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Molecular Defects in Hemophilia A

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Recombinant Technology in Hemostasis and Thrombosis

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Abstract

Hemophilia A, classic hemophilia, is an X chromosomc-linked inherited coagulation disorder characterized by deficient factor VIII activity. Clinically, and when characterized by procoagulant or immunologic assays, it is a heterogeneous disorder. However, disease severity usually corresponds to the extent of factor VIII deficiency.1 Severe hemophilia with recurrent hemarthroses usually means that there is no detectable plasma factor VIII (< 1% of normal factor VIII activity). Individuals with 1–5% of normal factor VIII levels tend to have moderately severe disease, with most bleeding episodes due to trauma. Mild hemophilia (6–25% of normal factor VIII activity) may only be detected when excessive bleeding occurs during surgery or after severe injuries. Nonfunctional, immunoreactive factor VIII-like protein, at levels comparable to those in normal plasma, is detected in 10% of plasmas from patients with mild or moderate hemophilia A.2, 3 In addition, low levels of factor VIII antigen (1–10% of those in normal plasma) can be detected by sensitive immunoassays in the plasma of 20% of patients with severe hemophilia A.4 The basis for this heterogeneity has been clarified by recent studies that have examined the molecular basis for the factor VIII deficiency in families with hemophilia.

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References

  1. Hoyer LW: Factor VIII: New perspectives. Trans Med Rev 1: 113, 1987

    Article  CAS  Google Scholar 

  2. Hoyer LW, Breckenridge RT: Immunologic studies of antihemophilic factor (AHF, factor VIII): Cross-reacting material in a genetic variant of hemophilia A. Blood 32: 962, 1968

    PubMed  CAS  Google Scholar 

  3. Lazarchick J, Hoyer LW: Immunoradiometric measurement of the factor VIII procoagulant antigen. J Clin Invest 62: 1048, 1978

    Article  PubMed  CAS  Google Scholar 

  4. McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J, Hemophilia Study Group: The natural history of factor VIII: C inhibitors in patients with hemophilia A: A national cooperative study. II. Observations on the initial development of factor VIII: C inhibitors. Blood 71: 344, 1988

    PubMed  CAS  Google Scholar 

  5. Antonarakis SE: The molecular genetics of hemophilia A and B in man. Factor VIII and factor IX deficiency. Adv in Hum Gene 17: 27, 1988

    Article  CAS  Google Scholar 

  6. Gitschier J: The molecular genetics of hemophilia A, in Zimmerman TS, Ruggeri ZM: (eds): Coagulation and bleeding disorders: the role of factor VIII and von Willebrand factor, New York, Dekker, M., 1989, p 23

    Google Scholar 

  7. White GC, Shoemaker CB: Factor VIII gene and hemophilia A. Blood 73: 1, 1989

    PubMed  CAS  Google Scholar 

  8. Thompson AR: Molecular biology of the hemophilias, in Coller BS (ed): Progress in Hemostasis and Thrombosis, Volume 10, Philadelphia, WB Saunders, 1990, (in press)

    Google Scholar 

  9. Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM: Characterization of the human factor VIII gene. Nature 312: 326, 1984.

    Article  PubMed  CAS  Google Scholar 

  10. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC, Amphlett GW, Foster WB, Coe ML, Knutson GJ, Fass DN, Hewick RM: Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312: 342, 1984

    Article  PubMed  CAS  Google Scholar 

  11. Haldane JBS: The rate of spontaneous mutation of the human gene. J Genet 31: 317, 1935

    Article  Google Scholar 

  12. Youssoufian H, Kazazian HH Jr, Phillips DG, Aronis S, Tsiftis G, Brown VA, Antonarakis SE: Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324: 380, 1986

    Article  PubMed  CAS  Google Scholar 

  13. Antonarakis SE, Kazazian HH Jr: The molecular basis of hemophilia A in man. Trends in Genetics 4: 233, 1988

    Article  PubMed  CAS  Google Scholar 

  14. Higuchi M, Kochhan L, Schwaab R, Egli H, Brackman H-H, Horst J, Olek K: Molecular defects in hemophilia A: Identification and Characterization of mutations in the factor VIII gene and family analysis. Blood 74: 1045, 1989

    PubMed  CAS  Google Scholar 

  15. Casula L, Murru S, Pecorara M, Ristaldi MS, Restagno G, Mancuso G, Morfini M, DeBiasi R, Baudo F, Carbonara A, Mori PG, Cao A, Pirastu M: Recurrent mutations and three novel rearrangements in the factor VIII gene of hemophilia A patients of Italian descent. Blood 75: 662, 1990

    PubMed  CAS  Google Scholar 

  16. Bardoni B, Sampietro M, Romano M, Crapanzano M, Mannucci PM, Camerino G: Characterization of a partial deletion of the factor VIII gene in a haemophiliac with inhibitor. Hum Genet 79: 86, 1988

    Article  PubMed  CAS  Google Scholar 

  17. Bernardi F, Volinia S, Patracchini P, Gemmati D, Boninsegna S, Schwienbacher C, Marchetti G: A recurrent missense mutation (Arg — Gin) and a partial deletion in factor VIII gene causing severe haemophilia A. Br J Haematol 71: 271, 1989

    Article  PubMed  CAS  Google Scholar 

  18. Mikami S: Gene analysis in haemophilia A — restriction fragment length polymorphism and molecular defects in the factor VIII gene. Acta Haem Japonica 51: 1680, 1988

    CAS  Google Scholar 

  19. Gitschier J, Wood WI, Tuddenham EGD, Shuman MA, Goralka TM, Chen EY, Lawn RM: Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature 315: 427, 1985 (abstr)

    Article  PubMed  CAS  Google Scholar 

  20. Levinson B, Lehesjoki A-E, De La Chapelle A, Gitschier J: Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet 46: 53, 1990

    PubMed  CAS  Google Scholar 

  21. Youssoufian H, Antonarakis SE, Aronis S, Tsiftis G, Phillips DG, Kazazian HH Jr: Characterization of five partial deletions of the factor VIII gene. Proc Natl Acad Sci USA 84: 3772, 1987

    Article  PubMed  CAS  Google Scholar 

  22. Youssoufian H, Kasper CK, Phillips DG, Kazazian HH Jr, Antonarakis SE: Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A. Hum Genet 80: 143, 1988

    Article  PubMed  CAS  Google Scholar 

  23. Casarino L, Pecorara M, Mori PG, Morfini M, Mancuso G, Scrivano L, Molinati AC, Giavarella LT, Giavarella G, Loi A, Perseu L, Cao A, Pirastu M: Molecular basis for hemophilia A in Italians. Ric Clin Lab 16: 227, 1986 (abstr)

    Google Scholar 

  24. Lillicrap DP, Taylor SAM, Grover H, Teitel J, Giles AR, Holden JJA, White BN: Genetic analysis in hemophilia A: Identification of a large F.VIII gene deletion in a patient with high titre antibodies to human and porcine F.VIII. Blood 68: 337a, 1986

    Google Scholar 

  25. Kariya K, Silverman L, Friedman K, Perry T, Highsmith W, Cooper H: Major rearrangement of the factor VIII gene in severe hemophilia A. Thromb Haem 62: 201, 1989 (abstr)

    Google Scholar 

  26. Dreesen JCFM, Bakker E, Briet E: A somatic mutation that caused inherited hemophilia A. Thromb Haem 62: 200, 1989 (abstr)

    Google Scholar 

  27. Higuchi M, Wong C, Kochran L, Olek K, Aronis S, Kasper CK, Kazazian HH Jr, Antonarakis SE: Characterization of mutations in the factor VIII gene by direct sequencing of amplified genomic DNA. Genomics 6: 65, 1989

    Article  Google Scholar 

  28. Kogan S, Gitschier J: Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 87: 2092, 1990

    Article  PubMed  CAS  Google Scholar 

  29. Antonarakis SE, Waber PG, Smita MS, Kittur SD, Patel AS, Kazazian HH Jr, Mellis MA, Counts RB, Stamatoyannopoulos G, Bowie EJW, Fass DN, Pittman DD, Wozney JM, Toole JJ: Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med 313: 842, 1985

    Article  PubMed  CAS  Google Scholar 

  30. Mikami S, Nishimura T, Naka H, Kuze K, Fukui H: A deletion involving intron 13 and exon 14 of factor VIII gene in a haemophiliac with anti-factor VIII antibody. Jpn J Human Genet 33: 401, 1988

    Article  CAS  Google Scholar 

  31. Woods-Samuels AP, Kazazian HH Jr, Antonarakis SE: Molecular characterization of four deletions in the human factor VIII gene in patients with hemophilia A. Amer J Hum Gen 45: A230, 1989 (abstr)

    Google Scholar 

  32. Reisner HM, Price WA, Blatt PM, Barrow ES, Graham JB: Factor VIII coagulant antigen in hemophilie plasma: A comparison of five alloantibodies. Blood 56: 615, 1980

    PubMed  CAS  Google Scholar 

  33. Din N, Schwartz M, Kruse T, Vestergaard SR, Ahrens P, Scheibel E, Nordfang O, Ezban M: Factor VIII gene specific probes used to study heritage and molecular defects in hemophilia A. Ric Clin Lab 16: 182, 1986 (abstr)

    Google Scholar 

  34. Shelton-Inloes BB, Chehab FF, Mannucci PM, Federici AB, Sadler JE: Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J Clin Invest 79: 1459, 1987

    Article  PubMed  CAS  Google Scholar 

  35. Chan V, Chan TK, Tong TMF, Todd D: A novel missense mutation in Exon 4 of the factor VIII: C gene resulting in moderately severe hemophilia A. Blood 74: 2688, 1989

    PubMed  CAS  Google Scholar 

  36. Youssoufian H, Kazazian HH Jr, Patel A, Aronis S, Tsiftis G, Hoyer LW, Antonarakis SE: Mild hemophilia A associated with a cryptic donor splice site mutation in intron4 of the factor VIII gene. Genomics 2: 32, 1988

    Article  PubMed  CAS  Google Scholar 

  37. Youssoufian H, Wong C, Aronis S, Platokoukis H, Kazazian HH Jr, Antonarakis SE: Moderately Severe Hemophilia A Resulting from Glu-Gly Substitution in Exon 7 of the Factor VIII Gene. Am J Hum Genet 42: 867, 1988

    PubMed  CAS  Google Scholar 

  38. Kogan SC, Gitschier J: Detection of hemophilia A mutations near the acidic region of factor VIII by DNA amplifications and denaturing gradient gel electrophoresis. Blood 72: 1110, 1988 (abstr)

    Google Scholar 

  39. Gitschier J, Kogan S, Levinson B, Tuddenham EGD: Mutations of Factor VIII Cleavage Sites in Hemophilia A. Blood 72: 1022, 1988

    PubMed  CAS  Google Scholar 

  40. Shima M, Ware J, Yoshioka A, Fukui H, Fulcher CA: An arginine to cysteine amino acid substitution at a critical thrombin cleavage site in a dysfunctional factor VIII molecule. Blood 74: 1612, 1989

    PubMed  CAS  Google Scholar 

  41. Arai M, Inaba H, Higuchi M, Antonarakis SE, Kazazian HH Jr, Fujimaki M, Hoyer LW: Direct characterization of factor VIII in plasma — Detection of a mutation altering a thrombin cleavage site (Arginine-372 — Histidine). Proc Natl Acad Sci USA 86: 4277, 1989

    Article  PubMed  CAS  Google Scholar 

  42. Arai M, Higuchi M, Antonarakis SE, Kazazian HH Jr, Phillips JA, Janco RL, Hoyer LW: Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of 2 unrelated patients with cross reacting material positive hemophilia A. Blood 75: 384, 1990

    PubMed  CAS  Google Scholar 

  43. Traystman MD, Higuchi M, Kasper CK, Antonarakis SE, Kazazian HH Jr: Use of denaturing gradient gel electrophoresis to detect point mutations in the factor VIII gene. Genomics 6: 293, 1990

    Article  PubMed  CAS  Google Scholar 

  44. Lillicrap D, Holden JJA, Giles AR, White BN, The Ontario Haemophilia Study Group: Carrier detection strategy in haemophilia A: the benefits of combined DNA marker analysis and coagulation testing in sporadic haemophiic families. Br J Haematol 70: 321, 1988

    Article  PubMed  CAS  Google Scholar 

  45. Levinson B, Janco R, Phillips III JA, Gitschier J: A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences. Nucl Acids Res 15: 9797, 1987

    Article  PubMed  CAS  Google Scholar 

  46. Youssoufian H, Antonarakis SE, Bell W, Griffin AM, Kazazian HH Jr: Nonsense and missense mutations in hemophilia A: Estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet 42: 718, 1988

    PubMed  CAS  Google Scholar 

  47. Hellman L, Smedsrod B, Sandberg H, Pettersson U: Secretion of coagulant factor VIII activity and antigen by in vitro cultivated rat liver sinusoidal endothelial cells. Br J Haematol 73: 348, 1989

    Article  PubMed  CAS  Google Scholar 

  48. Mikami S, Nishimura T, Naka H, Kuze K, Fukui H, Tone M, Hashimoto-Gotoh T: Nonsense mutation in factor VIII gene of a severe haemophiliac patient with anti-factor VIII antibody. Jpn J Human Genet 33: 409, 1988

    Article  CAS  Google Scholar 

  49. Gitschier J, Wood WE, Shuman MA, Lawn RM: Identification of a missense mutation in the factor VIII gene of a mild hemophilia. Science 232: 1415, 1986

    Article  PubMed  CAS  Google Scholar 

  50. Inaba H, Fujimaki M, Kazazian HH Jr, Antonarakis SE: Mild hemophilia A resulting from Arg-to-Leu substitution in exon 26 of the factor VIII gene. Hum Genet 81: 335, 1989 (abstr)

    Article  PubMed  CAS  Google Scholar 

  51. Kazazian HH Jr, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE: Haemophilia A resulting from de novo insertion of LI sequences represents a novel mechanism for mutation in man. Nature 332: 164, 1988

    Article  PubMed  CAS  Google Scholar 

  52. Pittman DD, Kaufman RJ: Proteolytic requirements for thrombin activation of anti-hemophilie factor (factor VIII). Proc Natl Acad Sci USA 85: 2429, 1988

    Article  PubMed  CAS  Google Scholar 

  53. Rapaport SI, Schiffman S, Patch MJ, Ames SB: The importance of activation of antihemophilic globulin and proaccelerin by traces of thrombin in the generation of intrinsic prothrombinase activity. Blood 21: 221, 1963

    PubMed  CAS  Google Scholar 

  54. O’Brien DP, Pattinson JK, Tuddenham EGD: Purification and characterization of factor VIII 372-Cys: A hypofunctional cofactor from a patient with moderately severe hemophilia A. Blood 75: 1664, 1990

    PubMed  Google Scholar 

  55. Myers RM, Larin Z, Maniatis T: Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA: DNA duplexes. Science 230: 1242, 1990

    Article  Google Scholar 

  56. Novack DF, Casma NJ, Fischer SG, Ford JP: Detection of single base-pair mismatches in DNA by chemical modification followed by electrophoresis in 15% polyacrylamide gel. Proc Natl Acad Sci USA 83: 586, 1986

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Jerome H. Holland Laboratory, American Red Cross Blood Services, Rockville, MD, 20855, USA

    Leon W. Hoyer

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  1. Jerome H. Holland Laboratory, American Red Cross Blood Services, Rockville, Maryland, USA

    Leon W. Hoyer  & William N. Drohan  & 

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Hoyer, L.W. (1991). Molecular Defects in Hemophilia A. In: Hoyer, L.W., Drohan, W.N. (eds) Recombinant Technology in Hemostasis and Thrombosis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3698-7_7

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  • DOI: https://doi.org/10.1007/978-1-4615-3698-7_7

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6644-7

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