Factor VIII explained

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.^{[1] [2]} Defects in this gene result in hemophilia A, an X-linked bleeding disorder.^[3]

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.^[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]

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.^[8]

Genetics

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 (F8A1) 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.

The factor VIII protein has a half-life of 12 hours in the blood stream when stabilized by the von Willebrand factor. ^[16]

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.^{[17] [18]}

Medical use

See 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.^[19]

Immunostain target

Factor VIII related antigen is used as a target for immunohistochemistry, where endothelial cells, megakaryocytes, platelets and mast cells normally stain positive.^[20]

Contamination scandal

See 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.^[21] 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).^[21]

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.^{[22] [23]}

See also

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

Further reading

• Gitschier J . The molecular basis of hemophilia A . Annals of the New York Academy of Sciences . 614 . 1 Process in Va . 89–96 . 1991 . 1902642 . 10.1111/j.1749-6632.1991.tb43694.x . 26493612 . 1991NYASA.614...89G .
• White GC, Shoemaker CB . Factor VIII gene and hemophilia A . Blood . 73 . 1 . 1–12 . January 1989 . 2491949 .
• Antonarakis SE, Kazazian HH, Tuddenham EG . Molecular etiology of factor VIII deficiency in hemophilia A . Human Mutation . 5 . 1 . 1–22 . 1995 . 7728145 . 10.1002/humu.1380050102 . 2346510 . free .
• Lenting PJ, van Mourik JA, Mertens K . The life cycle of coagulation factor VIII in view of its structure and function . Blood . 92 . 11 . 3983–3996 . December 1998 . 9834200 . 10.1182/blood.V92.11.3983 .
• Saenko EL, Ananyeva N, Kouiavskaia D, Schwinn H, Josic D, Shima M, Hauser CA, Pipe S . Molecular defects in coagulation Factor VIII and their impact on Factor VIII function . Vox Sanguinis . 83 . 2 . 89–96 . August 2002 . 12201837 . 10.1046/j.1423-0410.2002.00183.x . free . 2027.42/74861 . free .
• Lollar P . Molecular characterization of the immune response to factor VIII . Vox Sanguinis . 83 . Suppl 1 . 403–408 . August 2002 . 12617176 . 10.1111/j.1423-0410.2002.tb05342.x . 83 . 26050729 .
• Fay PJ . Activation of factor VIII and mechanisms of cofactor action . Blood Reviews . 18 . 1 . 1–15 . March 2004 . 14684146 . 10.1016/S0268-960X(03)00025-0 .
• Lavigne-Lissalde G, Schved JF, Granier C, Villard S . Anti-factor VIII antibodies: a 2005 update . Thrombosis and Haemostasis . 94 . 4 . 760–769 . October 2005 . 16270627 . 10.1160/TH05-02-0118 . 38533008 .
• Fang H, Wang L, Wang H . The protein structure and effect of factor VIII . Thrombosis Research . 119 . 1 . 1–13 . 2007 . 16487577 . 10.1016/j.thromres.2005.12.015 .

External links

• GeneReviews/NCBI/NIH/UW entry on Hemophilia A
• The Coagulation Factor VIII Protein

Notes and References

1. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC . Molecular cloning of a cDNA encoding human antihaemophilic factor . Nature . 312 . 5992 . 342–347 . 1984 . 6438528 . 10.1038/312342a0 . 4313575 . 1984Natur.312..342T .
2. Truett MA, Blacher R, Burke RL, Caput D, Chu C, Dina D, Hartog K, Kuo CH, Masiarz FR, Merryweather JP . Characterization of the polypeptide composition of human factor VIII:C and the nucleotide sequence and expression of the human kidney cDNA . Dna . 4 . 5 . 333–349 . October 1985 . 3935400 . 10.1089/dna.1985.4.333 .
3. Antonarakis SE . Molecular genetics of coagulation factor VIII gene and hemophilia A . Thrombosis and Haemostasis . 74 . 1 . 322–328 . July 1995 . 8578479 . 10.1055/s-0038-1642697 . 23435953 .
4. Web site: NIH: F8 – coagulation factor VIII. National Institutes of Health.
5. Web site: Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A).
6. Jenkins PV, Rawley O, Smith OP, O'Donnell JS . Elevated factor VIII levels and risk of venous thrombosis . British Journal of Haematology . 157 . 6 . 653–663 . June 2012 . 22530883 . 10.1111/j.1365-2141.2012.09134.x . free .
7. Milne DB, Nielsen FH . Effects of a diet low in copper on copper-status indicators in postmenopausal women . The American Journal of Clinical Nutrition . 63 . 3 . 358–364 . March 1996 . 8602593 . 10.1093/ajcn/63.3.358 . free .
8. Web site: 19th WHO Model List of Essential Medicines . April 2015 . May 10, 2015 . WHO .
9. Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM . Characterization of the human factor VIII gene . Nature . 312 . 5992 . 326–330 . November 1984 . 6438525 . 10.1038/312326a0 . 4358041 . 1984Natur.312..326G .
10. Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J . A transcribed gene in an intron of the human factor VIII gene . Genomics . 7 . 1 . 1–11 . May 1990 . 2110545 . 10.1016/0888-7543(90)90512-S .
11. Villoutreix BO, Dahlbäck B . Structural investigation of the A domains of human blood coagulation factor V by molecular modeling . Protein Science . 7 . 6 . 1317–1325 . June 1998 . 9655335 . 2144041 . 10.1002/pro.5560070607 .
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 . Crystal structures of the membrane-binding C2 domain of human coagulation factor V . Nature . 402 . 6760 . 434–439 . November 1999 . 10586886 . 10.1038/46594 . 4393638 . 1999Natur.402..434M .
13. Thorelli E, Kaufman RJ, Dahlbäck B . 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 . 16140–16145 . June 1998 . 9632668 . 10.1074/jbc.273.26.16140 . free .
14. Book: Kumar V, Abbas A, Aster J . Robbins and Cotran Pathologic Basis of Disease . Elsevier . Pennsylvania . 2005 . 655 . 978-0-8089-2450-0 . 9th .
15. Book: Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U . 2010 . 8th . Williams Hematology . McGraw-Hill . 978-0-07-162151-9 .
16. Fischer K, Pendu R, van Schooten CJ, van Dijk K, Denis CV, van den Berg HM, Lenting PJ . Models for prediction of factor VIII half-life in severe haemophiliacs: distinct approaches for blood group O and non-O patients . PloS One . 4 . 8 . e6745 . August 2009 . 19707594 . 2727052 . 10.1371/journal.pone.0006745 . free . 2009PLoSO...4.6745F .
17. Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA . Factor VIII expression in liver disease . Thrombosis and Haemostasis . 91 . 2 . 267–275 . February 2004 . 14961153 . 10.1160/th03-05-0310 . 20091477 .
18. Book: Rubin R, Leopold L . Hematologic Pathophysiology . Fence Creek Publishing . Madison, Conn . 1998 . 1-889325-04-X .
19. Web site: Overview of Factor VIII Inhibitors . Lozier J . 2004 . CMEonHemophilia.com . https://web.archive.org/web/20081216021020/http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php . 2008-12-16 . 2009-01-07 . dead .
20. Web site: Stains & CD markers - Factor VIII related antigen. Pernick N . Pathology Outlines. Topic Completed: 1 July 2012. Minor changes: 25 June 2021
21. Bogdanich W, Koli E . 2 paths of Bayer drug in 80's: riskier one steered overseas . The New York Times on the Web . A1, C5 . May 2003 . 12812170 . 2009-01-07 .
22. Tuddenham EG, Trabold NC, Collins JA, Hoyer LW . The properties of factor VIII coagulant activity prepared by immunoadsorbent chromatography . The Journal of Laboratory and Clinical Medicine . 93 . 1 . 40–53 . January 1979 . 366050 .
23. News: The Times. Frances Rotblat obituary. 12 June 2021. 12 June 2021.