Metabolic landscape in venous thrombosis: insights into molecular biology and therapeutic implications

Abstract

The findings of the last decade suggest a complex link between inflammatory cells, coagulation, and the activation of platelets and their synergistic interaction to promote venous thrombosis. Inflammation is present throughout the process of venous thrombosis, and various metabolic pathways of erythrocytes, endothelial cells, and immune cells involved in venous thrombosis, including glucose metabolism, lipid metabolism, homocysteine metabolism, and oxidative stress, are associated with inflammation. While the metabolic microenvironment has been identified as a marker of malignancy, recent studies have revealed that for cancer thrombosis, alterations in the metabolic microenvironment appear to also be a potential risk. In this review, we discuss how the synergy between metabolism and thrombosis drives thrombotic disease. We also explore the great potential of anti-inflammatory strategies targeting venous thrombosis and the complex link between anti-inflammation and metabolism. Furthermore, we suggest how we can use our existing knowledge to reduce the risk of venous thrombosis.

Keywords: Venous thrombosis, metabolism; inflammatory; oxidative stress.

Figure 1.

The process of venous thrombosis and the risk factors for DVT.

Figure 2.

The propagation of immunothrombosis by leukocytes and platelets. Under hypoxic conditions, ROS leads to an increase in HIF-1α, which in turn induces the expression of NLRP3 inflammatory vesicles in endothelial cells. This leads to the secretion of IL-1β and promotes platelet activation and thrombosis. ROS also leads to mast cell activation, histamine release and complement activation. These substances induce the release of vWF and P-selectin-containing WPB vesicles from endothelial cells, followed by the aggregation of natural immune cells and platelets on the endothelial surface. The combination of HMGB1 released from platelets, TLR2 from monocytes and CXCR2 from neutrophils induces the release of NETs, a process regulated mainly by the PAD4 enzyme. In addition, the release of tissue factor by monocytes activates the exogenous coagulation cascade. TLR2: Toll-like receptor 2; CXCR2: chemokine receptor 2; PSGL-1: P-selectin glycoprotein ligand 1; ROS: reactive oxygen species; HIF-1α: hypoxia inducible factor-1; IL: interleukin; vWF: von Willebrand Factor; WPB: Weibel-Palade body; HMGB: high-mobility group protein; NETs: neutrophil extracellular traps; PAD4: peptidylarginine deiminase 4.

Figure 3.

Erythrocytes and their cells metabolize sugars and secrete lactic acid and other acidic substances, resulting in an acidic microenvironment. After converting macrophages from the M1 type to the M2 type, M2-type macrophages secrete various inflammatory factors (IL-1, IL-8, and TNF-α) that promote the aggregation of immune cells and thrombus formation. Lipids and metabolites affect the fluidity of immune cells and platelet membranes, exacerbating their aggregation and activating their surface receptors (TLR and PPAR receptors). This leads to the recognition of immune cells by platelets and further promotes thrombus formation. IL: interleukin; TNF: tumor necrosis factor; TLR: Toll-like receptor; PPAR: peroxisome proliferator-activated receptor.