new heat-treated versions were available.<ref>{{cite web | title = 2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas| url = http://query.nytimes.com/gst/fullpage.html?res=9A00E4DA1F3EF931A15756C0A9659C8B63&sec=&spon=&pagewanted=1=2157| accessdate = }}</ref>
== References ==
{{reflist|32em}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|32em}}
==Further reading==
* {{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 }}
{{refbegin | 2}}
* {{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 | doi =  }}
{{PBB_Further_reading
* {{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 }}
| citations =
* {{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 = 3983–96 | date = December 1998 | pmid = 9834200 | doi =  }}
*{{cite journal | author=Gitschier J |title=The molecular basis of hemophilia A. |journal=Ann. N. Y. Acad. Sci. |volume=614 |issue= |pages= 89-96 |year= 1991 |pmid= 1902642 |doi= }}
* {{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 }}
*{{cite journal | author=White GC, Shoemaker CB |title=Factor VIII gene and hemophilia A. |journal=Blood |volume=73 |issue= 1 |pages= 1-12 |year= 1989 |pmid= 2491949 |doi=  }}
* {{cite journal | vauthors = Lollar P | title = Molecular characterization of the immune response to factor VIII | journal = Vox Sanguinis | volume = 83 Suppl 1 | issue =  | pages = 403–8 | date = August 2002 | pmid = 12617176 | doi = 10.1111/j.1423-0410.2002.tb05342.x | series = 83 }}
*{{cite journal | author=Antonarakis SE, Kazazian HH, Tuddenham EG |title=Molecular etiology of factor VIII deficiency in hemophilia A. |journal=Hum. Mutat. |volume=5 |issue= 1 |pages= 1-22 |year= 1995 |pmid= 7728145 |doi= 10.1002/humu.1380050102 }}
* {{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 | author=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= 3983-96 |year= 1999 |pmid= 9834200 |doi=  }}
* {{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 = 760–9 | date = October 2005 | pmid = 16270627 | doi = 10.1160/TH05-02-0118 }}
*{{cite journal | author=Saenko EL, Ananyeva N, Kouiavskaia D, ''et al.'' |title=Molecular defects in coagulation Factor VIII and their impact on Factor VIII function. |journal=Vox Sang. |volume=83 |issue= 2 |pages= 89-96 |year= 2003 |pmid= 12201837 |doi= }}
* {{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 }}
*{{cite journal | author=Lollar P |title=Molecular characterization of the immune response to factor VIII. |journal=Vox Sang. |volume=83 Suppl 1 |issue=  |pages= 403-8 |year= 2003 |pmid= 12617176 |doi= }}
*{{cite journal | author=Fay PJ |title=Activation of factor VIII and mechanisms of cofactor action. |journal=Blood Rev. |volume=18 |issue= 1 |pages= 1-15 |year= 2004 |pmid= 14684146 |doi= }}
*{{cite journal | author=Lavigne-Lissalde G, Schved JF, Granier C, Villard S |title=Anti-factor VIII antibodies: a 2005 update. |journal=Thromb. Haemost. |volume=94 |issue= 4 |pages= 760-9 |year= 2005 |pmid= 16270627 |doi= 10.1160/TH05-04-0760 }}
*{{cite journal | author=Fang H, Wang L, Wang H |title=The protein structure and effect of factor VIII. |journal=Thromb. Res. |volume=119 |issue= 1 |pages= 1-13 |year= 2007 |pmid= 16487577 |doi= 10.1016/j.thromres.2005.12.015 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1404/  GeneReviews/NCBI/NIH/UW entry on Hemophilia A]
* [http://macromoleculeinsights.com/coagulationfactorviii.php The Coagulation Factor VIII Protein]
* [http://macromoleculeinsights.com/coagulationfactorviii.php The Coagulation Factor VIII Protein]
* {{MeshName|Factor+VIII}}
* {{MeshName|Factor+VIII}}


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


[[Category:Acute phase proteins]]
[[Category:Acute phase proteins]]
[[Category:Recombinant proteins]]
[[Category:Recombinant proteins]]
[[Category:Coagulation system]]
[[Category:Coagulation system]]
[[Category:Genes associated with genetic disorders]]
[[Category:Cofactors]]
[[Category:Cofactors]]
[[Category:Hematology]]
[[de:Antihämophiles Globulin A]]
[[es:Factor VIII de coagulación]]
[[fr:Facteur VIII]]
[[pl:Czynnik VIII]]
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Latest revision as of 05:29, 12 January 2019

For the documentary, see Factor 8: The Arkansas Prison Blood Scandal
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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.[1][2] Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder.[3] 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.[4] 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.[4]

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.[5]

People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism.[6] Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.[7]

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.[8]

Genetics

File:F8 gene location.png
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.[9] 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.[10]

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.[11] The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.[12]

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.[13]

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.[14] Hemophilia A has been corrected by liver transplantation.[15] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.[15]

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.[16][17]

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.[18]

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.[19] 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).[19]

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.

See also

References

  1. ↑ 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): 342–7. doi:10.1038/312342a0. PMID 6438528.
  2. ↑ 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.
  3. ↑ Antonarakis SE (July 1995). "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thrombosis and Haemostasis. 74 (1): 322–8. PMID 8578479.
  4. ↑ 4.0 4.1 "NIH: F8 - coagulation factor VIII". National Institutes of Health.
  5. ↑ "Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)".
  6. ↑ 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.
  7. ↑ 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. PMID 8602593.
  8. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  9. ↑ 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. PMID 6438525.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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): 434–9. doi:10.1038/46594. PMID 10586886.
  13. ↑ 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): 16140–5. doi:10.1074/jbc.273.26.16140. PMID 9632668.
  14. ↑ Kumar; Abbas; Fausto (2005). Robbins and Cotran Pathologic Basis of Disease. Pennsylvania: Elsevier. p. 655. ISBN 1-889325-04-X.
  15. ↑ 15.0 15.1 Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U. (2010; edition 8) Williams Hematology. McGraw-Hill. ISBN 978-0-07-162151-9
  16. ↑ 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.
  17. ↑ R. Rubin; L. Leopold (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. ISBN 1-889325-04-X.
  18. ↑ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. Archived from the original on 2008-12-16. Retrieved 2009-01-07.
  19. ↑ 19.0 19.1 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.

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. doi:10.1111/j.1749-6632.1991.tb43694.x. PMID 1902642.
  • 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. doi:10.1002/humu.1380050102. PMID 7728145.
  • 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". Vox Sanguinis. 83 (2): 89–96. doi:10.1046/j.1423-0410.2002.00183.x. PMID 12201837.
  • Lollar P (August 2002). "Molecular characterization of the immune response to factor VIII". Vox Sanguinis. 83. 83 Suppl 1: 403–8. doi:10.1111/j.1423-0410.2002.tb05342.x. PMID 12617176.
  • Fay PJ (March 2004). "Activation of factor VIII and mechanisms of cofactor action". Blood Reviews. 18 (1): 1–15. doi:10.1016/S0268-960X(03)00025-0. 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): 760–9. doi:10.1160/TH05-02-0118. PMID 16270627.
  • Fang H, Wang L, Wang H (2007). "The protein structure and effect of factor VIII". Thrombosis Research. 119 (1): 1–13. doi:10.1016/j.thromres.2005.12.015. PMID 16487577.

External links

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