Autophagy, NET formation, and inflammation crosstalk in thrombotic autoimmune diseases

Neutrophil extracellular traps (NETs), released by activated neutrophils, are essential components of innate immunity, capturing and neutralizing pathogens. Dysregulated NET formation can both initiate and perpetuate inflammation, autoimmunity, and thrombosis.

When NETs are excessively produced or insufficiently cleared, they expose autoantigens, fuel cytokine and interferon responses, and induce endothelial damage. In addition, NETs promote platelet adhesion, activate coagulation, and impair fibrinolysis, thereby establishing them as central drivers of immune-mediated thrombotic pathology.This review focuses on three representative thrombotic autoimmune diseases, namely immune thrombocytopenia (ITP), heparin-induced thrombocytopenia (HIT), and immune-mediated thrombotic thrombocytopenic purpura (iTTP), in which pathogenic autoantibodies and persistent NETs contribute to both thrombocytopenia and thrombosis.

In ITP, endothelial activation and excessive NET release are associated with increased thrombotic risk. In HIT, platelet factor 4 (PF4)-NET complexes enhance thrombus formation while showing resistance to DNase-mediated degradation.

Lastly, in iTTP, elevated levels of NET components correlate with platelet consumption and disease severity. Autophagy emerges as a central regulatory mechanism that shapes NET formation and immune activation.