<i>F8</i> gene variants influence the response to desmopressin in hemophilia A carriers
Abstract
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 &lt; 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 &lt; 5 × 10–6), and shorter mean time with FVIII:C ≥0.8 IU/mL (1.9 vs 4.1 hours; P &lt; 6 × 10–6). HAC with body weight &lt;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.
Article Details
Authors (18)
Benoît Guillet
1Centre de Référence de l’Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles University Hospital, UMR_S 1085, Rennes, France
Roseline d’Oiron
3Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Rares, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin Bicêtre, France
Marc Trossaërt
9Nantes University Hospital, Haemostasis Clinical Center, Nantes, France
Bénédicte Wibaut
6Centre de Référence maladie de Willebrand, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles, University Hospital, Lille, France
Brigitte Pan-Petesch
7Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles, Service Hématologie Hémostase Clinique, Morvan University Hospital, Brest, France
Birgit Frotscher
8Hemophilia Treatment Center, University Hospital, Nancy, France
Fabienne Volot
9Hemophilia Treatment Center, University Hospital, Dijon, France
Laurent Ardillon
10Hemophilia Treatment Center, University Hospital, Trousseau Hospital, Tours, France
Stéphanie Désage
11Centre de Référence de l’Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles, Hospices Civils de Lyon, Bron, France
Céline Falaise
12Assistance Publique–Hôpitaux de Marseille, Hemophilia Centre, La Timone Children's Hospital, Marseille, France
Christine Biron-Andréani
13Hemophilia Treatment Center, University Hospital, Montpellier, France
Vincent Cussac
14Hemophilia Treatment Center, Le Mans Hospital Center, Le Mans, France
Brigitte Tardy
15CRC Hémophilie et Maladies Hémorragiques, CIC 1408, Centre Hospitalier Universitaire Saint-Etienne, Saint-Etienne, France
Yoann Huguenin
8Division of Pediatric Hematology-Oncology, Bordeaux University Hospital, Bordeaux, France
Hervé Chambost
17Assistance Publique–Hôpitaux de Marseille, Hemophilia Centre, Children La Timone Children's Hospital and Aix Marseille University, INSERM, INRA, C2VN, Marseille, France
Sophie Bayart
1Centre de Référence de l’Hémophilie, Centre de Ressource et de Compétence des Maladies Hémorragiques Constitutionnelles University Hospital, UMR_S 1085, Rennes, France
Sabine-Marie Castet
2Bordeaux University Hospital, Haemostasis Clinical Center, Bordeaux, France
Xavier Delavenne
30University Jean Monnet Saint-Etienne, SAINBIOSE Inserm U1059, Saint-Etienne, France