Haemophilia A: Mutation Type Determines Risk of Inhibitor Formation

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.

[1]  J. Oldenburg,et al.  Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs , 1995, British journal of haematology.

[2]  L. Hoyer.  WHY DO SO MANY HAEMOPHILIA A PATIENTS DEVELOP AN INHIBITOR? , 1995, British journal of haematology.

[3]  L. Aledort.  Inhibitors in hemophilia patients: Current status and management , 1994, American journal of hematology.

[4]  E G Tuddenham,et al.  Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. , 1994, Nucleic acids research.

[5]  E. Gordon,et al.  A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. , 1994, Blood.

[6]  J. Lavinha,et al.  Analysis of the essential sequences of the factor VIII gene in twelve haemophilia A patients by single‐stranded conformation polymorphism , 1994, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[7]  J. Lau,et al.  Risk of gastrointestinal bleeding from dexamethasone in children with bacterial meningitis , 1994, The Lancet.

[8]  M. Baiget,et al.  Intron 22 Inversions and haemophilia , 1994, The Lancet.

[9]  F. Preston,et al.  Factor VIII gene rearrangements in patients with severe haemophilia A , 1994, The Lancet.

[10]  I. Scharrer,et al.  Incidence of inhibitors in haemophiliacs. A review of the literature. , 1993, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[11]  S. Arkin,et al.  Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. , 1993, The New England journal of medicine.

[12]  W. Kreuz,et al.  Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs , 1992, The Lancet.

[13]  E G Tuddenham,et al.  Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. , 1994, Nucleic acids research.

[14]  L. Schook,et al.  Relationship of Major Histocompatibility Complex Class II Genes to Inhibitor Antibody Formation in Hemophilia A , 1990, Thrombosis and Haemostasis.

[15]  R. D. Campbell,et al.  Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Shapiro,et al.  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. , 1988, Blood.

[17]  W. Mayr,et al.  HLA-DR and Factor VIII Antibodies in Hemophilia A , 1984, Thrombosis and Haemostasis.

[18]  D. Rees,et al.  Gene deletions in patients with haemophilia B and anti-factor IX antibodies , 1983, Nature.

[19]  M. Blombäck,et al.  HLA Antigens and Factor VIII Antibody in Classic Hemophilia , 1981, Thrombosis and Haemostasis.

[20]  L. Hoyer.  The factor VIII complex: structure and function. , 1981, Progress in clinical and biological research.

[21]  J. Muller,et al.  Possible Linkage between the Major Histocompatibility Complex and the Immune Response to Factor VIII in Classic Haemophilia , 1977, Vox sanguinis.

[22]  H. Brackmann,et al.  MASSIVE FACTOR-VIII INFUSION IN HÆMOPHILIAC WITH FACTOR-VIII INHIBITOR, HIGH RESPONDER , 1977, The Lancet.

[23]  S. Antonarakis,et al.  Molecular etiology of factor VIII deficiency in hemophilia A , 1995, Human mutation.

[24]  P. Reitsma,et al.  Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. , 1994, Nucleic acids research.

[25]  W. Poller,et al.  The molecular basis of α1-antichymotrypsin deficiency in a heterozygote with liver and lung disease , 1993 .

[26]  P. Reitsma,et al.  Haemophilia B: database of point mutations and short additions and deletions. , 1990, Nucleic acids research.

[27]  V. Sheffield,et al.  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. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Myers,et al.  Detection and localization of single base changes by denaturing gradient gel electrophoresis. , 1987, Methods in enzymology.

[29]  L. Lerman,et al.  Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. , 1987, Methods in enzymology.

[30]  D. Green,et al.  A More Uniform Measurement of Factor VIII Inhibitors , 1975, Thrombosis and Haemostasis.