Investigation of the role of the VWF-ADAMTS13 axis in the pathogenesis of sickle cell vasculopathy in children
Wellcome Trust
Royal College of Surgeons in Ireland
Sickle cell disease (SCD) is responsible for major global morbidity and mortality and more than 1,000 SCD children are born every day. Globally over half will die before five years of age and <10% survive to adulthood. Even in developed countries, SCD causes significant morbidity with 10% of US patients developing strokes and potentially lifelong disabilities. The World Health Organisation and United Nations have recently designated SCD as a global health priority, highlighting the need for research into the biological mechanisms underlying SCD.    A critical step in blood vessel blockage in SCD involves sickle red cells sticking to the blood vessel wall. Interestingly, evidence suggests a new role for the plasma clotting protein von Willebrand factor (VWF) in this process with increased VWF and reduced levels of ADAMTS13, the main protein responsible for breaking down VWF.   This study aims to define the molecular mechanisms underlying blood vessel blockage in SCD, including how VWF and abnormally large forms of VWF, influence paediatric SCD biology. We will specifically investigate the hypothesis that sickle red cell occlusion is promoted by a dysfunctional VWF-ADAMTS13 axis, leading to characteristic clinical complications. novel findings from this research may inform future treatments to improve clinical outcomes.
2.1 Biological and endogenous factors