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Fatal dysfunction and disintegration of thrombin-stimulated platelets

Platelets play a key role in the formation of hemostatic clots and obstructive thrombi as well as in other biological processes. In response to physiological stimulants, including thrombin, platelets change shape, express adhesive molecules, aggregate, and secrete bioactive substances, but their sub...

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Autores principales: Kim, Oleg V., Nevzorova, Tatiana A., Mordakhanova, Elmira R., Ponomareva, Anastasia A., Andrianova, Izabella A., Le Minh, Giang, Daminova, Amina G., Peshkova, Alina D., Alber, Mark S., Vagin, Olga, Litvinov, Rustem I., Weisel, John W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717590/
https://www.ncbi.nlm.nih.gov/pubmed/30792211
http://dx.doi.org/10.3324/haematol.2018.202309
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author Kim, Oleg V.
Nevzorova, Tatiana A.
Mordakhanova, Elmira R.
Ponomareva, Anastasia A.
Andrianova, Izabella A.
Le Minh, Giang
Daminova, Amina G.
Peshkova, Alina D.
Alber, Mark S.
Vagin, Olga
Litvinov, Rustem I.
Weisel, John W.
author_facet Kim, Oleg V.
Nevzorova, Tatiana A.
Mordakhanova, Elmira R.
Ponomareva, Anastasia A.
Andrianova, Izabella A.
Le Minh, Giang
Daminova, Amina G.
Peshkova, Alina D.
Alber, Mark S.
Vagin, Olga
Litvinov, Rustem I.
Weisel, John W.
author_sort Kim, Oleg V.
collection PubMed
description Platelets play a key role in the formation of hemostatic clots and obstructive thrombi as well as in other biological processes. In response to physiological stimulants, including thrombin, platelets change shape, express adhesive molecules, aggregate, and secrete bioactive substances, but their subsequent fate is largely unknown. Here we examined late-stage structural, metabolic, and functional consequences of thrombin-induced platelet activation. Using a combination of confocal microscopy, scanning and transmission electron microscopy, flow cytometry, biochemical and biomechanical measurements, we showed that thrombin-induced activation is followed by time-dependent platelet dysfunction and disintegration. After ~30 minutes of incubation with thrombin, unlike with collagen or ADP, human platelets disintegrated into cellular fragments containing organelles, such as mitochondria, glycogen granules, and vacuoles. This platelet fragmentation was preceded by Ca(2+) influx, integrin α(IIb)β(3) activation and phosphatidylserine exposure (activation phase), followed by mitochondrial depolarization, generation of reactive oxygen species, metabolic ATP depletion and impairment of platelet contractility along with dramatic cytoskeletal rearrangements, concomitant with platelet disintegration (death phase). Coincidentally with the platelet fragmentation, thrombin caused calpain activation but not activation of caspases 3 and 7. Our findings indicate that the late functional and structural damage of thrombin-activated platelets comprise a calpain-dependent platelet death pathway that shares some similarities with the programmed death of nucleated cells, but is unique to platelets, therefore representing a special form of cellular destruction. Fragmentation of activated platelets suggests that there is an underappreciated pathway of enhanced elimination of platelets from the circulation in (pro)thrombotic conditions once these cells have performed their functions.
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spelling pubmed-67175902019-09-06 Fatal dysfunction and disintegration of thrombin-stimulated platelets Kim, Oleg V. Nevzorova, Tatiana A. Mordakhanova, Elmira R. Ponomareva, Anastasia A. Andrianova, Izabella A. Le Minh, Giang Daminova, Amina G. Peshkova, Alina D. Alber, Mark S. Vagin, Olga Litvinov, Rustem I. Weisel, John W. Haematologica Article Platelets play a key role in the formation of hemostatic clots and obstructive thrombi as well as in other biological processes. In response to physiological stimulants, including thrombin, platelets change shape, express adhesive molecules, aggregate, and secrete bioactive substances, but their subsequent fate is largely unknown. Here we examined late-stage structural, metabolic, and functional consequences of thrombin-induced platelet activation. Using a combination of confocal microscopy, scanning and transmission electron microscopy, flow cytometry, biochemical and biomechanical measurements, we showed that thrombin-induced activation is followed by time-dependent platelet dysfunction and disintegration. After ~30 minutes of incubation with thrombin, unlike with collagen or ADP, human platelets disintegrated into cellular fragments containing organelles, such as mitochondria, glycogen granules, and vacuoles. This platelet fragmentation was preceded by Ca(2+) influx, integrin α(IIb)β(3) activation and phosphatidylserine exposure (activation phase), followed by mitochondrial depolarization, generation of reactive oxygen species, metabolic ATP depletion and impairment of platelet contractility along with dramatic cytoskeletal rearrangements, concomitant with platelet disintegration (death phase). Coincidentally with the platelet fragmentation, thrombin caused calpain activation but not activation of caspases 3 and 7. Our findings indicate that the late functional and structural damage of thrombin-activated platelets comprise a calpain-dependent platelet death pathway that shares some similarities with the programmed death of nucleated cells, but is unique to platelets, therefore representing a special form of cellular destruction. Fragmentation of activated platelets suggests that there is an underappreciated pathway of enhanced elimination of platelets from the circulation in (pro)thrombotic conditions once these cells have performed their functions. Ferrata Storti Foundation 2019-09 /pmc/articles/PMC6717590/ /pubmed/30792211 http://dx.doi.org/10.3324/haematol.2018.202309 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
Kim, Oleg V.
Nevzorova, Tatiana A.
Mordakhanova, Elmira R.
Ponomareva, Anastasia A.
Andrianova, Izabella A.
Le Minh, Giang
Daminova, Amina G.
Peshkova, Alina D.
Alber, Mark S.
Vagin, Olga
Litvinov, Rustem I.
Weisel, John W.
Fatal dysfunction and disintegration of thrombin-stimulated platelets
title Fatal dysfunction and disintegration of thrombin-stimulated platelets
title_full Fatal dysfunction and disintegration of thrombin-stimulated platelets
title_fullStr Fatal dysfunction and disintegration of thrombin-stimulated platelets
title_full_unstemmed Fatal dysfunction and disintegration of thrombin-stimulated platelets
title_short Fatal dysfunction and disintegration of thrombin-stimulated platelets
title_sort fatal dysfunction and disintegration of thrombin-stimulated platelets
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717590/
https://www.ncbi.nlm.nih.gov/pubmed/30792211
http://dx.doi.org/10.3324/haematol.2018.202309
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