Modulators of Von Willebrand factor (VWF) multimers size in thrombotic processes

SUMMARY : during this doctorate, we evaluated how the presence of von Willebrand factor (VWF) multimers in plasma is regulated and how this process might influence the onset of thrombotic thrombocytopenic purpura (TTP) and myocardial infarction (MI). We demonstrated that: - salts, and particularly anions, in physiological conditions determine an inhibition of VWF cleavage by ADAMTS-13, causing a conformational change of the VWF. Finally we demonstrated the presence of a negative association between the GpIb or ristocetin binding and ions binding to VWF; - TSP-1 display a inhibiting effect on ADAMTS-13 activity and the entire A1A2A3 region is necessary to achieve an optimal inhibition. The A3 domain plays a central role, although its effect is dependent on the allosteric role of the A1 domain; - an association between the N700S polymorphism in the Tsp-1 gene and the development of MI. Nevertheless this association can be hardly explained by an alteration of TSP-1 reductase activity, that, differently from previous data, was not confirmed. In conclusion the obtained results allowed to identifying new modulators of the VWF multimers size in vitro (chloride ions and TSP-1) and to deepen their modes of action, increasing the knowledge of this physiological process that remains indeed very complex. The understanding of all involved mechanisms might clarify the pathogenesis of both thrombotic and haemorrhagic diseases, improve diagnosis and treatment , mainly for a rare but highly disabling disease, such as TTP