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Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks

Authors

  • L. C. Rossetti,

    Corresponding author
    1. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
    • Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
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  • I. Szurkalo,

    1. Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
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  • C. P. Radic,

    1. Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
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  • M. M. Abelleyro,

    1. Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
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  • L. Primiani,

    1. Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
    2. Grupo Argentino de Estudio de Inhibidores en Hemofilia (GADEI), Buenos Aires, Argentina
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  • D. Neme,

    1. Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
    2. Grupo Argentino de Estudio de Inhibidores en Hemofilia (GADEI), Buenos Aires, Argentina
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  • M. Candela,

    1. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
    3. Grupo Argentino de Estudio de Inhibidores en Hemofilia (GADEI), Buenos Aires, Argentina
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  • R. P. Bianco,

    1. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
    3. Grupo Argentino de Estudio de Inhibidores en Hemofilia (GADEI), Buenos Aires, Argentina
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  • M. de Tezanos Pinto,

    1. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Fundación de la Hemofilia Alfredo Pavlovsky, Buenos Aires, Argentina
    3. Grupo Argentino de Estudio de Inhibidores en Hemofilia (GADEI), Buenos Aires, Argentina
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  • I. B. Larripa,

    1. Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
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  • C. D. De Brasi

    1. Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina
    2. Instituto de Investigaciones Hematológicas Mariano R Castex, Academia Nacional de Medicina, Buenos Aires, Argentina
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  • GADEI members are listed in Appendix

Correspondence: Liliana C. Rossetti, Molecular Genetics of Haemophilia Section, Academia Nacional de Medicina. Pacheco de Melo 3081, Buenos Aires (1425), Argentina.

Tel.: 5411 4805 8803; fax: 5411 4803 9475;

e-mail: rossetti@hematologia.anm.edu.ar

Summary

Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype–specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19–100)], Inv22 [1.8; 24% (19–100)] and nonsense in FVIII-LCh [1.2; 21% (7–59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6–11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype–stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.

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