Inhibitor risks estimation associated with F9 genotype types in patients with severe Haemophilia B: Argentine vs EAHAD database.

ZIEGLER B; ABELLEYRO MM; DE BRASI CD; RADIC CP; WAISMAN K; NEME D; MARCHIONE VD; WILLAMS M; ROSSETTI LC

Milan

Congreso; Virtual Meeting of the International Society on Thrombosis and Haemostasis ISTH; 2020

International Society on Thrombosis and Haemostasis

Background: Haemophilia B (HB), an X-linked coagulopathy affecting 1:30,000 males worldwide, is successfully treated by substitution of the deficient FIX. Development of inhibitory antibodies against therapeutic FIX represents a major clinical complication impacting patient?s quality of life and the economy of National health systems. FIX-inhibitors typically associate with severe allergic and/or anaphylactic reactions.Aims: We aimed to estimate the FIX inhibitor-risks associated with F9-genotypes in previously untreated patients (PUP) with severe-HB from Argentina (about 1/3 of all HB-cases countrywide) and from the International F9-variant database EAHAD (European Association for Haemophilia and Allied Disorders, http://f9-db.eahad.org/).Methods: HB-causative variants were characterised by application of a cost-effective F9-analysis algorithm including 12 PCR-amplifications, primary detecting large-F9-deletions in hemizygous probands, small-variant screening by high-resolution CSGE and Sanger sequencing. Variant pathogenicity was evaluated following ACMG criteria (American College of Medical Genetics).Results: Our Argentine case/control study, inhibitor[+]/inhibitor[-], included separated random samples of 13 cases and 67 controls. To correct the relative enrichment in inhibitor[+] cases(all inhibitor[+] cases with severe-HB were included) -as literature estimates 3-12% of FIX-inhibitor development in severe-HB, F9-genotype inhibitor-risks were estimated by ORs (CI95%)(Fisher exact P-values) that normalise those case/control unbalance. Severe-HB patient series from EAHAD, in which inhibitor status was reported, present a similar enrichment in inhibitor[+] cases.Argentine series of F9-missense variants showed the lowest FIX-inhibitor-risks, equal to EAHAD, while nonsense showed moderately augmented inhibitor-risks, similar to EAHAD. Argentina vs EAHAD figures were consistent indicating the highest inhibitor-risks classifying all types of F9-deletions together, which is even more important in cases with deletions of the entire-F9, and just doubling the inhibitor-risks but non-significantly in partial F9-deletions. Table.Conclusions: Our findings reveal similar estimations of F9-genotype associated inhibitor-risks in severe-HB PUPs series from Argentina and EAHAD. Data of F9-variant-specific inhibitor-risks may provide haematologists with key evidence for designing therapeutics and follow-up regimes.