B. Guillet, Maxime Pawlowski, Pierre Boisseau, Y. Repesse, Philippe Beurrier, Sophie Bayart, X. Delavenne, Marc Trossaërt, Peter J Lenting
{"title":"Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score.","authors":"B. Guillet, Maxime Pawlowski, Pierre Boisseau, Y. Repesse, Philippe Beurrier, Sophie Bayart, X. Delavenne, Marc Trossaërt, Peter J Lenting","doi":"10.1055/a-2329-3375","DOIUrl":null,"url":null,"abstract":"Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) 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. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 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). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). 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 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into 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)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.","PeriodicalId":23036,"journal":{"name":"Thrombosis and haemostasis","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thrombosis and haemostasis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1055/a-2329-3375","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMH) 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. The study collected the evolution of FVIII levels from therapeutic intravenous DDAVP tests in 4 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). From enrolled 439 PWMH, 327 had a hot-spot F8 variant (with ≥5 PWMH). 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 3.9h (0.7-15.9h). FVIII was normalized (≥0.50 IU.mL-1) in 224/327 PWMH (69%) and the median time with normalized FVIII was 3.9h (0.0-54.1h). Following the response profiles to DDAVP defined by the 4 efficacy scores, 4 groups of F8 variants were isolated then compared into 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)]. In view of our data, we propose indications for DDAVP-use in PWMH based on F8 variants for minor and major invasive procedures.
期刊介绍:
Thrombosis and Haemostasis publishes reports on basic, translational and clinical research dedicated to novel results and highest quality in any area of thrombosis and haemostasis, vascular biology and medicine, inflammation and infection, platelet and leukocyte biology, from genetic, molecular & cellular studies, diagnostic, therapeutic & preventative studies to high-level translational and clinical research. The journal provides position and guideline papers, state-of-the-art papers, expert analysis and commentaries, and dedicated theme issues covering recent developments and key topics in the field.