Francesca Santilli

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

Extracellular vesicles (EVs) are small vesicles deriving from all cell types during cell activation, involved in transcellular communication, and regarded as predictors of vascular damage and of cardiovascular events. We tested the hypothesis that, in patients on chronic low‐dose aspirin treatment for cardiovascular prevention, aspirin may affect the release of EVs within the 24‐hour interval. We enrolled 84 patients, mostly at high or very high cardiovascular risk, on chronic low‐dose aspirin treatment. The numbers of circulating EVs (cEVs) and annexinV+ cEVs ( total , platelet‐derived , endothelial ‐ derived , and leucocyte‐derived ) were assessed immediately before, and after 10 and 24 hours of a witnessed aspirin administration. Platelet cyclooxygenase 1 (COX‐1) recovery was characterized by measuring serum thromboxane B 2 (sTXB 2 ) at the same timepoints. Nine healthy participants were also enrolled. In patients, daily aspirin administration acutely inhibited after 10 hours following aspirin administrations the release of cEVs ( total and leukocyte‐derived ) and annexinV+ cEVs ( total , platelet‐derived , endothelial ‐ derived , and leukocyte‐derived ), with a rapid recovery at 24 hours. The inhibition after 10 hours suggests a COX‐1–dependent mechanism. Interestingly, the slope of platelet‐derived and of annexinV+ platelet‐derived cEVs were both directly related to sTXB 2 slope and COX‐1 messenger RNA, raising the hypothesis that vice versa , cEVs may affect the rate of COX‐1 recovery and the subsequent duration of aspirin effect. In healthy participants, no circadian difference was observed, except for leukocyte‐derived cEVs. Our findings suggest a previously unappreciated effect of aspirin on the kinetics of a subset of cEVs possibly contributing to the cardioprotective effects of this drug.