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Coagulation factor VIII, procoagulant component (hemophilia A)

PDB rendering based on 1d7p.
Available structures
1d7p, 1iqd, 3cdz
Identifiers
Symbols F8; AHF; DXS1253E; F8 protein; F8B; F8C; FVIII; HEMA
External IDs OMIM306700 MGI88383 HomoloGene49153 GeneCards: F8 Gene
RNA expression pattern
PBB GE F8 205756 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2157 14069
Ensembl ENSG00000185010 ENSMUSG00000031196
UniProt P00451 Q684Q7
RefSeq (mRNA) NM_000132 NM_007977
RefSeq (protein) NP_000123 NP_032003
Location (UCSC) Chr X:
153.72 - 153.9 Mb
Chr X:
71.43 - 71.64 Mb
PubMed search [1] [2]

Factor VIII (FVIII) is an essential blood clotting factor 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 well known recessive X-linked coagulation disorder.[3]

Factor VIII participates in blood coagulation; it is a cofactor for factor IXa which, in the presence of Ca+2 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.[4]

Contents

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.[5]

Physiology

FVIII is a glycoprotein procofactor. It has been found to be synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver[6], though there is still considerable ambiguity as to what the primary site of release in humans is. In the circulating blood, it is mainly bound to von Willebrand factor to form a stable complex. 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.[7]

Therapeutic use

FVIII concentrated from donated blood plasma (Aafact), 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.[8 ]

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. [9] 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. 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. PMID 3935400.  
  3. ^ Antonarakis SE (July 1995). "Molecular genetics of coagulation factor VIII gene and hemophilia A". Thromb. Haemost. 74 (1): 322–8. PMID 8578479.  
  4. ^ "Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2157.  
  5. ^ 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. doi:10.1016/0888-7543(90)90512-S. PMID 2110545.  
  6. ^ Kumar, Abbas, Fausto (2005). Robbins and Cotran Pathologic Basis of Disease. Pennsylvania: Elsevier. pp. 655. ISBN 1-889325-04-X.  
  7. ^ R. Rubin, L. Leopold (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. ISBN 1-889325-04-X.  
  8. ^ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. http://www.cmeonhemophilia.com/pub/overview.of.factor.viii.inhibitors.php. Retrieved 2009-01-07.  
  9. ^ Bogdanich W, Koli E (2003-05-22). "2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas". The New York Times. http://query.nytimes.com/gst/fullpage.html?res=9A00E4DA1F3EF931A15756C0A9659C8B63&sec=&spon=&pagewanted=1=2157. Retrieved 2009-01-07.  

Further reading

  • Gitschier J (1991). "The molecular basis of hemophilia A". Ann. N. Y. Acad. Sci. 614: 89–96. doi:10.1111/j.1749-6632.1991.tb43694.x. PMID 1902642.  
  • White GC, Shoemaker CB (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". Hum. Mutat. 5 (1): 1–22. doi:10.1002/humu.1380050102. PMID 7728145.  
  • 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. PMID 9834200.  
  • 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. doi:10.1046/j.1423-0410.2002.00183.x. PMID 12201837.  
  • Lollar P (2003). "Molecular characterization of the immune response to factor VIII". Vox Sang. 83 Suppl 1: 403–8. PMID 12617176.  
  • Fay PJ (2004). "Activation of factor VIII and mechanisms of cofactor action". Blood Rev. 18 (1): 1–15. doi:10.1016/S0268-960X(03)00025-0. PMID 14684146.  
  • Lavigne-Lissalde G, Schved JF, Granier C, Villard S (2005). "Anti-factor VIII antibodies: a 2005 update". Thromb. Haemost. 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". Thromb. Res. 119 (1): 1–13. doi:10.1016/j.thromres.2005.12.015. PMID 16487577.  

External links


Simple English

Factor VIII (FVIII) is a blood clotting factor that is also called anti-hemophilic factor (AHF). In humans, Factor VII is in the F8 gene. If there is something wrong with this gene, you get hemophilia A, which is a recessive disorder. The gene for Factor VIII is on the X chromosome.








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