Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies
Ferdows Atiq 1,2; Robin Blok 2; Calvin B. van Kwawegen 2; Dearbhla Doherty 1,3; Michelle Lavin 1,3; Johanna G. van der Bom 4; Niamh M. O’Connell 3; Joke de Meris 5; Kevin Ryan 3; Saskia E. M. Schols 6; Mary Byrne 3; Floor C. J. I. Heubel-Moenen 7; Karin P. M. van Galen 8; Roger J. S. Preston 1; Marjon H. Cnossen 9; Karin Fijnvandraat 10; Ross I. Baker 11,12; Karina Meijer 13; Paula James 14; Jorge Di Paola 15; Jeroen Eikenboom 16; Frank W. G. Leebeek 2,*; and James S. O’Donnell 1,3,12,*
1-Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; 2-Department of Haematology, Erasmus University Medical Center-Erasmus MC, Rotterdam, The Netherlands; 3-National Coagulation Centre, St James’s Hospital, Dublin, Ireland; 4-Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; 5-Netherlands Hemophilia Society, Leiden, The Netherlands; 6-Department of Hematology, Radboud University Medical Center, Nijmegen and Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, The Netherlands; 7-Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands; 8-Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 9-Department of Pediatric Hematology and Oncology, Erasmus MC, University Medical Center–Sophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands; 10-Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands; 11-Western Australia Centre for Thrombosis and Haemostasis, Perth Blood Institute, Murdoch University, Perth, WA, Australia; 12-Irish-Australian Blood Collaborative Network, Dublin, Ireland; 13-Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands; 14-Department of Medicine, Queen’s University, Kingston, ON, Canada; 15-Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO; and 16-Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (β = 0.00; 95% confidence interval, −0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF doesnot constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.