Biology:Factor VIII

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Short description: Blood-clotting protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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, an 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

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 (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

Main page: Medicine: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.[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

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.[21][22]

See also

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

References

  1. ↑ "Molecular cloning of a cDNA encoding human antihaemophilic factor". Nature 312 (5992): 342–47. 1984. doi:10.1038/312342a0. PMID 6438528. Bibcode: 1984Natur.312..342T. 
  2. ↑ "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. October 1985. doi:10.1089/dna.1985.4.333. PMID 3935400. 
  3. ↑ "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thrombosis and Haemostasis 74 (1): 322–28. July 1995. doi:10.1055/s-0038-1642697. PMID 8578479. 
  4. ↑ 4.0 4.1 "NIH: F8 – coagulation factor VIII". National Institutes of Health. http://ghr.nlm.nih.gov/gene/F8. 
  5. ↑ "Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2157. 
  6. ↑ "Elevated factor VIII levels and risk of venous thrombosis". British Journal of Haematology 157 (6): 653–63. June 2012. doi:10.1111/j.1365-2141.2012.09134.x. PMID 22530883. 
  7. ↑ "Effects of a diet low in copper on copper-status indicators in postmenopausal women". The American Journal of Clinical Nutrition 63 (3): 358–64. March 1996. doi:10.1093/ajcn/63.3.358. PMID 8602593. 
  8. ↑ "19th WHO Model List of Essential Medicines". WHO. April 2015. https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf. 
  9. ↑ "Characterization of the human factor VIII gene". Nature 312 (5992): 326–30. November 1984. doi:10.1038/312326a0. PMID 6438525. Bibcode: 1984Natur.312..326G. 
  10. ↑ "A transcribed gene in an intron of the human factor VIII gene". Genomics 7 (1): 1–11. May 1990. doi:10.1016/0888-7543(90)90512-S. PMID 2110545. 
  11. ↑ "Structural investigation of the A domains of human blood coagulation factor V by molecular modeling". Protein Science 7 (6): 1317–25. June 1998. doi:10.1002/pro.5560070607. PMID 9655335. 
  12. ↑ "Crystal structures of the membrane-binding C2 domain of human coagulation factor V". Nature 402 (6760): 434–39. November 1999. doi:10.1038/46594. PMID 10586886. Bibcode: 1999Natur.402..434M. 
  13. ↑ "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): 16140–45. June 1998. doi:10.1074/jbc.273.26.16140. PMID 9632668. 
  14. ↑ Robbins and Cotran Pathologic Basis of Disease (9th ed.). Pennsylvania: Elsevier. 2005. p. 655. ISBN 978-0-8089-2450-0. 
  15. ↑ 15.0 15.1 Williams Hematology (8th ed.). McGraw-Hill. 2010. ISBN 978-0-07-162151-9. 
  16. ↑ Fischer, Kathelijn; Pendu, Ronan; van Schooten, Carina J.; van Dijk, Karin; Denis, Cécile V.; van den Berg, H. Marijke; Lenting, Peter J. (2009-08-25). "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. doi:10.1371/journal.pone.0006745. ISSN 1932-6203. PMID 19707594. Bibcode: 2009PLoSO...4.6745F. 
  17. ↑ "Factor VIII expression in liver disease". Thrombosis and Haemostasis 91 (2): 267–75. February 2004. doi:10.1160/th03-05-0310. PMID 14961153. 
  18. ↑ Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. 1998. ISBN 1-889325-04-X. 
  19. ↑ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php. 
  20. ↑ Nat Pernick, M.D.. "Stains & CD markers - Factor VIII related antigen". https://www.pathologyoutlines.com/topic/stainsfactorviii.html.  Topic Completed: 1 July 2012. Minor changes: 25 June 2021
  21. ↑ Tuddenham EG, Trabold NC, Collins JA, Hoyer LW (1979). "The properties of factor VIII coagulant activity prepared by immunoadsorbent chromatography". J Lab Clin Med 93 (1): 40–53. PMID 366050. 
  22. ↑ "Frances Rotblat obituary". The Times. 12 June 2021. https://www.thetimes.co.uk/article/frances-rotblat-obituary-q9nbkp07d. Retrieved 12 June 2021. 

Further reading

External links



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