Von Willebrand factor (VWF) is a plasma glycoprotein that plays critical roles in maintaining vascular haemostasis. Inherited deficiency of VWF occurs in approximately 1% of children and constitutes the commonest inherited bleeding disorder (von Willebrand disease or VWD). Recent large international cohort studies have provided insights into the pathophysiology underlying type I VWD, particularly in patients with significantly reduced plasma VWF levels (< 0.3U/ml). In contrast however, the molecular mechanisms that are responsible for causing mild to moderate reductions in plasma VWF levels (Low VWF levels in the range 0.3- 0.5U/ml) remain poorly understood. Importantly, VWF gene mutations are rare in this cohort, and linkage analysis suggests that additional unknown genes are involved in modulating the reduction in plasma VWF levels. Since the pathophysiology underlying Low VWF remains largely undefined, diagnosis, genetic counselling and clinical management of these children poses significant challenges. To address these questions, we propose to establish the Low VWF Ireland Cohort of Kids (LoVIC-K) study. This longitudinal follow-up paediatric study will utilise an existing international collaborative network previously established through a successful HRB-funded LoVIC adult study. In particular, we will (1) investigate the relationship between Low VWF levels and bleeding phenotype in children in collaboration with Dr Paula James (University of Kingston, Canada); (2) determine the roles of VWF synthesis, secretion and clearance in modulating the Low VWF phenotype for each individual child; (3) characterize the genetic basis underlying the Low VWF phenotype in children in collaboration with Dr. Jorge di Paola (University of Colorado, USA); (4) characterise the variations in VWF glycans associated with Low VWF in children in collaboration with Prof. Lokesh Joshi (NUI, Galway). Collectively, these studies will not only be of scientific interest, but also of direct clinical relevance in terms of optimizing paediatric care.