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Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs
Maan H Harbi1,2, Christopher W Smith1, Fawaz O Alenazy1
1Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Insights
Spleen tyrosine kinase (Syk) inhibitor R406 mildly inhibits platelet activation by atherosclerotic plaque. This effect is enhanced by aspirin and ticagrelor, suggesting potential for novel antiplatelet therapies in acute coronary syndromes (ACS).
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Hematology
Background:
- Acute coronary syndromes (ACS) require long-term antithrombotic treatments with minimal impact on hemostasis.
- Platelet receptor glycoprotein VI (GPVI) plays a key role in atherothrombosis by mediating platelet activation at atherosclerotic plaques.
- Spleen tyrosine kinase (Syk) inhibition effectively blocks GPVI-mediated platelet function.
Purpose of the Study:
- To investigate the potential repurposing of the Syk inhibitor fostamatinib (active metabolite R406) as an antiplatelet drug.
- To evaluate R406's efficacy alone and in combination with conventional antiplatelet agents (aspirin, ticagrelor).
- To assess R406's effects on platelet activation and function induced by atherosclerotic plaque and various agonists.
Main Methods:
- Ex vivo assessment of R406's effect on platelet activation using blood from healthy volunteers and ACS patients treated with aspirin/ticagrelor.
- Evaluation of platelet responses induced by atherosclerotic plaque homogenate and agonists.
- Assessment of fostamatinib in murine models of thrombosis.
Main Results:
- R406 demonstrated mild inhibition of platelet responses to atherosclerotic plaque homogenate, attributed to GPVI inhibition.
- The anti-GPVI effects of R406 were potentiated by aspirin and ticagrelor.
- R406's efficacy was concentration-dependent and reduced by plasma proteins, potentially explaining limited inhibition in murine thrombosis models.
Conclusions:
- The Syk inhibitor R406 offers mild inhibition of platelet responses triggered by atherosclerotic plaque.
- Combination therapy with aspirin and ticagrelor mildly amplifies R406's antiplatelet effects.
- Fostamatinib's clinical utility as an antiplatelet agent may be influenced by plasma protein interactions and concentration-dependent effects.
Abstract:
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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