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Identification of a Distinct Platelet Phenotype in the Elderly: ADP Hypersensitivity Coexists With Platelet PAR (Protease-Activated Receptor)-1 and PAR-4-Mediated Thrombin Resistance.
Gnanenthiran, Sonali R; Pennings, Gabrielle J; Reddel, Caroline J; Campbell, Heather; Kockx, Maaike; Hamilton, Justin R; Chen, Vivien M; Kritharides, Leonard.
Afiliación
  • Gnanenthiran SR; Cardiology Department, Concord Repatriation General Hospital, NSW, Australia (S.R.G., L.K.).
  • Pennings GJ; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
  • Reddel CJ; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
  • Campbell H; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
  • Kockx M; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
  • Hamilton JR; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
  • Chen VM; Australian Centre of Blood Diseases, Monash University, Victoria, Australia (J.R.H.).
  • Kritharides L; ANZAC Research Institute, Concord Repatriation General Hospital, and University of Sydney, Sydney, NSW, Australia (S.R.G., G.J.P., C.J.R., H.C., M.K., V.M.C., L.K.).
Arterioscler Thromb Vasc Biol ; 42(8): 960-972, 2022 08.
Article en En | MEDLINE | ID: mdl-35708029
ABSTRACT

BACKGROUND:

Thrombin (via PAR [protease-activated receptor]-1 and PAR-4) and ADP (via P2Y12 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]-1ß/IL-6). The elderly demonstrated higher P2Y12 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 EC50) 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Receptor PAR-1 Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Aged / Humans Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Receptor PAR-1 Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Aged / Humans Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2022 Tipo del documento: Article
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