OC 60.5 - Response to desmopressin in type 2N von Willebrand's disease: a genotype-phenotype analysis on a cohort of 121 patients

Tuesday, June 27, 2023

15:45 – 16:00 ET

Room: 516

Session Available As: Live-Stream and On-Demand

Presenting Author(s)

Melanie Daniel, MD

MD
Hematology Transfusion, Lille Hospital University, 59000, Lille, France
Lille, Nord-Pas-de-Calais, France

Co-Author(s)

Antoine Rauch (he/him/his)

Associate Professor
Univ.Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
Lille, Nord-Pas-de-Calais, France
FV

Fabienne Volot

MD
Dijon University Hospital, Hemostasis Clinical Center, Dijon, France
Dijon, Bourgogne, France
KP

Katia Pouymayou

MD
Marseille University Hospital, Hemostasis Clinical Center, APHM, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
BP

Brigitte Pan-Petesch

MD
CRC-MHC Brest – Service Hématologie, Unité Hémostase Clinique
BREST, Bretagne, France
SC

Sabine Castet

MD
Bordeaux University Hospital, Hemostasis Clinical Center, Bordeaux, France
Bordeaux, Aquitaine, France
NI

Nathalie Itzhar

MD
Service d’Hématologie Biologique, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris, Paris
Paris, Ile-de-France, France
AV

Agnès Veyradier

Professor
Service d’Hématologie Biologique, Hôpital Lariboisière, Assistance Publique–Hôpitaux de Paris and EA3518, Institut de Recherche Saint Louis, Université de Paris, Paris
Paris, Ile-de-France, France
Yohann Repessé, MD-PhD (he/him/his)

MD, PhD
CRC-MHC Caen
Caen, Basse-Normandie, France
CT

Catherine Ternisien

MD
Nantes University, CHU, Haemostasis Clinical Center, Nantes, France
Lille, Pays de la Loire, France
MT

Marc Trossaert

MD
Nantes University Hospital, Haemostasis Clinical Center, Nantes, France
Nantes, Pays de la Loire, France
PB

Pierre Boisseau

PhD
CHU Nantes, Service de Génétique Médicale, Nantes, France
Nantes, Pays de la Loire, France
EJ

Emmanuelle Jeanpierre

PharmD
Lille University Hospital, Hematology Transfusion, 59000, Lille, France
LILLE, Nord-Pas-de-Calais, France
CP

Camille Paris

MD
Hematology Transfusion, Lille Hospital University, 59000, Lille, France
Lille, Nord-Pas-de-Calais, France
CZ

Christophe Zawadzki, PharmD PhD

PharmD, PhD
Lille University, CHU, Department of Haematology, Lille, France
Lille, Nord-Pas-de-Calais, France
MD

Maximilien DESVAGES

PharmD
Lille University Hospital, Hematology Transfusion, 59000, Lille, France
LILLE, Nord-Pas-de-Calais, France
AD

Annabelle Dupont, Pharm D PhD

PharmD, PhD
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F5900 Lille, France
59000 Lille, Nord-Pas-de-Calais, France
JG

Jenny Goudemand

MD, PhD
Hematology Transfusion, Lille Hospital University, 59000, Lille, France
Lille, Nord-Pas-de-Calais, France
Sophie Susen, MD, PhD (she/her/hers)

MD, PhD
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
Lille, Nord-Pas-de-Calais, France

Background: Patients with type 2N von Willebrand disease (VWD) can be treated with desmopressin. A large proportion of them are compound heterozygous or homozygous for another mutation than p.(Arg854Gln) (R854Q), the most frequent causative variant. The association between VWF 2N variants and response to desmopressin is not yet fully understood.

Aims: To assess desmopressin response in VWD type 2N according to VWF genotype.

Methods: All type 2N VWD patients with a complete genotype/phenotype (including FVIII coagulant activity [FVIII:C], VWF antigen [VWF:Ag] , activity [VWF:Act and VWF:FVIIIB] levels) characterized by the French VWD reference center and with a desmopressin trial were eligible to this study. Age at diagnosis and bleeding score (Tosetto) were also collected.

Results: Among the 121 patients (median age: 23[9-41], M/F: 45/76, 114 unrelated families) included, 112 of them were positive for the R854Q variant (R854QPos) including 55 homozygous for R854Q (R854QHmz), 46 compound heterozygous for R854Q and a null allele (R854Q/3) and 11 compound heterozygous for R854Q and another 2N variant (R854Q/2N). The 9 remaining patients were compound heterozygous or homozygous for another 2N variants (R854QNeg). Baseline FVIII:C levels are shown in Figure1. R854QNeg patients were diagnosed at a young age (5 yo) mostly due to bleeding (89%) whereas R854QPos patients were diagnosed later (25 yo) and fortuitously (61%). Bleeding scores were clearly higher in R854QNeg patients than in R854QPos (median 14 vs 4, p< 0.001). In R854QNeg patients, FVIII:C deficiency was initially corrected upon desmopressin infusion but rapidly collapsed from 2h post-infusion onwards. In R854QPos patients, a more consistent and sustained response to desmopressin was observed including in R854Q/3 patients (Figure2) despite lower baseline VWF levels (VWF:Ag=51%[R854Q/3] vs 88%[R854QPos], p< 0.01).

Conclusion(s): Desmopressin response depends on the genetic variants in VWD type 2N. If genotyping is unavailable, a cut-off baseline FVIII:C >15 IU/dL, seems predictive of a good response to desmopressin.

Learning Objectives:

After attending this presentation, participants will be able to describe the different phenotypes of type 2N von Willebrand disease(VWD).
They will have knowledge of the genetic landscape associated with type 2N VWD.
Participants will also be able to evaluate poor candidates for desmopressin treatment in VWD type 2N.