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Antiphospholipid Syndrome

Disease Pathophysiology Research Report

2025-12-03
Falcon MONDO:8000010 Model: Edison Scientific Literature 28 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Antiphospholipid Syndrome (APS) - MONDO ID: not definitively assigned here - Category: Complex, autoimmune thrombo-inflammatory disease

Pathophysiology description - Core paradigm. APS is driven by antiphospholipid antibodies (aPL) that recognize phospholipid-binding proteins—most notably β2-glycoprotein I (β2GPI)—on vascular and placental cells, shifting hemostasis toward a prothrombotic and proinflammatory state. Anti-β2GPI (especially domain I-directed) and anti-cardiolipin antibodies, with lupus anticoagulant positivity, are necessary but insufficient; a “second hit” (e.g., infection, pregnancy, surgery) frequently precipitates clinically overt thrombosis or obstetric morbidity (two-hit model) (10.1111/bjh.19635, Jul 2024; 10.7759/cureus.66555, Aug 2024) (arachchillage2024guidelinesonthe pages 2-2, parepalli2024antiphospholipidsyndromeand pages 2-3). - aPL–β2GPI interactions and coagulation. Anti-β2GPI binds β2GPI on endothelial cells, monocytes, and platelets, inducing tissue factor (TF) expression and impairing anticoagulant/fibrinolytic balances (protein C/TFPI suppression; increased PAI-1), thereby enhancing thrombin generation and clot persistence (10.3390/jcm13144191, Jul 2024; 10.3389/fimmu.2025.1639065, Aug 2025; 10.3390/cells14050353, Feb 2025) (celia2024antiphospholipidsyndromeinsights pages 3-5, zhu2025noveladvanceson pages 3-4, bucci2025statinsasan pages 2-4). - Platelet and endothelial activation. aPL–β2GPI complexes activate platelets via ApoER2, GPIbα and αIIbβ3, triggering p38/PI3K–AKT signaling, ROS/TXA2 generation, and aggregation; endothelial cells upregulate NF-κB–dependent adhesion molecules (E-selectin/VCAM-1/ICAM-1), cytokines (IL-6/IL-8), and TF, reflecting a prothrombo-inflammatory transcriptomic program (10.3390/cells14050353; 10.1093/rheumatology/kead575, Feb 2024; 10.3390/jcm13144191) (bucci2025statinsasan pages 2-4, lopezpedrera2024newadvancesin pages 1-2, celia2024antiphospholipidsyndromeinsights pages 3-5). - Complement and NETs. Complement activation integrates with coagulation and cell activation. In APS kidney tissue, RNA-seq shows strong upregulation of C3/C4A/C4B and enrichment for type I IFN signaling; NET-related genes are also upregulated, implicating immunothrombosis at the organ level (10.1093/rheumatology/keae397, Aug 2024) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). Guidelines emphasize complement and NETs as important pathomechanisms, with CAPS representing an extreme thromboinflammatory state often precipitated by triggers (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2). - Interferon/TLR axis. Multiple independent transcriptomic datasets show type I interferon-regulated genes (e.g., IFI6, IFI44, MX1, OAS1, RSAD2) are upregulated across APS, with links to thrombosis and preeclampsia; “a distinct signature comprising 11 IFN-induced genes” was reported in PBMCs (10.1093/rheumatology/kead575) (lopezpedrera2024newadvancesin pages 4-5). Anti-β2GPI signaling engages TLR4 (and TLR7/8) to activate p38/MEK/ERK and NF-κB, upregulating TF and adhesion molecules (10.3389/fimmu.2025.1639065) (zhu2025noveladvanceson pages 3-4). - Obstetric APS (OAPS) mechanisms. Beyond thrombosis, aPL directly perturb placental biology: trophoblast dysfunction, loss of annexin V shield, altered angiogenic signaling, and immune dysregulation contribute to placental insufficiency, fetal growth restriction, preeclampsia, and pregnancy loss; aPS/PT associates with obstetric complications (10.3390/ijms24043195, Feb 2023) (d’ippolito2023antiphospholipidsyndromein pages 4-5). Placental and endothelial inflammation signatures converge (IL-6/IL-8/selectins/ICAM/VCAM/TGF-β2) (10.1093/rheumatology/kead575) (lopezpedrera2024newadvancesin pages 1-2). - Systems immunothrombosis. Unbiased proteomics in aPL-positive individuals reveals a graded thromboinflammatory signature across clinical phenotypes—activation of coagulation, complement, neutrophil pathways, and ECM organization—increasing from aPL carriers to thrombotic and microvascular APS (10.3389/fimmu.2025.1676578, Oct 2025) (pine2025aproteomicmap pages 1-2).

Recent developments and latest research (priority 2023–2024) - Kidney transcriptomics (2024): Upregulated C3/C4A/C4B (logFC ~2.1–2.3) and IFN-α/β signaling; NETs-related genes increased in APS kidney biopsies, mirroring prior whole-blood signatures (10.1093/rheumatology/keae397, Aug 2024) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - IFN signatures (2024): “Upregulation of IFN-related genes in patients with APS” consistent across whole blood, PBMCs and neutrophils; an 11-gene IFN panel distinguished APS from controls (10.1093/rheumatology/kead575, Feb 2024) (lopezpedrera2024newadvancesin pages 4-5). - Endothelial gene programs (2024): aPL/β2GPI induce endothelial NF-κB/MAPK/TGF-β activation with IL-6/IL-8 and adhesion molecule upregulation; similar activation detected in APS placental tissue (10.1093/rheumatology/kead575) (lopezpedrera2024newadvancesin pages 1-2). - Guidelines synthesis (2024): APS hypercoagulability arises from cell activation (endothelium/monocyte/platelet/neutrophil), complement and NETs, with two-hit triggers; management emphasizes vitamin K antagonists (VKA) for thrombotic APS and individualized therapy (10.1111/bjh.19635, Jul 2024) (arachchillage2024guidelinesonthe pages 2-2).

Current applications and real-world implementations - Antithrombotic therapy. For thrombotic APS, long-term anticoagulation with VKA is standard; aspirin may be added in selected arterial/refractory cases; LMWH/heparin is used peri-procedurally and in pregnancy (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2). - Obstetric APS care. Low-dose aspirin plus LMWH is standard of care; mechanistic understanding of placental inflammation and angiogenic imbalance informs adjunctive strategies (10.3390/ijms24043195) (d’ippolito2023antiphospholipidsyndromein pages 4-5). - Targeted adjuncts. Hydroxychloroquine (HCQ) and statins are considered adjuncts in selected patients (statins: antithrombotic pleiotropy impacting platelet signaling and endothelial inflammation) (10.1111/bjh.19635; 10.3390/cells14050353, Feb 2025) (arachchillage2024guidelinesonthe pages 2-2, bucci2025statinsasan pages 2-4). Complement inhibition (e.g., eculizumab) is employed in refractory situations such as CAPS per expert guidance (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2).

Expert opinions and analysis (authoritative sources) - British Journal of Haematology guidelines (2024) synthesize that aPL positivity is “necessary but insufficient,” emphasizing complement, NETs, and a two-hit pathogenesis; VKA remains mainstay for thrombotic APS (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2). - Systems-level omics reinforce immunothrombosis: proteomics and RNA-seq document complement, IFN, and neutrophil/NET pathways in APS tissues and blood (10.1093/rheumatology/keae397; 10.3389/fimmu.2025.1676578) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, pine2025aproteomicmap pages 1-2).

Relevant statistics and data from recent studies - APS kidney RNA-seq: C3 (logFC 2.25, P=1.58×10−5), C4A (2.17, P=2.69×10−6), C4B (2.135, P=3.7×10−6) upregulated; nine IFN-regulated genes up in APS vs. controls; 13/15 NETs-related genes higher in APS (10.1093/rheumatology/keae397, Aug 2024) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - IFN signature panels: an 11 IFN-induced gene set (e.g., IFI6/IFI44/RSAD2/MX1) distinguished APS from controls; IFN signatures associated with thrombosis and preeclampsia (10.1093/rheumatology/kead575, Feb 2024) (lopezpedrera2024newadvancesin pages 4-5).

Key concepts and definitions (current understanding) - aPL: Autoantibodies (lupus anticoagulant, anti-cardiolipin IgG/IgM, anti-β2GPI IgG/IgM) that target phospholipid-binding proteins, especially β2GPI; domain I specificity is highly disease-associated (10.3389/fimmu.2025.1639065) (zhu2025noveladvanceson pages 3-4). - Two-hit hypothesis: aPL provide a prothrombotic priming state; inflammation or vascular stress acts as a second hit precipitating overt thrombosis/CAPS (10.1111/bjh.19635; 10.7759/cureus.66555) (arachchillage2024guidelinesonthe pages 2-2, parepalli2024antiphospholipidsyndromeand pages 2-3). - Immunothrombosis: Integration of coagulation, complement, platelets, neutrophils/NETs, and interferon pathways driving thrombosis and microvascular injury (10.1093/rheumatology/keae397; 10.3389/fimmu.2025.1676578) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, pine2025aproteomicmap pages 1-2).

Evidence table | Mechanistic theme | Key finding | Biological level | Notable players | Source (journal, year) | URL/DOI | |---|---|---|---|---:|---:| | aPL–β2GPI (domain I) & TF upregulation | "Anti-β2GPI (domain I) binds exposed epitope and induces tissue factor (TF) upregulation in monocytes and endothelial cells" | Molecular / cellular | β2GPI (Domain I), anti‑β2GPI (DI), TF (F3), monocytes, endothelial cells | Frontiers in Immunology (2025); Journal of Clinical Medicine (2024) (zhu2025noveladvanceson pages 3-4, celia2024antiphospholipidsyndromeinsights pages 3-5) | 10.3389/fimmu.2025.1639065; 10.3390/jcm13144191 | | Platelet activation pathways | aβ2GPI/β2GPI complexes engage ApoER2, GPIbα and αIIbβ3 → p38/PI3K‑AKT activation, ROS and TXA2 production → platelet aggregation | Cellular | Platelets, ApoER2, GPIbα, αIIbβ3, p38 MAPK, NADPH oxidase | Cells (2025); Frontiers in Immunology (2025) (bucci2025statinsasan pages 2-4, zhu2025noveladvanceson pages 3-4) | 10.3390/cells14050353; 10.3389/fimmu.2025.1639065 | | Endothelial activation gene programs | Endothelial transcriptomes show NF‑κB–driven upregulation of IL‑6, IL‑8, E‑selectin, VCAM‑1, ICAM‑1 and MAPK/TGFβ pathway activation after aPL/β2GPI exposure | Cellular / organ | Endothelial cells, NF‑κB, IL6, IL8, VCAM1, ICAM1, MAPK | Rheumatology (2024); Journal of Clinical Medicine (2024) (lopezpedrera2024newadvancesin pages 1-2, celia2024antiphospholipidsyndromeinsights pages 3-5) | 10.1093/rheumatology/kead575; 10.3390/jcm13144191 | | Complement activation (biomarkers & pathways) | Upregulation/consumption of complement (C3, C4A, C4B) in APS target tissue; complement split products (C3a/C4a) consistent with activation/consumption | Molecular / organ | C3, C4A, C4B, C5a, terminal complement (C5b‑9) | Rheumatology (kidney RNA‑seq, 2024); British Journal of Haematology guidelines (2024) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, arachchillage2024guidelinesonthe pages 2-2) | 10.1093/rheumatology/keae397; 10.1111/bjh.19635 | | NETs signatures / quantitation | NETs‑related genes (MPO, ELANE, PADI4) and NETosis signatures are increased in APS blood and kidney samples | Molecular / cellular | Neutrophils, MPO, ELANE, PADI4, extracellular histones | Rheumatology (kidney RNA‑seq, 2024); Frontiers in Immunology review (2025) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, zhu2025noveladvanceson pages 1-3) | 10.1093/rheumatology/keae397; 10.3389/fimmu.2025.1639065 | | Type I interferon transcriptomic signatures (blood & kidney) | "Type I IFN‑regulated genes (IFI6, IFI44, MX1, OAS1) are upregulated across the APS spectrum" (blood and kidney transcriptomes) | Molecular / cellular | IFI6, IFI44, IFI44L, MX1, OAS1, RSAD2 | Rheumatology (IFN signatures, 2024); Rheumatology kidney transcriptome (2024) (lopezpedrera2024newadvancesin pages 5-6, tektonidou2024kidneywholetranscriptomeprofiling pages 4-6) | 10.1093/rheumatology/kead575; 10.1093/rheumatology/keae397 | | Obstetric APS — placental lesions & mechanisms | Placental findings: infarction, decidual vasculopathy, ↑ syncytial knots, ↓ vasculosyncytial membranes; trophoblast dysfunction, altered uNK cell function and angiogenesis | Tissue / organ | Trophoblasts, uterine NK cells, spiral arteries, sFlt‑1/PlGF imbalance | Int J Mol Sci (2023); Rheumatology (2024) (d’ippolito2023antiphospholipidsyndromein pages 4-5, lopezpedrera2024newadvancesin pages 1-2) | 10.3390/ijms24043195; 10.1093/rheumatology/kead575 | | Two‑hit hypothesis (triggers) | aPL constitute a "first hit" creating prothrombotic milieu; infection, pregnancy, surgery, or endothelial injury act as a "second hit" precipitating thrombosis/CAPS | Systemic / clinical | aPLs, infections (e.g., viral), pregnancy, endothelial injury | Cureus review (2024); BJH guidelines (2024) (parepalli2024antiphospholipidsyndromeand pages 2-3, arachchillage2024guidelinesonthe pages 2-2) | 10.7759/cureus.66555; 10.1111/bjh.19635 | | Platelet–complement crosstalk | Platelet activation correlates with lectin pathway proteins and C3dg; platelet–complement interactions modulate thromboinflammatory responses | Cellular / molecular | Platelets, MASP‑2, lectin pathway proteins, C3dg, C3 | Cells/Rheumatology summaries and guidelines (2023–2024) (bucci2025statinsasan pages 2-4, arachchillage2024guidelinesonthe pages 2-2) | 10.3390/cells14050353; 10.1111/bjh.19635 | | Biomarkers — anti‑β2GPI‑DI, aPS/PT, triple positivity | Anti‑β2GPI‑domain I shows high specificity for APS; aPS/PT associates with obstetric loss; triple/double aPL positivity increases thrombotic/obstetric risk | Clinical / molecular | anti‑β2GPI‑DI, aPS/PT, LA, aCL (IgG/IgM) | Front Immunol / J Clin Med summaries (2025, 2024) (zhu2025noveladvanceson pages 3-4, celia2024antiphospholipidsyndromeinsights pages 3-5) | 10.3389/fimmu.2025.1639065; 10.3390/jcm13144191 | | Therapeutic implications / targets | Standard: anticoagulation (LMWH/heparin, VKA) ± aspirin; adjuncts with HCQ, statins; complement inhibitors (eculizumab) for refractory/CAPS cases | Clinical | Heparin/LMWH, VKA, aspirin, hydroxychloroquine, statins, eculizumab | BJH guidelines (2024); Cells (statins review, 2025) (arachchillage2024guidelinesonthe pages 2-2, bucci2025statinsasan pages 2-4) | 10.1111/bjh.19635; 10.3390/cells14050353 |

Table: Concise, sourced evidence summarizing key mechanistic themes in antiphospholipid syndrome (APS), with biological level, primary players, and citations to the supporting literature (context IDs). This table is designed for rapid knowledge‑base ingestion and mechanistic mapping.

Key Molecular Players and Ontology-aligned annotations - Genes/Proteins (HGNC): APOER2/LRP8; GP1BA; ITGA2B/ITGB3; F3 (Tissue factor); TFPI; SERPINE1 (PAI-1); PROS1 (Protein S); C3, C4A, C4B; IFI6, IFI44, MX1, OAS1, RSAD2; MPO, ELANE, PADI4; VCAM1, ICAM1, SELE; NFKB1 (bucci2025statinsasan pages 2-4, zhu2025noveladvanceson pages 3-4, tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, lopezpedrera2024newadvancesin pages 1-2, lopezpedrera2024newadvancesin pages 4-5). - Chemical entities (CHEBI): Thromboxane A2; Prostacyclin; Reactive oxygen species; Heparin; Warfarin; Acetylsalicylic acid (aspirin) (bucci2025statinsasan pages 2-4, arachchillage2024guidelinesonthe pages 2-2). - Cell types (CL): Platelet; Endothelial cell; Monocyte; Neutrophil; Trophoblast; Uterine NK cell (bucci2025statinsasan pages 2-4, d’ippolito2023antiphospholipidsyndromein pages 4-5, lopezpedrera2024newadvancesin pages 1-2). - Anatomical locations (UBERON): Blood vessel endothelium; Placenta; Kidney (nephron); Decidua; Spiral artery (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, d’ippolito2023antiphospholipidsyndromein pages 4-5, lopezpedrera2024newadvancesin pages 1-2). - Biomarkers: anti-β2GPI (domain I); lupus anticoagulant; anti-cardiolipin; anti-phosphatidylserine/prothrombin (aPS/PT); complement split products (C3a/C4a); IFN gene signature panels (zhu2025noveladvanceson pages 3-4, d’ippolito2023antiphospholipidsyndromein pages 4-5, celia2024antiphospholipidsyndromeinsights pages 3-5, lopezpedrera2024newadvancesin pages 4-5).

Biological Processes (GO-style terms) disrupted - Blood coagulation and regulation of thrombin generation; extrinsic coagulation via tissue factor; fibrinolysis and regulation of plasminogen activation (bucci2025statinsasan pages 2-4, celia2024antiphospholipidsyndromeinsights pages 3-5). - Complement activation (classical/lectin/alternative collectively implicated by C3/C4 upregulation and C3a/C4a split products) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, celia2024antiphospholipidsyndromeinsights pages 3-5). - Neutrophil activation and neutrophil extracellular trap formation (NETosis) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, arachchillage2024guidelinesonthe pages 2-2). - Type I interferon signaling; innate immune activation; TLR signaling pathways (TLR4/TLR7/8) (lopezpedrera2024newadvancesin pages 4-5, zhu2025noveladvanceson pages 3-4). - Endothelial activation: NF-κB signaling, cytokine production (IL-6/IL-8), cell adhesion (VCAM-1/ICAM-1/E-selectin) (lopezpedrera2024newadvancesin pages 1-2). - Placental development and angiogenesis; trophoblast differentiation and invasion; decidual vasculature remodeling (d’ippolito2023antiphospholipidsyndromein pages 4-5, lopezpedrera2024newadvancesin pages 1-2).

Cellular Components implicated - Plasma membrane complexes (β2GPI–aPL complexes on endothelial cells, platelets, monocytes); lipid rafts; integrin αIIbβ3 (bucci2025statinsasan pages 2-4, celia2024antiphospholipidsyndromeinsights pages 3-5). - Extracellular space: NETs (DNA–histone complexes with MPO/ELANE), complement components (C3, C4), and thrombin/fibrin (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, arachchillage2024guidelinesonthe pages 2-2). - Endothelial Weibel–Palade bodies/adhesion molecule-rich surfaces; platelet granules (lopezpedrera2024newadvancesin pages 1-2, bucci2025statinsasan pages 2-4).

Disease progression: sequence of events - Initiation: Persistent aPL (often triple-positive) bind β2GPI/prothrombin on cell surfaces; endothelial cells, monocytes, platelets are primed; IFN/TLR pathways heighten inflammatory tone (zhu2025noveladvanceson pages 3-4, lopezpedrera2024newadvancesin pages 4-5). - Trigger (“second hit”): Infection, surgery, pregnancy, or vascular injury causes overt cell activation, TF exposure, complement amplification, and NETosis (arachchillage2024guidelinesonthe pages 2-2, parepalli2024antiphospholipidsyndromeand pages 2-3). - Thromboinflammation: Thrombin generation increases; platelets aggregate (ApoER2/GPIbα/αIIbβ3; PI3K–AKT, p38); endothelium upregulates adhesion molecules and cytokines; complement split products (C3a/C5a) amplify (bucci2025statinsasan pages 2-4, lopezpedrera2024newadvancesin pages 1-2, tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - Clinical manifestation: Macrovascular thrombosis (venous/arterial) or microvascular occlusion (e.g., APS nephropathy); obstetric morbidity via placental dysfunction and insufficiency (arachchillage2024guidelinesonthe pages 2-2, tektonidou2024kidneywholetranscriptomeprofiling pages 4-6, d’ippolito2023antiphospholipidsyndromein pages 4-5). - Severe phenotype: Catastrophic APS with disseminated microvascular thromboses, often following a strong trigger and with complement involvement (arachchillage2024guidelinesonthe pages 2-2).

Phenotypic manifestations and mechanistic links - Thrombosis (HP:0001907 venous; HP:0005110 arterial): TF-driven thrombin generation, platelet hyperreactivity, NETs and complement amplification (bucci2025statinsasan pages 2-4, arachchillage2024guidelinesonthe pages 2-2, tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - Obstetric complications: Recurrent pregnancy loss (HP:0005268), preeclampsia (HP:0002372), fetal growth restriction (HP:0001511), placental insufficiency (HP:0001987) due to trophoblast dysfunction, decidual vasculopathy, and placental inflammation (10.3390/ijms24043195; 10.1093/rheumatology/kead575) (d’ippolito2023antiphospholipidsyndromein pages 4-5, lopezpedrera2024newadvancesin pages 1-2). - APS nephropathy (HP:0033411 microangiopathy): Complement/IFN/NETs-related transcriptional programs in kidney (10.1093/rheumatology/keae397) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - CAPS: Multiorgan microvascular thromboses with high mortality; driven by aPL with strong second hits and complement activation (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2).

Direct quotes supporting key statements - “Interferon (IFN) alpha/beta signalling was revealed by Reactome” in APS kidney transcriptomes; complement genes C3/C4A/C4B were upregulated (10.1093/rheumatology/keae397, Aug 2024) (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - “Upregulation of IFN-related genes in patients with APS” was observed across whole blood, PBMCs and neutrophils; a PBMC panel identified “a distinct signature comprising 11 IFN-induced genes” (10.1093/rheumatology/kead575, Feb 2024) (lopezpedrera2024newadvancesin pages 4-5).

Therapeutic implications/targets informed by pathophysiology - Anticoagulation (VKA) remains first-line for thrombotic APS; heparin/LMWH and aspirin applied per risk/setting (10.1111/bjh.19635) (arachchillage2024guidelinesonthe pages 2-2). - Targeting cell activation and inflammation: HCQ as adjunct; statins for selected high-risk thrombotic APS to attenuate platelet/endothelial activation; investigational complement inhibition for refractory/CAPS (10.1111/bjh.19635; 10.3390/cells14050353) (arachchillage2024guidelinesonthe pages 2-2, bucci2025statinsasan pages 2-4).

Evidence items (PMIDs/DOIs/URLs; publication dates) - Arachchillage DJ et al. Guidelines on the investigation and management of antiphospholipid syndrome. British Journal of Haematology. Jul 2024. doi:10.1111/bjh.19635; https://doi.org/10.1111/bjh.19635 (arachchillage2024guidelinesonthe pages 2-2). - Tektonidou MG et al. Kidney whole-transcriptome profiling… Rheumatology (Oxford). Aug 2024. doi:10.1093/rheumatology/keae397; https://doi.org/10.1093/rheumatology/keae397 (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6). - López‑Pedrera C et al. New advances in genomics and epigenetics in APS. Rheumatology. Feb 2024. doi:10.1093/rheumatology/kead575; https://doi.org/10.1093/rheumatology/kead575 (lopezpedrera2024newadvancesin pages 1-2, lopezpedrera2024newadvancesin pages 4-5). - Celia AI et al. Antiphospholipid syndrome: insights… Journal of Clinical Medicine. Jul 2024. doi:10.3390/jcm13144191; https://doi.org/10.3390/jcm13144191 (celia2024antiphospholipidsyndromeinsights pages 3-5). - Zhu Q‑N et al. Novel advances… Frontiers in Immunology. Aug 2025. doi:10.3389/fimmu.2025.1639065; https://doi.org/10.3389/fimmu.2025.1639065 (zhu2025noveladvanceson pages 3-4, zhu2025noveladvanceson pages 1-3). - Bucci T et al. Statins as an adjunctive antithrombotic agent in T‑APS. Cells. Feb 2025. doi:10.3390/cells14050353; https://doi.org/10.3390/cells14050353 (bucci2025statinsasan pages 2-4). - Pine A et al. A proteomic map of thromboinflammatory signatures in APS. Frontiers in Immunology. Oct 2025. doi:10.3389/fimmu.2025.1676578; https://doi.org/10.3389/fimmu.2025.1676578 (pine2025aproteomicmap pages 1-2). - D’Ippolito S et al. APS in pregnancy: pathogenetic mechanisms. Int J Mol Sci. Feb 2023. doi:10.3390/ijms24043195; https://doi.org/10.3390/ijms24043195 (d’ippolito2023antiphospholipidsyndromein pages 4-5).

Note on scope and gaps - Where detailed quantitative NET biomarker cutoffs and specific complement split-product levels in APS cohorts are needed, additional prospective studies are emerging but were beyond the scope of the cited transcripts/guidelines.

References

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  5. (bucci2025statinsasan pages 2-4): Tommaso Bucci, Danilo Menichelli, Ilaria Maria Palumbo, Daniele Pastori, Paul R. J. Ames, Gregory Y. H. Lip, and Pasquale Pignatelli. Statins as an adjunctive antithrombotic agent in thrombotic antiphospholipid syndrome: mechanisms and clinical implications. Cells, 14:353, Feb 2025. URL: https://doi.org/10.3390/cells14050353, doi:10.3390/cells14050353. This article has 4 citations and is from a poor quality or predatory journal.

  6. (lopezpedrera2024newadvancesin pages 1-2): Chary López-Pedrera, Tomás Cerdó, Elizabeth C Jury, Laura Muñoz-Barrera, Alejandro Escudero-Contreras, M A Aguirre, and Carlos Pérez-Sánchez. New advances in genomics and epigenetics in antiphospholipid syndrome. Rheumatology, 63:SI14-SI23, Feb 2024. URL: https://doi.org/10.1093/rheumatology/kead575, doi:10.1093/rheumatology/kead575. This article has 8 citations and is from a peer-reviewed journal.

  7. (tektonidou2024kidneywholetranscriptomeprofiling pages 4-6): Maria G Tektonidou, Kleio-Maria Verrou, Harikleia Gakiopoulou, Menelaos Manoloukos, Panagiotis Lembessis, Pantelis Hatzis, and Petros P Sfikakis. Kidney whole-transcriptome profiling in primary antiphospholipid syndrome reveals complement, interferons and nets-related gene expression. Rheumatology (Oxford, England), 63:3184-3190, Aug 2024. URL: https://doi.org/10.1093/rheumatology/keae397, doi:10.1093/rheumatology/keae397. This article has 9 citations.

  8. (lopezpedrera2024newadvancesin pages 4-5): Chary López-Pedrera, Tomás Cerdó, Elizabeth C Jury, Laura Muñoz-Barrera, Alejandro Escudero-Contreras, M A Aguirre, and Carlos Pérez-Sánchez. New advances in genomics and epigenetics in antiphospholipid syndrome. Rheumatology, 63:SI14-SI23, Feb 2024. URL: https://doi.org/10.1093/rheumatology/kead575, doi:10.1093/rheumatology/kead575. This article has 8 citations and is from a peer-reviewed journal.

  9. (d’ippolito2023antiphospholipidsyndromein pages 4-5): Silvia D’Ippolito, Greta Barbaro, Carmela Paciullo, Chiara Tersigni, Giovanni Scambia, and Nicoletta Di Simone. Antiphospholipid syndrome in pregnancy: new and old pathogenetic mechanisms. International Journal of Molecular Sciences, 24:3195, Feb 2023. URL: https://doi.org/10.3390/ijms24043195, doi:10.3390/ijms24043195. This article has 60 citations and is from a poor quality or predatory journal.

  10. (pine2025aproteomicmap pages 1-2): Alexander Pine, Ayesha Butt, Laura Andreoli, Jason S. Knight, Maria Gerosa, Irene Cecchi, D. Ware Branch, Rosario Lopez-Pedrera, H. Michael Belmont, Nina Kello, Michelle Petri, Ricard Cervera, Vittorio Pengo, Pier Luigi Meroni, Hannah Cohen, Rohan Willis, Maria Laura Bertolccini, George Goshua, Sean Gu, John Hwa, Alfred I. Lee, Doruk Erkan, and Anish V. Sharda. A proteomic map of thromboinflammatory signatures in antiphospholipid syndrome: results from antiphospholipid syndrome alliance for clinical trials and international networking (aps action) registry. Frontiers in Immunology, Oct 2025. URL: https://doi.org/10.3389/fimmu.2025.1676578, doi:10.3389/fimmu.2025.1676578. This article has 0 citations and is from a peer-reviewed journal.

  11. (zhu2025noveladvanceson pages 1-3): Qing-Nan Zhu, Xiang-Bo Qi, Shu-Wei Ren, Yu-Ye Li, Ze-Wen Yan, Yu Sun, Yan Shi, Qing-Si Wen, Mao-Mao Wu, and Da-Peng Wang. Novel advances on pathophysiological mechanisms, clinical manifestations, and treatment of antiphospholipid syndrome. Frontiers in Immunology, Aug 2025. URL: https://doi.org/10.3389/fimmu.2025.1639065, doi:10.3389/fimmu.2025.1639065. This article has 3 citations and is from a peer-reviewed journal.

  12. (lopezpedrera2024newadvancesin pages 5-6): Chary López-Pedrera, Tomás Cerdó, Elizabeth C Jury, Laura Muñoz-Barrera, Alejandro Escudero-Contreras, M A Aguirre, and Carlos Pérez-Sánchez. New advances in genomics and epigenetics in antiphospholipid syndrome. Rheumatology, 63:SI14-SI23, Feb 2024. URL: https://doi.org/10.1093/rheumatology/kead575, doi:10.1093/rheumatology/kead575. This article has 8 citations and is from a peer-reviewed journal.