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Factor VIII: Diferenzas entre revisións

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Revisión como estaba o 4 de setembro de 2018 ás 15:42

O factor VIII (FVIII) é unha proteína esencial par a coagulación do sangue, tamén chamado factor anihemofílico (AHF). Nos humanos o factor VIII está codificado polo xene F8 do cromosoma X.[1][2] 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.[3]

Xenética

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.[4] 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]

Estrutura

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.[6] The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.[7]

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.[8]

Fisioloxía

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.[9] Hemophilia A has been corrected by liver 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]

Uso médico

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.[13]

Contamination scandal

Modelo:Main articleIn the 1980s, some pharmaceutical companies such as Baxter International and Bayer[14] sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.[15] 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[16], a concern that had been discussed by Bayer and the U.S. Food and Drug Administration (FDA).[15]

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. -->

Notas

  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. doi:10.1038/312342a0. 
  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. doi:10.1089/dna.1985.4.333. 
  3. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Consultado o May 10, 2015. 
  4. ↑ Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM (November 1984). "Characterization of the human factor VIII gene". Nature 312 (5992): 326–30. PMID 6438525. 
  5. ↑ Levinson B, Kenwrick S, Lakich D, Hammonds G, Gitschier J (May 1990). "A transcribed gene in an intron of the human factor VIII gene". Genomics 7 (1): 1–11. PMID 2110545. doi:10.1016/0888-7543(90)90512-S. 
  6. ↑ Villoutreix BO, Dahlbäck B (June 1998). "Structural investigation of the A domains of human blood coagulation factor V by molecular modeling". Protein Science 7 (6): 1317–25. PMC 2144041. PMID 9655335. doi:10.1002/pro.5560070607. 
  7. ↑ 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 (November 1999). "Crystal structures of the membrane-binding C2 domain of human coagulation factor V". Nature 402 (6760): 434–9. PMID 10586886. doi:10.1038/46594. 
  8. ↑ Thorelli E, Kaufman RJ, Dahlbäck B (June 1998). "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): 16140–5. PMID 9632668. doi:10.1074/jbc.273.26.16140. 
  9. ↑ Kumar; Abbas; Fausto (2005). Robbins and Cotran Pathologic Basis of Disease. Pennsylvania: Elsevier. p. 655. ISBN 1-889325-04-X. 
  10. ↑ 10,0 10,1 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 (February 2004). "Factor VIII expression in liver disease". Thrombosis and Haemostasis 91 (2): 267–75. PMID 14961153. doi:10.1160/th03-05-0310. 
  12. ↑ R. Rubin; L. Leopold (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. ISBN 1-889325-04-X. 
  13. ↑ Lozier J (2004). "Overview of Factor VIII Inhibitors". CMEonHemophilia.com. Arquivado dende o orixinal o 2008-12-16. Consultado o 2009-01-07. 
  14. ↑ "Companies". Factor 8 Campaign UK. 
  15. ↑ 15,0 15,1 Bogdanich W, Koli E (2003-05-22). "2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas". The New York Times. Consultado o 2009-01-07. 
  16. ↑ "Contaminated Blood Scandal". Factor 8 Campaign UK. 

Véxase tmén

Bibliografía

  • Gitschier J (1991). "The molecular basis of hemophilia A". Annals of the New York Academy of Sciences 614 (1 Process in Va): 89–96. PMID 1902642. doi:10.1111/j.1749-6632.1991.tb43694.x. 
  • 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. PMID 7728145. doi:10.1002/humu.1380050102. 
  • 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): 3983–96. PMID 9834200. 
  • Saenko EL, Ananyeva N, Kouiavskaia D, Schwinn H, Josic D, Shima M, Hauser CA, Pipe S (August 2002). "Molecular defects in coagulation Factor VIII and their impact on Factor VIII function". Vox Sanguinis 83 (2): 89–96. PMID 12201837. doi:10.1046/j.1423-0410.2002.00183.x. 
  • Lollar P (August 2002). "Molecular characterization of the immune response to factor VIII". Vox Sanguinis. 83. 83 Suppl 1: 403–8. PMID 12617176. doi:10.1111/j.1423-0410.2002.tb05342.x. 
  • Fay PJ (March 2004). "Activation of factor VIII and mechanisms of cofactor action". Blood Reviews 18 (1): 1–15. PMID 14684146. doi:10.1016/S0268-960X(03)00025-0. 
  • Lavigne-Lissalde G, Schved JF, Granier C, Villard S (October 2005). "Anti-factor VIII antibodies: a 2005 update". Thrombosis and Haemostasis 94 (4): 760–9. PMID 16270627. doi:10.1160/TH05-02-0118. 
  • Fang H, Wang L, Wang H (2007). "The protein structure and effect of factor VIII". Thrombosis Research 119 (1): 1–13. PMID 16487577. doi:10.1016/j.thromres.2005.12.015. 

Ligazóns externas

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