World Library  
Flag as Inappropriate
Email this Article

Factor VIII

Article Id: WHEBN0000546073
Reproduction Date:

Title: Factor VIII  
Author: World Heritage Encyclopedia
Language: English
Subject: Coagulation, Von Willebrand factor, Aafact, Haemophilia, Protein S deficiency
Collection: Acute Phase Proteins, Coagulation System, Cofactors, Recombinant Proteins
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Factor VIII

Coagulation factor VIII, procoagulant component
PDB rendering based on 2R7E.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; AHF; DXS1253E; F8B; F8C; FVIII; HEMA
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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 results in hemophilia A, a recessive X-linked coagulation disorder.[3] Factor VIII is produced in liver sinusoidal cells and endothelial cells outside of 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 decrease levels of factor VIII.[7]

Contents

  • Genetics 1
  • Physiology 2
  • Therapeutic use 3
  • Contamination scandal 4
  • See also 5
  • References 6
  • Further reading 7
  • External links 8

Genetics

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.[8]

Physiology

FVIII is a transplantation.[10] Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.[10]

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.[11][12]

Therapeutic use

FVIII concentrated from donated blood plasma (Aafact or Alphanate, Monoclate-P®), or alternatively recombinant FVIII can be given to hemophiliacs to restore hemostasis.

The transfer of a plasma byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as hepatitis B and C and HIV before purification methods were improved.

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.[13]

Contamination scandal

In the 1980s, some pharmaceutical companies such as Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.[14] 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).[14]

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.  
  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.  
  3. ^ Antonarakis SE (July 1995). "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thromb. Haemost. 74 (1): 322–8.  
  4. ^ a b "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, et al. (2012). "Elevated factor VIII levels and risk of venous thrombosis". Br J Haematol 157 (6): 653–63.  
  7. ^ Milne, David B, Nielsen Forrest H. (1996). "Effects of a diet low in copper on copper-status indicators in postmenopausal women.". Am J Clin Nutr. 63 (3): 358–64.  
  8. ^ Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J (1990). "A transcribed gene in an intron of the human factor VIII gene". Genomics 7 (1): 1–11.  
  9. ^ Kumar, Abbas, Fausto (2005). Robbins and Cotran Pathologic Basis of Disease. Pennsylvania: Elsevier. p. 655.  
  10. ^ a b 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
  11. ^ Hollestelle, MJ; Geertzen, HG; Straatsburg, IH; van Gulik, TM; van Mourik, JA (Feb 2004). "Factor VIII expression in liver disease.". Thrombosis and haemostasis 91 (2): 267–75.  
  12. ^ R. Rubin, L. Leopold (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing.  
  13. ^ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. Retrieved 2009-01-07. 
  14. ^ a b 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". Ann. N. Y. Acad. Sci. 614 (1 Process in Va): 89–96.  
  • White GC, Shoemaker CB (1989). "Factor VIII gene and hemophilia A". Blood 73 (1): 1–12.  
  • Antonarakis SE, Kazazian HH, Tuddenham EG (1995). "Molecular etiology of factor VIII deficiency in hemophilia A". Hum. Mutat. 5 (1): 1–22.  
  • Lenting PJ, van Mourik JA, Mertens K (1999). "The life cycle of coagulation factor VIII in view of its structure and function". Blood 92 (11): 3983–96.  
  • Saenko EL, Ananyeva N, Kouiavskaia D, et al. (2003). "Molecular defects in coagulation Factor VIII and their impact on Factor VIII function". Vox Sang. 83 (2): 89–96.  
  • Lollar P (2003). "Molecular characterization of the immune response to factor VIII". Vox Sang. 83. Suppl 1: 403–8.  
  • Fay PJ (2004). "Activation of factor VIII and mechanisms of cofactor action". Blood Rev. 18 (1): 1–15.  
  • Lavigne-Lissalde G, Schved JF, Granier C, Villard S (2005). "Anti-factor VIII antibodies: a 2005 update". Thromb. Haemost. 94 (4): 760–9.  
  • Fang H, Wang L, Wang H (2007). "The protein structure and effect of factor VIII". Thromb. Res. 119 (1): 1–13.  

External links

  • GeneReviews/NCBI/NIH/UW entry on Hemophilia A
  • The Coagulation Factor VIII Protein
  • Factor VIII at the US National Library of Medicine Medical Subject Headings (MeSH)
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 


Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.