Guillet Benoît, Pawlowski Maxime, Boisseau Pierre, Répessé Yohann, Beurrier Philippe, Bayart Sophie, Delavenne Xavier, Trossaërt Marc, Lenting Peter J
CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France.
Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail). UMR_S 1085, Rennes, France.
Thromb Haemost. 2024 Oct;124(10):922-936. doi: 10.1055/a-2329-3375. Epub 2024 May 17.
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 gene variants.
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 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥ 0.50 IU.mL) and relative duration (based on half-life).
From enrolled 439 PWMHs, 327 had a hot-spot 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 respectively, with FVIII recovery being 3.80 IU.ml (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) 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 variants were isolated, and then compared using survival curves with normalized FVIII ( < 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 variants for minor and major invasive procedures.
