<i>F8</i> gene variants influence the response to desmopressin in hemophilia A carriers

Desmopressin (DDAVP) is often administered to correct factor VIII (FVIII) levels in female hemophilia A carriers (HACs). However, the post-DDAVP FVIII pharmacokinetic profiles have been reported only in small series in HACs. Therefore, this study analyzed the post-DDAVP FVIII and von Willebrand factor (VWF) response in 361 HACs. A population pharmacokinetic/pharmacodynamic model was developed to analyze the VWF and FVIII levels by taking into account the F8 gene variants (n = 143 [39.6%] with null; and n = 218 [60.4%] with non-null variants), demographic and laboratory covariates. The before/after DDAVP mean basal, peak and recovery FVIII activity (FVIII:C) levels were 0.34 IU/mL (0.08-0.65), 1.13 IU/mL (0.19-2.69), and 2.85 IU/mL (1.06-7.13), respectively. Peak FVIII:C was ≥0.5 IU/mL in 95.6% (345/361) and ≥0.8 IU/mL in 78.7% (284/361) of patients. The covariate analysis showed a poorer DDAVP FVIII:C response for null than non-null F8 variants: lower mean FVIII:C peak (1.04 vs 1.23 IU/mL; P < 5 × 10-5) and patients percentage with normalized FVIII:C (91.6% vs 98.1%; P = .0068), higher mean FVIII:C clearance (5898.83 vs 2704.06 IU/h; P = 1.58 × 10-15), lower mean FVIII:C area under the curve during the first 12 hours (AUC0-12h =7.73 vs 9.06 IU/mL per hour; P < 5 × 10-6), and shorter mean time with FVIII:C ≥0.8 IU/mL (1.9 vs 4.1 hours; P < 6 × 10-6). HAC with body weight <35 kg had lower peak FVIII:C, higher FVIII:C clearance, lower AUC0-12h, and shorter time with FVIII:C ≥0.8 IU/mL than HAC with body weight 35 to 70 kg. In HACs, the post-DDAVP FVIII response is strongly influenced by the F8 genotype and body weight.

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Journal
Blood
Published
2025-08-22
DOI
https://doi.org/10.1182/blood.2025029829
Citations
1
Primary Topic
Hemophilia Treatment and Research
Type
article
Field-Weighted Citation Impact
1.77
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article

F8 gene variants influence the response to desmopressin in hemophilia A carriers

Marc Trossaërt, Benoît Guillet, Birgit Frotscher, Hérvè Chambost et al.
1 citations
Blood
Hemophilia Treatment and Research
1.77
article

F8 gene variants influence the response to desmopressin in hemophilia A carriers

Marc Trossaërt, Benoît Guillet, Birgit Frotscher, Hérvè Chambost, Sabine Castet, Brigitte Pan‐Petesch, Christine Biron‐Andréani, B. Wibaut, Brigitte Tardy, Céline Falaise, Xavier Delavenne, Roseline d’Oiron, Stéphanie Desage, Vincent Cussac, Fabienne Genre-Volot, Yoann Huguenin, Sophie Bayart, Laurent Ardillon
article en
1 citations

Abstract

Desmopressin (DDAVP) is often administered to correct factor VIII (FVIII) levels in female hemophilia A carriers (HACs). However, the post-DDAVP FVIII pharmacokinetic profiles have been reported only in small series in HACs. Therefore, this study analyzed the post-DDAVP FVIII and von Willebrand factor (VWF) response in 361 HACs. A population pharmacokinetic/pharmacodynamic model was developed to analyze the VWF and FVIII levels by taking into account the F8 gene variants (n = 143 [39.6%] with null; and n = 218 [60.4%] with non-null variants), demographic and laboratory covariates. The before/after DDAVP mean basal, peak and recovery FVIII activity (FVIII:C) levels were 0.34 IU/mL (0.08-0.65), 1.13 IU/mL (0.19-2.69), and 2.85 IU/mL (1.06-7.13), respectively. Peak FVIII:C was ≥0.5 IU/mL in 95.6% (345/361) and ≥0.8 IU/mL in 78.7% (284/361) of patients. The covariate analysis showed a poorer DDAVP FVIII:C response for null than non-null F8 variants: lower mean FVIII:C peak (1.04 vs 1.23 IU/mL; P < 5 × 10-5) and patients percentage with normalized FVIII:C (91.6% vs 98.1%; P = .0068), higher mean FVIII:C clearance (5898.83 vs 2704.06 IU/h; P = 1.58 × 10-15), lower mean FVIII:C area under the curve during the first 12 hours (AUC0-12h =7.73 vs 9.06 IU/mL per hour; P < 5 × 10-6), and shorter mean time with FVIII:C ≥0.8 IU/mL (1.9 vs 4.1 hours; P < 6 × 10-6). HAC with body weight <35 kg had lower peak FVIII:C, higher FVIII:C clearance, lower AUC0-12h, and shorter time with FVIII:C ≥0.8 IU/mL than HAC with body weight 35 to 70 kg. In HACs, the post-DDAVP FVIII response is strongly influenced by the F8 genotype and body weight.

BloodVol. 146(16)
Université Claude Bernard Lyon 1 (FR), Université de Tours (FR), Université de Bordeaux (FR), Inserm (FR), Bethlehem University (PS), Université de Montpellier (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Centre Hospitalier Universitaire de Lille (FR), Université Rennes 2 (FR), Assistance Publique Hôpitaux de Marseille (FR), Centre Hospitalier Universitaire de Montpellier (FR), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Bretonneau (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Institut de Recherche en Santé, Environnement et Travail (FR), Société Française de Médecine Vasculaire (FR), Laboratoire National de Référence (MA), Hôpital Pellegrin (FR), Centre Hospitalier du Mans (FR), Centre d'Investigation Clinique de Nantes (FR), Centre Hospitalier Régional Universitaire de Brest (FR), Fundação Hemopa (BR), Maison des Sciences sociales et des Humanités de Dijon (FR), Centre Hospitalier Universitaire de Rennes (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Société Francophone du Diabète (FR), Hôpital de la Timone (FR), Bicêtre Hospital (FR), Université de Rennes (FR), Université Jean Monnet (FR)
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Openalex Percentile: Top 13%
Hemophilia Treatment and Research
1.77
DOISourceOpenAlex
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