Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic and non-thrombotic macro- and microvascular manifestations and pregnancy complications in the setting of persistent antiphospholipid antibodies (aPL), namely anticardiolipin antibodies, anti-β2 glycoprotein-I antibodies and lupus anticoagulant. Four decades after its first description, APS prevalence and incidence are still not completely understood due to the limited number of well-designed, population-based multi-ethnic studies. Furthermore, despite decades of efforts to standardise aPL immunoassays, considerable intraassay and interlaboratory variances in aPL measures still exist. Large multicentre APS cohorts have shown a 10-year survival of ∼91% and the presence of catastrophic APS occurs in about 1% of the entire population, associated with a 50% mortality rate. Clinically, any organ can be affected in the context of large, medium or small vessel (artery and/or vein) thrombosis. Macrovascular thrombosis is the hallmark of the disease and veins are more frequently affected than arteries. Deep vein thrombosis/pulmonary embolism thromboembolic disease is the most common APS manifestation, while stroke and transient ischaemic attack are the most frequent arterial thrombosis events. Myocardial infarction can also occur and contributes to increased mortality in APS. A minority of patients present with thrombosis affecting the intraabdominal organs, including the liver, spleen, small and large bowel, and the kidneys. Microvascular thrombosis, including APS nephropathy, chronic skin ulcers and livedoid vasculopathy represent a diagnostic challenge requiring histologic confirmation. In this narrative review we summarize the available evidence on APS epidemiology, focusing on the description of the prevalence of macro- and microvascular manifestations of the disease.

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized, according to the Sydney criteria, by the persistent presence of autoantibodies directed against phospholipid-binding proteins associated with thrombosis and/or obstetrical complications. The most frequent complications in obstetric antiphospholipid syndrome are recurrent pregnancy losses and premature birth due to placental insufficiency or severe preeclampsia. In recent years, vascular APS (VAPS) and obstetric APS (OAPS) have been described as two different clinical entities. In VAPS, antiphospholipid antibodies (aPL) interfere with the mechanisms of coagulation cascade and the 'two hit hypothesis' has been suggested to explain why aPL positivity does not always lead to thrombosis. OAPS seems to involve additional mechanisms, such as the direct action of anti-β2 glycoprotein-I on trophoblast cells that can lead to a direct placental functional damage. Furthermore, new actors seem to play a role in the pathogenesis of OAPS, including extracellular vesicles, micro-RNAs and the release of neutrophil extracellular traps. The aim of this review is to investigate the state-of-the-art antiphospholipid syndrome pathogenesis in pregnancy, in order to provide a comprehensive overview of both old and new pathogenetic mechanisms involved in this complex disease.

Antiphospholipid syndrome (APS) is an acquired highly prothrombotic disorder in which thrombo-inflammatory antiphospholipid antibodies (aPL) cause thrombosis via multiple mechanisms, including endothelial damage and activation. Obstetric complications in APS are caused by placental thrombosis, inflammation and complement activation. Anticoagulation is poorly effective in some patients especially those with triple positive aPL who are at ~30% risk of thrombosis recurrence within 10 years. Increasing therapeutic anticoagulation intensity may be beneficial but leads to excess bleeding with serious complications, such as intracerebral haemorrhage. Nonetheless, anticoagulation is still the mainstay of treatment despite the autoimmune nature of APS. The antimalarial immunomodulatory drug hydroxychloroquine (HCQ) has been used for many years for the treatment of inflammatory rheumatic diseases. HCQ has complex pleiotropic mechanisms of action upon multiple cell types. The proposed biological processes that HCQ regulates support the hypothesis that it may be a successful adjunctive treatment in the prevention of recurrent thrombosis and pregnancy complications.

ObjectiveAntiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)-positive patients using whole-blood transcriptomics.MethodsWhole-blood RNA sequencing was performed on 174 aPL-positive patients, including those with primary APS (n = 102), secondary APS (n = 29), and aPL positivity without classifiable APS (n = 43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes.ResultsFour transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up-regulation of ribosomal and metabolic pathways and down-regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo/interleukin-6 (IL-6) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up-regulation of mTOR, NETosis, and Hippo/IL-6 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo/IL-6 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti-β2-glycoprotein I positivity, elevated neutrophil counts, and increased urine protein-to-creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease.ConclusionThis study reveals four endotypes of aPL-positive patients, a step toward personalized medicine for APS through pathway-informed stratification and therapy.