F8 GENOTYPE SPECIFIC INHIBITOR RISKS IN ARGENTINE PATIENTS WITH SEVERE HA AND PARTICULAR RISK ESTIMATION OF DIFFERENT MUTATION TYPES.

ROSSETTI LC; RADIC CP; ABELLEYRO MM; MARCHIONE VD; SZURKALO I; PRIMIANI L; NEME D; CANDELA M; DE TEZANOS PINTO M; DE BRASI CD

Melbourne

Congreso; The XXXI International Congress of the World Federation of Hemophilia; 2014

World Federation of Hemophilia

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.