Background:The role of sirtuins in regulating platelet aging is largely unexplored. Results: Sirtuin inhibitors induced apoptosis-like changes in blood platelets, associated with a rise in active Bax and a significant drop in platelet count. Conclusion: Sirtuins act as a central player in the determination of platelet aging. Significance: This study refocuses attention on the potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis.

xygen-compromised environments, such as high altitude, are associated with platelet hyperactivity. Platelets confined within the relatively impervious core of an aggregate/thrombus have restricted access to oxygen, yet they continue to perform energy-intensive procoagulant activities that sustain the thrombus. Studying platelet signaling under hypoxia is, therefore, critical to our understanding of the mechanistic basis of thrombus stability. We report here that hypoxia-inducible factor (HIF)-2a is translated from pre-existing mRNA and stabilized against proteolytic degradation in enucleate platelets exposed to hypoxia. Hypoxic stress, too, stimulates platelets to synthesize plasminogen-activator inhibitor-1 (PAI-1) and shed extracellular vesicles, both of which potentially contribute to the prothrombotic phenotype associated with hypoxia. Stabilization of HIF-a by administering hypoxia-mimetics to mice accelerates thrombus formation in mesenteric arterioles. In agreement, platelets from patients with chronic obstructive pulmonary disease and high altitude residents exhibiting thrombogenic attributes have abundant expression of HIF-2a and PAI-1. Thus, targeting platelet hypoxia signaling could be an effective antithrombotic strategy.

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