Session: 301. Platelets and Megakaryocytes: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research
Methods: We studied platelets from healthy younger (<45 years) and older volunteers (>50 years), as well as from young (<3 months) and old (>18 months) mice. The autophagic and mitophagic fluxes were assessed using chloroquine (CQ) as per the current guidelines for monitoring autophagy. Platelet bioenergetics were analyzed with a Seahorse analyzer (Agilent). Thrombus formation was assessed with a microfluidics assay (T-TAS analyzer). Platelet contractile forces were quantified using the ATLAS system. Clot contraction was evaluated with a thrombin-based assay.
Results: Both autophagy and mitophagy were blocked in platelets from aged individuals, while platelets from younger adults exhibited robust flux (p<0.05, 0.05). Similar results were observed in mouse platelets (p<0.01, 0.05). To determine the metabolic impact of these differences, we evaluated the bioenergetic profiles of younger and older platelets. Compared to those from younger individuals, aged platelets displayed significantly decreased basal, maximal, and ATP-linked respiration (p<0.001, 0.05, 0.05). These metabolic abnormalities were accompanied by lower clot formation under flow conditions (p<0.01), decreased contractile forces (p<0.05), and reduced clot contraction (p<0.01). Pharmacological inhibition of these pathways in platelets from younger individuals with either CQ or EACC recapitulated the metabolic and functional deficits observed in platelets from older adults. These inhibitors significantly decreased mitochondrial respiration (p< 0.01, 0.05), clot formation (p<0.01, p<0.05), and contraction (p<0.05, 0.001).
Conclusion: This research is the first to demonstrate an age-related decline in autophagy and mitophagy in both human and mouse platelets, establishing a link between these deficits and metabolic as well as functional alterations critical for effective clot formation and contraction. Considering the association between impaired clot contraction and thrombotic and hemorrhagic events, these findings suggest that declining platelet autophagy and mitophagy may significantly contribute to the increased incidence of these events with aging. This work not only opens new avenues for understanding the role of platelets in hemostasis and thrombosis in aging but also paves the way for developing targeted interventions, such as modulators of these autophagic pathways, to mitigate these age-related complications.
Disclosures: Ting: Stasys: Current Employment. Manco-Johnson: BioMarin: Honoraria; CSL Behring: Honoraria; Genentech/Roche: Honoraria; NovoNordisk: Honoraria; Spark/Pfizer: Honoraria.
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