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Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071132/ https://www.ncbi.nlm.nih.gov/pubmed/36453103 http://dx.doi.org/10.3324/haematol.2022.280651 |
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author | Tellier, Edwige Widemann, Agnès Cauchois, Raphaël Faccini, Julien Lagarde, Marie Brun, Marion Robert, Philippe Robert, Stéphane Bachelier, Richard Poullin, Pascale Roose, Elien Vanhoorelbeke, Karen Coppo, Paul Dignat-George, Françoise Kaplanski, Gilles |
author_facet | Tellier, Edwige Widemann, Agnès Cauchois, Raphaël Faccini, Julien Lagarde, Marie Brun, Marion Robert, Philippe Robert, Stéphane Bachelier, Richard Poullin, Pascale Roose, Elien Vanhoorelbeke, Karen Coppo, Paul Dignat-George, Françoise Kaplanski, Gilles |
author_sort | Tellier, Edwige |
collection | PubMed |
description | Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca(2+)) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca(2+) flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)’2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients’ B cells, but not serum from hereditary TTP, induced endothelial Ca(2+) flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca(2+)-mediated endothelial cell activation constitutes a “second hit” of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target. |
format | Online Article Text |
id | pubmed-10071132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-100711322023-04-05 Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity Tellier, Edwige Widemann, Agnès Cauchois, Raphaël Faccini, Julien Lagarde, Marie Brun, Marion Robert, Philippe Robert, Stéphane Bachelier, Richard Poullin, Pascale Roose, Elien Vanhoorelbeke, Karen Coppo, Paul Dignat-George, Françoise Kaplanski, Gilles Haematologica Article - Platelet Biology & its Disorders Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca(2+)) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca(2+) flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)’2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients’ B cells, but not serum from hereditary TTP, induced endothelial Ca(2+) flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca(2+)-mediated endothelial cell activation constitutes a “second hit” of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target. Fondazione Ferrata Storti 2022-12-01 /pmc/articles/PMC10071132/ /pubmed/36453103 http://dx.doi.org/10.3324/haematol.2022.280651 Text en Copyright© 2023 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article - Platelet Biology & its Disorders Tellier, Edwige Widemann, Agnès Cauchois, Raphaël Faccini, Julien Lagarde, Marie Brun, Marion Robert, Philippe Robert, Stéphane Bachelier, Richard Poullin, Pascale Roose, Elien Vanhoorelbeke, Karen Coppo, Paul Dignat-George, Françoise Kaplanski, Gilles Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title | Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title_full | Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title_fullStr | Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title_full_unstemmed | Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title_short | Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity |
title_sort | immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and igg-dependent endothelial activation: correlations with disease severity |
topic | Article - Platelet Biology & its Disorders |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071132/ https://www.ncbi.nlm.nih.gov/pubmed/36453103 http://dx.doi.org/10.3324/haematol.2022.280651 |
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