Key result
Elderly individuals exhibit a distinct platelet phenotype characterized by increased basal activation, greater ADP-induced aggregation (P<0.05), and resistance to thrombin-mediated activation (P<0.05).
Why the study?
Thrombin and ADP are potent endogenous platelet activators implicated in cardiovascular disease, but whether platelet pathways alter with aging was unknown.
Cross-Sectional (n=174)
Aging is associated with a distinct platelet phenotype characterized by increased basal activation, ADP hyperreactivity, and thrombin resistance, which may have implications for cardiovascular disease prevention in the elderly.
Answers are grounded in this paper and cite their sources.
Age-related platelet ADP hypersensitivity with thrombin resistance may influence antithrombotic choices; hypothesis-generating for inflammation-targeted CVD prevention in the elderly.
Background: Thrombin (via PAR [protease-activated receptor]-1 and PAR-4) and ADP (via P2Y 12 receptors) are potent endogenous platelet activators implicated in the development of cardiovascular disease. We aimed to assess whether platelet pathways alter with aging. Methods: We characterized platelet activity in community-dwelling volunteers (n=174) in the following age groups: (1) 20 to 30 (young); (2) 40 to 55 (middle-aged); (3) ≥70 years (elderly). Platelet activity was assessed by aggregometry; flow cytometry (surface markers [P-selectin: alpha granule release, CD63: dense granule release, PAC-1: measure of conformationally active GPIIb/IIIa at the fibrinogen binding site]) measured under basal conditions and after agonist stimulation [ADP, thrombin, PAR-1 agonist or PAR-4 agonist]); receptor cleavage and quantification; fluorometry; calcium flux; ELISA. Results: The elderly had higher basal platelet activation than the young, evidenced by increased expression of P-selectin, CD63, and PAC-1, which correlated with increasing inflammation (IL [interleukin]-1β/IL-6). The elderly demonstrated higher P2Y 12 receptor density, with greater ADP-induced platelet aggregation ( P <0.05). However, elderly subjects were resistant to thrombin, achieving less activation in response to thrombin (higher EC 50 ) and to selective stimulation of both PAR-1 and PAR-4, with higher basal PAR-1/PAR-4 cleavage and less inducible PAR-1/PAR-4 cleavage (all P <0.05). Thrombin resistance was attributable to a combination of reduced thrombin orienting receptor GPIbα (glycoprotein Ibα), reduced secondary ADP contribution to thrombin-mediated activation, and blunted calcium flux. D-Dimer, a marker of in situ thrombin generation, correlated with platelet activation in the circulation, ex vivo thrombin resistance, and circulating inflammatory mediators (TNF [tumor necrosis factor]-α/IL-6). Conclusions: Aging is associated with a distinctive platelet phenotype of increased basal activation, ADP hyperreactivity, and thrombin resistance. In situ thrombin generation associated with systemic inflammation may be novel target to prevent cardiovascular disease in the elderly.
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Gnanenthiran et al. (2022) conducted a cross-sectional in Healthy volunteers (n=174). Advanced age (Elderly) vs. Young (20-30 years) and middle-aged (40-55 years) individuals was evaluated on Platelet activity including basal activation, ADP-induced aggregation, and thrombin response (p=<0.05). Elderly individuals exhibit a distinct platelet phenotype characterized by increased basal activation, greater ADP-induced aggregation (P<0.05), and resistance to thrombin-mediated activation (P<0.05).
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