LRP5, a WNT signalling pathway receptor, and platelet activation

Background and Aims Platelets are essential for haemostasis, thrombosis, and inflammation, with their functions controlled by receptor signalling pathways. This study examined the role of LRP5, a member of the Wnt signalling cascade, in platelet function and haemostasis. Methods Human platelets, as well as platelets isolated from wild-type (Wt) and Lrp5-deficient (Lrp5−/−) mice, were challenged with ADP, collagen, LRP5-specific inhibitors, and standard platelet inhibitor drugs. Results Both platelet aggregation (LTA) and flow-dependent platelet deposition on collagen-coated surfaces were significantly lower in Lrp5−/− than in Wt mice. In vivo carotid artery occlusion time measured by real-time blood flow monitoring was significantly prolonged in Lrp5−/− mice. While GPVI signalling remained intact, Lrp5−/− platelets displayed reduced α- and dense granule release after ADP stimulation, along with reduced membrane levels of purinergic receptors. VASP phosphorylation confirmed that P2Y12 downstream signalling pathway was dysfunctional in the LRP5-deficient platelets. Finally, human platelets express high levels of LRP5 and flow-mediated human platelet deposition and LTA was highly reduced by LRP5 inhibition. Under the experimental conditions tested, LRP5 deletion did not significantly affect coagulation nor induce bleeding. Conclusions These findings reveal for the first time that LRP5 plays a critical role in platelet adhesion and thrombus formation. Genetic deletion and biochemical inhibition of LRP5 markedly impair platelet aggregation and thrombosis in preclinical models, without major effects on haemostasis. Although further research is needed to evaluate its clinical applicability, LRP5 appears as a novel and actionable target to modulate platelet reactivity and thrombosis.