Platelet, Antiplatelet Therapy and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review

Abstract

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.

Keywords: MASLD; NAFLD; aspirin; cancer; thromboxane.

Figure 1

Summary figure on the role of platelets in patients with MASLD (NAFLD). Platelets are players and aggressors 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. Furthermore, platelets are included in the majority of clinical scores linked to liver disease and risk of evolution towards cirrhosis. Created in https://www.biorender.com/.

Figure 2

Obesity and insulin resistance are correlated with platelet hyper-activation. Upon activation, platelets release some molecules and mediators harbored in their granules such as 5-HT, CD40L, and TXA_2. Those molecules are involved in determining a pro-thrombotic and pro-coagulant state. Moreover, many pathways are involved in direct liver damage by HSC activation, ER stress, lipotoxicity, and oxidative stress. Eventually, there is a cross-talking between platelets and immune cells, thus inducing a dysregulated immune response involved in liver damage and in determining coagulative disorder. Abbreviations: chemokine (C-X-C motif) ligand 4, CXCL4; 5-hydroxytryptamine, 5-HT; CD40 ligand, CD40L; thromboxane A₂, TXA₂; von Willebrand factor, vWF; plasminogen activator inhibitor 1, PAI-1; hepatic stem cell, HSC; endoplasmic reticulum, ER. Created in https://www.biorender.com/.

Figure 3

Summary figure on the anti-cancer mechanisms of antiplatelet therapy (aspirin). Aspirin can block COX-2 both at the platelet level and in tumor cells. At the platelet level, COX blockade reduces platelet activation and the release of mediators that may be involved in tumorigenesis (e.g., TGF-β, VEGF, TXA2). At the tumor cell level, COX-2 blockade appears to be able to reduce cell proliferation and epithelial–mesenchymal transition. Abbreviations: thromboxane A₂, TXA₂; interleukin, IL; platelet-factor-4, PF-4; vascular endothelial growth factor, VEGF; platelet-derived growth factor, PDGF; transforming growth factor β, TGF-β; cyclooxygenase, COX; prostaglandin E, PGE; prostaglandin E receptor, EP; epithelial–mesenchymal transition, EMT. Created in https://www.biorender.com/.