Neutrophil Extracellular Traps in Thrombotic Disorders

Neutrophil extracellular traps (NETs) represent web-like fibres of chromatin and antimicrobial proteins extruded by activated neutrophils. Initially characterised as an innate defence against pathogens, NETs have emerged as pivotal drivers of thrombosis by providing a scaffold for platelet adhesion, fibrin deposition and coagulation factor assembly. In diverse settings—from deep vein thrombosis and arterial atherothrombosis to immune-mediated thrombotic syndromes—NETs have been implicated in clot initiation, propagation and resistance to fibrinolysis. The enzymatic activity of peptidylarginine deiminase 4 (PAD4) mediates histone citrullination, a critical step in chromatin decondensation and NET release. High mobility group box 1 (HMGB1) and platelet-derived microparticles further amplify NET formation and stabilise thrombi. In conditions such as heparin-induced thrombocytopenia, immunothrombosis links autoantibody-driven platelet activation to NETosis and occlusive clotting. Beyond venous and arterial occlusion, NET-rich clots resist endogenous and therapeutic proteolysis, heightening the risk of recurrent events. Interventions targeting PAD4, DNA scaffolds or NET-associated proteins—alongside conventional anticoagulation—offer promising avenues to restore vascular patency without compromising host defence. The global burden of thrombotic disease underscores the need for tailored strategies that mitigate NET-driven coagulation across clinical contexts.

Research from Nature Portfolio

Recent investigations have redefined the role of NETs in immune-mediated thrombosis. Studies in heparin-induced thrombocytopenia reveal that antibody–platelet factor 4 complexes engage neutrophil FcγRIIa receptors, triggering PAD4-dependent NETosis and driving occlusive thrombus formation independently of thrombocytopaenia. Genetic ablation or pharmacological inhibition of PAD4 abrogates NET release and prevents thrombus growth, indicating distinct pathways for platelet reduction and clot formation. In venous thrombosis models, platelet-derived high mobility group box 1 has been shown to recruit neutrophils and provoke robust NET release; deletion of platelet HMGB1 markedly reduces clot burden, implicating this alarmin in thrombus initiation. Complementary work demonstrates that NET–microparticle complexes serve as functional platforms for intrinsic coagulation via factor XII activation, with DNase treatment or factor XII deficiency normalising thrombin generation in sepsis-associated coagulopathy.

Neutrophil Extracellular Traps in Thrombotic Disorders publication trend

The graph below shows the total number of articles in neutrophil extracellular traps in thrombotic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil extracellular traps (NETs): Networks of decondensed chromatin decorated with granular proteins released by neutrophils during activation.

NETosis: A specialised form of neutrophil cell death leading to NET release, distinct from apoptosis and necrosis.

Peptidylarginine deiminase 4 (PAD4): An enzyme that citrullinates histones, promoting chromatin decondensation essential for NET formation.

High mobility group box 1 (HMGB1): A nuclear alarmin released by activated platelets and stressed cells that amplifies inflammatory signalling and NETosis.

Immunothrombosis: A physiological process in which innate immune mechanisms, including NETs, contribute to intravascular clot formation.

References

1. Interaction between neutrophil extracellular traps and cardiomyocytes contributes to atrial fibrillation progression. Signal Transduction and Targeted Therapy (2023).
2. Neutrophil Targeting Platform Reduces Neutrophil Extracellular Traps for Improved Traumatic Brain Injury and Stroke Theranostics. Advanced Science (2024).
3. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nature Communications (2019).
4. Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones*. Journal of Biological Chemistry (2013).
5. The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Frontiers in Immunology (2016).
6. Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA. Scientific Reports (2018).
7. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Scientific Reports (2018).