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The brain-derived neurotrophic factor prompts platelet aggregation and secretion. / Boukhatem, Imane; Fleury, Samuel; Welman, Melanie; Le Blanc, Jessica; Thys, Chantal; Freson, Kathleen; Best, Myron G; Würdinger, Thomas; Allen, Bruce G; Lordkipanidzé, Marie.

In: Blood advances, Vol. 5, No. 18, 28.09.2021, p. 3568-3580.

Research output: Contribution to journalArticleAcademicpeer-review

Harvard

Boukhatem, I, Fleury, S, Welman, M, Le Blanc, J, Thys, C, Freson, K, Best, MG, Würdinger, T, Allen, BG & Lordkipanidzé, M 2021, 'The brain-derived neurotrophic factor prompts platelet aggregation and secretion', Blood advances, vol. 5, no. 18, pp. 3568-3580. https://doi.org/10.1182/bloodadvances.2020004098

APA

Boukhatem, I., Fleury, S., Welman, M., Le Blanc, J., Thys, C., Freson, K., Best, M. G., Würdinger, T., Allen, B. G., & Lordkipanidzé, M. (2021). The brain-derived neurotrophic factor prompts platelet aggregation and secretion. Blood advances, 5(18), 3568-3580. https://doi.org/10.1182/bloodadvances.2020004098

Vancouver

Boukhatem I, Fleury S, Welman M, Le Blanc J, Thys C, Freson K et al. The brain-derived neurotrophic factor prompts platelet aggregation and secretion. Blood advances. 2021 Sep 28;5(18):3568-3580. https://doi.org/10.1182/bloodadvances.2020004098

Author

Boukhatem, Imane ; Fleury, Samuel ; Welman, Melanie ; Le Blanc, Jessica ; Thys, Chantal ; Freson, Kathleen ; Best, Myron G ; Würdinger, Thomas ; Allen, Bruce G ; Lordkipanidzé, Marie. / The brain-derived neurotrophic factor prompts platelet aggregation and secretion. In: Blood advances. 2021 ; Vol. 5, No. 18. pp. 3568-3580.

BibTeX

@article{0fcd0398095942aeb0ba255b915c4cc8,
title = "The brain-derived neurotrophic factor prompts platelet aggregation and secretion",
abstract = "Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in neurons, and its release and signaling mechanisms have been extensively studied in the central nervous system. Large quantities of BDNF have been reported in circulation, essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons. Despite this abundance, the function of BDNF in platelet biology has not been explored. At low concentrations, BDNF primed platelets, acting synergistically with classical agonists. At high concentrations, BDNF induced complete biphasic platelet aggregation that in part relied on amplification from secondary mediators. Neurotrophin-4, but not nerve growth factor, and an activating antibody against the canonical BDNF receptor tropomyosin-related kinase B (TrkB) induced similar platelet responses to BDNF, suggesting TrkB could be the mediator. Platelets expressed, both at their surface and in their intracellular compartment, a truncated form of TrkB lacking its tyrosine kinase domain. BDNF-induced platelet aggregation was prevented by inhibitors of Ras-related C3 botulinum toxin substrate 1 (Rac1), protein kinase C, and phosphoinositide 3-kinase. BDNF-stimulated platelets secreted a panel of angiogenic and inflammatory cytokines, which may play a role in maintaining vascular homeostasis. Two families with autism spectrum disorder were found to carry rare missense variants in the BDNF gene. Platelet studies revealed defects in platelet aggregation to low concentrations of collagen, as well as reduced adenosine triphosphate secretion in response to adenosine diphosphate. In summary, circulating BDNF levels appear to regulate platelet activation, aggregation, and secretion through activation of a truncated TrkB receptor and downstream kinase-dependent signaling.",
author = "Imane Boukhatem and Samuel Fleury and Melanie Welman and {Le Blanc}, Jessica and Chantal Thys and Kathleen Freson and Best, {Myron G} and Thomas W{\"u}rdinger and Allen, {Bruce G} and Marie Lordkipanidz{\'e}",
note = "Funding Information: This work was supported by the Canadian Institutes of Health Research (PJT-159569) and the Canada Foundation for Innovation Leaders Opportunity Fund (32797). I.B. was supported by scholarships from the Facult{\'e} de pharmacie and the Facult{\'e} des {\'e}tudes sup{\'e}rieures et postdoctorales of the Universit{\'e} de Montr{\'e}al. S.F. was supported by scholarships from the Facult{\'e} de pharmacie and the Facult{\'e} des {\'e}tudes sup{\'e}rieures et postdoctorales of the Uni-versit{\'e} de Montr{\'e}al and the Montreal Heart Institute Foundation and is a Canadian Vascular Network Scholar. J.L.B. was supported by summer internships from the Facult{\'e} de pharmacie of the Universit{\'e} de Montr{\'e}al. K.F. is supported by the Research Council of the University of Leuven (BOF KU Leuven, Belgium, C14/19/096). M.L. was supported by the Fonds de recherche du Qu{\'e}bec en Sant{\'e} Junior 1 Research Scholarship (33048) and is a Canada Research Chair in Platelets as biomarkers and vectors (950-232706). Funding Information: Conflict-of-interest disclosure: K.F. has received unrestricted grants from CSL Behring, Novo Nordisk, Bayer, and SOBI. T.W. Funding Information: The authors would like to thank Louis Villeneuve at the Montreal Heart Institute core imaging facility for support with confocal microscopy and H. Uri Saragovi, Yahye Merhi, and Rahma Boulahya for their insights and suggestions. The visual abstract was created using BioRender. This work was supported by the Canadian Institutes of Health Research (PJT-159569) and the Canada Foundation for Innovation Leaders Opportunity Fund (32797). I.B. was supported by scholarships from the Facult? de pharmacie and the Facult? des ?tudes sup?rieures et postdoctorales of the Universit? de Montr?al. S.F. was supported by scholarships from the Facult? de pharmacie and the Facult? des ?tudes sup?rieures et postdoctorales of the Universit? de Montr?al and the Montreal Heart Institute Foundation and is a Canadian Vascular Network Scholar. J.L.B. was supported by summer internships from the Facult? de pharmacie of the Universit? de Montr?al. K.F. is supported by the Research Council of the University of Leuven (BOF KU Leuven, Belgium, C14/19/096). M.L. was supported by the Fonds de recherche du Qu?bec en Sant? Junior 1 Research Scholarship (33048) and is a Canada Research Chair in Platelets as biomarkers and vectors (950-232706). Funding Information: is a shareholder of GRAIL. M.L. has received speaker honoraria from Bayer; has received research grants to the institution from Idorsia; has served on a national advisory board for Servier; and has received in-kind and financial support for investigator-initiated grants from Leo Pharma, Roche Diagnostics, Aggredyne, and Fujimori Kogyo. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2021 by The American Society of Hematology.",
year = "2021",
month = sep,
day = "28",
doi = "10.1182/bloodadvances.2020004098",
language = "English",
volume = "5",
pages = "3568--3580",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "18",

}

RIS

TY - JOUR

T1 - The brain-derived neurotrophic factor prompts platelet aggregation and secretion

AU - Boukhatem, Imane

AU - Fleury, Samuel

AU - Welman, Melanie

AU - Le Blanc, Jessica

AU - Thys, Chantal

AU - Freson, Kathleen

AU - Best, Myron G

AU - Würdinger, Thomas

AU - Allen, Bruce G

AU - Lordkipanidzé, Marie

N1 - Funding Information: This work was supported by the Canadian Institutes of Health Research (PJT-159569) and the Canada Foundation for Innovation Leaders Opportunity Fund (32797). I.B. was supported by scholarships from the Faculté de pharmacie and the Faculté des études supérieures et postdoctorales of the Université de Montréal. S.F. was supported by scholarships from the Faculté de pharmacie and the Faculté des études supérieures et postdoctorales of the Uni-versité de Montréal and the Montreal Heart Institute Foundation and is a Canadian Vascular Network Scholar. J.L.B. was supported by summer internships from the Faculté de pharmacie of the Université de Montréal. K.F. is supported by the Research Council of the University of Leuven (BOF KU Leuven, Belgium, C14/19/096). M.L. was supported by the Fonds de recherche du Québec en Santé Junior 1 Research Scholarship (33048) and is a Canada Research Chair in Platelets as biomarkers and vectors (950-232706). Funding Information: Conflict-of-interest disclosure: K.F. has received unrestricted grants from CSL Behring, Novo Nordisk, Bayer, and SOBI. T.W. Funding Information: The authors would like to thank Louis Villeneuve at the Montreal Heart Institute core imaging facility for support with confocal microscopy and H. Uri Saragovi, Yahye Merhi, and Rahma Boulahya for their insights and suggestions. The visual abstract was created using BioRender. This work was supported by the Canadian Institutes of Health Research (PJT-159569) and the Canada Foundation for Innovation Leaders Opportunity Fund (32797). I.B. was supported by scholarships from the Facult? de pharmacie and the Facult? des ?tudes sup?rieures et postdoctorales of the Universit? de Montr?al. S.F. was supported by scholarships from the Facult? de pharmacie and the Facult? des ?tudes sup?rieures et postdoctorales of the Universit? de Montr?al and the Montreal Heart Institute Foundation and is a Canadian Vascular Network Scholar. J.L.B. was supported by summer internships from the Facult? de pharmacie of the Universit? de Montr?al. K.F. is supported by the Research Council of the University of Leuven (BOF KU Leuven, Belgium, C14/19/096). M.L. was supported by the Fonds de recherche du Qu?bec en Sant? Junior 1 Research Scholarship (33048) and is a Canada Research Chair in Platelets as biomarkers and vectors (950-232706). Funding Information: is a shareholder of GRAIL. M.L. has received speaker honoraria from Bayer; has received research grants to the institution from Idorsia; has served on a national advisory board for Servier; and has received in-kind and financial support for investigator-initiated grants from Leo Pharma, Roche Diagnostics, Aggredyne, and Fujimori Kogyo. The remaining authors declare no competing financial interests. Publisher Copyright: © 2021 by The American Society of Hematology.

PY - 2021/9/28

Y1 - 2021/9/28

N2 - Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in neurons, and its release and signaling mechanisms have been extensively studied in the central nervous system. Large quantities of BDNF have been reported in circulation, essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons. Despite this abundance, the function of BDNF in platelet biology has not been explored. At low concentrations, BDNF primed platelets, acting synergistically with classical agonists. At high concentrations, BDNF induced complete biphasic platelet aggregation that in part relied on amplification from secondary mediators. Neurotrophin-4, but not nerve growth factor, and an activating antibody against the canonical BDNF receptor tropomyosin-related kinase B (TrkB) induced similar platelet responses to BDNF, suggesting TrkB could be the mediator. Platelets expressed, both at their surface and in their intracellular compartment, a truncated form of TrkB lacking its tyrosine kinase domain. BDNF-induced platelet aggregation was prevented by inhibitors of Ras-related C3 botulinum toxin substrate 1 (Rac1), protein kinase C, and phosphoinositide 3-kinase. BDNF-stimulated platelets secreted a panel of angiogenic and inflammatory cytokines, which may play a role in maintaining vascular homeostasis. Two families with autism spectrum disorder were found to carry rare missense variants in the BDNF gene. Platelet studies revealed defects in platelet aggregation to low concentrations of collagen, as well as reduced adenosine triphosphate secretion in response to adenosine diphosphate. In summary, circulating BDNF levels appear to regulate platelet activation, aggregation, and secretion through activation of a truncated TrkB receptor and downstream kinase-dependent signaling.

AB - Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in neurons, and its release and signaling mechanisms have been extensively studied in the central nervous system. Large quantities of BDNF have been reported in circulation, essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons. Despite this abundance, the function of BDNF in platelet biology has not been explored. At low concentrations, BDNF primed platelets, acting synergistically with classical agonists. At high concentrations, BDNF induced complete biphasic platelet aggregation that in part relied on amplification from secondary mediators. Neurotrophin-4, but not nerve growth factor, and an activating antibody against the canonical BDNF receptor tropomyosin-related kinase B (TrkB) induced similar platelet responses to BDNF, suggesting TrkB could be the mediator. Platelets expressed, both at their surface and in their intracellular compartment, a truncated form of TrkB lacking its tyrosine kinase domain. BDNF-induced platelet aggregation was prevented by inhibitors of Ras-related C3 botulinum toxin substrate 1 (Rac1), protein kinase C, and phosphoinositide 3-kinase. BDNF-stimulated platelets secreted a panel of angiogenic and inflammatory cytokines, which may play a role in maintaining vascular homeostasis. Two families with autism spectrum disorder were found to carry rare missense variants in the BDNF gene. Platelet studies revealed defects in platelet aggregation to low concentrations of collagen, as well as reduced adenosine triphosphate secretion in response to adenosine diphosphate. In summary, circulating BDNF levels appear to regulate platelet activation, aggregation, and secretion through activation of a truncated TrkB receptor and downstream kinase-dependent signaling.

UR - http://www.scopus.com/inward/record.url?scp=85116078608&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2020004098

DO - 10.1182/bloodadvances.2020004098

M3 - Article

C2 - 34546355

VL - 5

SP - 3568

EP - 3580

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 18

ER -

ID: 20860902