Inflammation mediated platelet hyperactivity in aging.

© Annals of Blood. All rights reserved. Ann Blood 2020 | http://dx.doi. org/10.21037/aob.2020. 03.01 Aging is intrinsically linked with physical decline and is a major risk factor for a broad range of diseases including cardiovascular disease and thrombosis. There is growing appreciation for the role of platelets as pathological mediators of age-related thrombosis. It is well documented that platelet hyperactivity is a key alteration associated with aging that appears to be driven in part by oxidative and metabolic pathways (1,2). In addition, chronic inflammation caused by increased local and systemic mediators has been shown to accompany the aging process and can further contribute to vascular disease and thrombosis. Nevertheless, a clear mechanistic link between inflammation and platelet hyperreactivity during aging is not well established. In the August 29, 2019 issue of Blood (3), a study by DavizonCastillo et al. provide compelling evidence that ageassociated inflammation promotes platelet activity and platelet thrombi formation. Using a well-designed crosssectional study in mice and humans the authors reported a critical role of TNF-α as a proinflammatory mediator in platelet activation during aging. The authors utilized several complementary approaches. Studies in murine models showed that aged mice have elevated plasma TNF-α levels and they exhibit increased platelet reactivity and accelerated platelet thrombi formation ex vivo. Interestingly, similar results were observed with human platelets isolated from volunteers despite over 60% of older individuals (versus less than 10% of younger individuals) were receiving aspirin at the time of sample collection. It is noted that about 72% of older individuals were on statins but the co-morbidities of the study population were not listed. Many agerelated comorbidities such as atherosclerosis, obesity, hyperlipidemia, etc. are known to be associated with an increased inflammatory state and thrombotic complications. Given that aging is a complex and multifactorial process, inclusion of samples only from healthy individuals will be a better study design to assess the effects of aging alone on platelets that would eliminate many of the confounding factors associated with the aged population. To assess the relationship between TNF-α and platelet reactivity, the authors utilized several different murine models of TNF-α elevation or depletion. They demonstrated that daily injections of young mice with TNF-α, which increased plasma TNF-α to a level similar to aged mice, closely recapitulated the platelet hyperreactivity of aged mice. Similar results of platelet hyperreactivity was found using a genetic murine model of chronically elevated TNF-α (TNFΔARE). The authors then performed in vivo neutralization studies using a monoclonal anti-TNF-α antibody that significantly lowered plasma TNF-α levels and decreased platelet activation responses in aged mice similar to the levels observed in young mice. Furthermore, injection of TNF-α into young p55/p75 KO mice (deficient for both TNF-α receptors) did not increase platelet activation responses suggesting a direct role of TNF-α in platelet activation. One limitation of these studies is that the platelet activation and adhesion assays were performed ex vivo. In vivo thrombosis models would provide more physiological relevance to establish TNF-α as a mediator of thrombosis. Additionally, it remains unclear whether these Editorial Commentary