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Thromb Haemost 1995; 74(06): 1402-1406
DOI: 10.1055/s-0038-1649954
Rapid Communications
Schattauer GmbH Stuttgart

Haemophilia A: Mutation Type Determines Risk of Inhibitor Formation

R Schwaab
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
,
H-H Brackmann
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
,
C Meyer
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
,
J Seehafer
2   The Institut für Hormon- und Fortpflanzungsforschung, Hamburg, Germany
,
M Kirchgesser
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
,
A Haack
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
,
K Olek
2   The Institut für Hormon- und Fortpflanzungsforschung, Hamburg, Germany
,
E G D Tuddenham
3   The Haemostasis Research Group, M. R. C. Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK
,
J Oldenburg
1   The Institut für Experimentelle Hämatologie und Transfusionsmedizin, Bonn, Germany
› Author Affiliations
Further Information

Publication History

Received: 13 April 1995

Accepted after resubmission 30 August 1995

Publication Date:
10 July 2018 (online)

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Summary

The formation of factor VIII antibodies is a major problem for replacement therapy of haemophilia A patients. Antibodies occur in 5-30% of patients with severe haemophilia A. The reason for antibody formation is still unknown. In this study we correlate for the first time different factor VIII gene mutations, stop- and missense mutations, large and small deletions and intrachromosomal intron 22 recombinations to antibody formation. A total of 364 patients with known inhibitor status of our institute, of the database, and of 3 studies representing intron-22-inversion data are included. The results show that the risk for developing factor VIII antibodies is strongly related to stop mutations, large deletions and intrachromosomal recombinations. A probable explanation could be the complete lack of endogenous circulating factor VIII protein in these cases. Other factors that might be important for the pathogenesis of inhibitor formation, e. g. the antenatal period, as well as possible therapeutic effects, are discussed.

 

  • References

  • 1 Kazazian HH, Tuddenham EG D, Antonarakis SH. Haemophilia A and parahaemophilia: deficiencies of coagulation factor VIII and V. In: The metabolic and molecular bases of inherited disease. Seriver CR, Beaudet AL, Sly WS, Valle D. eds. New York: McGraw-Hill 1995 7th edition 3241-3267
    Google Scholar
  • 2 Tuddenham EG D, Schwaab R, Seehafer J, Millar DS, Gitschier J, Higuchi M, Bidichandani S, Connor JM, Hoyer LW, Yoshioka A, Peake IR, Olek K, Kazazian HH, Lavergne J-M, Giannelli F, Antonarakis SE, Cooper DN. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res 1994; 22: 3511-3533
    CrossrefPubMedGoogle Scholar
  • 3 Scharrer I, Neutzling O. Incidence of inhibitors in haemophiliacs. A review of the literature Blood Coag Fibrinol 1993; 4: 753-758
    CrossrefPubMedGoogle Scholar
  • 4 Bray G, Gomperts ED, Courier S, Gruppo R, Gordon EM, Manco-Johnson M, Shapiro A, Scheibel E, White III G, Lee M. Recombinate® Study Group. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy and inhibitor risk in previously untreated patients with hemophilia A Blood 1994; 83: 2428-2435
    PubMedGoogle Scholar
  • 5 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Kogenate previously untreated patient study group: recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and the development of inhibitors N Engl J Med 1993; 328: 453-459
    CrossrefPubMedGoogle Scholar
  • 6 Brackmann HH, Gormsen J. Massive factor VIII infusion in a haemophiliac with factor VIII inhibitor, high response. Lancet 1977; 2: 933
    PubMedGoogle Scholar
  • 7 Frommel D, Muller JY, Prou-Wartelle O, Allain JP. Possible linkage between the major histocompatibility complex and the immune response to factor VIII in classical hemophilia. Vox Sang 1977; 33: 270-272
    CrossrefPubMedGoogle Scholar
  • 8 Lippert LE, Fisher JM c A, Schook LB. Relationship of major histocompatibility complex class II genes to inhibitor antibody formation in hemophilia A. Thromb Haemost 1990; 64: 564-568
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
    CrossrefPubMedGoogle Scholar
  • 10 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 1988; 71: 344-348
    PubMedGoogle Scholar
  • 11 Aledort L. Inhibitors in hemophilia patients: current status and management. Am J Hematol 1994; 47: 208-217
    CrossrefPubMedGoogle Scholar
  • 12 Millar DS, Steinbrecher RA, Wieland K, Grundy CB, Martinowitz U, Krawczak M, Zoll B, Whitmore D, Stephenson J, Mibashan RS, Kakkar VV, Cooper DN. The molecular genetic analysis of haemophilia A; characterization of six partial deletions in the factor VIII gene. Hum Genet 1990; 86: 219-227
    PubMedGoogle Scholar
  • 13 Lakich S, Kazazian HH Jr, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene as a common cause of severe hemophilia. Nature Genetics 1993; 5: 236-241
    CrossrefPubMedGoogle Scholar
  • 14 Goodeve AC, Preston FE, Peake IR. Factor VIII gene rearrangements in patients with severe haemophilia A. Lancet 1994; 343: 329-330
    CrossrefPubMedGoogle Scholar
  • 15 Ljung RC R. Intron 22 inversions and haemophilia. Lancet 1994; 343: 791
    CrossrefPubMedGoogle Scholar
  • 16 Tizzano EF, Altisent C, Tusell J, Domenech M, Baiget M. Intron 22 inversions and haemophilia. Lancet 1994; 343: 792
    PubMedGoogle Scholar
  • 17 Antonarakis SE, Kazazian HH, Tuddenham EG D. Molecular etiology of factor VIII defiency in hemophilia A. Hum Mut 1995; 5: 1-22
    CrossrefPubMedGoogle Scholar
  • 18 Kasper CK, Aledort LM, Counts RB, Edson JR, Frantatoni J, Green D, Hampton JW, Hilgardner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, von Eys J. A more uniform measurement of factor VIII inhibitors. Thrombos Diathes Haemorrh 1975; 34: 869-872
    PubMedGoogle Scholar
  • 19 Cotton RG, Rodrigues NR, Campbell RD. Reactivity of cytosine and thymine in single-base pair mismatches with hydroxylamine and osmiumtetroxyde and its application to the study of mutations. Proc Natl Acad Sci USA 1988; 85: 4397-4401
    CrossrefPubMedGoogle Scholar
  • 20 Sheffield VC, Cox DR, Lerman LS, Myers RM. Attachment of a 40-base- pair G+C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes. Proc Natl Acad Sci USA 1989; 86: 232-236
    CrossrefPubMedGoogle Scholar
  • 21 Schwaab R, Oldenburg J, Schwaab U, Johnson DJ D, Schmidt W, Olek K, Brackmann H-H, Tuddenham EG D. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Brit J Haematol. 1995 in press
    PubMedGoogle Scholar
  • 22 David D, Moreira J, Lalloz MR A, Rosa HA V, Schwaab R, Morais S, Diniz MJ, de Deus G, Campos M, Lavinha J, Johnson D, Tuddenham EG D. Analysis of the essential sequences of the factor VIII gene in twelve haemophilia A patients by single-stranded conformation polymorphism. Blood Coagulation & Fibrinolysis 1993; 5: 257-264
    PubMedGoogle Scholar
  • 23 Lerman L, Silverstein K. Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods Enzymol 1987; 155: 482-501
    PubMedGoogle Scholar
  • 24 Myers RM, Maniatis T, Lerman LS. Detection and localisation of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol 1987; 155: 501-527
    PubMedGoogle Scholar
  • 25 Faber JP, Poller W, Olek K, Baumann U, Carlson J, Lindmark B, Eriksson S. The molecular basis of alphal-antitrypsin deficiency in a heterzygote with liver and lung disease. J Hepatol 1993; 18: 313-321
    CrossrefPubMedGoogle Scholar
  • 26 Hoyer LW. The factor VIII complex: structure and function. Blood 1981; 58: 1-13
    PubMedGoogle Scholar
  • 27 Hoyer LW. Why do so many haemophilia A patients develop an inhibitor. Brit J Haematol 1995; 90: 498-501
    CrossrefPubMedGoogle Scholar
  • 28 Frommel D, Allain JP, Saint-Paul E, Bosser C, Noel B, Mannucci PM, Pannicucci F, Blomback M, Prou-Wartelle O, Muller JY. HLA antigens and factor VIII antibody in classic hemophilia. Thromb Haemost 1981; 46: 687-689
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Mayr WR, Lechner K, Niessner H, Pabinger-Fasching I. HLA-DR and factor VIII antibodies in hemophilia A. Thromb Haemost 1984; 51: 293 (letter)
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Aledort L. Inhibitors in hemophilia patients: current status and management. Am J Hematol 1994; 47: 208-217
    CrossrefPubMedGoogle Scholar
  • 31 Zuckerman AJ. Hepatitis A and non-A, non-B Hepatitis, Hepatitis C, Hepatitis E. In: Principles and Practice of Clinical Virology (second edition). Zuckerman AJ, Banatvala JE, Pattison JR. eds. Oxford: Alden Press; 1990: 143-151
    Google Scholar
  • 32 Giannelli F, Choo KH, Rees DJ G, Boyd Y, Rizza CR, Brownlee GG. Gene deletions in patients with haemophilia B and anti-factor IX antibodies. Nature 1983; 303: 181-182
    CrossrefPubMedGoogle Scholar
  • 33 Giannelli F, Green PM, Sommer SS, Lillicrap DP, Ludwig M, Schwaab R, Reitsma PH, Goossens M, Yoshioka A, Brownlee GG, Haemophilia B. Database of point mutations and short additions and deletions, fifth edition. 1994; Nucleic Acid Res 1994; 22: 3534-3546
    CrossrefPubMedGoogle Scholar