Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF

Previous reports have highlighted that some patients with low von Willebrand factor (VWF) with significant bleeding were diagnosed based on an isolated but persistent reduction in plasma VWF activity levels in the 30 to 50 IU/dL range. These patients had plasma VWF antigen (VWF:Ag) levels >50 IU/dL and thus had qualitative low VWF (low VWF-QL) rather than quantitative low VWF. Although the clinical importance of functional VWF defects in type 2 von Willebrand disease (VWD) is well recognized, the translational implications of mild functional defects in patients with low VWF-QL have not been defined. To address this clinically important question, we combined low VWF data sets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for ∼50% of our combined low VWF cohort. Importantly, our findings demonstrated that many of these patients with mild isolated functional VWF defects in the 30 to 50 IU/dL range had significant bleeding phenotypes, although their plasma VWF:Ag levels were within the normal range. In addition, we further showed that low VWF-QL is a distinct clinicopathological entity compared to type 2 VWD. Finally, our studies highlighted that low VWF-QL is predominantly caused by abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.

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Publication Details

Journal
Blood
Published
2025-04-25
DOI
https://doi.org/10.1182/blood.2024028035
Citations
4
Primary Topic
Platelet Disorders and Treatments
Type
article
Field-Weighted Citation Impact
7.08

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article

Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF

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Platelet Disorders and Treatments
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article

Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF

Jorge Di Paola, Frank W.G. Leebeek, Robin D. Blok, James S. O’Donnell, Jeroen C.J. Eikenboom, Joke de Meris, Roger J. S. Preston, Paula James, Mairead M. Doyle, Dearbhla Doherty, Ross Baker, Johanna G. van der Bom, Marjon H. Cnossen, Kevin M. Ryan, Karin P. M. van Galen, Saskia E.M. Schols, Mary Byrne, Niamh O’Connell, Ferdows Atiq, Michelle Lavin, Karina Meijer, Floor Heubel-Moenen, Anne‐Marije Hulshof, Karin Fijnvandraat, Waander L. van Heerde, Calvin van Kwawegen
article en
4 citations

Abstract

Previous reports have highlighted that some patients with low von Willebrand factor (VWF) with significant bleeding were diagnosed based on an isolated but persistent reduction in plasma VWF activity levels in the 30 to 50 IU/dL range. These patients had plasma VWF antigen (VWF:Ag) levels >50 IU/dL and thus had qualitative low VWF (low VWF-QL) rather than quantitative low VWF. Although the clinical importance of functional VWF defects in type 2 von Willebrand disease (VWD) is well recognized, the translational implications of mild functional defects in patients with low VWF-QL have not been defined. To address this clinically important question, we combined low VWF data sets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for ∼50% of our combined low VWF cohort. Importantly, our findings demonstrated that many of these patients with mild isolated functional VWF defects in the 30 to 50 IU/dL range had significant bleeding phenotypes, although their plasma VWF:Ag levels were within the normal range. In addition, we further showed that low VWF-QL is a distinct clinicopathological entity compared to type 2 VWD. Finally, our studies highlighted that low VWF-QL is predominantly caused by abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.

BloodVol. 146(3)
HAN University of Applied Sciences (NL), University Medical Center Groningen (NL), Royal College of Surgeons in Ireland (IE), Radboud University Nijmegen (NL), University of Groningen (NL), Murdoch University (AU), Utrecht University (NL), Washington University in St. Louis (US), Queen's University (CA), Leiden University Medical Center (NL), Maastricht University Medical Centre (NL), Erasmus MC (NL), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Maastricht University (NL), Emma Kinderziekenhuis (NL), Nederlandse Vereniging voor Kindergeneeskunde (NL), Erasmus MC - Sophia Children’s Hospital (NL), Irish Blood Transfusion Service (IE), Amsterdam University Medical Centers (NL), St. James's Hospital (IE), Netherlands Haemophilia Society, University of Amsterdam (NL)
Amgen, Bristol-Myers Squibb, Pfizer, Sanofi, Alexion Pharmaceuticals, CSL Behring, Science Foundation Ireland, ZonMw, Novo Nordisk, Swedish Orphan Biovitrum, LEO Pharma, National Institutes of Health, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 3%
Platelet Disorders and Treatments
7.08
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