Von Willebrand factor (VWF) is a large multimeric plasma sialoglycoprotein that plays an essential role in normal haemostasis. Inherited VWF deficiency is responsible for the commonest inherited bleeding disorder (von Willebrand disease or VWD) that affects up to 1% of the general population. Although substantial progress has been achieved in understanding VWF biology in recent years, the molecular mechanisms that are responsible for causing VWD remain poorly understood. This is particularly true for patients with mild to moderate reductions in plasma VWF levels (‘Low VWF levels’ 0.3 – 0.5U/ml). Interestingly in these individuals, VWF gene mutations are only rarely identified, suggesting that additional as yet unknown genes are responsible for modulating the reduction in plasma VWF levels. Since the pathophysiology involved remains largely undefined, diagnosis, genetic counseling and clinical management of these patients continue to pose significant challenges.
To address these questions, we propose to establish the Low VWF Ireland Cohort (LoVIC) study. This longitudinal follow-up study will enable us to investigate in a systematic manner the relationship between Low VWF levels and bleeding phenotype. In addition, we will determine the roles played by VWF secretion and/or clearance in modulating the Low VWF phenotype in each individual patient. In collaboration with Dr. Jorge di Paola (University of Colorado, USA) we will characterize the molecular basis underlying the Low VWF phenotype in our cohort. Finally, in collaboration with Prof. Lokesh Joshi (NUI, Galway), we will study how variations in the N-linked and O-linked glycan structures of VWF influence plasma VWF levels.
Cumulatively our findings will be of direct clinical importance in terms of optimizing patient care. In addition, given the remarkable population prevalence of this poorly understood condition, our results will also have important public health implications.