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Thromb Haemost
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
1   CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France
2   Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en santé, Environnement et Travail). UMR_S 1085, Rennes, France
,
Maxime Pawlowski
1   CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France
,
Pierre Boisseau
3   Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, CHU de Nantes, France
,
Yohann Répessé
4   Haemophilia Treatment Center, University Hospital of Caen, Caen, France
,
Philippe Beurrier
5   Haemophilia Treatment Center, University Hospital of Angers, Pays de la Loire, France
,
Sophie Bayart
1   CRH, CRC-MHC (Centre de Référence de l'Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles), University Hospital, Rennes, France
,
Xavier Delavenne 
6   INSERM, UMR 1059, Dysfonction Vasculaire et de l'Hémostase, Université de Lyon, Saint Etienne, France
7   Laboratoire de Pharmacologie – Toxicologie, CHU de Saint-Etienne, Saint-Etienne, France
,
Marc Trossaërt
8   Haemophilia Treatment Center, University Hospital of Nantes, Nantes, France
,
Peter J. Lenting
9   Laboratory 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 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.
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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

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.


Supplementary Material



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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