von Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or... Show morevon Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or qualitative alterations of VWF cause von Willebrand disease (VWD), an inherited bleeding disorder. Conversely, increased VWF levels have been associated with various thrombotic conditions. In this thesis, we investigated the dual role of VWF in bleeding and thrombosis, focusing on VWD and deep vein thrombosis (DVT). In the first part of the thesis, we demonstrated the utility of in silico tools and heterologous cell systems in proving the disease-causing role of VWF variants thus contributing to the confirmation of patient diagnoses. In the second part, we focused on type 3 VWD, the most severe form of this disorder caused by a lack of VWF. We showed that patients with missense variants had a higher VWF propeptide/VWF antigen ratio than carriers of VWF null alleles. This suggested that secreted VWF is rapidly removed from circulation in these patients. Subsequently, we estimated the prevalence of VWF neutralizing and non-neutralizing antibodies, confirming that they are rare side effects of replacement therapy. We also demonstrated that the detection of epitope-specific VWF inhibitors is affected by the test used. In the last part of the thesis, we evaluated the role of ADAMTS13-VWF equilibrium in the pathogenesis of DVT, showing that a slight decrease in ADAMTS13 activity, particularly when combined with increased VWF levels, increases DVT risk. We then sequenced ADAMTS13, VWF, and F8 genes and confirmed that DVT patients carrying a rare ADAMTS13 variant exhibited lower ADAMTS13 activity than non-carriers. Show less
