IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Factor VIII genotype characterisation of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks.
Autor/es:
ROSSETTI LC; MARCHIONE VD; DE BRASI CD
Lugar:
Melbourne
Reunión:
Congreso; XXXI International Congress of the World Federation of Hemophilia; 2014
Institución organizadora:
World Federation of Hemophilia
Resumen:
About 20% of severe cases
with HA from Argentina
developed FVIII neutralizing antibodies (inhibitors, INH). Several studies have
shown that the causative mutation is the most decisive risk factor for
inhibitor formation.
Our objective was to
estimate locally specific risks for developing inhibitors associated with each F8 genotype in Argentine patients with
severe HA (sHA).
To estimate the risks for
developing FVIII INH associated with each F8
mutation type/location, we considered an Argentine unbiased group of sHA patients
(n = 107) showing an Inhibitor Prevalence (IP) of 17.6%.
The comprehensive
population of Argentine patients with sHA (n = 227, 84 cases and 143 controls)
was considered to estimate relative inhibitor risks (OR) associated with each
mutation type/F8-location. We
characterized the causative mutation by application of a laboratory algorithm
including inverse shifting-PCR for F8
inversions, 37 PCR-amplifications for gross deletion detection, and for
small-mutation screening by CSGE, and DNA-sequencing.
The case/control study
(84/143) permitted estimation of F8
genotype?specific inhibitor risks [OR; IP (CI)] in sHA 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)].
In addition, this
approach allowed performing multiple mutation associations of more than one
molecular defect, e.g.: small mutations vs
INV22/1 & deletions resulted in [0.42; 10% (6.2?15)] predicting more than
twice times less risk of INH developing for sHA patients without large
rearrangements. This analysis may be associated side-by-side with the
techniques forming the traditional algorithm used in most laboratories for sHA
molecular diagnosis worldwide (1st INV22/1 analysis and 2nd large deletion
detection) that normally requires less time than small mutation screening allowing
a rapid estimation of patient-specific INH risks.
In conclusion, the Argentine series of sHA patients presents similar
global and mutation-specific inhibitor risks than the HA database and published
series. This case-specific information may be valuable in designing fitted
therapies and follow-up protocols.