Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF
Blood, vol. 146, pp. 369–381
Abstract
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.
Authors 24
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Ferdows Atiq corresponding
Royal College of Surgeons in Ireland · Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
2Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands
Erasmus MC, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
2Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands
Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
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Royal College of Surgeons in Ireland
Affiliation as printed
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Royal College of Surgeons in Ireland, Ireland
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Royal College of Surgeons in Ireland · St. James's Hospital
Affiliation as printed
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland, Dublin 6, Ireland
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Royal College of Surgeons in Ireland · St. James's Hospital
Affiliation as printed
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
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Leiden University Medical Center
Affiliation as printed
4Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden University Medical Center, Leiden, Netherlands
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Affiliation as printed
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
St James's Hospital, Dublin, Ireland
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Netherlands Haemophilia Society
Affiliation as printed
5Netherlands Hemophilia Society, Leiden, The Netherlands
NVHP, Zoetermeer, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
6Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
7Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands
Radboud university medical center, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
6Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
7Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands
Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
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Affiliation as printed
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
St James Hospital, Dublin, Ireland
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Affiliation as printed
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
St James's Hospital, Dublin, Ireland
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
7Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands
8Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands
9Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
Maastricht University Medical Center+, Department of Hematology, Internal Medicine, Maastricht, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
10Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
University Medical Center Utrecht, Utrecht, Netherlands
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Royal College of Surgeons in Ireland
Affiliation as printed
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
11Department of Pediatric Hematology and Oncology, Erasmus MC, University Medical Center-Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands
Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
12Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands
Amsterdam UMC, Amsterdam, Netherlands
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Affiliation as printed
13Western Australia Centre for Thrombosis and Haemostasis, Perth Blood Institute, Murdoch University, Perth, WA, Australia
14Irish-Australian Blood Collaborative Network, Dublin, Ireland
Perth Blood Institute, PERTH, Australia
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University Medical Center Groningen · University of Groningen
Affiliation as printed
15Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands
University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Affiliation as printed
16Department of Medicine, Queen’s University, Kingston, ON, Canada
Queen's University, Kingston, Ontario, Canada
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Washington University in St. Louis
Affiliation as printed
17Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO
Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
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Jeroen C.J. Eikenboom Aachen 18Division of Thrombosis and Hemostasis Department of Internal Medicine
Leiden University Medical Center
Affiliation as printed
18Division of Thrombosis and Hemostasis, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Leiden University Medical Center, Leiden, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
2Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands
Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
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Royal College of Surgeons in Ireland · St. James's Hospital
Affiliation as printed
14Irish-Australian Blood Collaborative Network, Dublin, Ireland
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
National Coagulation Centre, St James's Hospital, Dublin, Ireland, Ireland
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