Key result
In a mouse thrombosis model, selatogrel maintained hemostatic seal stability without the off-target interference on endothelial activation and neutrophil function seen with ticagrelor and clopidogrel.
Why the study?
In rat models, selatogrel was associated with lower blood loss than clopidogrel or ticagrelor at equivalent antithrombotic effect, but the underlying mechanism was unknown.
Does selatogrel have less off-target interference with hemostatic factors compared to ticagrelor and clopidogrel in a mouse thrombosis model?
Does selatogrel have less off-target interference with hemostatic factors compared to ticagrelor and clopidogrel in a mouse thrombosis model?
Selatogrel demonstrates a more favorable hemostatic profile than ticagrelor and clopidogrel in preclinical models by avoiding off-target interference with endothelial and neutrophil functions.
Answers are grounded in this paper and cite their sources.
May support selatogrel's lower bleeding in models; leaves open clinical translation versus other P2Y12 inhibitors.
INTRODUCTION: Selatogrel is a reversible antagonist of the P2Y12 receptor. In rat thrombosis/haemostasis models, selatogrel was associated with lower blood loss than clopidogrel or ticagrelor at equivalent anti-thrombotic effect. MATERIAL AND METHODS: We sought to elucidate the mechanism underlying the observed differences in blood loss, using real-time intravital microscopy in mouse. RESULTS: Selatogrel, ticagrelor and clopidogrel dose-dependently inhibited laser-induced platelet thrombus formation. At maximal antithrombotic effect, only small mural platelets aggregates, corresponding to hemostatic seals, were present. The phenotype of these hemostatic seals was dependent on the type of P2Y12 receptor antagonist. In the presence of clopidogrel and ticagrelor, detachment of platelets from the hemostatic seals was increased, indicative of reduced stability. In contrast, in the presence of selatogrel, platelet detachment was not increased. Moreover, equivalent antithrombotic dosing regimens of ticagrelor and clopidogrel reduced laser-induced calcium mobilization in the endothelium, restricted neutrophil adhesion and subsequent fibrin formation and thus reduced fibrin-mediated stabilization of the hemostatic seals. The effects of ticagrelor were also observed in P2Y12 receptor deficient mice, indicating that the effects are off-target and independent of the P2Y12 receptor. In contrast, selatogrel did not interfere with these elements of haemostasis in wild-type or in P2Y12 receptor deficient mice. CONCLUSION: In the presence of selatogrel the stability of hemostatic seals was unperturbed, translating to an improved blood loss profile. Our data suggest that the mechanism underlying the differences in blood loss profiles of P2Y12 receptor antagonists is by off-target interference with endothelial activation, neutrophil function and thus, fibrin-mediated stabilization of haemostatic seals.
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Crescence et al. (2021) studied Thrombosis. Selatogrel vs. Ticagrelor and clopidogrel was evaluated on Platelet thrombus formation and hemostatic seal stability. In a mouse thrombosis model, selatogrel maintained hemostatic seal stability without the off-target interference on endothelial activation and neutrophil function seen with ticagrelor and clopidogrel.
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