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

Bettoni, Serena LU orcid ; Galbusera, Miriam ; Gastoldi, Sara ; Donadelli, Roberta ; Tentori, Chiara ; Spartà, Giuseppina ; Bresin, Elena ; Mele, Caterina ; Alberti, Marta and Tortajada, Agustin , et al. (2017) In Journal of immunology 199(3). p.1021-1040
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
ADAMTS13 Protein/blood, Adolescent, Adult, Child, Child, Preschool, Complement C3-C5 Convertases/metabolism, Complement C3b/immunology, Complement C5a/immunology, Complement Membrane Attack Complex/immunology, Complement Pathway, Alternative, Endothelial Cells/immunology, Female, Humans, Infant, Newborn, Male, Microvessels/immunology, Purpura, Thrombotic Thrombocytopenic/congenital, Thrombosis/immunology, Young Adult, von Willebrand Factor/immunology
in
Journal of immunology
volume
199
issue
3
pages
20 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85026216890
  • pmid:28652401
ISSN
1550-6606
DOI
10.4049/jimmunol.1601121
language
English
LU publication?
no
additional info
Copyright © 2017 by The American Association of Immunologists, Inc.
id
98703f3c-ef22-4405-809b-2dfcfcd6404b
date added to LUP
2020-09-28 22:15:17
date last changed
2024-09-19 07:46:14
@article{98703f3c-ef22-4405-809b-2dfcfcd6404b,
  abstract     = {{<p>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.</p>}},
  author       = {{Bettoni, Serena and Galbusera, Miriam and Gastoldi, Sara and Donadelli, Roberta and Tentori, Chiara and Spartà, Giuseppina and Bresin, Elena and Mele, Caterina and Alberti, Marta and Tortajada, Agustin and Yebenes, Hugo and Remuzzi, Giuseppe and Noris, Marina}},
  issn         = {{1550-6606}},
  keywords     = {{ADAMTS13 Protein/blood; Adolescent; Adult; Child; Child, Preschool; Complement C3-C5 Convertases/metabolism; Complement C3b/immunology; Complement C5a/immunology; Complement Membrane Attack Complex/immunology; Complement Pathway, Alternative; Endothelial Cells/immunology; Female; Humans; Infant, Newborn; Male; Microvessels/immunology; Purpura, Thrombotic Thrombocytopenic/congenital; Thrombosis/immunology; Young Adult; von Willebrand Factor/immunology}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{3}},
  pages        = {{1021--1040}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology}},
  title        = {{Interaction between Multimeric von Willebrand Factor and Complement : A Fresh Look to the Pathophysiology of Microvascular Thrombosis}},
  url          = {{http://dx.doi.org/10.4049/jimmunol.1601121}},
  doi          = {{10.4049/jimmunol.1601121}},
  volume       = {{199}},
  year         = {{2017}},
}