info:eu-repo/semantics/article
Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
Fecha
2013-07Registro en:
Rossetti, Liliana Carmen; Szurkalo, Irupé; Radic, Claudia Pamela; Abelleyro, Miguel Martin; Primiani, Laura; et al.; Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks; Wiley Blackwell Publishing, Inc; Haemophilia The Official Journal Of The World Federation Of Hemophilia; 19; 4; 7-2013; 511-518
1351-8216
CONICET Digital
CONICET
Autor
Rossetti, Liliana Carmen
Szurkalo, Irupé
Radic, Claudia Pamela
Abelleyro, Miguel Martin
Primiani, Laura
Neme, Daniela
Miguel, Candela
Pérez Bianco, Raúl
De Tezanos Pinto, Miguel
Larripa, Irene Beatriz
de Brasi, Carlos Daniel
Resumen
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.