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Gene Review

F5  -  coagulation factor V (proaccelerin, labile...

Homo sapiens

Synonyms: Activated protein C cofactor, Coagulation factor V, FVL, PCCF, Proaccelerin, labile factor, ...
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Disease relevance of F5


Psychiatry related information on F5

  • Their use as adjuncts for the diagnosis, prognosis, prediction of disease or targeting therapy for these disorders has begun, good examples being the Factor V Leiden mutation for venous-thromboembolism, lipoprotein lipase mutations for hypertriglyceridaemia and the apolipoprotein E4 variant for Alzheimer's dementia [6].

High impact information on F5


Chemical compound and disease context of F5

  • FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only [11].
  • Protein C inhibitory activity is not detectable in plasmas from four unrelated patients with combined Factor V/VIII deficiency but is present in normal amounts in plasmas from patients with simple factor V deficiency or Factor VIII deficiency [12].
  • These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism [13].
  • CONCLUSIONS: The authors propose that inheritance of Factor V Leiden significantly increases the risk of thrombosis in patients who receive tamoxifen therapy [14].
  • In these cases, immune-equilibrating interventions appear to be more appropriate than heparin therapy. - Coagulation disorders, namely thrombophilia, are a frequent cause of RSA and probably RIF as well, the most relevant being antithrombin deficiency, Factor V Leiden and prothrombin mutations [15].

Biological context of F5

  • However, the region on chromosome 1 that contains the F5 structural gene showed little evidence of linkage to APCR (LOD, < 1) [1].
  • A combination of the heterozygous FV G1691A mutation with increased Lp(a) (n = 11) or the MTHFR TT677 genotype (n = 5) was found in 10 [16].
  • This indicates that apart from the FVL, the F5 locus itself plays a relatively minor role in normal variation in APCR, including the HR2 haplotype polymorphisms [1].
  • RESULTS: Among the controls, 2 (2.2%) carried the FV Leiden mutation, 19 (20.4%) were TT MTHFR homozygotes and 1 (1.6%) carried the prothrombin A20210 allele [17].
  • Maternal, paternal, and fetal DNA were genotyped for the methylenetetrahydrofolate reductase (MTHFR) C677T and Factor V Leiden (FVL) G1691A SNPs [4].

Anatomical context of F5

  • Alterations in the level of anticoagulant proteins, disturbances of endothelial cell function, and the presence of cardiolipin antibodies and Factor V Leiden mutation may increase the cumulative thrombotic risk in MPD besides the risk imposed by platelet activation [18].
  • Plasmas containing varying concentrations of normal FV, FV(Leiden), or FV(R2) were assayed with an APC resistance assay that specifically measures the APC cofactor activity of FV in FVIIIa inactivation, and with the activated partial thromboplastin time (aPTT)-based assay, which probes both the susceptibility and APC cofactor components [19].
  • Site-directed mutagenesis of FV cDNA was used to introduce the identified mutation, and wild-type as well as mutant FV proteins were expressed by transient transfection in COS-1 cells [20].
  • The Asp2194Gly mutation was found to play a key role in the impaired secretion of the mutant FV by interfering with its transport from the endoplasmic reticulum to the Golgi complex [21].
  • The prevalence of the prothrombin 20210 G-->A mutation, factor V Leiden (FVL) mutation and the C677T mutation in the MTHFR gene was compared in cases to that observed in random unselected cord blood controls [22].

Associations of F5 with chemical compounds

  • We conclude that FVL and the PT-20210A are risk factors for VT as well as Hcy levels, but the MTHFR and PAI-1 polymorphisms do not appear to be associated with VT in our country [23].
  • These mutations affect the APC cleavage site at arginine (Arg) 306 in the heavy chain of activated FV [24].
  • In the three models, the generation of thrombin can be described in terms of an initiation phase in which pmol/l concentrations of the coagulation serine proteases are generated and the cofactor proteins factor V (FV) and FVIII are activated [25].
  • Activated protein C (APC) acts as a potent anticoagulant enzyme by inactivating Factor V and Factor VIII [26].
  • This mutation creates an additional potential N-linked glycosylation site (Asn-X-Ser/Thr) in factor V (FV) at Asn357 that could interfere with secretion and/or protein interactions [27].

Physical interactions of F5

  • RESULTS: Western blot analysis showed TSP1 forming a complex with FVa(HNE) within a region corresponding to the heavy chain of FV [28].
  • COAT-FV platelets bound annexin-V, indicating exposure of aminophospholipids and were enriched in young platelets as identified by the binding of thiazole orange [29].

Enzymatic interactions of F5

  • Western blotting using a monoclonal antibody that recognizes an epitope between amino acid residues 307 and 506 of human FV showed that FV was completely cleaved by APC at the beginning of the rhFVIII inactivation process [30].
  • Human factor V (FV) can be cleaved by HNE thereby providing FV with cofactor activity (FVa(HNE)) [28].

Regulatory relationships of F5

  • The protein C pathway cannot act in the absence of thrombin and therefore only influences the duration of the propagation phase by inactivating activated FV [25].
  • However, the ORs for carriers of the FV R506Q mutation were not significantly influenced by MTHFR gene C677T homozygosity [31].
  • The relative importance of these cleavages in tissue factor (TF) induced thrombin generation in plasma and in a purified system was elucidated with recombinant FV in which the three sites had been eliminated one by one or in combinations [32].
  • In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present [33].
  • Our results are consistent with hyperproduction of IL-2 by some patients with RA which is suppressed by F5 [34].

Other interactions of F5

  • Frequencies of PS deficiency, FVL and FII 20210A allele were similar to the reference population as well as to published data in the general caucasian population [35].
  • As a result of its high prevalence, the FV mutation is not uncommon among patients with other inherited defects such as deficiency of PS, PC, or antithrombin [3].
  • Wild-type and mutant probes are used to identify triplexes containing FVL G1691A, MTHFR C677T and CFTR mutations [36].
  • When glycosidase-treated FV was analyzed in an aPTT (activated partial thromboplastin time)-based APC sensitivity assay, the APC sensitivity ratio (APC-SR) increased from 2.34 to 3.33 [37].
  • Treatment of purified FV with N-glycanase and neuraminidase under nonprotein-denaturing conditions removed approximately 20-30% of the carbohydrate from the heavy chain region of the molecule [37].

Analytical, diagnostic and therapeutic context of F5


  1. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Soria, J.M., Almasy, L., Souto, J.C., Buil, A., Martinez-Sanchez, E., Mateo, J., Borrell, M., Stone, W.H., Lathrop, M., Fontcuberta, J., Blangero, J. Blood (2003) [Pubmed]
  2. Incidence of venous thromboembolism in families with inherited thrombophilia. Simioni, P., Sanson, B.J., Prandoni, P., Tormene, D., Friederich, P.W., Girolami, B., Gavasso, S., Huisman, M.V., Büller, H.R., Wouter ten Cate, J., Girolami, A., Prins, M.H. Thromb. Haemost. (1999) [Pubmed]
  3. Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Dahlbäck, B. Semin. Hematol. (1997) [Pubmed]
  4. Maternal and fetal variants of genetic thrombophilias and the risk of preeclampsia. Vefring, H., Lie, R.T., ØDegård, R., Mansoor, M.A., Nilsen, S.T. Epidemiology (Cambridge, Mass.) (2004) [Pubmed]
  5. Improved distinction of factor V wild-type and factor V Leiden using a novel prothrombin-based activated protein C resistance assay. Wilmer, M., Stocker, C., Bühler, B., Conell, B., Calatzis, A. Am. J. Clin. Pathol. (2004) [Pubmed]
  6. Genetic markers to predict polygenic disease: a new problem for social genetics. Galton, D.J., Ferns, G.A. QJM : monthly journal of the Association of Physicians. (1999) [Pubmed]
  7. Mutations in coagulation factors in women with unexplained late fetal loss. Martinelli, I., Taioli, E., Cetin, I., Marinoni, A., Gerosa, S., Villa, M.V., Bozzo, M., Mannucci, P.M. N. Engl. J. Med. (2000) [Pubmed]
  8. Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1. Watson, M.L., Kingsmore, S.F., Johnston, G.I., Siegelman, M.H., Le Beau, M.M., Lemons, R.S., Bora, N.S., Howard, T.A., Weissman, I.L., McEver, R.P. J. Exp. Med. (1990) [Pubmed]
  9. Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping. Nichols, W.C., Seligsohn, U., Zivelin, A., Terry, V.H., Arnold, N.D., Siemieniak, D.R., Kaufman, R.J., Ginsburg, D. J. Clin. Invest. (1997) [Pubmed]
  10. Characterization of an acquired inhibitor to coagulation factor V. Antibody binding to the second C-type domain of factor V inhibits the binding of factor V to phosphatidylserine and neutralizes procoagulant activity. Ortel, T.L., Quinn-Allen, M.A., Charles, L.A., Devore-Carter, D., Kane, W.H. J. Clin. Invest. (1992) [Pubmed]
  11. Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors - a multicentre case-control study. For the Childhood Thrombophilia Study Group. Heller, C., Schobess, R., Kurnik, K., Junker, R., Günther, G., Kreuz, W., Nowak-Göttl, U. Br. J. Haematol. (2000) [Pubmed]
  12. Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease. Marlar, R.A., Griffin, J.H. J. Clin. Invest. (1980) [Pubmed]
  13. Homozygous cystathionine beta-synthase deficiency, combined with factor V Leiden or thermolabile methylenetetrahydrofolate reductase in the risk of venous thrombosis. Kluijtmans, L.A., Boers, G.H., Verbruggen, B., Trijbels, F.J., Novakova, I.R., Blom, H.J. Blood (1998) [Pubmed]
  14. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Weitz, I.C., Israel, V.K., Liebman, H.A. Cancer (1997) [Pubmed]
  15. Effectivity of heparin in assisted reproduction. Fiedler, K., Würfel, W. Eur. J. Med. Res. (2004) [Pubmed]
  16. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Nowak-Göttl, U., Sträter, R., Heinecke, A., Junker, R., Koch, H.G., Schuierer, G., von Eckardstein, A. Blood (1999) [Pubmed]
  17. Familial thrombophilia and the occurrence of fetal growth restriction. Martinelli, P., Grandone, E., Colaizzo, D., Paladini, D., Sciannamé, N., Margaglione, M., Di Minno, G. Haematologica (2001) [Pubmed]
  18. Frequent occurrence of anticardiolipin antibodies, Factor V Leiden mutation, and perturbed endothelial function in chronic myeloproliferative disorders. Jensen, M.K., de Nully Brown, P., Thorsen, S., Hasselbalch, H.C. Am. J. Hematol. (2002) [Pubmed]
  19. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Castoldi, E., Brugge, J.M., Nicolaes, G.A., Girelli, D., Tans, G., Rosing, J. Blood (2004) [Pubmed]
  20. Arg2074Cys missense mutation in the C2 domain of factor V causing moderately severe factor V deficiency: molecular characterization by expression of the recombinant protein. Duga, S., Montefusco, M.C., Asselta, R., Malcovati, M., Peyvandi, F., Santagostino, E., Mannucci, P.M., Tenchini, M.L. Blood (2003) [Pubmed]
  21. Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype. Yamazaki, T., Nicolaes, G.A., Sørensen, K.W., Dahlbäck, B. Blood (2002) [Pubmed]
  22. Factor V Leiden, prothrombin 20210G-->A and the MTHFR C677T mutations in childhood stroke. McColl, M.D., Chalmers, E.A., Thomas, A., Sproul, A., Healey, C., Rafferty, I., McWilliam, R., Eunson, P. Thromb. Haemost. (1999) [Pubmed]
  23. Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Varela, M.L., Adamczuk, Y.P., Forastiero, R.R., Martinuzzo, M.E., Cerrato, G.S., Pombo, G., Carreras, L.O. Thromb. Res. (2001) [Pubmed]
  24. The activated protein C (APC)-resistant phenotype of APC cleavage site mutants of recombinant factor V in a reconstituted plasma model. van der Neut Kolfschoten, M., Dirven, R.J., Tans, G., Rosing, J., Vos, H.L., Bertina, R.M. Blood Coagul. Fibrinolysis (2002) [Pubmed]
  25. The role of the tissue factor pathway in initiation of coagulation. Mann, K.G., van't Veer, C., Cawthern, K., Butenas, S. Blood Coagul. Fibrinolysis (1998) [Pubmed]
  26. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. Koedam, J.A., Meijers, J.C., Sixma, J.J., Bouma, B.N. J. Clin. Invest. (1988) [Pubmed]
  27. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Steen, M., Norstrøm, E.A., Tholander, A.L., Bolton-Maggs, P.H., Mumford, A., McVey, J.H., Tuddenham, E.G., Dahlbäck, B. Blood (2004) [Pubmed]
  28. Thromsbospondin-1 binds to the heavy chain of elastase activated coagulation factor V (FVaHNE) and enhances thrombin generation on the surface of a promyelocytic cell line. Isordia-Salas, I., Manns, J.M., Sainz, I., Parekh, H., DeLa Cadena, R.A. Thromb. Res. (2005) [Pubmed]
  29. Surface expression and functional characterization of alpha-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Alberio, L., Safa, O., Clemetson, K.J., Esmon, C.T., Dale, G.L. Blood (2000) [Pubmed]
  30. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Lu, D., Kalafatis, M., Mann, K.G., Long, G.L. Blood (1996) [Pubmed]
  31. Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes. Alhenc-Gelas, M., Arnaud, E., Nicaud, V., Aubry, M.L., Fiessinger, J.N., Aiach, M., Emmerich, J. Thromb. Haemost. (1999) [Pubmed]
  32. Cleavage requirements of factor V in tissue-factor induced thrombin generation. Thorelli, E., Kaufman, R.J., Dahlbäck, B. Thromb. Haemost. (1998) [Pubmed]
  33. Factor Xa and prothrombin: mechanism of action of FEIBA. Turecek, P.L., Varadi, K., Gritsch, H., Auer, W., Pichler, L., Eder, G., Schwarz, H.P. Vox Sang. (1999) [Pubmed]
  34. Interleukin-2 production and effect of thymosin fraction 5 on interleukin-2 production in rheumatoid arthritis. Wolf, R.E., Hall, V.C. J. Rheumatol. (1987) [Pubmed]
  35. Increased prevalence of factor V Leiden in patients with retinal vein occlusion and under 60 years of age. Arsène, S., Delahousse, B., Regina, S., Le Lez, M.L., Pisella, P.J., Gruel, Y. Thromb. Haemost. (2005) [Pubmed]
  36. Heteropolymeric triplex-based genomic assay(r) to detect pathogens or single-nucleotide polymorphisms in human genomic samples. Daksis, J.I., Erikson, G.H. PLoS ONE (2007) [Pubmed]
  37. Carbohydrate moieties on the procofactor factor V, but not the derived cofactor factor Va, regulate its inactivation by activated protein C. Silveira, J.R., Kalafatis, M., Tracy, P.B. Biochemistry (2002) [Pubmed]
  38. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Carp, H., Salomon, O., Seidman, D., Dardik, R., Rosenberg, N., Inbal, A. Hum. Reprod. (2002) [Pubmed]
  39. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Simioni, P., Castoldi, E., Lunghi, B., Tormene, D., Rosing, J., Bernardi, F. Blood (2005) [Pubmed]
  40. Localization of the gene encoding human factor V to chromosome 1q21-25. Wang, H., Riddell, D.C., Guinto, E.R., MacGillivray, R.T., Hamerton, J.L. Genomics (1988) [Pubmed]
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