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Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease
  1. Konstantinos Kambas1,
  2. Akrivi Chrysanthopoulou1,
  3. Dimitrios Vassilopoulos2,
  4. Eirini Apostolidou1,
  5. Panagiotis Skendros3,
  6. Andreas Girod4,
  7. Stella Arelaki1,
  8. Marios Froudarakis5,
  9. Lydia Nakopoulou6,
  10. Alexandra Giatromanolaki7,
  11. Prodromos Sidiropoulos8,
  12. Maria Koffa9,
  13. Dimitrios T Boumpas10,11,
  14. Konstantinos Ritis1,3,
  15. Ioannis Mitroulis1,3,12
  1. 1Laboratory of Molecular Haematology, Democritus University of Thrace, Alexandroupolis, Greece
  2. 2Second Department of Medicine, Athens University School of Medicine, Hippokration General Hospital, Athens, Greece
  3. 3First Department of Internal Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
  4. 4Life Sciences Research Unit-FSTC, University of Luxembourg, Walferdange, Luxembourg
  5. 5Department of Pneumonology, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
  6. 6First Department of Pathology, Medical School, University of Athens, Athens, Greece
  7. 7Department of Pathology, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
  8. 8Department of Rheumatology, Clinical Immunology and Allergy, University Hospital, Medical School, University of Crete, Heraklion, Greece
  9. 9Laboratory of Cellular and Molecular Biology, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
  10. 10Third Department of Internal Medicine, National University of Athens Medical School, Sotiria Hospital, Athens, Greece
  11. 11Biomedical Research Foundation of Academy of Athens, Centre for Immunology and Transplantations, Athens, Greece
  12. 12Department of Internal Medicine III, Division of Vascular Inflammation, Diabetes and Kidney, University Clinic Carl-Gustav-Carus, University of Dresden, Dresden, Germany
  1. Correspondence to Professor K Ritis, First Department of Internal Medicine, University Hospital of Alexandroupolis, Dragana, Alexandroupolis, Greece; ritis2{at} Ioannis Mitroulis, Division of Vascular Inflammation, Diabetes and Kidney, Department of Medicine and Institute of Physiology, Technical University Dresden, Dresden, Germany;


Objectives Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is characterised by neutrophil activation. An elevated prevalence of venous thromboembolic events has been reported in AAV. Because of the critical role of neutrophils in inflammation associated thrombosis, we asked whether neutrophil tissue factor (TF) may be implicated in the thrombotic diathesis in AAV.

Methods Neutrophils from four patients and sera from 17 patients with ANCA associated vasculitis with active disease and remission were studied. TF expression was assessed by immunoblotting and confocal microscopy. Circulating DNA levels were evaluated. TF expressing microparticles (MPs) were measured by flow cytometry and thrombin–antithrombin complex levels by ELISA.

Results Peripheral blood neutrophils from four patients with active disease expressed elevated TF levels and released TF expressing neutrophil extracellular traps (NETs) and MPs. TF positive NETs were released by neutrophils isolated from the bronchoalveolar lavage and were detected in nasal and renal biopsy specimens. Elevated levels of circulating DNA and TF expressing neutrophil derived MPs were further observed in sera from patients with active disease. Induction of remission attenuated the aforementioned effects. Control neutrophils treated with sera from patients with active disease released TF bearing NETs and MPs which were abolished after IgG depletion. Treatment of control neutrophils with isolated IgG from sera from patients with active disease also resulted in the release of TF bearing NETs. TF implication in MP dependent thrombin generation was demonstrated by antibody neutralisation studies.

Conclusions Expression of TF in NETs and neutrophil derived MPs proposes a novel mechanism for the induction of thrombosis and inflammation in active AAV.

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