Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score

Benoît Guillet; Maxime Pawlowski; Pierre Boisseau; Yohann Répessé; Philippe Beurrier; Sophie Bayart; Xavier Delavenne; Marc Trossaërt; Peter J. Lenting

doi:10.1055/a-2329-3375

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2024; 124(10): 922-936
DOI: 10.1055/a-2329-3375

Coagulation and Fibrinolysis

Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score

Benoît Guillet

¹CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France

²Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail). UMR_S 1085, Rennes, France

,

Maxime Pawlowski

¹CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France

,

Pierre Boisseau

³Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHU de Nantes, France

,

Yohann Répessé

⁴Haemophilia Treatment Center, University Hospital of Caen, Caen, France

,

Philippe Beurrier

⁵Haemophilia Treatment Center, University Hospital of Angers, Pays de la Loire, France

,

Sophie Bayart

¹CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France

,

Xavier Delavenne

⁶INSERM, UMR 1059, Dysfonction Vasculaire et de l'Hémostase, Université de Lyon, Saint Etienne, France

⁷Laboratoire de Pharmacologie – Toxicologie, CHU de Saint-Etienne, Saint-Etienne, France

,

Marc Trossaërt

⁸Haemophilia Treatment Center, University Hospital of Nantes, Nantes, France

,

Peter J. Lenting

⁹Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixe de Recherche 1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France

› Author Affiliations

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.

Keywords

hemophilia A - factor VIII - desmopressin - F8 variants

Full Text

References

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Supplementary Material

Supplementary Material