Antithrombotic Effects of Fostamatinib in Combination with Conventional Antiplatelet Drugs

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.

Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection

“…Our network shows the anti-platelet effects offostamatinib via its targets in addition to SYK and we computationally and experimentally validated its inhibitory effect on SYK and SFKs. Its effects through SYK have been shown before as interfering with thrombosis but not with hemostasis (78,79) and its potential use in COVID-19 has also been suggested by a computational study that confirmed fostamatinib's targets by molecular docking (80). It was shown to counteract the platelet hyperactivity in vitro on platelets from COVID-19 patients with potentially actionable pathways as central for platelet activation and/ or vascular complications (81).…”

Impact of antiplatelet therapy on microvascular thrombosis during ST-elevation myocardial infarction

“…There was also noticeable improvement in microperfusion in the ischaemic area after reperfusion ( Pachel et al, 2016 ). It has not been possible to find a small molecule inhibitor of GPVI, but novel antagonists have now been produced (described in the following paragraphs) and it is also possible to block GPVI-mediated platelet responses by inhibition of Btk and Syk which are part of its downstream signalling pathway ( Harbi et al, 2022 ; Harbi et al, 2021 ; Smith et al, 2022 ).…”

Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

“…Fostamatinib may therefore be a drug to consider for patients with an increased thrombotic risk, such as those with coronary artery disease, diabetes, advanced age or obesity. Indeed, in a recent in vitro study, R406 had synergistic effects with existing antiplatelet agents on atherosclerotic plaque-induced platelet activation [86].…”