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Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs

New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyr...

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Autores principales: Harbi, Maan H., Smith, Christopher W., Alenazy, Fawaz O., Nicolson, Phillip L. R., Tiwari, Alok, Watson, Steve P., Thomas, Mark R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266367/
https://www.ncbi.nlm.nih.gov/pubmed/35805988
http://dx.doi.org/10.3390/ijms23136982
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author Harbi, Maan H.
Smith, Christopher W.
Alenazy, Fawaz O.
Nicolson, Phillip L. R.
Tiwari, Alok
Watson, Steve P.
Thomas, Mark R.
author_facet Harbi, Maan H.
Smith, Christopher W.
Alenazy, Fawaz O.
Nicolson, Phillip L. R.
Tiwari, Alok
Watson, Steve P.
Thomas, Mark R.
author_sort Harbi, Maan H.
collection PubMed
description New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyrosine kinase (Syk) has been shown to block GPVI-mediated platelet function. The aim of our study was to investigate if the Syk inhibitor fostamatinib could be repurposed as an antiplatelet drug, either alone or in combination with conventional antiplatelet therapy. The effect of the active metabolite of fostamatinib (R406) was assessed on platelet activation and function induced by atherosclerotic plaque and a range of agonists in the presence and absence of the commonly used antiplatelet agents aspirin and ticagrelor. The effects were determined ex vivo using blood from healthy volunteers and aspirin- and ticagrelor-treated patients with ACS. Fostamatinib was also assessed in murine models of thrombosis. R406 mildly inhibited platelet responses induced by atherosclerotic plaque homogenate, likely due to GPVI inhibition. The anti-GPVI effects of R406 were amplified by the commonly-used antiplatelet medications aspirin and ticagrelor; however, the effects of R406 were concentration-dependent and diminished in the presence of plasma proteins, which may explain why fostamatinib did not significantly inhibit thrombosis in murine models. For the first time, we demonstrate that the Syk inhibitor R406 provides mild inhibition of platelet responses induced by atherosclerotic plaque and that this is mildly amplified by aspirin and ticagrelor.
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spelling pubmed-92663672022-07-09 Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs Harbi, Maan H. Smith, Christopher W. Alenazy, Fawaz O. Nicolson, Phillip L. R. Tiwari, Alok Watson, Steve P. Thomas, Mark R. Int J Mol Sci Article New antithrombotic medications with less effect on haemostasis are needed for the long-term treatment of acute coronary syndromes (ACS). The platelet receptor glycoprotein VI (GPVI) is critical in atherothrombosis, mediating platelet activation at atherosclerotic plaque. The inhibition of spleen tyrosine kinase (Syk) has been shown to block GPVI-mediated platelet function. The aim of our study was to investigate if the Syk inhibitor fostamatinib could be repurposed as an antiplatelet drug, either alone or in combination with conventional antiplatelet therapy. The effect of the active metabolite of fostamatinib (R406) was assessed on platelet activation and function induced by atherosclerotic plaque and a range of agonists in the presence and absence of the commonly used antiplatelet agents aspirin and ticagrelor. The effects were determined ex vivo using blood from healthy volunteers and aspirin- and ticagrelor-treated patients with ACS. Fostamatinib was also assessed in murine models of thrombosis. R406 mildly inhibited platelet responses induced by atherosclerotic plaque homogenate, likely due to GPVI inhibition. The anti-GPVI effects of R406 were amplified by the commonly-used antiplatelet medications aspirin and ticagrelor; however, the effects of R406 were concentration-dependent and diminished in the presence of plasma proteins, which may explain why fostamatinib did not significantly inhibit thrombosis in murine models. For the first time, we demonstrate that the Syk inhibitor R406 provides mild inhibition of platelet responses induced by atherosclerotic plaque and that this is mildly amplified by aspirin and ticagrelor. MDPI 2022-06-23 /pmc/articles/PMC9266367/ /pubmed/35805988 http://dx.doi.org/10.3390/ijms23136982 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Harbi, Maan H.
Smith, Christopher W.
Alenazy, Fawaz O.
Nicolson, Phillip L. R.
Tiwari, Alok
Watson, Steve P.
Thomas, Mark R.
Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title_full Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title_fullStr Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title_full_unstemmed Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title_short Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
title_sort antithrombotic effects of fostamatinib in combination with conventional antiplatelet drugs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266367/
https://www.ncbi.nlm.nih.gov/pubmed/35805988
http://dx.doi.org/10.3390/ijms23136982
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