Abstract 16292: Selective Platelet Protease-Activated-Receptor (PAR)1 and PAR4 Mediated Thrombin Desensitisation in the Elderly is Correlated With Inflammation and Chronic Thrombin Receptor Stimulation

Abstract

Introduction: Platelet activation, by adenosine diphosphate (ADP) via P2Y 12 receptors and thrombin via PAR1 and PAR4, is a key therapeutic target in cardiovascular disease (CVD). The efficacy of antiplatelet agents diminishes in the elderly, but it is unknown whether these pathways change with aging. Hypothesis: Platelet activation pathways change with aging. Methods: Platelet activity was evaluated in young (20-30yrs), middle-aged (40-55yrs) and elderly (≥70yrs) healthy volunteers (n=174). Whole blood aggregometry and flow cytometry (P-selectin: α-granule release; CD63: dense granule release; PAC1 binding: activated GPIIb/IIIa) were performed under basal conditions and post ex vivo stimulation with ADP, thrombin, PAR1 agonist or PAR4 agonist. EC 50 and E max values were derived for each agonist. Receptor cleavage and quantification (P2Y 12 ; PAR1; PAR4; GPIbα) were assessed with flow cytometry. Thrombin generation (D-Dimer) and inflammation (interleukin [IL]-1β; tumour necrosis factor [TNF]-α) were assessed via ELISA. Results: The elderly had higher basal platelet activation markers (P-selectin, CD63, activated GPIIb/IIIa) than the young, with higher basal activity correlating with increasing IL-1β. P2Y 12 receptor density was higher in the elderly and associated with greater ADP-induced platelet aggregation and activation. Elderly subjects had less platelet activation in response to thrombin (higher EC 50 ), demonstrating hyporeactivity to selective stimulation of PAR1 or PAR4, more basal PAR1/PAR4 cleavage, and less inducible PAR1/PAR4 cleavage. This was associated with reduced thrombin binding receptor GPIbα and reduced secondary ADP contribution to thrombin-mediated activation. D-Dimer and TNF-α levels were elevated in the elderly, and inversely correlated with platelet thrombin sensitivity, implying a role of desensitization from chronic thrombin receptor stimulation. Conclusion: Aging is associated with increased basal platelet activation and hyperreactivity to ADP, but selective desensitization to thrombin. The latter appears mediated by chronic thrombin receptor stimulation and inflammation. Age-specific antiplatelet strategies may require selective targeting of these pathways to treat CVD in the elderly.