Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF
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.
Article Details
Authors (26)
Ferdows Atiq
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Robin Blok
2Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands
Calvin B. van Kwawegen
2Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands
Anne-Marije Hulshof
2Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Dearbhla Doherty
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Michelle Lavin
National Coagulation Centre, St. James's Hospital, Dublin, Ireland
Johanna G. van der Bom
4Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Niamh M. O’Connell
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Joke de Meris
5Netherlands Hemophilia Society, Leiden, The Netherlands
Kevin Ryan
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Saskia E. M. Schols
6Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
Waander L. van Heerde
6Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
Mairead Doyle
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Mary Byrne
3National Coagulation Centre, St James’s Hospital, Dublin, Ireland
Floor C. J. I. Heubel-Moenen
7Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands
Karin P. M. van Galen
10Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
Roger J. S. Preston
Marjon H. Cnossen
Karin Fijnvandraat
Ross I. Baker
13Western Australia Centre for Thrombosis and Haemostasis, Perth Blood Institute, Murdoch University, Perth, WA, Australia
Karina Meijer
Paula James
16Department of Medicine, Queen’s University, Kingston, ON, Canada
Jorge Di Paola
Division of Hematology, Department of Pediatrics, Washington University
Jeroen Eikenboom
18Division of Thrombosis and Hemostasis, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Frank W. G. Leebeek
1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
James S. O’Donnell