Abstract Number: PB0325
Meeting: ISTH 2020 Congress
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.
|F9-genotype||Argentine (n=80) [case/control]||EAHAD (n=210) [case/control]||FIX inhibitor-risks|
|F9-missense||[0/34] OR=0.036(0.002-0.63) (P=0.0004***)||[1/85] OR=0.016(0.002-0.12) (P<0.0001****)||extremely low (highly-significant)|
|All-F9-deletions||[5/2] OR=7.35(1.92-28.1) (P=0.005**)||[21/1] OR=28.2(9.11-87.3) (P<0.0001****)||extremely high (highly-significant)|
|Entire-F9-deletions||[6/7] OR=46(7.08-298.8) (P=0.0001***)||[23/4] OR=99(12.8-759.7) (P<0.0001****)||extremely high (highly-significant)|
|F9-nonsense||[5/13] OR=2.6(0.73-9.26) (P=0.15)||[21/35] OR=2.2(1.13-4.27) (P=0.02*)||high (non-significant)|
|Partial-F9-deletions||[1/5] OR=2.5(0.25-24.4) (P=0.403)||[2/3] OR=1.96(0.32-12.1) (P=0.605)||high (non-significant)|
[F9-genotype inhibitor risks]
To cite this abstract in AMA style:Radic P, Ziegler B, Marchione V, Waisman K, Abelleyro MM, Williams M, Neme D, De Brasi CD, Rossetti L. Inhibitor Risks Estimation Associated with F9 Genotype Types in Patients with Severe Haemophilia B: Argentine vs EAHAD Database [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/inhibitor-risks-estimation-associated-with-f9-genotype-types-in-patients-with-severe-haemophilia-b-argentine-vs-eahad-database/. Accessed January 28, 2022.
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