Evaluation of the hemostatic stress response in Type 1 von Willebrand Disease
Type 1 von Willebrand Disease (VWD) is an inherited bleeding disorder resulting from a quantitative deficiency in the procoagulant protein von Willebrand factor (VWF). Diagnosis is dependent on a reduction in VWF levels and the identification of an abnormal bleeding history. However, diagnosis and management of this condition are challenging due to the significant heterogeneity reported in bleeding symptoms and the absence of a correlation between circulating VWF levels and bleeding severity. The ability to increase VWF levels in response to hemostatic stress (i.e. vascular injury) is important in managing bleeding. To date, this ability, referred to as the hemostatic stress response, has not been prospectively evaluated as a disease modifier of the bleeding symptoms seen in Type 1 VWD. Desmopressin, used therapeutically, can also be used as a hemostatic stress surrogate, as can exercise, to study the response to injury. By performing desmopressin trials over two consecutive days, the response to repeated stress can be evaluated. The hemostatic stress response can also be characterized by studying subject-derived endothelial colony-forming cells (ECFCs). We aim to show that a decreased and less sustained rise in VWF in response to hemostatic stress surrogates contributes to a more severe bleeding phenotype in individuals with Type 1 VWD. This thesis demonstrated that Type 1 VWD individuals have a decreased and less sustained rise in VWF in response to hemostatic stress surrogates compared to controls. We demonstrated that the differences in VWF and FVIII levels between Type 1 VWD and control groups increases in response to desmopressin and that this increased difference was maintained for at least twenty-four hours. Further, Type 1 VWD participants exhibited indicators of increased clearance and decreased synthesis of VWF. Overall, we demonstrated that the decreased response is correlated with increased bleeding. ECFCs isolated from these participants were further characterized for VWF expression and secretion demonstrating that the hemostatic stress response may be modelled ex vivo. In conclusion, these data may be used to provide clinicians with a better understanding of the determinants of bleeding in Type 1 VWD and allow for better risk stratification in this patient population.