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Genetic Analyses in 391 VWD Patients: Novel VWF Gene Variations, and Important Differences in the Phenotype of Type 1 VWD Patients with- and without – a VWF Gene Mutation

1Erasmus University Medical Center, Department of Hematology, Rotterdam, the Netherlands, 2Radboud University Medical Center, Department of Hematology, Nijmegen, the Netherlands, 3Erasmus University Medical Center-Sophia Children's Hospital, Department of Pediatric Hematology, Rotterdam, the Netherlands, 4Netherlands Hemophilia Society, Nijkerk, the Netherlands, 5Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Pediatric Hematology, Amsterdam, the Netherlands, 6Sanquin Research, Department of Molecular Cellular Hemostasis, Amsterdam, the Netherlands, 7Leiden University Medical Center, Department of Clinical Epidemiology, Leiden, the Netherlands, 8Sanquin Research, Jon J van Rood Center for Clinical Transfusion Medicine, Leiden, the Netherlands, 9University Medical Center Groningen, Department of Hematology, Groningen, the Netherlands, 10University Medical Center Utrecht, University Utrecht, Department of Hematology, van Creveldkliniek, Utrecht, the Netherlands, 11Leiden University Medical Center, Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden, the Netherlands, 12Leiden University Medical Center, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden, the Netherlands

Abstract Number: OC 13.2

Meeting: ISTH 2020 Congress

Theme: Platelet Disorders and von Willebrand Disease » VWF and von Willebrand Factor Disorders - Clinical Conditions

Background: Genotyping von Willebrand factor (VWF) gene is not yet routine clinical practice in patients with von Willebrand disease (VWD), but may improve VWD diagnosis and can be used for genetic counseling.

Aims: We analyzed the VWF gene in a large cohort of VWD patients, to identify novel VWF gene variations and to perform phenotype-genotype analyses.

Methods: Analysis of VWF gene was performed in 391 VWD patients (VWF levels ≤0.30 IU/mL) from the nationwide “Willebrand in the Netherlands” (WiN) study. Genetic analysis was performed using Iontorrent and Sanger sequencing of all 52 exons including exon-intron boundaries (±20bp). We did MLPA to identify large deletions. VWF and FVIII levels were measured centrally.

Results: Variations were identified in 158/253 type 1 patients, 123/125 type 2 and 13/13 type 3 VWD patients (Table 1). Type 1 VWD patients without a VWF gene variation had slightly higher historically lowest VWF antigen compared to type 1 patients with a VWF gene variation (0.37IU/mL ±0.13 vs 0.30IU/mL ±0.29, p=0.013), and about two times higher centrally measured VWF antigen (0.55IU/mL ±0.20 vs 0.29IU/mL ±0.19, p< 0.001)). Interestingly, there was a clear distinction in pathophysiology of type 1 VWD with- and without VWF gene variations: an increased clearance of VWF with a high VWFpropeptide/VWF:Ag ratio was only seen in type 1 VWD patients with varations (Figure 1). In 57 patients we found novel VWF gene variations, of which several were found in unrelated patients who had a similar laboratory phenotype, confirming pathogenicity. Twenty novel variations were classified as class 5(/5) pathogenicity. For instance, several unrelated patients with a type 2A laboratory phenotype had c.3845T>C (p.Leu1282Pro), and type 3 VWD patients with novel homozygous VWF variations.

Conclusions: We provide new insights in the molecular background of VWD, and illustrate important phenotypic differences between type 1 VWD patients with- and without a VWF gene variation.


[Figure 1. There is a clear distinction in pathophysiology of type 1 VWD patients with- and without a VWF gene mutation]

  Type 1 VWD
n=253		 Type 2 VWD
n=125		 Type 3 VWD
n=13
Age, mean (std) 44 (18)* 42 (19)* 31 (21)*
Female, n (%) 167 (66%) 76 (61%) 7 (53.8%)
Blood group O, n (%) 170 (69%)* 67* (54%)* 6 (46.2%)
Mutation found, n (%) 158 (63%)* 123 (98.4%)* 13 (100%)*
VWF:Ag 0.38 [0.25-0.54]* 0.26 [0.16-0.37]* 0.00 [0.00-0.04]*
VWF:Ab 0.47 [0.23-0.73]* 0.08 [0.03-0.18]* 0.00 [0.00-0.00]*
FVIII:C 0.68 [0.49-0.88]* 0.37 [0.25-0.51]* 0.01 [0.01-0.29]*
Bleeding score 9 [6-15]* 11 [8-17]* 20 [14-25]*
Data are presented as median [interquartile ranges], unless otherwise specified. * P-value < 0.05 comparing patients with type 1, 2 and 3 VWD.

[Table 1. Baseline characteristics]

To cite this abstract in AMA style:

Atiq F, van Heerde WL, Boender J, Cnossen MH, Laros-van Gorkom BAP, de Meris J, Fijnvandraat K, Schoormans S, van der Bom JG, Meijer K, van Galen KPM, Eikenboom J, Leebeek FWG, WiN Study Group . Genetic Analyses in 391 VWD Patients: Novel VWF Gene Variations, and Important Differences in the Phenotype of Type 1 VWD Patients with- and without – a VWF Gene Mutation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/genetic-analyses-in-391-vwd-patients-novel-vwf-gene-variations-and-important-differences-in-the-phenotype-of-type-1-vwd-patients-with-and-without-a-vwf-gene-mutation/. Accessed October 2, 2023.

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