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Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that neutrophils from patients with APS used glycolysis more avidly than neutrophils from people in the healthy control group, especially when the neutrophils were from patients with APS with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate- and APS IgG-induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG-induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.

Abstract: Many patients with antiphospholipid syndrome had decreased ectonucleotidase activity on neutrophils and platelets, which enabled extracellular nucleotides to trigger neutrophil-platelet aggregates. This phenotype was replicated by treating healthy neutrophils and platelets with patient-derived antiphospholipid antibodies or ectonucleotidase inhibitors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Beta-2 glycoprotein I (β 2 GPI) is a phospholipid-binding plasma protein and prominent autoantigen in antiphospholipid syndrome (APS). Here, we tested the hypothesis that β 2 GPI might bind to not only phospholipids, but also cell-free DNA and neutrophil extracellular traps (NETs). We report that β 2 GPI interacts with cell-free DNA from different species, as well as NETs, in a dose-dependent manner, retarding their migration in an agarose-gel electrophoretic mobility shift assay. We confirm the direct binding interaction of β 2 GPI with DNA and NETs by ELISA. We also demonstrate that β 2 GPI colocalizes with NET strands by immunofluorescence microscopy. Finally, we provide evidence that β 2 GPI-DNA complexes can be detected in the plasma of APS patients, where they positively correlate with an established biomarker of NET remnants. Taken together, our findings indicate that β 2 GPI interacts with DNA and NETs, and suggest that this interaction may play a role as a perpetuator and/or instigator of autoimmunity in APS., Competing Interests: Declaration of Competing Interest None of the authors has any financial conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/purpose: Pediatric antiphospholipid syndrome (APS) is a thromboinflammatory disease characterized by the presence of circulating antiphospholipid antibodies and either thrombotic events or pregnancy morbidity. The objective of this study was to review a large institution's experience to better understand the characteristics of children with APS., Methods: We conducted a retrospective review of pediatric APS at a tertiary referral center. The electronic medical record system was queried from 2000 through 2019, and 21 cases were included based on meeting the revised Sapporo Classification criteria by age 18 or younger. Comparisons between primary and secondary APS patients were made with two-tailed t-tests., Results: Twenty-one patients were included with a median age at diagnosis of 16 years and median follow-up of 5.8 years. Secondary APS was slightly more common than primary APS (11 vs. 10 cases) and was primarily diagnosed in the context of systemic lupus erythematosus. Two thirds of patients (67%) also had "non-criteria" manifestations of APS including thrombocytopenia, autoimmune hemolytic anemia, and livedo reticularis/racemosa. Almost half of patients (43%) had recurrent thrombosis, typically when patients were subtherapeutic or non-adherent with anticoagulation. Damage Index in Patients with Thrombotic APS (DIAPS) scores indicated a chronic burden of disease in both primary and secondary APS patients., Conclusion: This case series of pediatric APS provides important context regarding disease phenotypes displayed by children with APS. High prevalence of non-criteria clinical manifestations highlights the need to consider these characteristics when developing pediatric-specific classification criteria and when considering this relatively rare diagnosis in pediatric practice., (© 2022. The Author(s).)

Introduction: Antiphospholipid Syndrome (APS) is a systemic autoimmune disease with a complex multifactorial pathogenesis, combining genetic background, traditional cardiovascular risk factors, disease-specific features such as the presence of antiphospholipid antibodies (aPL), and an imbalance of various immune system functions. Recent data support the role of interferons (IFNs), especially type IIFN (IFN-I), in the onset and development of APS clinical manifestations, including thrombotic events and obstetric complications., Areas Covered: In this review, the authors aimed to discuss the growing body of evidence on the relevance of IFN-I pathways in APS, both from a basic mechanistic perspective, focusing on its possible use in disease/patients stratification. The IFN-I signature has shown promising, although preliminary, results in segregating aPL-positive subjects by aPL profile, association with other autoimmune conditions, such as lupus, age at onset, and current treatment, among others., Expert Opinion: To date, the scarce available data as well as methodological and technical heterogeneity among studies limit the comparability of the results, thus requiring further validation to translate these findings to routine clinical practice. Therefore, further research is required in pursuit of more nuanced patient profiling and the development of new immunomodulatory therapeutic strategies for APS beyond anti-coagulant and antiplatelet agents.

Purpose of Review: Antiphospholipid syndrome (APS) is a thrombo-inflammatory disease that is primarily treated with anticoagulation. Better understanding the inflammatory aspects of APS could lead to safer, more effective, and more personalized therapeutic options. To this end, we sought to understand recent literature related to the role of neutrophils and, in particular, neutrophil extracellular traps (NETs) in APS., Recent Findings: Expression of genes associated with type I interferons, endothelial adhesion, and pregnancy regulation are increased in APS neutrophils. APS neutrophils have a reduced threshold for NET release, which likely potentiates thrombotic events and perhaps especially large-vein thrombosis. Neutrophil-derived reactive oxygen species also appear to play a role in APS pathogenesis. There are new approaches for preventing and disrupting NETs that could potentially be leveraged to reduce the risk of APS-associated thrombosis. Neutrophils and NETs contribute to APS pathophysiology. More precisely understanding their roles at a mechanistic level should help identify new therapeutic targets for inhibiting NET formation, enhancing NET dissolution, and altering neutrophil adhesion. Such approaches may ultimately lead to better clinical management of APS patients and thereby reduce the chronic burden of this disease.

Objective: This study assessed patient‐reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life. Methods: Patients completed Patient‐Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1‐10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression. Results: Of 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43‐0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF. Conclusion: Individuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs. [ABSTRACT FROM AUTHOR]