Factor VIII

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 PDB Ortholog search: PDBe RCSB List of PDB id codes 1CFG, 1D7P, 1IQD, 2R7E, 3CDZ, 3HNB, 3HNY, 3HOB, 4BDV, 1FAC, 3J2Q, 3J2S, 4KI5, 4PT6, 4XZU
Identifiers
Aliases	F8, AHF, DXS1253E, F8B, F8C, FVIII, HEMA, coagulation factor VIII, THPH13
External IDs	OMIM: 300841; MGI: 88383; HomoloGene: 49153; GeneCards: F8; OMA:F8 - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xq28 Start 154,835,788 bp End 155,026,940 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A7.3|X 38.17 cM Start 74,216,321 bp End 74,426,221 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in myocardium of left ventricle right ventricle right auricle cardiac muscle tissue of right atrium tibialis anterior muscle apex of heart pericardium abdominal fat lower lobe of lung Epithelium of choroid plexus Top expressed in mesenteric lymph nodes olfactory epithelium liver embryo right kidney embryo left lobe of liver genital tubercle proximal tubule tail of embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding protein binding oxidoreductase activity copper ion binding Cellular component endoplasmic reticulum lumen plasma membrane extracellular region COPII-coated ER to Golgi transport vesicle endoplasmic reticulum-Golgi intermediate compartment membrane platelet alpha granule lumen Golgi membrane extracellular space Biological process hemostasis platelet degranulation blood coagulation endoplasmic reticulum to Golgi vesicle-mediated transport COPII vesicle coating acute-phase response blood coagulation, intrinsic pathway platelet activation Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr X: 74.22 – 74.43 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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. Defects in this gene result in hemophilia A, an X-linked bleeding disorder.

Factor VIII is produced in the liver's 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. 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.

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.

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

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.

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. 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.

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

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.

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

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.

The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor.

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.

Medical use

Main article: 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.

Immunostain target

Factor VIII related antigen is used as a target for immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.

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. 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.

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.

See also

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

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. Bibcode:1991NYASA.614...89G. doi:10.1111/j.1749-6632.1991.tb43694.x. PMID 1902642. 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. doi:10.1002/humu.1380050102. PMID 7728145. 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): 3983–3996. doi:10.1182/blood.V92.11.3983. PMID 9834200.
• Saenko EL, Ananyeva N, Kouiavskaia D, Schwinn H, Josic D, Shima M, et al. (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. hdl:2027.42/74861. PMID 12201837.
• Lollar P (August 2002). "Molecular characterization of the immune response to factor VIII". Vox Sanguinis. 83. 83 (Suppl 1): 403–408. doi:10.1111/j.1423-0410.2002.tb05342.x. PMID 12617176. S2CID 26050729.
• 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): 760–769. doi:10.1160/TH05-02-0118. PMID 16270627. S2CID 38533008.
• 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

• 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.