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Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies

INTRODUCTION: Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents o...

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Autores principales: Perzborn, Elisabeth, Heitmeier, Stefan, Laux, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598653/
https://www.ncbi.nlm.nih.gov/pubmed/25848131
http://dx.doi.org/10.1177/1074248415578172
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author Perzborn, Elisabeth
Heitmeier, Stefan
Laux, Volker
author_facet Perzborn, Elisabeth
Heitmeier, Stefan
Laux, Volker
author_sort Perzborn, Elisabeth
collection PubMed
description INTRODUCTION: Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models. MATERIALS AND METHODS: Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis. RESULTS: Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect. CONCLUSION: These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency.
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spelling pubmed-45986532015-10-31 Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies Perzborn, Elisabeth Heitmeier, Stefan Laux, Volker J Cardiovasc Pharmacol Ther Experimental Studies INTRODUCTION: Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models. MATERIALS AND METHODS: Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis. RESULTS: Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect. CONCLUSION: These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency. SAGE Publications 2015-11 /pmc/articles/PMC4598653/ /pubmed/25848131 http://dx.doi.org/10.1177/1074248415578172 Text en © The Author(s) 2015 http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Experimental Studies
Perzborn, Elisabeth
Heitmeier, Stefan
Laux, Volker
Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title_full Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title_fullStr Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title_full_unstemmed Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title_short Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction: In Vitro and In Vivo Studies
title_sort effects of rivaroxaban on platelet activation and platelet–coagulation pathway interaction: in vitro and in vivo studies
topic Experimental Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598653/
https://www.ncbi.nlm.nih.gov/pubmed/25848131
http://dx.doi.org/10.1177/1074248415578172
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