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

LILIANA CARMEN ROSSETTI; IRUPÉ SZURKALO; CLAUDIA PAMELA RADIC; MIGUEL MARTÍN ABELLEYRO; LAURA PRIMIANI; DANIELA NEME; MIGUEL CANDELA; RAÚL PÉREZ BIANCO; MIGUEL DE TEZANOS PINTO; IRENE BEATRIZ LARRIPA; CARLOS DANIEL DE BRASI

HAEMOPHILIA

Blackwell Publishing Ltd

Lugar: Oxford; Año: 2013 vol. 19 p. 511 - 518

1351-8216

Inhibitor development against exogenous FVIII 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) was predicted by structural modelling to cause a dramatic change in the electrostatic potential of A3-domain surface. 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, ins/del-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.