Abstract
Selatogrel, a potent and reversible antagonist of the P2Y12 receptor, inhibited FeCl3-induced thrombosis in rats. Here, we report the anti-thrombotic effect of selatogrel after subcutaneous applications in guinea pigs and mice. Selatogrel inhibited platelet function only 10 min after subcutaneous application in mice. In addition, in a modified Folts thrombosis model in guinea pigs, selatogrel prevented a decrease in blood-flow, indicative of the inhibition of ongoing thrombosis, approximately 10 min after subcutaneous injection. Selatogrel fully normalised blood flow; therefore, we speculate that it may not only prevent, but also dissolve, platelet thrombi. Thrombus dissolution was investigated using real-time intravital microscopy in mice. The infusion of selatogrel during ongoing platelet thrombus formation stopped growth and induced the dissolution of the preformed platelet thrombus. In addition, platelet-rich thrombi were given 30 min to consolidate in vivo. The infusion of selatogrel dissolved the preformed and consolidated platelet thrombi. Dissolution was limited to the disintegration of the occluding part of the platelet thrombi, leaving small mural platelet aggregates to seal the blood vessel. Therefore, our experiments uncovered a novel advantage of selatogrel: the dissolution of pre-formed thrombi without the disintegration of haemostatic seals, suggesting a bipartite benefit of the early application of selatogrel in patients with acute thrombosis.
Highlights
Pathological imbalances of the regulatory mechanisms of haemostasis enhance the probability for the formation of occlusive platelet-rich thrombi, causing major adverse cardiac events (MACEs) [1]
The presence of antithrombotic concentrations of selatogrel was assessed by a functional platelet assay where the binding of fluorescently labelled fibrinogen (AF488–fibrinogen) to platelets was quantified by FACS analysis (mean fluorescence intensity (MFI))
Fibrinogen) to platelets was quantified by FACS analysis (mean fluorescence intensity (MFI))
Summary
Pathological imbalances of the regulatory mechanisms of haemostasis enhance the probability for the formation of occlusive platelet-rich thrombi, causing major adverse cardiac events (MACEs) [1]. Coronary thrombosis is a dynamic process, with platelet thrombi being formed and broken down, a process that can take hours or even days to result in symptomatic ischemic occlusion [7]. Acute administration of a rapid-onset P2Y12 receptor antagonist is relevant in the context of early thrombus formation in acute myocardial infarction. Such an approach represents an additional option to be investigated with the possibility of preventing early thrombotic propagation [8,9]
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