β₂-Glycoprotein-I (β₂GPI) is a 50-kDa plasma glycoprotein also termed apolipoprotein H (ApoH). β₂GPI consists of five short consensus repeats, called “sushi” domains. Its C-terminal domain V binds negatively charged cell surface receptors (10). β₂GPI circulates in three conformations: a circular plasma conformation, S-shaped, and open fishhook. The cryptic epitope on the N-terminal domain I serves as the immunodominant target for pathogenic IgG/IgM anti-β₂GPI antibodies. This cationic phospholipid-binding glycoprotein is secreted by hepatocytes, monocytes, trophoblasts, ECs, and platelets. Under oxidative stress, positively charged residues and hydrophobic regions engage phospholipid membranes, disrupting circular conformation and exposing the domain I epitope of β₂GPI (10, 11).

Anti-β₂GPI antibodies promote a prothrombotic state by inhibiting natural anticoagulants and fibrinolytic pathways and by activating monocytes, neutrophils, platelets, and vascular ECs. APS patients show altered T-cell reactivity to β₂GPI, possibly due to neoepitopes formed by protein structural changes induced by chronic inflammation and oxidative stress. Oxidized and glucose-modified β₂GPI activate immature monocyte-derived dendritic cells, enhance allostimulatory capacity in mixed lymphocyte reaction, and modulate dendritic cell activation (12). Additionally, aPLs stimulate the expression of TNFα in monocytes through activation of the Toll-like receptor TLR4, TLR7, and TLR8 pathways and induce the release of TF from the surface of monocytes and ECs (13). TLR4 facilitates anti-β₂GPI/β₂GPI complex binding to monocytes and ECs, activating p38 MAPK, MEK-1/ERK, and NF-κB via TLR4/MyD88 and TLR4/TRIF pathways. NF-κB activation upregulates the tissue factor (TF) and increases the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM), and E-selectin (14). Molecular simulations demonstrate that IgG anti-β₂GPI binding to TLR4 induces IRAK phosphorylation, NF-κB nuclear translocation, enhanced EC VCAM-1 expression, and monocyte TNF-α release. Inhibitors of TLR4, p38 MAPK, or NF-κB significantly reduce TNF-α, IL-1β, and IL-6 mRNA in anti-β₂GPI antibody-stimulated macrophages (14). Anti-β₂GPI antibodies bind and downregulate thrombin activity. These antibodies also adhere to platelets, enhance platelet and endothelial cell activation, and initiate thrombotic and inflammatory cascades. Consequently, they activate proatherogenic pathways and induce vascular cell dysfunction, directly contributing to thrombotic pathogenesis (15). Genetic engineering-mediated β₂GPI-deficient murine models revealed that β₂GPI potentiates platelet activation and thrombus formation through facilitating PAR3-dependent thrombin signaling transduction. Experimental data demonstrated that β₂GPI deficiency resulted in attenuated thrombosis across multiple in vivo models concomitant with prolonged bleeding time, indicating β₂GPI’s dual regulatory roles in both physiological hemostasis and pathological thrombogenesis (16). The anti-β₂GPI antibody significantly increased thrombus size after laser-induced arterial injury in a mouse model (17). The 13th International Antiphospholipid Antibody Congress proposed that the IgA β₂GPI test could be considered for APS patients with typical negative IgG and IgM (18). A European cohort study of 137 primary APS patients found that high-affinity anti-β₂GPI antibodies were linked to venous thrombosis occurrence, whereas low-affinity antibodies predominated in non-APS, especially those with SLE (19).

aCL and anti-β₂GPI antibodies induce TF expression in monocytes and ECs, contributing to the prothrombotic state of APS. LA confers a higher thrombotic risk than aCL by forming bivalent complexes with increased phospholipid affinity, competing with coagulation factors (20). Diluted Russell viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) are often used in clinical practice. LA is the primary predictor of adverse pregnancy outcomes related to aPL beyond 12 weeks of pregnancy (21). Among aPLs, aCL demonstrates higher sensitivity, whereas anti-β₂GPI antibody exhibits superior specificity (2). Triple antibody testing provides greater diagnostic accuracy than single assays, enabling improved APS diagnosis and risk stratification (22).

In a consecutive cohort of 175 patients with suspected APS, approximately one-third of seronegative APS (SN-APS) cases exhibited reactivity to ≥1 non-standard antibody (23). The combination of non-standard aPLs improved diagnostic accuracy. Other APS antigen targets may include non-standard APS components such as IgA aCL and anti-β₂GPI antibodies, antibodies against phospholipid or phospholipid/protein antigens such as anti-phosphatidylserine/prothrombin (aPS/PT), PS, activated protein C (APC), and Annexin II/V resistance (24). IgA aCL and anti-β₂GPI antibodies provide supplementary diagnostic value in APS. In vivo studies in mice demonstrated that IgA anti-β₂GPI antibodies induced larger thrombi and elevated TF and were significantly associated with arterial thrombosis (25).

Anti-prothrombin antibodies (aPT) targeting phosphatidylserine/prothrombin (aPS/PT) complexes represent unclassified biomarkers. Clinical studies demonstrate that persistent aPS/PT antibody positivity, thrombosis events, triple positivity for aPS/PT IgG/IgM antibodies, and LA activity significantly correlate with higher Global Antiphospholipid Syndrome Scores (GAPSS) (23). Annexin II and V have high affinity for phospholipids and play a key role in the regulation of the coagulation cascade (26). Annexin V is a glycoprotein abundant in vascular ECs, binds negatively charged phospholipids, and forms protective crystals on phosphatidylserine surfaces. These crystals block phospholipid-dependent thrombin binding sites, thereby inhibiting procoagulant/proinflammatory activities and regulating apoptosis (27). In the placenta, Annexin V is expressed by syncytiotrophoblasts and plays a key role in maintaining placental integrity and regulating thrombosis. IgG anti-ANXA5 antibodies were associated with arterial thrombotic events in 170 APS patients and 104 non-APS patients (OR 2.60; 95% CI, 1.44–4.71) and with venous thrombosis events (OR, 2.80; 95% CI, 1.55–5.06); thus, IgG anti-ANXA5 antibodies can be used as predictive biomarkers to identify patients at high risk of thrombosis (28–30). Prothrombin is also one of the target antigens of aPLs. Annexin II (A2) is a fibrinolytic receptor on the surface of ECs, which binds tissue plasminogen activator (tPA) and β₂GPI, serving as a high-affinity receptor for anti-β₂GPI antibody complexes. The serum anti-A2 antibodies were significantly elevated in 434 APS patients versus healthy controls (P = 0.017), non-autoimmune thrombosis patients, and non-thrombotic lupus patients (P = 0.001) (31). A2 antibodies increased cerebral infarct volume (133.9 ± 3.3 mm³ vs. 113.7 ± 7.4 mm³; P = 0.017) and worsened neurological outcomes (2.2 ± 0.2 vs. 1.5 ± 0.18; P = 0.03) in murine stroke models, establishing A2 as an independent cerebral thrombosis risk factor (32, 33).

Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin, DNA, histones, and granular proteins released during NETosis. These structures trap pathogens and exhibit pro-inflammatory and pro-thrombotic properties, contributing to malignancies, sepsis, SLE, and APS (34).

In SLE and APS, enhanced NET release and impaired clearance of NET components lead to autoantigen exposure, activating autoreactive B cells and triggering autoantibody production, whereas NET-associated cytokines stimulate plasmacytoid dendritic cells to secrete IFNα. Additionally, the presence of neutrophil proteases such as elastase and cathepsin G in NET lysates degrades anticoagulants, including antithrombin III, heparin cofactor II, and TFPI, generating a pro-coagulant microenvironment and leading to activation of the coagulation cascade, facilitating platelet adhesion and aggregation, and providing structural scaffolds for thrombus formation (35). The process requires coordinated actions of peptidyl arginine deiminase 4 (PADI4), neutrophil elastase (ELANE), and myeloperoxidase (36) and is dependent on NADPH oxidase-derived reactive oxygen species and autophagy regulation.

Additionally, aPL monoclonal antibodies and β₂GPI monoclonal antibodies in the serum of APS patients can enhance NETosis. Clinical studies demonstrated that elevated MPO-DNA complexes in thrombotic APS and SLE patients correlated with increased MPO and PADI4 mRNA expression (37). NETs have been confirmed to be associated with thrombosis in APS. Patients with primary APS have high levels of anti-NET antibodies, which hinder NET clearance and activate the complement cascade, thereby increasing thrombotic risk and aiding in risk stratification of APS (38).

During tissue injury, exposed collagen on damaged blood vessel walls attracts platelet adhesion. Interactions between platelet surface receptors and ECM components induce platelet conformational changes, membrane phospholipid redistribution, and increased exposure of phosphatidylserine and chondroitin, thereby supporting complement activation (39, 40). Activated platelets degranulate, releasing coagulation factors such as factor V, FXI, FXIII, and complement components (41). Secondary hemostasis initiates through the TF pathway or the contact pathway; these pathways converge to produce activated FX (FXa), which then cleaves prothrombin into thrombin. Thrombin cleaves fibrinogen to form fibrin. Fibrin deposition exacerbates platelet thrombosis, with its regulation potentially influenced by the complement system function (42). Complement activation products (C3a, C5a, and C5b-9) induce ECs and monocytes to release pro-thrombotic factors and pro-inflammatory cytokines, resulting in overexpression of TF and molecules that facilitate platelet adhesion and coagulation (43). In individuals with positive aPL, aPL can independently activate ECs and platelets to participate in blood coagulation and induce monocyte TF expression and the generation of FXa upon activation of the TF pathway (44).

Beyond aPL, anti-NET and anti-FH antibodies also drive complement activation in APS. aPL initiates NET formation, elevating circulating NET levels in APS patients and facilitating complement activation (34, 45). Zuo et al. demonstrated elevated IgM anti-NET antibodies in primary APS patients, correlating with complement activation. This association likely stems from IgM antibody complement component interactions on NET surfaces (46, 47).

Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membranes of endothelial cells, monocytes, and platelets. These highly ordered structures regulate cell polarity, vesicular trafficking, receptor aggregation, and signaling (48, 49). Upon interaction with aPL target antigens, lipid rafts initiate proinflammatory and procoagulant signaling cascades. This leads to excessive platelet activation, endothelial dysfunction, enhanced procoagulant states, and thrombophilia (50).

Hao Wei et al. demonstrated that activated platelet-derived EVs enriched in phosphatidylserine (PS) amplify thrombosis and inflammation through lipid raft-mediated mechanisms (51). Lipid rafts facilitate β₂GPI antibody signaling by serving as platforms for Toll-like receptors TLR2, TLR4, and lipoprotein receptors LRP6 and LRP8/ApoER2. These interactions induce IRAK phosphorylation and NF-κB activation, promoting expression of TNF-α and TF (52, 53).

Gloria Riitano et al. demonstrated that disruption of lipid rafts with methyl-β-cyclodextrin (MβCD) or inhibition of LRP6 by Dickkopf-1 (DKK1) abolished IRAK phosphorylation and prevented formation of the β₂GPI-LRP6-PAR-2 complex. This intervention significantly suppressed aPL-induced platelet activation, endothelial procoagulant responses, and proinflammatory activity, thereby inhibiting autoimmune thrombosis. Additionally, they discovered that β₂GPI antibody activation of TLR8 induced eNOS phosphorylation and reduced intracellular NO levels (54, 55).

Collectively, this evidence establishes lipid rafts as essential platforms for initiating aPL/β₂GPI complex-mediated signaling through TLR, LRP6, and LRP8 receptors.

In chronic inflammation, neutrophils exhibit significant phenotypic heterogeneity as terminally differentiated cells. The peripheral blood of SLE patients contains two distinct low-density granulocyte subsets. These are pro-inflammatory low-density granulocytes (LDG) and immunosuppressive myeloid-derived suppressor cells (PMN-MDSC). LDGs display reduced phagocytic activity but abnormally increased NET formation. By releasing inflammatory mediators such as interferon, IL-6, IL-8, and TNF-α, these cells exacerbate vascular complications in SLE and APS, acting synergistically with NET-mediated vascular endothelial injury. PMN-MDSCs exert immunosuppressive effects via regulatory lymphocyte pathways (56).

B lymphocyte dysfunction is central to the pathogenesis of primary APS. The low-affinity natural antibodies produced by CD5+ B cells may be involved in cross-reactivity to autoantigens. Plasmablasts, key precursors for antibody production, play an important role in aPL formation. Notably, β₂GPI on the apoptotic cells’ surface can be recognized by specific B cells, leading to the activation of T-cell responses through antigen presentation. This process may involve MHC class II-mediated antigen processing mechanisms (57). The increased level of B-cell-activating factor (BAFF) is closely related to disease activity. Moreover, the up-regulation of BAFF mRNA expression in monocytes suggests that these cells may be the main source of circulating BAFF. BAFF promotes the survival and maturation of B cells by binding to BAFF-R, TACI, and BCMA receptors, thereby activating the nuclear factor-κB signaling pathway (58).

T-lymphocyte subset imbalance significantly contributes to APS pathogenesis. Peripheral blood proportions of helper T-cell subsets 1 and 17 (Th1 and Th17) are significantly increased, whereas regulatory T cell (Treg) numbers are reduced in thrombotic and obstetric APS patients. Moreover, oxidized β₂GPI promotes the dendritic cells’ maturation, induces the differentiation of Th1 cells, and stimulates the release of pro-inflammatory cytokines (59). At the molecular level, β₂GPI-reactive CD4+ T cells participate in thrombosis through IFN-γ-mediated monocyte activation and perforin and Fas ligand-dependent cytotoxicity. Additionally, specific β₂GPI binding to NETs may exacerbate immune thrombotic events through epitope exposure mechanisms (60).

The imbalance of exogenous pathogenic bacteria or endogenous strains in the body may induce infection and trigger aPL as a secondary event following the initial formation of autoantibodies (61). Humans harbor vast symbiotic microbial communities in the gut, skin, and oral cavity, forming a metabolic ecosystem that critically influences host immune regulation. When the intestinal barrier is compromised, the intestinal microbiome can disrupt the mucosal barrier and induce the production of mucosal-specific memory T cells. Microbiome-driven thrombosis in APS involves pro-inflammatory autoantibodies, bacterial translocation, antigen cross-reactivity, immune-modulating metabolites, and non-immune modifiers (62–64).

Compared with healthy individuals, it has been found that Bifidobacteria, Streptococci, and Clostridia related to intestinal inflammation and permeability are increased in patients with autoimmune diseases (63). Conversely, Bilophila in the Coriobacteriaceae decreases significantly whereas Slackia increases by 59%. The production of enteric cardiolipin can lead to the formation of pathogenic T-cell and autoantibody responses through cross-reactivity with autoantigens such as Ro 60, dsDNA, and β₂GPI (65). Molecular simulations demonstrated that bacterial peptides homologous to β₂GPI can induce pathogenic anti-β₂GPI antibodies. The human intestinal bacterium Roseburia (R. intestinalis) possesses peptide sequences highly homologous to β₂GPI, which induce pathogenic anti-β₂GPI antibodies, which may stimulate lymphocytes and act as a chronic driver of β₂GPI autoreactivity. However, gut microbiome effects on the APS may not depend solely on bacterial overgrowth, short-chain fatty acid production, or local inflammation. Vancomycin treatment in APS-prone (NZW × BXSB) F1 mice reduces anti-β₂GPI antibody production, accompanied by lower Th17 and T follicular helper cell frequencies in secondary lymphoid tissues and reduced autoantibody levels (64).

SLE patients demonstrate reduced gut microbiota richness. Both the Firmicutes/Bacteroidetes ratio and fecal Lactobacillus abundance are significantly decreased in SLE cohorts (n=20), with reductions correlating with disease activity, particularly lupus nephritis (66, 67). In addition, Microbacterium and Pseudobutyrivibrio are reduced in SLE patients. Microbiota dysbiosis is related to local inflammatory responses, high circulating levels of anti-dsDNA and histone antibodies, and systemic immune activation, which promotes lymphocyte activity and Th17 cell differentiation (64).

Lactobacillus plantarum improves renal function in murine lupus nephritis models. Intestinal lactic acid bacteria colonization restores mucosal barrier function, reduces IL-6 and IL-18, and mitigates kidney damage by decreasing immune complex deposition and IFN-γ levels (68). Supplementation of Lactobacillus casei (Actimel) or yogurt in APS animal models effectively inhibited IL-10 production (P < 0.05) and enhanced IFN-γ secretion. Metagenomic analysis of 124 SLE patients compared with healthy populations showed significant associations between Escherichia coli, purine nucleotide metabolism, and peptidomature metabolic pathways with the SLE disease activity index (SLEDAI), as well as between multiple Escherichia coli epitopes and disease activity or renal involvement phenotypes (69).

The pathogenesis of APS involves both genetic susceptibility and environmental triggers. The Val247 variant is associated with anti-β₂GPI antibody production in primary APS patients, and STAT4 SNP T allele frequencies are significantly higher in Japanese SLE and APS patients than in healthy controls (70, 71). Among 276 upregulated genes in APS, enriched Gene Ontology (GO) terms included innate immune response, leukocyte activation, lymphocyte activation, cytokine production, T-cell activation, complement activation, and NET gene expression (72). Current evidence indicates that APS-associated genetic variants cluster primarily within the human leukocyte antigen (HLA) system and involve specific single-nucleotide polymorphisms (SNPs). HLA-DR and HLA-DQ alleles contribute to APS susceptibility through genetic and epigenetic mechanisms (73). The syndrome appears to involve two dominant complementary alleles localized to separate chromosomes (74). The expression of HLA alleles such as HLA-DR4, -DR7, -DRw53, and -DQB1*0302 is associated with aPL and is observed in both primary APS and APS secondary to SLE (75).

APS and SLE are frequently comorbid, with 40% of SLE patients testing positive for aPL. In contrast, primary APS often presents with the presence of circulating antinuclear antibodies or anti-dsDNA/chromatin antibodies. 30% to 50% of patients with SLE have been reported to test positive for at least one aPL test (76). Despite shared lupus susceptibility genes, primary APS patients rarely progress to full SLE even after a decade of follow-up, underscoring their distinct pathogenesis, likely due to differing immunological mechanisms (77, 78). Early observations by Harvey and Shulman suggested a genetic basis for aPLs, noting familial clustering of syphilis false-positive tests among SLE and primary APS patients with multiple affected first-degree relatives. These findings implied that genetic susceptibility promotes aPL expression and that extended kinship correlates with APS manifestations, supporting APS as a familial disorder (71).

Vascular thrombosis was initially regarded as the primary cause of pregnancy complications in APS. Current evidence from animal models demonstrates that aPL-mediated placental dysfunction and complement-driven inflammatory processes represent the predominant pathogenic mechanisms underlying adverse obstetric outcomes (79). During placenta formation, extensive trophoblast remodeling exposes anionic phospholipids on cell surfaces, facilitating aPL and β₂GPI complex formation (80). Further changes in trophoblastic cell function include reduced cell proliferation and migration, increased production of pro-inflammatory cytokines, and decreased secretion of human chorionic gonadotropin and pro-angiogenic factors such as vascular endothelial growth factor (VEGF) (81, 82). In addition, aPLs suppress endometrial angiogenesis both in vitro and in vivo by inhibiting endothelial cell differentiation and VEGF expression during neovascularization (83). Moreover, Marder et al. demonstrated that anti-β₂GPI antibodies bind to the surface of neutrophils and increase the release of NETs. NETs serve antimicrobial functions, and NETosis promotes sterile inflammation. In pregnant women with systemic lupus erythematosus, APS, and preeclampsia, a higher number of NETs in the placental villous space are associated with significant inflammation and vascular modification (84). Placental trophoblast-derived extracellular vesicles (EVs) contribute to APS pathogenesis by modulating decidual and maternal endothelial cell function (85). Notably, Wu et al. demonstrated that aPL-stimulated endothelial cells release EVs capable of activating TLR7-mediated inflammation via IL-1β and single-stranded RNA molecules (86).

Platelet activation: Antiphospholipid antibodies (aPLs) bind β₂-glycoprotein I (β₂GPI) complexes, engaging platelet surface receptors (GPIb-IX-V, GPIIb/IIIa) via lipid rafts and LDL receptor family members (LRP6, LRP8). This triggers platelet activation, promoting aggregation and impairing fibrinolysis.

Neutrophil-mediated inflammation and thrombosis: aPL/β₂GPI complexes activate TLR4 and C5aR, inducing NF-κB through the MyD88 pathway. This upregulates proinflammatory cytokines (TNF-α, IL-6, IL-8) and enhances ROS and tissue factor (TF) production. NETosis (neutrophil extracellular trap formation) further amplifies inflammation and coagulation via PI3K/AKT/mTOR signaling, with adhesion molecules (E-selectin, VCAM-1, ICAM-1) facilitating endothelial interaction.

Monocyte procoagulant activity: aPL/β₂GPI binding to TLR8, TLR6, and LDL receptors (LRP6/LRP8) activates NF-κB, driving TNF-α, IL-1β, IL-6, and TF expression, whereas ROS generation exacerbates endothelial dysfunction.

Lymphocyte dysregulation: aPLs stimulate lymphocytes to secrete IFN-γ and BAFF, promoting B-cell activation and autoantibody production, which sustains immune dysregulation.

Endothelial dysfunction and coagulation imbalance: activating complement (C5a, C3a, MAC) and impairing thrombomodulin (TM) and protein C pathways. Reducing NO and PGI2, while upregulating TF and proinflammatory cytokines (TNF-α, IL-6); dysregulating fibrinolysis via plasminogen, plasmin, PAI-1, and FDP, leading to a prothrombotic state.

The global prevalence of APS is approximately 2%, with recent studies demonstrating consistent epidemiological trends. A 2019 study showed that the annual incidence of APS was 2.1%; the incidence ratio between women and men is approximately 3.5:1. Incidence peaks after age 55, particularly beyond 75 years (87). A population-based cohort study from Olmsted County, Minnesota, estimated that the annual incidence of APS was 2.1 patients per 100,000 population, with a prevalence of 50 cases per 100,000 population (88). In a 2019 epidemiological study of individuals over the age of 18, the incidence of APS was estimated at 2.1 cases per 100,000 people, with an estimated prevalence of 50 cases per 100,000 (87).

The preliminary classification criteria were first established at an expert seminar held in Sapporo, Japan, in 1999. At a 2006 meeting in Sydney, Australia, experts proposed several changes to the previous classification criteria, such as adding tests for aCL and anti-β₂GPI antibodies, extending the time interval between serological tests, and providing clearer definitions of clinical presentations and laboratory titer thresholds (89, 90). Specific features associated with APS were highlighted, including heart valve involvement, reticular cyanosis, thrombocytopenia, APS nephropathy, and non-thrombotic central nervous system manifestations (Figure 2).

The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive aPL test within 3 years of identifying the clinical criteria associated with aPL. These criteria are divided into six clinical domains—macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular thrombosis, obstetrics, heart valve involvement, and hematology—and two laboratory domains: lupus anticoagulant functional coagulation assay and solid-phase ELISA tests for detecting IgG/IgM anti-cardiolipin and/or IgG/IgM anti-beta-2 glycoprotein I antibodies. Patients who accumulate at least three points in total from the clinical and laboratory criteria are classified as having APS (90). Compared with the Sapporo classification criteria revised in 2006, the new APS criteria demonstrate increased specificity from 86% to 99% and sensitivity from 84% to 99% (91).

Besides SLE, APS can occur secondary to malignant tumors, infections, and blood disorders such as autoimmune diseases. Antiphospholipid antibodies can be detected in approximately half of APS patients. The coexistence of APS and SLE is associated with increased mortality and poorer clinical outcomes. Therefore, early diagnosis and risk assessment.

APS is characterized by venous thrombosis and arterial thrombosis. APS can be divided into different phenotypes according to clinical manifestations, with thrombotic APS being more common. The main manifestation of venous thrombosis is deep vein thrombosis (DVT) of the lower extremity, which may lead to pulmonary embolism (PE). Arterial thromboses can cause ischemic stroke, transient ischemic attacks (TIAs), myocardial infarction, and thromboses in atypical sites such as renal veins, mesenteric arteries, and upper limbs. Vascular APS is a type that emphasizes thrombotic events as the core pathological mechanism; thrombosis leads to acute or chronic vascular obstruction, resulting in tissue damage and organ dysfunction.

Hematologic abnormalities include prolonged activated partial thromboplastin time, thrombocytopenia, and thrombotic microangiopathy. While leukopenia, lymphocytopenia, and autoimmune hemolytic anemia (AIHA) overlap with SLE, catastrophic APS (CAPS) and thrombotic thrombocytopenic purpura (TTP) distinguish APS severity (92, 93). Thrombocytopenia occurs in 15% of patients, typically mild but posing surgical or traumatic bleeding risks in severe cases. Neurological sequelae include stroke, TIAs, cognitive dysfunction, migraines, and rare seizures (94). In the latest ACR/EULAR classification criteria, thrombocytopenia was included in the clinical criteria, possibly due to increased depletion and destruction of peripheral blood platelets following aPL activation. Additionally, 29% of patients with SLE-associated APS had a significant history of thrombocytopenia (90). Systemic inflammatory manifestations in COVID-19 patients contribute to APS induction, and the cumulative effect of aPL further promotes this process (95).

Lupus antiphospholipid syndrome, also known as secondary APS, may occur in patients with systemic lupus erythematosus. It is characterized by one or more positive aPL, including LA, aCL, and/or anti-β₂GPI antibodies, detected over a period of at least 12 weeks. There is one or more typical clinical event associated with the syndrome. CAPS is an extreme variant of APS, characterized by a sudden onset of generalized thrombosis affecting multiple-organ systems, including vital organs such as the lungs, kidneys, brain, and heart.

In contrast to the above criteria, some patients present with clinical manifestations such as widespread thrombosis, recurrent arteriovenous thrombosis events, recurrent miscarriage, or unexplained thrombocytopenia, accompanied by aPL titers that are only temporarily positive or persistently negative. This type of APS, characterized by “non-criteria” clinical manifestations, is defined as SN-APS after excluding other causes of thrombosis, such as hereditary thrombophilic predisposition, including prothrombin factor V and factor II mutations, coagulation disorders, active cancer, trauma, major surgery, and prolonged bed rest (30).

Anticoagulation is central to thrombotic APS management, balancing thrombosis prevention against bleeding risk. Timely dose adjustment is critical, particularly in patients with severe renal impairment, refractory APS, pregnancy, or triple-positive aPL profiles, which are associated with an increased risk of secondary catastrophic APS. Monitoring strategies incorporate prothrombin time (PT-INR), point-of-care PT-INR testing, aPTT, TT, chromogenic anti-factor Xa assay, and thrombin generation assay.

According to the above indicators and the antibody titer measurement, the risk of thrombosis in aPL can be stratified. The GAPSS is a thrombosis risk assessment system for SLE, incorporating both aPL profiles, particularly aPS/PT antibodies, and cardiovascular risk factors like hyperlipidemia and hypertension (227, 228). This score ranges from 0 to 20 and can be used to predict thrombosis risk and pregnancy complications in SLE patients. Studies show that patients with thrombosis have higher GAPSS than those without thrombosis. In a retrospective cohort study, women with prior aPL-related pregnancy complications had elevated GAPSS. A score ≥16 predicts thrombosis and retains predictive value even without aPS/PT testing (96). These findings indicate GAPSS can effectively predict first thrombotic events in primary APS, but its accuracy requires broader validation (229). Other models that can be used to predict venous thromboembolism risk include the Padua score for hospitalized medical patients and the Caprini score for surgical and medical patients. Additionally, fully evaluating the anticoagulant pharmacodynamics and pharmacokinetics of NOACs is also an important means of monitoring the anticoagulant effect.

The ISTH guidelines recommend full-dose anticoagulation after acute VTE in cancer patients with a high risk of thrombus propagation and a platelet count > 50×10⁹/L. They also recommend platelet transfusion support for thrombocytopenic patients to maintain platelet counts. APS patients may increase platelets through immune regulation to prevent coagulation. Platelet counts should be monitored during the first 14 days and beyond LMWH treatment in patients at intermediate risk of HIT to guide consideration of dose reduction for secondary thromboprophylaxis. NOACs are anticoagulants for >48 h and, like VKA, should be used with caution in thrombocytopenic patients with thrombotic APS. For patients receiving anticoagulation with LMWH, its dosing should be adjusted for APS-associated thrombocytopenia (230).

The strategy for implementing a multidisciplinary approach to preconception counseling for SLE/APS patients is to follow a clinical pathway that guides comprehensive evaluation and management (231). Therefore, based on EULAR/ERA-EDTA/ACR recommendations, multidisciplinary pre-pregnancy counseling and family planning should be implemented for SLE/APS patients to improve adverse pregnancy outcomes (210). Current studies demonstrate that disease activity and serological activity are significantly associated with live birth rates in pregnant women with SLE and APO. These associations are consistent with previous findings. Therefore, accurate risk assessment for live birth is necessary to improve neonatal and maternal outcomes, and SLEDAI is a reliable measurement tool to assess disease activity and to predict preterm birth and pre-eclampsia pregnancies resulting in live births. Compared with the controls, OAPS patients with thrombocytopenia had higher rates of SGA infants (12.12% vs. 31.25%, p = 0.043), preterm birth before 37 weeks (16.16% vs. 43.75%, p = 0.010), and intrauterine fetal death (2.02% vs. 12.50%, p = 0.043). Pre-eclampsia and eclampsia have been associated with adverse pregnancy outcomes (232); women with SLE have a higher risk of eclampsia compared with healthy women; and the infiltration of angiogenesis-associated NETs into placental tissue is enhanced in patients with pre-eclampsia. The International Federation of Gynecology and Obstetrics (FIGO) recommends early pre-eclampsia screening and prevention, including first-trimester screening for early-onset PE and aspirin prophylaxis at a dose of 150 mg per night from 11 weeks to 14 weeks and 6 days of pregnancy until 36 weeks of pregnancy, delivery, or diagnosis of PE (233). During pregnancy, fetal testing, including Doppler ultrasonography and fetal biometry, should be performed to screen for placental insufficiency and SGA infants.

Regarding diagnosis and prevention, recent studies indicate that in aPL-positive pregnant women, whether with or without SLE, anti-phosphatidylserine-prothrombin IgG (aD1) can be an important independent predictor of adverse pregnancy outcomes. There is also a strong association with lupus anticoagulants, and the combination of these two tests can identify patients most likely to develop serious obstetric complications (234). Female fertility may be impaired by disease activity, immunosuppressive drugs, treatment-induced amenorrhea, and renal insufficiency. Cytotoxic drugs reduce fertility, with alkylating agents causing dose-dependent gonadotoxicity through cortical fibrosis, ovarian vascular damage, and ovarian function destruction. Gonadotropin-releasing hormone analogues should be considered before alkylating agent use to preserve fertility (235). APS patients need to use LMWH for anticoagulation during pregnancy, but warfarin is contraindicated. SLE patients should achieve low disease activity pre-pregnancy and take pregnancy-compatible medications, including HCQ, azathioprine, cyclosporin, tacrolimus, and LDA (236, 237). HCQ use during pregnancy improves obstetric complications and live birth rates. Vitamin D deficiency also correlates with adverse pregnancy outcomes; supplementation benefits immune regulation, inflammation prevention, and maternal–fetal health (238). Immunosuppressive therapy requires cervical cancer vigilance with preemptive vaccination. Leflunomide, methotrexate, mycophenolate, and cyclophosphamide are pregnancy-contraindicated.

CAPS primarily causes cell damage through the activation of the complement cascade by aPLs, leading to coagulation and thrombosis, with widespread systemic thrombosis and multiple organ failure as its hallmark features (239). Infection is the most common trigger, followed by surgery, malignancy, pregnancy, anticoagulant discontinuation or inadequate therapy, and SLE. CAPS has a high mortality rate and presents not only with widespread thrombosis but also with fatal systemic inflammation; some patients also develop skin, ocular, and brain involvement (92). The complex multisystem manifestations pose significant diagnostic and therapeutic challenges, complicating treatment planning and anticoagulant application. Thus, multidisciplinary team management is essential. Expert teams, including but not limited to rheumatology, hematology, intensive care, nephrology, obstetrics, and other specialties, collaborate to monitor indicators and adjust therapy (123, 169).

The CAPS Registry (European Antiphospholipid Antibody Forum initiative) indicates that early intervention prevents CAPS based on published cases, registry data, and analyses of cases from Shanghai. Preventive strategies include the use of anti-infective agents, monitoring anticoagulation intensity, and prevention measures (240). Warfarin or LMWH is recommended after assessment of bleeding risk; cyclophosphamide or rituximab is used when CAPS is combined with lupus or other vasculitis (169). Some scholars compared drug combinations in triple therapy, modified triple therapy, and other treatments, finding that the combination of anticoagulation, pulse-dose corticosteroids, and plasma exchange and intravenous immunoglobulin (IVIG) had the highest disease remission rate and was positively correlated with the survival rate of CAPS (241). Plasmapheresis can remove aPLs and cytokines from plasma (173). Perioperative management researchers recorded data from 584 patients and found that eculizumab is recommended for the treatment of refractory CAPS, including thrombotic microangiopathy (152).

The general management of APS in children and adolescents primarily involves the prevention of thrombosis by addressing risk factors, including obesity, arterial hypertension, smoking, and dyslipidemia, along with avoidance of estrogen-containing oral contraceptives and screening for other pre-thrombotic risk factors. Management of mental health issues related to lifestyle and treatment adherence is also recommended (242). The major manifestations of pAPS include large vessel thrombosis and thrombotic microangiopathy (174). Acute thrombosis treatment in pAPS follows adult primary APS protocols. For childhood-onset systemic lupus erythematosus (cSLE) and pAPS, care should address vaccination, exercise training, medication use, and complication monitoring. For APS patients taking anticoagulants, participation in contact sports should be avoided to prevent acute local or systemic bleeding. Nevertheless, exercise training is potentially beneficial for childhood rheumatic disorders such as cSLE and pAPS (243). Studies demonstrate that a 12-week supervised aerobic training program is safe and beneficial in increasing aerobic endurance and physical function in cSLE patients with pAPS. In addition, pAPS patients on long-term anticoagulant medication need regular monitoring of bone health to prevent osteoporosis. Vaccination serves as an effective thrombosis prevention strategy. cSLE patients, particularly those immunosuppressed, should receive inactivated vaccines; live attenuated vaccines are generally contraindicated (244). Additionally, inherited complement deficiency represents a key risk factor for cSLE and pAPS, with such individuals often developing lupus early. Screening cSLE patients for complement defects is therefore valuable. One study reported two cases of coagulation abnormalities after renal biopsy in children with SLE and APS, resulting in a mortality risk (245). Consequently, coagulation risk must be carefully monitored to ensure treatment safety and efficacy.

Daily management for cSLE patients requires sun protection against mucocutaneous damage. Case analyses reveal that pediatric APS patients with cSLE may present diverse ocular symptoms such as reticular rash and optic nerve disorders (246). Concurrently, common SLE medications, such as HCQ, may adversely affect eye health; thus, annual eye examinations are recommended. At the same time, medications such as common heparin, LMWH, and VKA can impair bone density and metabolism. Therefore, children and adolescents with APS should maintain adequate calcium and vitamin D intake for bone health.

Perioperative management of APS requires careful balancing of thrombotic risk and bleeding complications. Abrupt withdrawal of oral warfarin therapy may induce transient hypercoagulability through increased fibrin and thrombin generation. Guidelines recommend heparin bridging therapy for high-thrombotic-risk patients undergoing invasive procedures, as continuing therapeutic anticoagulation reduces thrombotic TMA risk (240). However, perioperative anticoagulation increases bleeding risk despite mitigating TMA risk. Furthermore, abrupt cessation of anticoagulants preoperatively can elevate fibrin and thrombin production, causing transient hypercoagulability (247). Both the American College of Chest Physicians (ACCP) and the UK National Institute for Health and Care Excellence (NICE) advise heparin bridging therapy for patients discontinuing warfarin to reduce surgical hemorrhage risk who also face significant thrombotic risk (248).

Barbour et al. reported a case of a patient with SLE and APS who underwent kidney transplantation. Preoperatively managed with LMWH and warfarin, the patient developed acute allograft dysfunction due to TMA despite continuous preoperative anticoagulation (249). This highlights that surgical interventions can trigger ischemia–reperfusion injury, complement activation, and CAPS through coagulation cascade activation. Uninterrupted UPH bridging therapy is recommended for triple-positive APS patients, particularly those with secondary APS, to minimize anticoagulation gaps.

Based on case studies, oral warfarin therapy should be reinstated postoperatively on the night of surgery, with extended thromboprophylaxis using low-dose heparin or LMWH for patients on long-term warfarin therapy, barring surgical contraindications. Intermittent pneumatic compression devices and graduated compression stockings help reduce DVT incidence by decreasing venous stasis (250).