Interaction Between the Metalloprotease ADAMTS-13 and the Proteins of the Alternative Pathway of the Complement System

Bettoni, Serena (2017). Interaction Between the Metalloprotease ADAMTS-13 and the Proteins of the Alternative Pathway of the Complement System. PhD thesis The Open University.



Von Willebrand factor (VWF), a multimeric protein that has a central role in hemostasis, has been shown to interact with complement components. However results are contrasting and inconclusive.

By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who can not cleave VWF multimers due to genetic ADAMTS13 deficiency, we investigated the mechanism through which VWF modulates complement, and its pathophysiological implications for human diseases.

Using assays of ex-vivo serum-induced C3 and C5b-9 deposits on endothelial cells we documented that in cTTP complement is activated via the alternative pathway on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF antibody. This study documented: 1) ADAMTS13 is able to interact with FB, but how this interaction could modulate complement activation remains still unknown; 2) VWF does not affect regulatory complement activity of FH for inactivation of C3b or dissociation of C3 convertase, in contrast to what reported in literature; 3) VWF interacts with C3b through its A2 domain and initiates a previously unrecognized Calcium-dependent mechanism of alternative pathway activation, with assembly of active C3 and C5 convertases and formation of the terminal complement products, C5a and C5b-9. Finally, this work documented that in condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial anti-thrombogenic properties and induces microvascular thrombosis in a perfusion system.

Altogether, the results demonstrated that VWF provides a platform for the activation of the alternative pathway of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the alternative pathway of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release and complement activation.

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