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Gene Review

F8  -  coagulation factor VIII, procoagulant...

Homo sapiens

Synonyms: AHF, Antihemophilic factor, Coagulation factor VIII, DXS1253E, F8B, ...
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Disease relevance of F8


Psychiatry related information on F8


High impact information on F8


Chemical compound and disease context of F8


Biological context of F8


Anatomical context of F8

  • LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi [21].
  • In addition, transfection in a glucosidase I-deficient Chinese hamster ovary cell line (Lec23) demonstrated that both degradation and secretion of FVIII were inhibited, with little effect on the secretion of FV [22].
  • In cirrhotic tissue enlarged portal veins appeared to overgrow FVIII producing sinusoidal endothelial cells [23].
  • This review attempts to sum up current knowledge of the nature and properties of anti-FVIII antibodies, their mechanism of action, their neutralization by anti-idiotypic antibodies, and the role of T cells in FVIII inhibitor formation [24].
  • During the last two years, however, a particular effort has been made to better understand their generation, with particular emphasis on the interplay of T cells and B cells specific for FVIII and the generation of anti-FVIII antibodies [24].

Associations of F8 with chemical compounds

  • This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain and inhibiting FVIII binding to VWF and phospholipids [12].
  • Evidence that functional subunits of antihemophilic factor (Factor VIII) are linked by noncovalent bonds [25].
  • The issue was examined by preparing partially purified AHF from fresh human plasma in the presence of protease inhibitors, including benzamidine, soybean trypsin inhibitor, epsilon-aminocaproic acid, heparin, and hirudin [25].
  • To capture the FVIII-VWF-complex, superparamagnetic polystyrene beads with covalently attached streptavidin were coated with biotinylated anti-rabbit Ig and incubated with rabbit anti-human VWF-Ig [3].
  • The AHF was prepared by sequential chromatography on solid-phase polyelectrolyte (PE E-5), and on Sepharose CL-4B in the presence of a high concentration of CaCl2 [26].

Physical interactions of F8

  • Competition studies using synthetic peptides suggested that LRP binding involves the FVIII-specific region Lys(1804)-Ala(1834) in the A3 domain [27].
  • In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro and that binding was inhibited by RAP [28].
  • The A2 domain of FVIII significantly increases the affinity and stoichiometry of FVIIIa binding to platelets and contributes to the stability of the FX-activating complex [29].
  • Heavy and light chains of FVIII were detected in plasma-derived immune complexes extracted by using protein G Sepharose [30].
  • Previous studies identified a 110-amino acid region within the FVIII A1-domain that inhibits its secretion and contains multiple short peptide sequences that have potential to bind immunoglobulin-binding protein (BiP) [31].

Enzymatic interactions of F8

  • The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1-15 [32].
  • In previous reports, plasmin was shown in vitro to inactivate FVIII and cleave the vWF subunit extensively, but to cause only a modest decrease in vWF platelet-agglutinating activity [33].
  • Isolex selected CD34+ cells from human G-CSF mobilized peripheral blood cells (PBC) and murine bone marrow were transduced with a retrovirus encoding the B-domain deleted form of human FVIII (BDD-FVIII) [34].

Regulatory relationships of F8

  • Addition of hemophilic plasma as a source of vWF did not cause additional improvement, nor did a potent antibody to vWF raised in rabbits inhibit the ability of AHF to shorten the clotting time of vWD plasma [26].
  • To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP- deficient mice (MX1cre(+)LRP(flox/flox)) [35].
  • The presence of EGR-FIXa and FX increases both the number and the affinity of binding sites on activated platelets for both FVIII and FVIIIa, emphasizing the validity of a three-receptor model in the assembly of the F-X-activating complex on the platelet surface [29].
  • We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change [36].
  • 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 [37].

Other interactions of F8

  • We studied nine bipolar pedigrees (in which there was no male-to-male transmission) in an attempt to detect linkage, using three tightly linked polymorphic DNA loci, DXS15, DXS52 and F8C (factor 8 gene), all of which are closely linked to the CB and glucose 6-phosphate dehydrogenase classic Xq28 markers [38].
  • The elevated expression of von Willebrand factor had no effect on the suppression of FVIII secretion by PAHX [17].
  • High level of plasma VII VWF was observed in diabetics with proliferative retinopathy while the VII AHF level was within normal limits [39].
  • By the use of an FV-dependent prothrombin activator, the assay is not influenced by FVIII concentration or lupus anticoagulants [18].
  • In both tests FXa formation plays a major role, as the effect of FVIII and TFPI on the tests seems to be executed via FXa [40].

Analytical, diagnostic and therapeutic context of F8

  • DDAVP also increased FVIII and VWF levels but did not normalize the GPIb-dependent VWF functions expressed as RIPA and VWF:RCo [41].
  • The F8C/G6PD (coagulation factor VIIIc) haplotype that spans the Xq28 region from the gene for coagulation factor VIIIc to the gene for G6PD was also investigated in Chinese using PCR and restriction enzyme digestion [20].
  • Using 2 common polymorphisms in F8 exon 14, we were able to show that the same allele shared by the patient, his mother, and his sister was not detected by reverse transcription-polymerase chain reaction (RT-PCR) from total blood mRNA [42].
  • We have purified factor VIII from a patient with moderately severe hemophilia A (FVIII, 4 U/dL; FVIII:Ag, 110 U/dL) and subjected the protein to Western blot analysis after time course activation with thrombin [43].
  • Immunoblotting of partially purified FVIII Okayama and normal FVIII showed that thrombin cleavage of the 92 kilodalton (Kd) heavy chain was impaired in the mutant protein [13].


  1. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Goudemand, J., Rothschild, C., Demiguel, V., Vinciguerrat, C., Lambert, T., Chambost, H., Borel-Derlon, A., Claeyssens, S., Laurian, Y., Calvez, T. Blood (2006) [Pubmed]
  2. Antihemophilic factor concentrate therapy in von Willebrand disease. Dissociation of bleeding-time factor and ristocetin-cofactor activities. Blatt, P.M., Brinkhous, K.M., Culp, H.R., Krauss, J.S., Roberts, H.R. JAMA (1976) [Pubmed]
  3. High factor VIII (FVIII) levels in venous thromboembolism: role of unbound FVIII. Schambeck, C.M., Grossmann, R., Zonnur, S., Berger, M., Teuchert, K., Spahn, A., Walter, U. Thromb. Haemost. (2004) [Pubmed]
  4. Haplotypes encoding the factor VIII 1241 Glu variation, factor VIII levels and the risk of venous thrombosis. Nossent, A.Y., Eikenboom, J.C., Vos, H.L., Bakker, E., Tanis, B.C., Doggen, C.J., Bertina, R.M., Rosendaal, F.R. Thromb. Haemost. (2006) [Pubmed]
  5. The effect of beta-receptor blockade on factor VIII levels and thrombin generation in patients with venous thromboembolism. Schönauer, V., Giannini, S., Christ, G., Quehenberger, P., Bieglmayer, C., Stain, M., Kyrle, P.A., Weltermann, A. Thromb. Haemost. (2003) [Pubmed]
  6. An engineered interdomain disulfide bond stabilizes human blood coagulation factor VIIIa. Gale, A.J., Pellequer, J.L. J. Thromb. Haemost. (2003) [Pubmed]
  7. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group. Schwartz, R.S., Abildgaard, C.F., Aledort, L.M., Arkin, S., Bloom, A.L., Brackmann, H.H., Brettler, D.B., Fukui, H., Hilgartner, M.W., Inwood, M.J. N. Engl. J. Med. (1990) [Pubmed]
  8. Pharmacokinetics of recombinant antihemophilic factor. Longo, G., Messori, A., Morfini, M., di Careggi, O. N. Engl. J. Med. (1989) [Pubmed]
  9. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. Weiss, H.J., Meyer, D., Rabinowitz, R., Pietu, G., Girma, J.P., Vicic, W.J., Rogers, J. N. Engl. J. Med. (1982) [Pubmed]
  10. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. Ruggeri, Z.M., Pareti, F.I., Mannucci, P.M., Ciavarella, N., Zimmerman, T.S. N. Engl. J. Med. (1980) [Pubmed]
  11. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Chao, H., Mansfield, S.G., Bartel, R.C., Hiriyanna, S., Mitchell, L.G., Garcia-Blanco, M.A., Walsh, C.E. Nat. Med. (2003) [Pubmed]
  12. Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development. d'Oiron, R., Lavergne, J.M., Lavend'homme, R., Benhida, A., Bordet, J.C., Negrier, C., Peerlinck, K., Vermylen, J., Saint-Remy, J.M., Jacquemin, M. Blood (2004) [Pubmed]
  13. An arginine to cysteine amino acid substitution at a critical thrombin cleavage site in a dysfunctional factor VIII molecule. Shima, M., Ware, J., Yoshioka, A., Fukui, H., Fulcher, C.A. Blood (1989) [Pubmed]
  14. Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders. Nolan, B., White, B., Smith, J., O'Reily, C., Fitzpatrick, B., Smith, O.P. Br. J. Haematol. (2000) [Pubmed]
  15. Identification of seven novel mutations of F8C by DHPLC. Frusconi, S., Passerini, I., Girolami, F., Masieri, M., Linari, S., Longo, G., Morfini, M., Torricelli, F. Hum. Mutat. (2002) [Pubmed]
  16. A 1.6-Mb contig of yeast artificial chromosomes around the human factor VIII gene reveals three regions homologous to probes for the DXS115 locus and two for the DXYS64 locus. Freije, D., Schlessinger, D. Am. J. Hum. Genet. (1992) [Pubmed]
  17. Roles of phytanoyl-CoA alpha-hydroxylase in mediating the expression of human coagulation factor VIII. Chen, C., Wang, Q., Fang, X., Xu, Q., Chi, C., Gu, J. J. Biol. Chem. (2001) [Pubmed]
  18. 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]
  19. G6PD haplotypes spanning Xq28 from F8C to red/green color vision. Filosa, S., Calabrò, V., Lania, G., Vulliamy, T.J., Brancati, C., Tagarelli, A., Luzzatto, L., Martini, G. Genomics (1993) [Pubmed]
  20. Two novel glucose 6-phosphate dehydrogenase deficiency mutations and association of such mutations with F8C/G6PD haplotype in Chinese. Chen, H.L., Huang, M.J., Huang, C.S., Tang, T.K. J. Formos. Med. Assoc. (1997) [Pubmed]
  21. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Zhang, B., McGee, B., Yamaoka, J.S., Guglielmone, H., Downes, K.A., Minoldo, S., Jarchum, G., Peyvandi, F., de Bosch, N.B., Ruiz-Saez, A., Chatelain, B., Olpinski, M., Bockenstedt, P., Sperl, W., Kaufman, R.J., Nichols, W.C., Tuddenham, E.G., Ginsburg, D. Blood (2006) [Pubmed]
  22. Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin. Pipe, S.W., Morris, J.A., Shah, J., Kaufman, R.J. J. Biol. Chem. (1998) [Pubmed]
  23. Factor VIII expression in liver disease. Hollestelle, M.J., Geertzen, H.G., Straatsburg, I.H., van Gulik, T.M., van Mourik, J.A. Thromb. Haemost. (2004) [Pubmed]
  24. Anti-factor VIII antibodies: a 2005 update. Lavigne-Lissalde, G., Schved, J.F., Granier, C., Villard, S. Thromb. Haemost. (2005) [Pubmed]
  25. Evidence that functional subunits of antihemophilic factor (Factor VIII) are linked by noncovalent bonds. Poon, M.C., Ratnoff, O.D. Blood (1976) [Pubmed]
  26. Evidence that von Willebrand factor is not required for the clotting of plasma in the presence of platelets and kaolin (Hardisty-Hutton test). McPherson, J., Soberano, M.E., Macdonald, C., Zucker, M.B. Thromb. Haemost. (1984) [Pubmed]
  27. Low density lipoprotein receptor-related protein and factor IXa share structural requirements for binding to the A3 domain of coagulation factor VIII. Bovenschen, N., Boertjes, R.C., van Stempvoort, G., Voorberg, J., Lenting, P.J., Meijer, A.B., Mertens, K. J. Biol. Chem. (2003) [Pubmed]
  28. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Bovenschen, N., Mertens, K., Hu, L., Havekes, L.M., van Vlijmen, B.J. Blood (2005) [Pubmed]
  29. Structural and functional characterization of platelet receptor-mediated factor VIII binding. Ahmad, S.S., Scandura, J.M., Walsh, P.N. J. Biol. Chem. (2000) [Pubmed]
  30. Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis. Nogami, K., Shima, M., Giddings, J.C., Hosokawa, K., Nagata, M., Kamisue, S., Suzuki, H., Shibata, M., Saenko, E.L., Tanaka, I., Yoshioka, A. Blood (2001) [Pubmed]
  31. Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII. Swaroop, M., Moussalli, M., Pipe, S.W., Kaufman, R.J. J. Biol. Chem. (1997) [Pubmed]
  32. Severe hemophilia A in a female by cryptic translocation: order and orientation of factor VIII within Xq28. Migeon, B.R., McGinniss, M.J., Antonarakis, S.E., Axelman, J., Stasiowski, B.A., Youssoufian, H., Kearns, W.G., Chung, A., Pearson, P.L., Kazazian, H.H. Genomics (1993) [Pubmed]
  33. Effects of plasmin on von Willebrand factor multimers. Degradation in vitro and stimulation of release in vivo. Hamilton, K.K., Fretto, L.J., Grierson, D.S., McKee, P.A. J. Clin. Invest. (1985) [Pubmed]
  34. Induction of megakaryocytes to synthesize and store a releasable pool of human factor VIII. Wilcox, D.A., Shi, Q., Nurden, P., Haberichter, S.L., Rosenberg, J.B., Johnson, B.D., Nurden, A.T., White, G.C., Montgomery, R.R. J. Thromb. Haemost. (2003) [Pubmed]
  35. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Bovenschen, N., Herz, J., Grimbergen, J.M., Lenting, P.J., Havekes, L.M., Mertens, K., van Vlijmen, B.J. Blood (2003) [Pubmed]
  36. The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels. Scanavini, D., Legnani, C., Lunghi, B., Mingozzi, F., Palareti, G., Bernardi, F. Thromb. Haemost. (2005) [Pubmed]
  37. 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]
  38. X-chromosome markers and manic-depressive illness. Rejection of linkage to Xq28 in nine bipolar pedigrees. Berrettini, W.H., Goldin, L.R., Gelernter, J., Gejman, P.V., Gershon, E.S., Detera-Wadleigh, S. Arch. Gen. Psychiatry (1990) [Pubmed]
  39. Platelet hyperaggregation and increased plasma level of Von Willebrand factor in diabetics with retinopathy. Bensoussan, D., Levy Toledano, S., Passa, P., Caen, J., Caniver, J. Diabetologia (1975) [Pubmed]
  40. Determinants of the APTT- and ETP-based APC sensitivity tests. de Visser, M.C., van Hylckama Vlieg, A., Tans, G., Rosing, J., Dahm, A.E., Sandset, P.M., Rosendaal, F.R., Bertina, R.M. J. Thromb. Haemost. (2005) [Pubmed]
  41. Type 2M von Willebrand disease variant characterized by abnormal von willebrand factor multimerization. Casonato, A., Pontara, E., Sartorello, F., Bertomoro, A., Durante, C., Girolami, A. J. Lab. Clin. Med. (2001) [Pubmed]
  42. Lack of F8 mRNA: a novel mechanism leading to hemophilia A. El-Maarri, O., Singer, H., Klein, C., Watzka, M., Herbiniaux, U., Brackmann, H.H., Schröder, J., Graw, J., Müller, C.R., Schramm, W., Schwaab, R., Haaf, T., Hanfland, P., Oldenburg, J. Blood (2006) [Pubmed]
  43. Purification and characterization of factor VIII 372-Cys: a hypofunctional cofactor from a patient with moderately severe hemophilia A. O'Brien, D.P., Pattinson, J.K., Tuddenham, E.G. Blood (1990) [Pubmed]
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