Type 1 VWD classification revisited - novel insights from combined analysis of the LoVIC and WiN studies

There is significant ongoing debate regarding type 1 VWD defintion. Previous guidelines recommended patients with VWF levels < 30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels 30-50 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 datasets from two 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 subjects, VWF levels remained < 30 IU/dL despite increasing age. Conversely, VWF levels increased into the Low VWF range (30-50 IU/dL) in 30%, and normalized (>50 IU/dL) in 23% of WiN cases. Crucially, absolute VWF:Ag levels and increase of VWF:Ag per year overlapped between Low VWF and normalized-WiN subjects. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in LoVIC cohort and WiN-normalized patients would not have been different had they been diagnosed at the same age (β=0.00, 95%CI -0.03-0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; FVIII:C/VWF:Ag or VWFpp/VWF:Ag ratios; or desmopressin responses between LoVIC and WiN-normalized patients. In conclusion, our findings demonstrate that Low VWF does not 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.