Factor VIII

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Coagulation factor VIII, procoagulant component (hemophilia A)
PDB rendering based on 1d7p.
Available structures: 1d7p, 1iqd
Identifiers
Symbol(s) F8; AHF; DXS1253E; F8 protein; F8B; F8C; FVIII; HEMA
External IDs OMIM: 306700 MGI: 88383 HomoloGene: 49153
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 2157 14069
Ensembl ENSG00000185010 ENSMUSG00000031196
Uniprot P00451 Q684Q7
Refseq NM_000132 (mRNA)
NP_000123 (protein)		 NM_007977 (mRNA)
NP_032003 (protein)
Location Chr X: 153.72 - 153.9 Mb Chr X: 71.43 - 71.64 Mb
Pubmed search [1] [2]

Factor VIII (FVIII) is an essential clotting factor. The lack of normal FVIII causes Hemophilia A, an inherited bleeding disorder. This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca2+ and phospholipids, converts factor X to the activated form Xa. This 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. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder.[1]

Contents

[edit] 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.[2].

[edit] Physiology

FVIII is a glycoprotein procofactor synthesized and released into the bloodstream by the endothelium. In the circulating blood, it is mainly bound to von Willebrand factor (vWF, also known as Factor VIII-related antigen) to form a stable complex. Upon activation by thrombin, (Factor IIa), it dissociates from the complex to interact with Factor IXa 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 synthesized predominantly in the vascular endothelium and is not affected by liver disease. In fact, levels usually are elevated in such instances.[3]

[edit] Therapeutic use

FVIII concentrated from donated blood plasma (Aafact), or alternatively recombinant FVIII can be given to hemophiliacs to restore hemostasis. Thus, FVIII is also known as Anti-hemophilic factor.

The transfer of a plasma byproduct into the blood stream of a patient with hemophilia often led to the transmission of diseases such as HIV and hepatitis B and C 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.[4]

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. In particular, some pharmaceutical companies such as Bayer sparked controversy by continuing to sell contaminated factor VIII after new heat-treated versions were available.[5]

[edit] References

  1. ^ Entrez Gene: F8 coagulation factor VIII, procoagulant component (hemophilia A).
  2. ^ 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. 
  3. ^ R. Rubin, L. Leopold (1998). Hematologic Pathophysiology. Madison, Conn: Fence Creek Publishing. ISBN 1-889325-04-X. 
  4. ^ = Overview of Factor VIII Inhibitors.
  5. ^ 2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas.

[edit] 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. 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. 

[edit] External links

v • d • e
Proteins: coagulation
Coagulation factors
primary hemostasis: vWF

intrinsic pathway: HMWK/Bradykinin - Kallikrein - Hageman / FXII - FXI - FIX - FVIII

extrinsic pathway: Tissue factor / FIII - FVII

common pathway: FX - FV - (Pro)thrombin / FII, Fibrin / FI - FXIII
Inhibitors
Fibrinolysis