Aging and chronic inflammation have been identified as independent risk factors for the development of atherothrombosis and cardiovascular disease.

Figure 1. Representative TEM images of platelets from healthy controls (left) and Jak2 V617F+ MPN patients (right) with black arrows depicting the significantly higher mitochondrial content in platelets from Jak2 V617F+ MPN patients

We recently identified TNF-α as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status and thrombocytosis. Single-cell RNA-sequencing (scRNA-seq) analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity (figure 2). Platelets from old mice (where TNF-α was endogenously increased), and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation (figure 1). These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously-unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Figure 2. Single-cell RNA-sequencing of native bone marrow megakaryocytes & heat map of mitochondrial dysfunction