Background/Purpose: Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by a hypercoagulable state, leading to arterial, venous, or microvascular thrombosis and accelerated atherosclerosis. Timely diagnosis and accurate monitoring are crucial for optimizing therapeutic interventions.

Methods: A cohort of primary APS patients (n=150) and 43 healthy donors (HD) underwent serum nuclear magnetic resonance (NMR) metabolomics ( >250 metabolites, Nightingale) analysis, covering glycolysis metabolites, amino acids, and 130 lipid measures. Serum levels of 92 cardiovascular-related proteins were evaluated using proximity extension immunoassay (PEA, Olink). Extensive clinical and analytical profiling was conducted. Unsupervised hierarchical clustering analyses explored molecular profile contributions to atherothrombotic risk. Additionally, 33 APS patients receiving adjuvant treatment with Ubiquinol (Qred, reduced CoQ10) at 200 mg/day for one month were studied.

Results: APS patients exhibited significant alterations in 53 metabolites compared to healthy donors. These included decreased levels of atheroprotective HDL subsets, sphingomyelins, and phospholipids, as well as increased levels of proatherogenic VLDL subsets and fatty acids. Unbiased hierarchical clustering analysis identified two patient groups with distinct metabolomic profiles. Cluster 2 (C2) patients had a higher prevalence of arterial thrombosis, elevated thrombotic risk score (aGAPSS over 9), and more CV risk factors such as atheroma plaques, dyslipidemia, and hypertension. Molecular analysis revealed 143 deregulated metabolites between clusters, including decreased HDL and increased VLDL and LDL lipoproteins, triglycerides, fatty acids, apolipoproteins (ApoB), glycolysis-related metabolites, and other lipids involved in immune cell activity. Proteomic analysis identified proteins associated with increased cardiovascular risk in these metabolomic clusters. Remarkably, significant correlations were found between deregulated protein and metabolite levels, suggesting their involvement in underlying disease mechanisms. In the in vivo study, Qred supplementation partially reversed the altered serum metabolic and proteomic profiles associated with APS-related thrombosis.

Conclusion:

1. APS patients exhibit distinct metabolomic and proteomic profiles associated with the disease’s pathogenesis, partially modifiable by in vivo Qred supplementation.
2. We have identified for the first time a combined metabolomic/proteomic fingerprint able to stratify APS disease according to their thrombotic risk. Ongoing studies will provide further insights into the underlying mechanisms and physiological implications of these alterations, potentially leading to the discovery of diagnostic biomarkers and therapeutic strategies for APS.

Supported by ISCIII: (PI21/0591), and RICORS (RD21/0002/0033) co-financed by FEDER.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/integrated-metabolomic-and-proteomic-analyses-stratified-patients-with-antiphospholipid-syndrome-according-to-their-atherothrombotic-risk/