Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

the Zimmerman Program Investigators

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). Objectives: As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. Patients/Methods: 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs. Results: 75% of subjects (46) had central testing confirming type 3, while 25% were re-classified as type 1-Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co-dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. Conclusion: This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co-dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

Original languageEnglish (US)
Pages (from-to)1576-1588
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number7
DOIs
StatePublished - Jul 2022

Keywords

  • bleeding
  • genotype-phenotype association
  • inherited blood coagulation disorders
  • type 3 VWD

ASJC Scopus subject areas

  • Hematology

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