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DOI: 10.1055/a-2329-3375
Genotype-Dependent Response to Desmopressin in Hemophilia A and Proposal of a Predictive Response Score
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.
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.
Publikationsverlauf
Eingereicht: 28. Februar 2024
Angenommen: 11. April 2024
Accepted Manuscript online:
17. Mai 2024
Artikel online veröffentlicht:
11. Juni 2024
© 2024. Thieme. All rights reserved.
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References
- 1 Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8 (03) 421-432
- 2 Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia 2014; 20 (02) 158-167
- 3 Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1 (04) 682-689
- 4 Kaufmann JE, Oksche A, Wollheim CB, Günther G, Rosenthal W, Vischer UM. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000; 106 (01) 107-116
- 5 Rosenberg JB, Greengard JS, Montgomery RR. Genetic induction of a releasable pool of factor VIII in human endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20 (12) 2689-2695
- 6 Lamont PA, Ragni MV. Lack of desmopressin (DDAVP) response in men with hemophilia A following liver transplantation. J Thromb Haemost 2005; 3 (10) 2259-2263
- 7 Schütte LM, van Hest RM, Stoof SCM. et al. Pharmacokinetic modelling to predict FVIII:C response to desmopressin and its reproducibility in nonsevere haemophilia A patients. Thromb Haemost 2018; 118 (04) 621-629
- 8 Hews-Girard J, Rydz N, Lee A, Goodyear MD, Poon M-C. Desmopressin in non-severe haemophilia A: test-response and clinical outcomes in a single Canadian centre review. Haemophilia 2018; 24 (05) 720-725
- 9 Di Perna C, Riccardi F, Franchini M, Rivolta GF, Pattacini C, Tagliaferri A. Clinical efficacy and determinants of response to treatment with desmopressin in mild hemophilia a. Semin Thromb Hemost 2013; 39 (07) 732-739
- 10 Nance D, Fletcher SN, Bolgiano DC, Thompson AR, Josephson NC, Konkle BA. Factor VIII mutation and desmopressin-responsiveness in 62 patients with mild haemophilia A. Haemophilia 2013; 19 (05) 720-726
- 11 Stoof SCM, Sanders YV, Petrij F. et al. Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A. Thromb Haemost 2013; 109 (03) 440-449
- 12 Seary ME, Feldman D, Carcao MD. DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype. Haemophilia 2012; 18 (01) 50-55
- 13 Castaman G, Mancuso ME, Giacomelli SH. et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost 2009; 7 (11) 1824-1831
- 14 Knöfler R, Koscielny J, Tauer JT. et al. Desmopressin testing in haemophilia A patients and carriers: results of a multi centre survey. Hamostaseologie 2012; 32 (04) 271-275
- 15 Loomans JI, Kruip MJHA, Carcao M. et al; RISE consortium. Desmopressin in moderate hemophilia A patients: a treatment worth considering. Haematologica 2018; 103 (03) 550-557
- 16 Guillet B, Lambert T, d'Oiron R. et al. Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution. Hum Mutat 2006; 27 (07) 676-685
- 17 Bastida JM, González-Porras JR, Jiménez C. et al. Application of a molecular diagnostic algorithm for haemophilia A and B using next-generation sequencing of entire F8, F9 and VWF genes. Thromb Haemost 2017; 117 (01) 66-74
- 18 Chiu P-L, Bou-Assaf GM, Chhabra ES. et al. Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry. Blood 2015; 126 (08) 935-938
- 19 Liu ML, Shen BW, Nakaya S. et al. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood 2000; 96 (03) 979-987
- 20 Spiegel PC, Murphy P, Stoddard BL. Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities. J Biol Chem 2004; 279 (51) 53691-53698
- 21 Loomans JI, van Velzen AS, Eckhardt CL. et al. Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations. J Thromb Haemost 2017; 15 (02) 246-254
- 22 Revel-Vilk S, Blanchette VS, Sparling C, Stain AM, Carcao MD. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J Haematol 2002; 117 (04) 947-951
- 23 Dai L, Cutler JA, Savidge GF, Mitchell MJ. Characterization of a causative mutation of hemophilia A identified in the promoter region of the factor VIII gene (F8). J Thromb Haemost 2008; 6 (01) 193-195
- 24 Nougier C, Roualdes O, Fretigny M. et al. Characterization of four novel molecular changes in the promoter region of the factor VIII gene. Haemophilia 2014; 20 (02) e149-e156
- 25 Jacquemin M. Factor VIII-von Willebrand factor binding defects in autosomal recessive von Willebrand disease type Normandy and in mild hemophilia A. New insights into factor VIII-von Willebrand factor interactions. Acta Haematol 2009; 121 (2–3): 102-105
- 26 Eckhardt CL, van Velzen AS, Peters M. et al; INSIGHT Study Group. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 2013; 122 (11) 1954-1962
- 27 Trossaërt M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype. J Thromb Haemost 2008; 6 (03) 486-493