Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis

Abstract

von Willebrand factor (VWF), a multimeric protein with 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 cannot cleave VWF multimers because of genetic 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 (AP) 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 Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP 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.

Immune Factors in Deep Vein Thrombosis Initiation

“…High levels of the C3 are associated with high risk of DVT in humans [37] . Mechanistically, high-molecular-weight multimers of VWF released from WPBs provide a scaffold for complement activation [38] . Complement components bind to VWF strings and become activated through the alternative activation pathway [39] .…”

Complement in glomerular diseases

“…Recent studies suggested that the alternative pathway activated in patients with TTP, and inhibition of complement could rescue the complement-mediated sheep red blood cell haemolysis and the deposition of C3 and complement activation end product membrane attack complex on the endothelial cells. [9][10][11] von Willebrand factor (VWF) could act as a cofactor for CFI-mediated cleavage of complement C3b, shutting down complement activation, while ultra-large VWF multimers lack inhibitory effect on complement and permit complement activation. 12 VWF could bind to CFH and the binding could inhibit ADAMTS-13-mediated proteolysis of VWF and promote platelet aggregation.…”

Potentially functional genetic variants in the complement‐related immunity gene‐set are associated with non‐small cell lung cancer survival

“…34 Most of our knowledge about the coagulation and complement systems comes from studies with the atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, in which VWF interacts with C3b and activates the complement by the alternative pathway, changing the phenotype of microvascular endothelial cells. 35 The molecular mechanism about how VWF regulates the complement components in cancer remains unknown. The immune response, such as a chronic inflammation, may affect the initiation and progression of cancer-based on several experimental and clinical studies, and VWF is thought as an antitumor factor to negatively modulate angiogenesis and apoptosis.…”