Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score.

IF 5 2区医学 Q1 HEMATOLOGY

Thrombosis and haemostasis Pub Date : 2024-05-17 DOI:10.1055/a-2329-3375

B. Guillet, Maxime Pawlowski, Pierre Boisseau, Y. Repesse, Philippe Beurrier, Sophie Bayart, X. Delavenne, Marc Trossaërt, Peter J Lenting

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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.

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血友病 A 基因型对去氨加压素的依赖性反应以及预测反应评分的建议。

去氨加压素（DDAVP）用于中度/轻度 A 型血友病（PWMH）患者，以提高他们的第八因子（FVIII）水平，并在可能的情况下使其恢复正常。然而，其疗效因人而异。GIDEMHA 研究旨在调查 F8 基因变异的影响。该研究收集了法国 4 家血友病治疗中心的治疗性静脉注射 DDAVP 试验中 FVIII 水平的变化情况。根据 F8 基因变异与疗效评分：绝对反应和相对反应，以及新评分：绝对持续时间（基于 FVIII ≥0.50 IU.mL-1 的持续时间）和相对持续时间（基于半衰期）进行了药理学分析。在登记的 439 例 PWMH 中，327 例有 F8 热点变异（≥5 例 PWMH）。这些患者的 FVIII 基础值和峰值的中位数（最小值-最大值）分别为 0.20（0.02-0.040）和 0.74（0.14-2.18）IU.ml-1，FVIII 恢复值为 3.80 IU.ml-1（1.15-14.75）。FVIII 的中位半衰期为 3.9 小时（0.7-15.9 小时）。224/327 例 PWMH（69%）的 FVIII 恢复正常（≥0.50 IU.ml-1），FVIII 恢复正常的中位时间为 3.9 小时（0.0-54.1 小时）。根据 4 项疗效评分确定的 DDAVP 反应曲线，分离出 4 组 F8 变体，然后将其与正常化 FVIII 的生存曲线（pT、p.(Cys2040Tyr)、p.(Tyr2169His)、p.(Pro2319Leu) 和 p.(Arg2326Gln)]进行比较。根据我们的数据，我们建议在 PWMH 中使用基于 F8 变体的 DDAVP，用于小手术和大手术。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thrombosis and haemostasis 医学-外周血管病

CiteScore

11.90

自引率

9.00%

发文量

140

审稿时长

1 months

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.