OC 63.2 - Molecular Pathogenesis and Mutational Profiles in Quantitative and Qualitative Types of Von Willebrand Disease: Results from a German Cohort Study

Tuesday, June 25, 2024

15:00 – 15:15 ICT

Room: Ballroom B3

Co-Author(s)

AK

Alexander Krahforst

Medical Student
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn
Bonn, Nordrhein-Westfalen, Germany

Presenting Author(s)

HY

Hamideh Yadegari, PhD

VWD and VWF Research Group Leader
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn
Bonn, Nordrhein-Westfalen, Germany

Co-Author(s)

AP

Anna Pavlova

Molecular Genetics Diagnostic Laboratory
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn
Bonn, Nordrhein-Westfalen, Germany
Behnaz Pezeshkpoor

Molecular Genetics Diagnostic Laboratory
Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn
Bonn, Nordrhein-Westfalen, Germany
JM

Jens Müller

Professor
Institute of Experimental Haematology and Transfusion Medicine
Bonn, Nordrhein-Westfalen, Germany
SH

Susan Halimeh

PD Dr.
Gerinnungszentrum rhein ruhr
Duisburg, Nordrhein-Westfalen, Germany
Johannes Oldenburg, MD

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine
Bonn, Nordrhein-Westfalen, Germany

Background: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder caused by deficiencies in von Willebrand factor (VWF), is classified into quantitative types (Low VWF, type 1, and type 3) and qualitative types (type 2).

Aims: This study seeks to conduct a comprehensive examination of laboratory phenotypes and mutation patterns within a substantial cohort of 417 patients diagnosed with VWD in Germany.

Methods: A thorough assessment, utilizing various VWF assays (VWF:Ag, VWF:GPIb/or VWF:RCo, VWF:CB, and multimer analysis) and FVIII coagulant activities, was undertaken. Genetic analyses included Sanger sequencing, targeted next-generation sequencing, copy number variation analysis, and bioinformatics evaluations.

Results: According to the updated ISTH-SSC VWF guidelines, 77 individuals were diagnosed with type 1 VWD, showcasing VWF:Ag levels below 30 IU/dL. Additionally, 111 patients exhibited VWF levels ranging from 30% to 50% and were categorized as Low VWF. Another 33 individuals were classified with type 3 VWD, while 196 individuals received a diagnosis of type 2 VWD (Figure 1). The mutation detection rates for these sub-cohorts were 88%, 66%, 95%, and 92%, respectively. A total of 147 distinctive VWF variants were identified in the cohort with quantitative VWF deficiencies (26% novel). In the type 1 VWD and Low VWF sub-cohorts, the majority of detected variants were missense variants (57% and 54% respectively), while in type 3, the majority of variants were null alleles (75%) (Figure 2A). There was an overexpression of blood group O prevalence (67%) within the Low VWF subgroup, especially among mutation-negative individuals (83%). The type 2 VWD sub-cohort revealed 118 distinct VWF variants, mainly missense (78%), with 34% being novel (Figure 2B).

Conclusion(s): This extensive patient cohort's data significantly contribute to our comprehension of the molecular basis and pathophysiological mechanisms underlying VWD. Distinctive mutation patterns were observed among different subtypes, providing valuable insights into the complexity of this disorder.