The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis

Abstract

Venous thrombosis (VT), a leading cause of morbidity and mortality worldwide, has recently been linked to neutrophil activation and release of neutrophil extracellular traps (NETs) via a process called NETosis. The use of various in vivo thrombosis models and genetically modified mice has more precisely defined the exact role of NETosis in the pathogenesis of VT. Translational large animal VT models and human studies have confirmed the presence of NETs in pathologic VT. Activation of neutrophils, with subsequent NETosis, has also been linked to acute infection. This innate immune response, while effective for bacterial clearance from the host by formation of an intravascular bactericidal “net,” also triggers thrombosis. Intravascular thrombosis related to such innate immune mechanisms has been coined immunothrombosis. Dysregulated immunothrombosis has been proposed as a mechanism of pathologic micro- and macrovascular thrombosis in sepsis and autoimmune disease. In this focused review, we will address the dual role of NETs in the pathogenesis of VT and immunothrombosis.

Type Three Secretion System-Dependent Microvascular Thrombosis and Ischemic Enteritis in Human Gut Xenografts Infected with Enteropathogenic Escherichia coli

“…This innate immune response is an effective bacterial clearance mechanism that involves the formation of an intravascular bactericidal net. NETosis has also been proposed to be a mechanism contributing to pathological microvascular thrombosis under septic disease conditions (19). However, although aggregates of mouse neutrophils and EPEC organisms were rampant in the gut microvasculature undergoing thrombosis, we were unable to demonstrate NETosis in this study.…”

Unfractionated and Low-Molecular-Weight Heparin and the Phosphodiesterase Inhibitors, IBMX and Cilostazol, Block Ex Vivo Equid Herpesvirus Type-1-Induced Platelet Activation

“…Activated platelets also help recruit and bind leukocytes to the developing thrombus by forming adhesive bonds between platelet surface-expressed P-selectin and leukocyte-expressed P-selectin glycoprotein ligand-1 (13). Once bound, leukocytes promote thrombus formation by expressing tissue factor (monocytes) or undergoing NETosis (neutrophil extracellular traps) (10, 14). Thus, inhibiting platelet activation and particularly P-selectin expression could substantially reduce thrombus formation and may provide therapeutic or prophylactic options for horses at-risk of abortion and EHM due to EHV-1 infection.…”

Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target

“…Our Western blotting data demonstrating increased NET content in APS-WT thrombi as compared with APS-PSGL-1 -/-thrombi support this hypothesis. Future studies should interrogate whether these concepts might also extend to other conditions prone to inflammatory thrombosis, such as cancer and sepsis (60,61).…”