Type 2N von Willebrand disease: Genotype drives different bleeding phenotypes and treatment needs.

desmopressin factor VIII genotype von Willebrand disease type 2N von Willebrand factor

Journal

Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508

Informations de publication

Date de publication:
09 Jul 2024
Historique:
received: 04 01 2024
revised: 29 05 2024
accepted: 17 06 2024
medline: 12 7 2024
pubmed: 12 7 2024
entrez: 11 7 2024
Statut: aheadofprint

Résumé

Von Willebrand disease type 2N (VWD2N) is usually perceived as a mild bleeding disorder that can be treated by desmopressin (DDAVP). However, VWD2N-patients can be compound heterozygous or homozygous for different variants, p.Arg854Gln (R854Q) being the most frequent causative one. There is limited data about the impact of 2N-variants on VWD2N phenotype and DDAVP-response. To describe the phenotype of VWD2N, including DDAVP-response, according to genotype. VWD2N-patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score (BS) were eligible to the study. Results of DDAVP-trial were also collected. A total of 123 VWD2N-patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n=114) or absence (R854QNeg, n=9) of at least one R854Q-allele. Three R854QPos-subgroups were further individualized: patients homozygous (R854QHmz, n=55), compound heterozygous for R854Q and a null allele (R854Q/3, n=48) or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n=11). C levels were significantly lower in R854QNeg- and R854Q/3-patients compared to R854QHmz-ones (p<0.001 and p<0.0001 respectively). R854QNeg-patients were diagnosed earlier due to bleeding symptoms and had a higher BS than R854QPos-patients (p<0.001). In DDAVP-trial, FVIII:C survival was lower in VWD type 2N than in type 1. R854QPos-patients had a heterogeneous DDAVP-response, which was best predicted by baseline FVIII:C level. The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP-trial to identify patients potentially eligible to alternative therapeutic options.

Sections du résumé

BACKGROUND BACKGROUND
Von Willebrand disease type 2N (VWD2N) is usually perceived as a mild bleeding disorder that can be treated by desmopressin (DDAVP). However, VWD2N-patients can be compound heterozygous or homozygous for different variants, p.Arg854Gln (R854Q) being the most frequent causative one. There is limited data about the impact of 2N-variants on VWD2N phenotype and DDAVP-response.
OBJECTIVES OBJECTIVE
To describe the phenotype of VWD2N, including DDAVP-response, according to genotype.
PATIENTS/METHODS METHODS
VWD2N-patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score (BS) were eligible to the study. Results of DDAVP-trial were also collected.
RESULTS RESULTS
A total of 123 VWD2N-patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n=114) or absence (R854QNeg, n=9) of at least one R854Q-allele. Three R854QPos-subgroups were further individualized: patients homozygous (R854QHmz, n=55), compound heterozygous for R854Q and a null allele (R854Q/3, n=48) or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n=11).
FVIII UNASSIGNED
C levels were significantly lower in R854QNeg- and R854Q/3-patients compared to R854QHmz-ones (p<0.001 and p<0.0001 respectively). R854QNeg-patients were diagnosed earlier due to bleeding symptoms and had a higher BS than R854QPos-patients (p<0.001). In DDAVP-trial, FVIII:C survival was lower in VWD type 2N than in type 1. R854QPos-patients had a heterogeneous DDAVP-response, which was best predicted by baseline FVIII:C level.
CONCLUSION CONCLUSIONS
The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP-trial to identify patients potentially eligible to alternative therapeutic options.

Identifiants

DOI: 10.1016/j.jtha.2024.06.020 PMID: 38992343
pubmed: 38992343
pii: S1538-7836(24)00381-7
doi: 10.1016/j.jtha.2024.06.020
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.

Auteurs

Mélanie Daniel (M)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Catherine Ternisien (C)

Nantes University Hospital, Haemostasis Clinical Center, Nantes, France.

Sabine Castet (S)

Bordeaux University Hospital, Hemostasis Clinical Center, Bordeaux, France.

Céline Falaise (C)

Marseille University Hospital, Hemostasis Clinical Center, APHM, Marseille, France.

Roseline D'Oiron (R)

Reference Center for Hemophilia and Rare Congenital Bleeding Disorders, Bicêtre Hospital Assistance Publique-Hôpitaux de Paris, University of Paris-Saclay and UMR_S1176 Inserm, Le Kremlin-Bicêtre, France.

Fabienne Volot (F)

Dijon University Hospital, Hemostasis Clinical Center, Dijon, France.

Nathalie Itzhar (N)

Lariboisière Hospital, Laboratory of Haemostasis, APHP, Paris, France.

Brigitte Pan-Petesch (B)

Brest University Hospital, Hemostasis Clinical Center, Brest; France.

Emmanuelle Jeanpierre (E)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Camille Paris (C)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Christophe Zawadzki (C)

Lille University Hospital, Hematology and Transfusion, Lille, France.

Maximilien Desvages (M)

Lille University Hospital, Hematology and Transfusion, Lille, France.

Annabelle Dupont (A)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Agnès Veyradier (A)

Lariboisière Hospital, Laboratory of Haemostasis, APHP, Paris, France.

Yohann Repessé (Y)

Caen University Hospital, Laboratory and Clinical Hemostasis, Caen, France.

Antoine Babuty (A)

Nantes University Hospital, Haemostasis Clinical Center, Nantes, France.

Marc Trossaërt (M)

Nantes University Hospital, Haemostasis Clinical Center, Nantes, France.

Pierre Boisseau (P)

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Cécile V Denis (CV)

Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, 94276, Le Kremlin-Bicêtre, France.

Peter J Lenting (PJ)

Université Paris-Saclay, INSERM, Hémostase Inflammation Thrombose HITh U1176, 94276, Le Kremlin-Bicêtre, France.

Jenny Goudemand (J)

Lille University Hospital, Hematology and Transfusion, Lille, France.

Antoine Rauch (A)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Sophie Susen (S)

Univ. Lille, Inserm, Hematology and Transfusion Department, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France. Electronic address: sophiesusen@aol.com.

Classifications MeSH