Cargando…
Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence
Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently s...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959185/ https://www.ncbi.nlm.nih.gov/pubmed/30819911 http://dx.doi.org/10.3324/haematol.2018.206250 |
_version_ | 1783487546144063488 |
---|---|
author | Dupont, Annabelle Soukaseum, Christelle Cheptou, Mathilde Adam, Frédéric Nipoti, Thomas Lourenco-Rodrigues, Marc-Damien Legendre, Paulette Proulle, Valérie Rauch, Antoine Kawecki, Charlotte Bryckaert, Marijke Rosa, Jean-Philippe Paris, Camille Ternisien, Catherine Boisseau, Pierre Goudemand, Jenny Borgel, Delphine Lasne, Dominique Maurice, Pascal Lenting, Peter J. Denis, Cécile V. Susen, Sophie Kauskot, Alexandre |
author_facet | Dupont, Annabelle Soukaseum, Christelle Cheptou, Mathilde Adam, Frédéric Nipoti, Thomas Lourenco-Rodrigues, Marc-Damien Legendre, Paulette Proulle, Valérie Rauch, Antoine Kawecki, Charlotte Bryckaert, Marijke Rosa, Jean-Philippe Paris, Camille Ternisien, Catherine Boisseau, Pierre Goudemand, Jenny Borgel, Delphine Lasne, Dominique Maurice, Pascal Lenting, Peter J. Denis, Cécile V. Susen, Sophie Kauskot, Alexandre |
author_sort | Dupont, Annabelle |
collection | PubMed |
description | Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia. |
format | Online Article Text |
id | pubmed-6959185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-69591852020-01-22 Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence Dupont, Annabelle Soukaseum, Christelle Cheptou, Mathilde Adam, Frédéric Nipoti, Thomas Lourenco-Rodrigues, Marc-Damien Legendre, Paulette Proulle, Valérie Rauch, Antoine Kawecki, Charlotte Bryckaert, Marijke Rosa, Jean-Philippe Paris, Camille Ternisien, Catherine Boisseau, Pierre Goudemand, Jenny Borgel, Delphine Lasne, Dominique Maurice, Pascal Lenting, Peter J. Denis, Cécile V. Susen, Sophie Kauskot, Alexandre Haematologica Article Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia. Ferrata Storti Foundation 2019-12 /pmc/articles/PMC6959185/ /pubmed/30819911 http://dx.doi.org/10.3324/haematol.2018.206250 Text en Copyright© 2019 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Article Dupont, Annabelle Soukaseum, Christelle Cheptou, Mathilde Adam, Frédéric Nipoti, Thomas Lourenco-Rodrigues, Marc-Damien Legendre, Paulette Proulle, Valérie Rauch, Antoine Kawecki, Charlotte Bryckaert, Marijke Rosa, Jean-Philippe Paris, Camille Ternisien, Catherine Boisseau, Pierre Goudemand, Jenny Borgel, Delphine Lasne, Dominique Maurice, Pascal Lenting, Peter J. Denis, Cécile V. Susen, Sophie Kauskot, Alexandre Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title | Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title_full | Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title_fullStr | Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title_full_unstemmed | Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title_short | Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence |
title_sort | relevance of platelet desialylation and thrombocytopenia in type 2b von willebrand disease: preclinical and clinical evidence |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959185/ https://www.ncbi.nlm.nih.gov/pubmed/30819911 http://dx.doi.org/10.3324/haematol.2018.206250 |
work_keys_str_mv | AT dupontannabelle relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT soukaseumchristelle relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT cheptoumathilde relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT adamfrederic relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT nipotithomas relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT lourencorodriguesmarcdamien relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT legendrepaulette relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT proullevalerie relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT rauchantoine relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT kaweckicharlotte relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT bryckaertmarijke relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT rosajeanphilippe relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT pariscamille relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT ternisiencatherine relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT boisseaupierre relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT goudemandjenny relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT borgeldelphine relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT lasnedominique relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT mauricepascal relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT lentingpeterj relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT deniscecilev relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT susensophie relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence AT kauskotalexandre relevanceofplateletdesialylationandthrombocytopeniaintype2bvonwillebranddiseasepreclinicalandclinicalevidence |