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      Antiphospholipid Antibodies Promote the Release of Neutrophil Extracellular Traps: A New Mechanism of Thrombosis in the Antiphospholipid Syndrome

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          Abstract

          Objective

          Antiphospholipid antibodies (aPL), especially those targeting beta-2-glycoprotein I (β 2GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. Here, we hypothesized that aPL might activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent to the antiphospholipid syndrome (APS).

          Methods

          Neutrophils, sera, and plasma were prepared and characterized from patients with primary APS (n=52), or from healthy volunteers. No patient carried a concomitant diagnosis of systemic lupus erythematosus.

          Results

          Sera and plasma from patients with primary APS have elevated levels of both cell-free DNA and NETs, as compared to healthy volunteers. Freshly-isolated APS neutrophils are predisposed to high levels of spontaneous NET release. Further, APS-patient sera, as well as IgG purified from APS patients, stimulate NET release from control neutrophils. Human aPL monoclonals, especially those targeting β 2GPI, also enhance NET release. The induction of APS NETs can be abrogated with inhibitors of reactive oxygen species formation and toll-like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promote thrombin generation.

          Conclusion

          Neutrophil NET release warrants further investigation as a novel therapeutic target in APS.

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          Author and article information

          Journal
          101623795
          42112
          Arthritis Rheumatol
          Arthritis & rheumatology (Hoboken, N.J.)
          2326-5191
          2326-5205
          24 June 2015
          November 2015
          01 November 2016
          : 67
          : 11
          : 2990-3003
          Affiliations
          [1 ]Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
          [2 ]Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
          [3 ]Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Department of Immunology and Rheumatology, Mexico City, Mexico
          [4 ]Department of Internal Medicine, Division of Hematology, University of Michigan, Ann Arbor, Michigan, USA
          Author notes
          Correspondence: Jason S. Knight, M.D., Ph.D., 5520A MSRB1, 1150 W Medical Center Drive, SPC 5680, Ann Arbor, MI 48109-5680, Tel: 734-763-3031, jsknight@ 123456umich.edu
          Article
          PMC4626310 PMC4626310 4626310 nihpa702240
          10.1002/art.39247
          4626310
          26097119
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