The studies presented in this thesis explored several pathogenic mechanisms underlying von Willebrand disease that is characterized by a quantitative or functional deficiency of von Willebrand... Show moreThe studies presented in this thesis explored several pathogenic mechanisms underlying von Willebrand disease that is characterized by a quantitative or functional deficiency of von Willebrand factor, in particular with respect to intracellular storage in Weibel-Palade body and regulated secretion of von Willebrand factor. By using molecular biology, confocal and electron microscopic techniques, storage and secretion of von Willebrand factor were analyzed for von Willebrand disease variants identified in the patients. These studies advanced our understanding of von Willebrand disease at the molecular and cellular levels. HEK293 cells and endothelial cells derived from patients__ peripheral blood were established as two useful model-systems for examining von Willebrand factor structure-function relationships in the context of von Willebrand disease. Using these model-systems we have demonstrated that von Willebrand factor mutations may impair its storage and secretion and thus lead to a quantitative deficiency of this factor in the patients. Furthermore, we demonstrated that alteration in the structure of von Willebrand factor, by natural mutations that occur in von Willebrand disease patients, modulates von Willebrand factor string formation and function. We propose that alteration in von Willebrand factor string formation and function may be another new mechanism that contributes to the bleeding tendency in von Willebrand disease. Show less