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Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 199(3)
- Publication Year :
- 2016
-
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 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 (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.
- Subjects :
- 0301 basic medicine
Adult
Male
Endothelium
Adolescent
Immunology
Complement Pathway, Alternative
ADAMTS13 Protein
Complement C5a
Complement C3-C5 Convertases
Complement Membrane Attack Complex
030204 cardiovascular system & hematology
03 medical and health sciences
Young Adult
0302 clinical medicine
Von Willebrand factor
hemic and lymphatic diseases
von Willebrand Factor
medicine
Immunology and Allergy
Humans
Child
biology
Purpura, Thrombotic Thrombocytopenic
Chemistry
Infant, Newborn
Endothelial Cells
Thrombosis
ADAMTS13
Complement system
Cell biology
030104 developmental biology
medicine.anatomical_structure
Child, Preschool
Complement C3b
Microvessels
Alternative complement pathway
biology.protein
Female
Complement membrane attack complex
circulatory and respiratory physiology
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 199
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....52237ad8913b64b99e294e66c8f7d3f2