Analytical Review: Neutrophil Extracellular Traps and Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder defined by the presence of one or more antiphospholipid antibodies (aPL) in conjunction with clinical manifestations such as thrombosis and/or obstetrical complications. One of the notable recent developments in APS research is the identification of a contributory role for neutrophil extracellular traps (NETs) in its pathogenesis, establishing a mechanistic link between thrombosis, inflammation, and complement activation. NETs, composed of decondensed chromatin and neutrophil-derived granule proteins, are released in response to various infectious and sterile triggers. In individuals with APS, elevated NET levels and the presence of anti-NET antibodies have been observed, aligning with thrombotic events and enhanced complement system activation. Studies support an emerging model that neutrophils are primed in APS to form NETs as a central mechanism in the development of thrombosis. This review explores multiple mechanisms linking NETs and thrombosis in APS including: contribution of aPL to enhanced leukocyte adhesion and the induction of NETosis via P-selectin glycoprotein ligand-1 (PSGL-1) and the transcription factor KLF2; cyclic AMP and the adenosine A_2A receptor on the neutrophil surface as negative regulators of NETosis and thrombus formation in APS; and NET-mediated resistance to activated protein C leading to hypercoagulability, amongst others. Intervening in NET-related pathways represents a promising therapeutic strategy to mitigate thrombotic risk in APS, underscoring the need for ongoing investigation into neutrophil-mediated mechanisms in this autoimmune disorder.