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Abstract Number: 2867

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

Srilakshmi Yalavarthi1, Levi F. Mazza1, Alexandra E. Morris1, Carlos Núñez-Álvarez2, Diego Hernández2, Paula L. Bockenstedt3, Antonio R. Cabral4 and Jason S. Knight1, 1Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, 2Immunology and Rheumatology, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico, 3Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, 4Immunology and Rheumatology, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Antiphospholipid antibodies, antiphospholipid syndrome, Neutrophil Extracellular Traps, neutrophils and thrombosis

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Session Information

Title: Antiphospholipid Syndrome

Session Type: Abstract Submissions (ACR)

Background/Purpose:  Antiphospholipid antibodies (aPL), especially those targeting beta-2-glycoprotein I, are known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications.  However, the interaction of aPL with the most abundant leukocyte in human blood, the neutrophil, has only rarely been considered.  Neutrophil extracellular trap (NET) release—a form of neutrophil cell death that results in the externalization of decondensed chromatin decorated with granular proteins—has recently been recognized as an important activator of the coagulation cascade, as well as an integral component of deep vein thrombi in both humans and animals.  Here, we hypothesized that aPL activate neutrophils to release NETs, thereby predisposing to thrombosis.

Methods:   Neutrophils, sera, and plasma were prepared from patients meeting criteria for primary antiphospholipid syndrome (APS) by the revised Sapporo classification criteria (n=50), or from healthy volunteers.  Circulating NETs were quantified in sera and plasma by a myeloperoxidase-DNA sandwich ELISA.  Neutrophils from APS patients were scored for their ability to release NETs by both immunofluorescence microscopy and fluorescence-based quantification of extracellular DNA.  Neutrophils from healthy volunteers were stimulated with APS patient sera, purified IgG, or aPL monoclonal antibodies, and NET release was quantified; dependence on generation of reactive oxygen species was also determined.  Expression of known aPL receptors, beta-2-glycoprotein and annexin A2, was measured on the neutrophil surface.

Results:   Sera and plasma from APS patients have elevated levels of NETs as compared to healthy volunteers (2.7-fold increase when comparing means; p=0.0279).  Neutrophils isolated from patients with primary APS are predisposed to spontaneous NET release when compared to healthy volunteers (p=0.0143).  Importantly, APS-patient sera and IgG purified from patients with aPL, stimulate NET release from healthy-volunteer neutrophils (p=0.004 and 0.0187, respectively).  Human aPL monoclonal antibodies, especially those that target beta-2 glycoprotein I, also enhance NET release; this enhancement can be abrogated by blockade of reactive oxygen species formation.  At baseline, both APS-patient neutrophils and healthy-volunteer neutrophils display beta-2 glycoprotein I on their surface.

Conclusion: APS patients have more circulating NETs than healthy volunteers, even between thrombotic episodes.  APS-patient neutrophils are predisposed to NET release, probably through exposure to aPL, since aPL can trigger NET release from healthy volunteer neutrophils in vitro.  Future experiments will explore the role of annexin-A2/Toll-like-receptor-4 pathways in aPL-mediated NET release, while also assessing the thrombotic implications of APS NETs.  Neutrophil netting warrants further investigation as a novel therapeutic target in APS patients.


Disclosure:

S. Yalavarthi,
None;

L. F. Mazza,
None;

A. E. Morris,
None;

C. Núñez-Álvarez,
None;

D. Hernández,
None;

P. L. Bockenstedt,
None;

A. R. Cabral,
None;

J. S. Knight,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antiphospholipid-antibodies-promote-the-release-of-neutrophil-extracellular-traps-a-new-mechanism-of-thrombosis-in-the-antiphospholipid-syndrome/

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