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Abstract Number: 0113

Plasma Proteomics Analysis Identifies Thromboinflammatory Signature Associated with Clinical Antiphospholipid Syndrome: Results from Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Registry

Alexander Pine1, Vittorio Pengo2, Savino Sciascia3, Nina Kello4, Rosario Lopez Pedrera5, H Michael Belmont6, David Branch7, Laura Andreoli8, Michelle Petri9, Ricard Cervera10, Jason Knight11, Pierluigi Meroni12, Hannah Cohen13, Rohan Willis14, Maria Laura Bertolaccini15, Alfred Lee16, Doruk Erkan17 and Anish Sharda16, 1Yale School of Medicine/VA Connecticut, West Haven, CT, 2Thrombosis Research Laboratory, Department of Cardio-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy, 3University of Turin, Torino, Turin, Italy, 4Northwell Health, Brooklyn, NY, 5IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, 6NYU School of Medicine, New York, NY, 7University of Utah and Intermountain Healthcare, Salt Lake City, UT, 8University of Brescia, Brescia, Italy, 9Johns Hopkins University School of Medicine, Timonium, MD, 10Hospital Clinic de Barcelona, Barcelona, Spain, 11University of Michigan, Ann Arbor, MI, 12IRCCS Istituto Auxologico Italiano 100%, Cusano Milanino, Milan, Milan, Italy, 13University College London Hospitals NHS Foundation Trust, London, United Kingdom, 14University of Texas Medical Branch, Galveston, TX, 15King's College London, London, United Kingdom, 16Yale School of Medicine, New Haven, CT, 17Hospital for Special Surgery, New York, NY

Meeting: ACR Convergence 2024

Keywords: antiphospholipid syndrome, Bioinformatics, proteomics

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Session Information

Date: Saturday, November 16, 2024

Title: Antiphospholipid Syndrome Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Antiphospholipid syndrome (APS) is an autoimmune disease with thromboembolic and obstetric morbidity arising via a model of immunothrombosis. Patients may present with thrombotic (tAPS), obstetric (oAPS), or catastrophic/microvascular (C/MAPS) disease, while many have circulating antiphospholipid antibodies (aPL) without clinical APS. To understand peripheral biologic mechanisms underlying different APS phenotypes, we profiled plasma proteome of persistently aPL-positive patients without other systemic autoimmune diseases, and present expanded analyses together with a validation cohort.

Methods: Plasma samples were obtained from APS ACTION Registry. Discovery cohort (DC): 10 each of tAPS, oAPS, C/MAPS, and aPL-only; 10 healthy controls; 6,398 unique proteins assayed using SomaScan. Differential proteins were determined by ANOVA and t-tests in log-normalized data (p-values< 0.05, false discovery rate q< 0.1) and functional enrichment analysis performed. Validation cohort: 10 tAPS, 10 oAPS, 4 C/MAPS, and 10 aPL-only; 1500 proteins derived from the DC assayed by SomaScan. Proteins likely to discriminate aPL, TAPS, and C/MAPS groups were derived from DC with stepwise feature selection using Wilks lambda criterion. The clustering accuracy of the identified protein set was then tested using linear discriminant analysis (LDA).

Results: The median age was 48 years, 30% were men, and 70% were triple aPL-positive. A set of proteins clustered individuals with four APS clinical phenotypes and controls (Figure 1; p< 0.0007; q< 0.05). Differential proteins belonged to highly enriched pathways including coagulation, complement, innate and adaptive immunity. Strikingly, the aPL-only cohort shared this thromboinflammatory signature with other groups, while oAPS appeared distinct from tAPS and C/MAPS. Pathway analysis of protein sets identified from pairwise comparisons (aPL vs tAPS, aPL vs C/MAPS, tAPS vs C/MAPS) revealed progressive enrichment and increasing statistical significance of extracellular matrix (ECM) signaling, coagulation, neutrophil degranulation, innate and adaptive immune responses, and cellular and cytoskeletal activation pathways, suggesting a model of increasing thromboinflammation, including tissue inflammation, in evolution from aPL to C/MAPS (Figure 2). Unbiased clustering of the discovery cohort by plasma proteomics revealed distinct clustering by APS subtype (Figure 3). TNFRSF21, tissue factor, BAG4, factor 13, lysozyme, pigment epithelium-derived factor, and TNFRSF4 were top hits among 21 proteins featured in this analysis. Importantly, these proteins successfully clustered the validation cohort by APS subtype.

Conclusion: A mere presence of aPL confers a distinct thromboinflammatory signature characterized by coagulation, complement, innate and adaptive immune response pathways shared by all APS subtypes with an increasing frequency of abnormalities in C/MAPS. Progressive thromboinflammation together with involvement of the ECM, intracellular immune cell signaling, cytoskeletal organization and vesicular trafficking underlies evolution of APS from aPL to C/MAPS.

Supporting image 1

Figure 1. Heat map of top differentially expressed proteins in different APS subtypes.

Supporting image 2

Figure2. Functional enrichment analysis of differential proteins obtained from aPL vs tAPS, aPL vs C/MAPS and tAPS vs C/MAPS pairwise analyses show shared but increasing enrichment of altered pathways from aPL to C/MAPS.

Supporting image 3

Figure 3. Clustering of APS subtypes by plasma proteomics. Top, Discovery cohort; bottom, validation cohort; right-hand panel, featured proteins.


Disclosures: A. Pine: None; V. Pengo: None; S. Sciascia: Chugai Pharmaceutical Co., Ltd., 2; N. Kello: None; R. Lopez Pedrera: None; H. Belmont: Alexion, 1, Aurinia, 6; D. Branch: UCB Pharma Inc, 5; L. Andreoli: Pfizer, 2, UCB, 2; M. Petri: Amgen, 2, AnaptysBio, 2, Annexon Bio, 2, Arthros-FocusMedEd, 6, AstraZeneca, 2, 5, Atara Biosciences, 2, Aurinia, 5, 6, Autolus, 2, Avoro Ventures, 2, Biocryst, 2, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CTI, 1, CVS Health, 1, Eli Lilly, 2, 5, Emergent Biosolutions, 1, Ermiium, 2, Escient Pharmaceuticals, 2, Exagen, 5, Exo Therapeutics, 2, Gentibio, 2, GlaxoSmithKlein(GSK), 2, 5, iCell Gene Therapeutics, 2, Innovaderm Research, 2, IQVIA, 1, Janssen, 5, Kira Pharmaceuticals, 2, Merck/EMD Serono, 1, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Novartis, 2, PPD Development, 2, Precision Biosciences, 2, Proviant, 2, Regeneron Pharmaceuticals, 2, Sanofi, 2, Seismic Therapeutic, 2, Senti Bioscienes, 2, Sinomab Biosciences, 2, Takeda, 2, Tenet Medicines Inc, 2, TG Therapeutics, 2, UCB, 2, Vertex Pharmaceuticals, 2, Worldwide Clinical Trials, 1, Zydus, 2; R. Cervera: None; J. Knight: ArgenX, 1, Visterra/Otsuka, 1, 2; P. Meroni: None; H. Cohen: argenx, 1, GlaxoSmithKlein(GSK), 6, Roche, 1, Technoclone (paid to Univ Coll London Hosp Charity), 6, UCB (paid to Univ College London Hosp Charity), 2; R. Willis: Louisville APL Diagnostics Inc, 2, 8; M. Bertolaccini: None; A. Lee: None; D. Erkan: ACR, 5, APS ACTION, 4, Argenx, 1, Cadrenal, 2, Chugai, 1, EULAR, 5, Exagen, 5, GlaxoSmithKlein(GSK), 2, 5, 6, Kyverna, 1, NIH, 5, Otsuka/Visterra, 1, Up-To-Date, 9; A. Sharda: None.

To cite this abstract in AMA style:

Pine A, Pengo V, Sciascia S, Kello N, Lopez Pedrera R, Belmont H, Branch D, Andreoli L, Petri M, Cervera R, Knight J, Meroni P, Cohen H, Willis R, Bertolaccini M, Lee A, Erkan D, Sharda A. Plasma Proteomics Analysis Identifies Thromboinflammatory Signature Associated with Clinical Antiphospholipid Syndrome: Results from Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Registry [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/plasma-proteomics-analysis-identifies-thromboinflammatory-signature-associated-with-clinical-antiphospholipid-syndrome-results-from-antiphospholipid-syndrome-alliance-for-clinical-trials-and-internat/. Accessed .
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