Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score.

Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥0.50 IU.mL-1) and relative duration (based on half-life). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL-1 respectively, with FVIII recovery being 3.80 IU.ml-1 (1.15-14.75). The median FVIII half-life was 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into survival curves with normalized FVIII (p<0.0001): "long lastingly effective" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu) and T-stretch deletion in intron 13]; "moderately effective" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser) and p.(Asp2150Asn)]; "moderately ineffective" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn) and p.(Arg2178Cys)]; and "frequently ineffective" [c.-219C>T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu) and p.(Arg2326Gln)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.

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Déclaration de conflit d'intérêts

Benoît Guillet has received grants or consultant fees from CSL-Behring, LFB, NovoNordisk, Octapharma, Roche/Chugaï and Sobi. Yohann Répessé has received funding or consultant fees from BioMarin, CSL-Behring, LFB, NovoNordisk, Octapharma, Roche, Shire, Sobi, Takeda. Xavier Delavenne has received honoraria for participation in symposia by CSL Behring, Shire, Octapharma and Sobi. Marc Trossaert has received funding or consultant fees from Bayer Healthcare, CSL-Behring, NovoNordisk, Octapharma, Parexel, Roche, Sanofi, Shire, Sobi, and Takeda. Peter Lenting has received grants from Pfizer, Sanofi, Sobi and Roche. Maxime Pawlowski, Sophie Bayart, Philippe Beurrier, and Pierre Boisseau declare no disclosure.