Von Willebrand disease is the most common inherited bleeding disorder and is characterized by reduced plasma von Willebrand factor (VWF) levels or functionally abnormal VWF. VWF is best known for... Show moreVon Willebrand disease is the most common inherited bleeding disorder and is characterized by reduced plasma von Willebrand factor (VWF) levels or functionally abnormal VWF. VWF is best known for its three classical hemostatic functions: (i) as a carrier protein for coagulation factor VIII, (ii) binding to exposed collagen upon vascular damage and (iii) as a mediator of the recruitment of platelets to sites of vascular injury. However, in recent years it has become clear that VWF has a versatile function beyond hemostasis, and has been implicated in several pathophysiological processes, such as tumor metastasis, angiogenesis, cell proliferation and inflammatory processes. So, apart from its evident role in hemostasis, it has become clear that VWF is a much more complex multifaceted protein then initially thought. Several aspects __ from synthesis, secretion and clearance, to functions in the circulation __ of this protein have been studied and the results are described in this thesis. These results will advance our knowledge about the mechanism(s) of VWF biosynthesis, clearance and its role in angiogenesis, which might lead to a more personalized treatment for von Willebrand disease and its complications in the future. Show less
Von Willebrand factor (VWF) plays an important role in both primary and secondary hemostasis as a molecular glue between platelets and subendothelial structures, and as a carrier of FVIII.... Show moreVon Willebrand factor (VWF) plays an important role in both primary and secondary hemostasis as a molecular glue between platelets and subendothelial structures, and as a carrier of FVIII. Mutations in VWF may cause von Willebrand disease (VWD), which is the most common bleeding disorder. It is characterized by symptoms ranging from very mild to severe bleeding. Mutations may influence the level of VWF (quantitative defect; type 1 or type 3) or may affect the function of VWF. Especially important for the generation of functional VWF is the formation of disulfide linked bonds. Firstly, intrachain linking is essential for the monomer structure. Secondly, interchain linking is necessary for both dimerization and multimerization of VWF. All 169 cysteine residues in the mature VWF subunit (8.2%) participate in these intra- or interchain disulfide bonds. The interaction between proVWF dimers ultimately yields high-molecular weight VWF that is active in primary hemostasis in the bloodstream.The main aims of the studies reported in this thesis were to examine how loss of cysteines located in different domains of VWF results in quantitative and qualitative VWF defects; how these mutations interfere with dimerization and multimerization; and how they influence intracellular routing, secretion and clearance of VWF. Show less
