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DOI: 10.1055/a-2329-3375
Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score
Funding The authors thank CoMETH (French medical society for bleeding disorders) and GIRCI-HUGO (Groupement Inter régional de la Recherche Clinique et de l'Innovation [GIRCI] hospitalo-universitaires du Grand-Ouest [HUGO]) for funding this research.
Abstract
Background Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMHs) 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.
Material and Methods The study collected the trajectory of FVIII levels from therapeutic intravenous DDAVP tests in four 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).
Results From enrolled 439 PWMHs, 327 had a hot-spot F8 variant (with ≥5 PWMHs). 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 3.9 hours (0.7–15.9 hours). FVIII was normalized (≥0.50 IU.mL−1) in 224/327 PWMHs (69%) and the median time with normalized FVIII was 3.9 hours (0.0–54.1 hours). Following the response profiles to DDAVP defined by the four efficacy scores, four groups of F8 variants were isolated, and then compared using 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)].
Conclusion In view of our data, we propose indications for DDAVP use in PWMH based on F8 variants for minor and major invasive procedures.
Authors' Contribution
B.G. designed the study, included patients, analyzed data, and wrote the paper. M.P., Y.R., P.B., and S.B. included patients. X.D. analyzed data. M.T. included patients, analyzed data, and wrote the paper. P.J.L. analyzed data and wrote the paper.
Publication History
Received: 28 February 2024
Accepted: 11 April 2024
Accepted Manuscript online:
17 May 2024
Article published online:
11 June 2024
© 2024. Thieme. All rights reserved.
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