Factor V

Factor V
Coagulation factor V (proaccelerin, labile factor)

PDB rendering based on 1czs.
Identifiers
Symbols F5; FVL; PCCF
External IDs OMIM612309 MGI88382 HomoloGene104 GeneCards: F5 Gene
RNA expression pattern
PBB GE F5 204714 s at tn.png
PBB GE F5 204713 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2153 14067
Ensembl ENSG00000198734 ENSMUSG00000026579
UniProt P12259 n/a
RefSeq (mRNA) NM_000130.4 NM_007976.2
RefSeq (protein) NP_000121.2 NP_032002.1
Location (UCSC) Chr 1:
169.48 – 169.56 Mb
Chr 1:
166.08 – 166.15 Mb
PubMed search [1] [2]

Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.

Contents

Genetics

The gene for factor V is located on the first chromosome (1q23). It is genomically related to the family of multicopper oxidases, and is homologous to coagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330000.

Physiology

Factor V circulates in plasma as a single-chain molecule with a plasma half-life of about 12 hours. Half-lives up to 36 hours have been reported, though.

Factor V is able to bind to activated platelets and is activated by thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. Factor V is active as a cofactor of the thrombinase complex. The activated factor X (FXa) enzyme requires Ca++ and activated factor V to convert prothrombin to thrombin on the cell surface membrane.

Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin, thrombin acts to decrease clotting by activating Protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.

Role in disease

Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion.

Other mutations of factor V are associated with venous thrombosis. They are the most common hereditary causes for thrombophilia (a tendency to form blood clots). The most common one of these, factor V Leiden, is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.

Condition Prothrombin time Partial thromboplastin time Bleeding time Platelet count
Vitamin K deficiency or warfarin prolonged prolonged unaffected unaffected
Disseminated intravascular coagulation prolonged prolonged prolonged decreased
von Willebrand disease unaffected prolonged prolonged unaffected
Haemophilia unaffected prolonged unaffected unaffected
Aspirin unaffected unaffected prolonged unaffected
Thrombocytopenia unaffected unaffected prolonged decreased
Early Liver failure prolonged unaffected unaffected unaffected
End-stage Liver failure prolonged prolonged prolonged decreased
Uremia unaffected unaffected prolonged unaffected
Congenital afibrinogenemia prolonged prolonged prolonged unaffected
Factor V deficiency prolonged prolonged unaffected unaffected
Factor X deficiency as seen in amyloid purpura prolonged prolonged unaffected unaffected
Glanzmann's thrombasthenia unaffected unaffected prolonged unaffected
Bernard-Soulier syndrome unaffected unaffected prolonged unaffected [1]

History

Until the discovery of factor V, coagulation was regarded as a product of four factors: calcium (IV) and thrombokinase (III) together acting on prothrombin (II) to produce fibrinogen (I); this model had been outlined by Paul Morawitz in 1905.[2]

The suggestion that an additional factor might exist was made by Dr Paul Owren (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and menorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolonged prothrombin time, suggesting either vitamin K deficiency or chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I-IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the Second World War, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in The Lancet in 1947.[2][3]

The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later.[2]

Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V.[2]

The complete amino acid sequence of the protein was published in 1987.[4] In 1994 factor V Leiden, resistant to inactivation by protein C, was described; this abnormality is the most common genetic cause for thrombosis.[5]

Interactions

Factor V has been shown to interact with Protein S.[6][7]

References

  1. ^ Kaplan QBook - USMLE Step 1 - 5th edition - page 254
  2. ^ a b c d Stormorken H (2003). "The discovery of factor V: a tricky clotting factor". J. Thromb. Haemost. 1 (2): 206–13. doi:10.1046/j.1538-7836.2003.00043.x. PMID 12871488. 
  3. ^ Owren, PA (1947). "Parahaemophilia. Haemorrhagic diathesis due to absence of a previously unknown clotting factor". Lancet 1 (6449): 446–51. doi:10.1016/S0140-6736(47)91941-7. PMID 20293060. 
  4. ^ Jenny RJ, Pittman DD, Toole JJ, et al. (1987). "Complete cDNA and derived amino acid sequence of human factor V". Proc. Natl. Acad. Sci. U.S.A. 84 (14): 4846–50. doi:10.1073/pnas.84.14.4846. PMC 305202. PMID 3110773. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=305202. 
  5. ^ Bertina RM, Koeleman BP, Koster T, et al. (1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C". Nature 369 (6475): 64–7. doi:10.1038/369064a0. PMID 8164741. 
  6. ^ Heeb, M J; Kojima Y, Rosing J, Tans G, Griffin J H (Dec. 1999). "C-terminal residues 621-635 of protein S are essential for binding to factor Va". J. Biol. Chem. (UNITED STATES) 274 (51): 36187–92. doi:10.1074/jbc.274.51.36187. ISSN 0021-9258. PMID 10593904. 
  7. ^ Heeb, M J; Mesters R M, Tans G, Rosing J, Griffin J H (Feb. 1993). "Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C". J. Biol. Chem. (UNITED STATES) 268 (4): 2872–7. ISSN 0021-9258. PMID 8428962. 

Further reading

External links


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