Srilakshmi Yalavarthi 1 , Travis J. Gould 2 , Ashish N. Rao 1 , Levi F. Mazza 1 , Alexandra E. Morris 1 , Carlos Núñez-Álvarez 3 , Diego Hernández-Ramírez 3 , Paula L. Bockenstedt 4 , Patricia C. Liaw 2 , Antonio R. Cabral 3 , Jason S. Knight 1
01 November 2016
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).
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.
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.