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Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses

Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the...

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Autores principales: Lund, Mikael, Macwan, Ankit S., Tunströmer, Kjersti, Lindahl, Tomas L., Boknäs, Niklas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511449/
https://www.ncbi.nlm.nih.gov/pubmed/34660719
http://dx.doi.org/10.3389/fcvm.2021.717835
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author Lund, Mikael
Macwan, Ankit S.
Tunströmer, Kjersti
Lindahl, Tomas L.
Boknäs, Niklas
author_facet Lund, Mikael
Macwan, Ankit S.
Tunströmer, Kjersti
Lindahl, Tomas L.
Boknäs, Niklas
author_sort Lund, Mikael
collection PubMed
description Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the effects of heparin/antithrombin and bivalirudin on PAR1- and PAR4-mediated intracellular calcium mobilization, aggregation, α-granule release, and procoagulant membrane exposure in platelets exposed to thrombin concentrations likely to be encountered in the thrombus microenvironment during thrombosis. At physiological antithrombin levels, heparin treatment resulted in complete and sustained inhibition of thrombin-induced PAR4-mediated platelet activation, but transient PAR1 signaling was sufficient to elicit significant α-granule release and platelet aggregation. In contrast, bivalirudin treatment resulted in rapid and profound inhibition of signaling from both PAR receptors, followed by a delayed phase of PAR4-mediated platelet activation, resulting in a robust prothrombotic response. Combination treatment with bivalirudin and subtherapeutic concentrations of heparin completely inhibited the residual platelet activation observed with single drug treatment at all time-points. Our results show that heparin and bivalirudin have different and complementary inhibitory effects on the activation of PAR1 and PAR4 by thrombin.
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spelling pubmed-85114492021-10-14 Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses Lund, Mikael Macwan, Ankit S. Tunströmer, Kjersti Lindahl, Tomas L. Boknäs, Niklas Front Cardiovasc Med Cardiovascular Medicine Heparin and bivalirudin are widely used as anticoagulants in the setting of acute thrombosis. In this study, we investigated how these drugs affect the ability of thrombin to generate a prothrombotic platelet response via activation of the protease-activated receptors (PARs) 1 and 4. We examined the effects of heparin/antithrombin and bivalirudin on PAR1- and PAR4-mediated intracellular calcium mobilization, aggregation, α-granule release, and procoagulant membrane exposure in platelets exposed to thrombin concentrations likely to be encountered in the thrombus microenvironment during thrombosis. At physiological antithrombin levels, heparin treatment resulted in complete and sustained inhibition of thrombin-induced PAR4-mediated platelet activation, but transient PAR1 signaling was sufficient to elicit significant α-granule release and platelet aggregation. In contrast, bivalirudin treatment resulted in rapid and profound inhibition of signaling from both PAR receptors, followed by a delayed phase of PAR4-mediated platelet activation, resulting in a robust prothrombotic response. Combination treatment with bivalirudin and subtherapeutic concentrations of heparin completely inhibited the residual platelet activation observed with single drug treatment at all time-points. Our results show that heparin and bivalirudin have different and complementary inhibitory effects on the activation of PAR1 and PAR4 by thrombin. Frontiers Media S.A. 2021-09-29 /pmc/articles/PMC8511449/ /pubmed/34660719 http://dx.doi.org/10.3389/fcvm.2021.717835 Text en Copyright © 2021 Lund, Macwan, Tunströmer, Lindahl and Boknäs. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Lund, Mikael
Macwan, Ankit S.
Tunströmer, Kjersti
Lindahl, Tomas L.
Boknäs, Niklas
Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title_full Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title_fullStr Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title_full_unstemmed Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title_short Effects of Heparin and Bivalirudin on Thrombin-Induced Platelet Activation: Differential Modulation of PAR Signaling Drives Divergent Prothrombotic Responses
title_sort effects of heparin and bivalirudin on thrombin-induced platelet activation: differential modulation of par signaling drives divergent prothrombotic responses
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511449/
https://www.ncbi.nlm.nih.gov/pubmed/34660719
http://dx.doi.org/10.3389/fcvm.2021.717835
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