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Abstract Number: 1789

Defibrotide Inhibits Antiphospholipid Antibody-Mediated NET Release and Endothelial Cell Activation

Ramadan Ali1, Hui Shi 1, Srilakshmi Yalavarthi 1 and Jason Knight 2, 1University of Michigan, Ann Arbor, MI, 2Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Defibrotide and catastrophic antiphospholipid syndrome, endothelial cells, NETosis, neutrophils

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Session Information

Date: Monday, November 11, 2019

Title: 4M087: Antiphospholipid Syndrome (1788–1793)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Defibrotide is a mixture of phosphodiester oligonucleotides derived from porcine intestinal mucosa, currently approved for treatment of hepatic sinusoidal obstruction syndrome. Defibrotide has been considered a “multi-target compound,” and may have a particular role in limiting endothelial cell activation. Having said that, older literature also demonstrates anti-leukocyte and anti-neutrophil properties, with all of that work done prior to the first descriptions of neutrophil extracellular traps (NETs) in 2004. Our group and others have recently revealed a role for neutrophils and particularly NETs in the thrombotic complications of antiphospholipid syndrome (APS). Although defibrotide has been suggested as a possible treatment for APS, especially the microangiopathic variant known as catastrophic APS (CAPS), this possibility has not been investigated in the laboratory. Here, we hypothesized that defibrotide may act at the thromboinflammatory neutrophil-endothelium interface to neutralize APS-relevant NET release and endothelial cell activation.

Methods: Human neutrophils were prepared from healthy volunteers and stimulated with total IgG isolated and pooled from three CAPS patients (CAPS IgG). Stimulation was in the presence or absence of different concentrations of defibrotide, and NET release was quantified via the enzymatic activity of NET-associated myeloperoxidase. In parallel, primary human umbilical vein cells (HUVECs) were isolated from human umbilical cord, and stimulated with 10% plasma pooled from three CAPS patients (CAPS plasma) in the presence or absence of defibrotide. Gene expression of ICAM-1, VCAM-1, and E-selectin were measured by real-time PCR. At this early stage of the study, statistical corrections were not made for multiple comparisons. P-values are therefore nominal, speaking to the scientific meaningfulness of the results, rather than statistical significance.

Results: We first assessed the effect of defibrotide on CAPS IgG-mediated NET release. As compared with control IgG, CAPS IgG triggered a significant increase in NET release from control neutrophils (~3-fold; p< 0.05). At doses ranging from 1 to 10 µg/ml, defibrotide significantly suppressed CAPS IgG-mediated NET release (40-50% suppression; p< 0.05). Interestingly, defibrotide also inhibited NET release induced by the canonical protein kinase C activator, phorbol 12-myristate 13-acetate (PMA). Regarding HUVEC activation, CAPS plasma significantly increased gene expression of ICAM-1 (~3-fold), VCAM-1 (2-fold), and E-selectin (2.5-fold), as compared with control plasma (p< 0.05 for each). Importantly, treatment with defibrotide returned the expression of all three genes essentially to baseline/control levels.

Conclusion: We demonstrate for the first time that defibrotide attenuates NET release and endothelial cell activation in the context of IgG and plasma derived from CAPS patients. Studies are underway to fully characterize defibrotide’s mechanism of action and to assess its therapeutic potential in preclinical models of APS.


Disclosure: R. Ali, None; H. Shi, None; S. Yalavarthi, None; J. Knight, None.

To cite this abstract in AMA style:

Ali R, Shi H, Yalavarthi S, Knight J. Defibrotide Inhibits Antiphospholipid Antibody-Mediated NET Release and Endothelial Cell Activation [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/defibrotide-inhibits-antiphospholipid-antibody-mediated-net-release-and-endothelial-cell-activation/. Accessed .
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