Inhibitory mechanism of fluoxetine in collagen-induced platelet aggregation

Fluoxetine, a selective serotonin reuptake inhibitor, is commonly prescribed as an antidepressant; however, studies have demonstrated that it increases bleeding risk. This study examined the potential mechanisms underlying the effects of fluoxetine on platelet activation.

Washed platelets and platelet-rich plasma were used to investigate the effects of fluoxetine on collagen- and collagen-related peptide-induced platelet aggregation and secretion. Flow cytometry was used to measure its effects on P-selectin expression in washed human platelets stimulated with collagen. Western blotting was used to detect protein phosphorylation.

Fluoxetine significantly reduced collagen-induced platelet aggregation in a dose-dependent manner. Fluoxetine decreased the levels of phospholipase C gamma 2 (PLCγ2), spleen tyrosine kinase (Syk), protein kinase B (Akt), and glycogen synthase kinase 3 beta (GSK3β) phosphorylation in the glycoprotein Ⅵ (GPⅥ) signaling pathway, as well as the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) family. However, fluoxetine did not affect p38 MAPK or c-Jun N-terminal kinase (JNK) phosphorylation. 5-HT analogs block the effects of fluoxetine on platelets and downstream signaling pathways of GPⅥ. Administration of an additional 5-HT2 receptor antagonist, ketanserin, resulted in a reduction of platelet aggregation levels; however, the values remained statistically distinct from those observed in the fluoxetine-alone group.

Fluoxetine attenuates collagen-induced platelet activation and interferes with the Syk-PLCγ2-Akt-GSK3β and ERK1/2 signaling pathways; this effect may be attributed to its dual inhibition of 5-HT receptors and Serotonin transporters (SERTs).