What question did this study set out to answer?

To integrate next-generation sequencing into the diagnostic workflow for von Willebrand Disease, aiming to improve accuracy.

April 17, 2026Seminars in Thrombosis and Hemostasis0 citations

Integrating Next-Generation Sequencing into von Willebrand Disease Diagnostics: Insights from the PCM-EVW-ES Multicenter Project

NBNina BorràsUniversitat Autònoma de Barcelona ICIrene CorralesUniversitat Autònoma de Barcelona FVFrancisco VidalUniversitat Autònoma de Barcelona

Key Points

To integrate next-generation sequencing into the diagnostic workflow for von Willebrand Disease, aiming to improve accuracy.
Review of current VWD diagnostic concepts
Integration of genetic testing in diagnostics
Centralized phenotypic testing involving 48 hospitals
Utilization of next-generation sequencing for the VWF coding region
Development of a diagnostic algorithm for VWD classification.
Definitive classification of 730 individuals with VWD.
Improved subtype assignment and identification of asymptomatic carriers.
Identification of recurrent disease-causing variants in Spain.
Enhanced diagnostic accuracy through early VWF molecular testing.
Proposed challenges including interpretation of uncertain variants.

Abstract

Abstract Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the VWF coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype–phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early VWF molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic VWF variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.

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