RARE DISEASE
Antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Synonyms: APLS, Antiphospholipid antibody syndrome, Classic APLS, Classic antiphospholipid syndrome, Hughes syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by venous/arterial thrombosis, recurrent pregnancy loss, or placental insufficiency in the presence of persistently elevated antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein-I antibodies). It may occur as a primary condition or secondary to autoimmune diseases like systemic lupus erythematosus. Diagnosis requires clinical events plus antibody positivity on ≥2 tests ≥12 weeks apart. Long-term anticoagulation is the mainstay of thrombotic APS management [1][6][14].
Population
Prevalence: 40-50 cases per 100,000 in the US, with 30-40% occurring in SLE patients [2][17]
Demographics: 3:1 female predominance; peak diagnosis between ages 20-50 [1][10][14]
High-risk profiles: Triple antibody positivity (lupus anticoagulant + IgG anticardiolipin + IgG anti-β2GPI) confers greatest thrombotic risk [3][6]
Therapies
Thrombosis: Lifelong warfarin (INR 2-3) for venous events; arterial thrombosis may require INR 3-4 or combined antiplatelet therapy [3][12][15]
Obstetric: Low-molecular-weight heparin + low-dose aspirin for pregnancy, reducing miscarriage risk from >70% to <30% [3][12][14]
Catastrophic APS: Triple therapy with anticoagulants, corticosteroids, and plasma exchange/IVIG (survival ↑ from 54% to 69%) [8][16]
Categories: rare gynecological and obstetric diseases, rare hematological diseases, rare systemic and rheumatological diseases
Research Papers
2,684 drug discovery papers about Antiphospholipid syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,684 drug discovery papers about Antiphospholipid syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-08 | Enhanced type I interferon signature in primary APS patients is associated with thrombocytopenia.
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or obstetric complications due to persistent antiphospholipid antibodies. Type I interferon (IFN) upregulation has been identified as a potential contributor to the pathophysiology of APS, however, the relationship between type I IFN and clinical manifestations of APS still needs to be delineated. The objective of this study was the evaluation of the potential role of type I IFN regarding different APS manifestations. We conducted a retrospective analysis of APS patients who presented to our clinic between 2017 and 2024, focusing on clinical manifestations, recurring events and serological profiles in relation to Siglec-1 expression on monocytes, as a surrogate marker of type I IFN signature. Out of the 218 APS patients included in the study, 123 were diagnosed with primary APS (pAPS) and 95 with secondary APS (sAPS), the latter mostly SLE associated, showing a general higher type I IFN signature as the pAPS cohort. While no significant differences in Siglec-1 expression were observed across most APS manifestations (venous, arterial, mixed and obstetric events), significantly higher type I IFN activity was detected in APS patients with thrombocytopenia compared to those without (p = 0.0061). Moreover, we found an inverse correlation between platelet numbers and Siglec-1 values. Interestingly, the difference in type I IFN signature was confirmed in the pAPS cohort with thrombocytopenia (p = 0.0242). In sAPS, Siglec-1 expression did not differ significantly between patients with and without thrombocytopenia (p = 0.4664). With regard to serological and clinical characteristics, patients with thrombocytopenia exhibited a higher prevalence of triple positivity, elevated levels of anti-cardiolipin IgG antibodies and an increased incidence of recurrent and mixed (arterial/venous) thromboembolic events. To conclude, the data indicate that type I IFN may be a relevant factor for the occurrence of thrombocytopenia in pAPS. Moreover, thrombocytopenia in APS was linked to increased prevalence of triple positivity, higher anti-cardiolipin IgG titres, and higher disease severity, underscoring the importance of closer monitoring in this subgroup. These results warrant validation in prospective studies and could support potential therapeutic targeting of type I IFN in a subset of APS patients.
2026-08-02 | The Dual Role of Uric Acid: Pathological Implications Across Chronic Diseases and Current Approaches to Hyperuricemia Management.
Uric acid is the end product of purine metabolism and plays a dichotomous role in the human body. On one hand, it exerts antioxidant and neuroprotective effects; on the other hand, chronic hyperuricemia has been strongly associated with diseases beyond gout, affecting the cardiovascular, renal, metabolic, autoimmune, and central nervous systems (CNS). Excess uric acid promotes oxidative stress, endothelial damage, neurodegeneration, inflammasome activation, and impairs energy metabolism. It exacerbates autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and antiphospholipid syndrome (APS), by increasing inflammatory and oxidative damage, leading to greater end-organ damage. The British Society for Rheumatology, European League Against Rheumatism, American College of Rheumatology, and National Institute for Health and Care Excellence (NICE) have all established a "treat-to-target" approach for hyperuricemia with serum urate levels below 6 mg/dL and below 5 mg/dL in severe cases. Allopurinol and Febuxostat, xanthine oxidase inhibitors, are used as first-line pharmacological therapies for the treatment of hyperuricemia, whereas uricosurics and Interleukin-1 (IL-1) inhibitors are preferred in cases of refractory hyperuricemia. Lifestyle modifications, such as the Dietary Approaches to Stop Hypertension (DASH) diet, weight reduction, and smoking cessation, are also recommended for the long-term management of the disease. Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, selective urate transport inhibitors, and plant-derived anti-inflammatory compounds have emerged as new treatments with promising responses. This review synthesizes the current literature on the multifaceted role of uric acid and emphasizes its systemic implications in chronic diseases. It also outlines the already established management options and new innovative therapies for managing this disease. Understanding this dichotomous role is essential for adopting a precise management approach that balances the protective and pathological effects of uric acid.
2026-07-30 | Hydroxychloroquine in pregnancy: therapeutic applications, mechanisms of action, and safety - a narrative review.
Hydroxychloroquine (HCQ), a 4-aminoquinoline originally developed as an antimalarial, is widely used as an immunomodulatory therapy in rheumatic diseases during pregnancy. It is recommended for women with Systemic lupus erythematosus (SLE) and Antiphospholipid syndrome (APS), with emerging interest in broader obstetric applications. To synthesise current evidence on the pharmacology, mechanisms of action, clinical applications, and safety of HCQ in pregnancy and lactation, and to appraise its place in contemporary obstetric practice. We conducted a structured narrative review of peer-reviewed literature indexed in PubMed, Embase, and the Cochrane Library (January 2005 to March 2026), and consultation of major international guidelines. Randomised controlled trials, cohort studies, systematic reviews, meta-analyses, mechanistic studies, and authoritative clinical guidelines were prioritised. Current data support the safety of HCQ at doses ≤ 400 mg/day, with no consistent increase in major congenital malformations or adverse birth outcomes. HCQ reduces disease flares in SLE pregnancies, lowers the risk of preeclampsia, and improves live-birth rates in obstetric APS. Emerging but lower-certainty evidence suggests a possible benefit in antinuclear antibody-positive recurrent pregnancy loss and recurrent implantation failure. HCQ is compatible with breastfeeding. Evidence for use in recurrent pregnancy loss and implantation failure remains limited. Current evidence affirms HCQ as a safe and effective pharmacotherapy in rheumatic disease pregnancies, with potential benefits in selected obstetric indications. Ongoing randomised trials are required.
2026-07-29 | OFDI-Guided Stentless PCI for Erosion-Related STEMI Unmasking Antiphospholipid Syndrome.
Antiphospholipid syndrome (APS) accounts for 2.8% to 5.5% of acute myocardial infarctions in young adults, yet it is often unrecognized at presentation. A 25-year-old man presented with anterior ST-segment elevation myocardial infarction, ventricular fibrillation, and cardiogenic shock. Angiography revealed a 99% proximal left anterior descending artery stenosis. Intracoronary imaging revealed an organized thrombus-dominant lesion without plaque rupture, suggestive of plaque erosion. Given his young age and large diagonal branch at risk, a prolonged perfusion-balloon inflation was used to achieve TIMI flow grade 3. Persistent antiphospholipid antibody positivity at ≥12 weeks confirmed definite APS; warfarin monotherapy was initiated. Post hoc confirmation of APS guided long-term vitamin K antagonist therapy, underscoring the value of thrombophilia screening in young-onset myocardial infarction. Stentless revascularization is a reasonable option in young patients with myocardial infarction and imaging features of plaque erosion. APS should be screened to guide appropriate anticoagulation therapy.
2026-07-28 | Nasal Mucosal Necrosis in a Patient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A Case Report and Literature Review.
Background: The clinical presentation of nasal mucosal necrosis, an exceedingly rare manifestation of secondary antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus, often mimics invasive fungal sinusitis (IFS), causing diagnostic challenges and potentially unnecessary surgical interventions. Here, we report a unique case of nasal necrosis exacerbation by thrombopoietin receptor agonist (TPO-RA) therapy. Case Description: A 54-year-old woman with systemic lupus erythematosus and APS developed rapid nasal mucosal necrosis after receiving TPO-RA. An initial clinical suspicion of IFS led to emergency surgical debridement, and histopathology revealed fibrin-rich intraluminal microthrombi without fungal elements. After replacing eltrombopag with fostamatinib (a Syk inhibitor), the nasal lesions improved markedly, with complete mucosal healing. Conclusions: Nasal mucosal necrosis, a rare but serious symptom of secondary APS, requires careful differential diagnosis from IFS or other necrotizing diseases. APS-related vasculopathy should be considered following TPO-RA therapy, particularly if repeat debridement fails to identify an infectious cause.
proteins
2026-04-09 | β2-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms.
Identified in the 1990s as the primary target of antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) remains a central focus in hematology and immunology. Anti-β2GPI antibodies are important not only for diagnosing APS but also play a key role in causing thrombosis and pregnancy complications in these patients. Elucidating the molecular basis of antibody-β2GPI interactions is therefore critical for advancing APS research and has broad implications for understanding related thrombotic autoimmune disorders. In this review, we summarize recent progress on the structural biology of β2GPI, discuss mechanisms of autoantibody recognition, and provide an update on genetic polymorphisms. By resolving longstanding controversies and uncovering new regulatory principles, structural insights are paving the way for targeted approaches aimed at selectively neutralizing pathogenic autoantibodies without broadly impairing coagulation or immune function, offering promising paths toward transformative APS therapies.
2026-03-12 | Autoimmunity beyond antibodies: alternative roles of beta-2-glycoprotein I in and out of antiphospholipid syndrome?
The term autoimmune disease refers to autoantibody-dependent pathophysiological conditions, in which characterising the autoantibodies is essential, as is studying their target(s), the (auto)antigen(s), which represent the other side of the coin. In this review, we aimed to go further inside the ultimate experimental works on the pathophysiology of Beta-2-Glycoprotein I (B2GPI), the main target of the antiphospholipid antibodies (aPL) in Antiphospholipid Syndrome (APS). This protein is almost unique in the body. It is able to up and down regulate the complement and the coagulative cascade and displays pleiotropic functions that are still to be fully understood. Many recent omics-based experimental approaches have found B2GPI among the proteins involved in both acute and chronic disease conditions. These range from inflammatory diseases to cancer. The protein's ability to modulate biological processes like apoptosis, redox impairment, cardiolipin binding, lipopolysacharide, and circulating mitochondria scavenging suggests its role in homeostasis, both as an acute phase modulator and a tolerogenic spark. We imagined B2GPI as a sentinel protein, patrolling tissues as part of a complex system of interacting molecules: the fine-tuning regulation of its threshold in circulation and on solid-target tissues may hold the key to its reactivity. The aPL might represent the prototypical way of this threshold dysfunction. The change in focus towards the antigen might help APS therapeutic approaches and aid in understanding different clinical outcomes. Moreover, it reveals a fascinating protein, acting like a safety net in the body, whose disruption can lead to a wide range of pathophysiological conditions.
2026-02-23 | Case Report: Telitacicept in the treatment of cSLE-APS: novel therapeutic perspectives on autoimmune thrombotic diseases in children.
Thrombotic antiphospholipid syndrome (APS) in Childhood-onset systemic lupus erythematosus (cSLE) remains a therapeutic frontier. Here, we report the first case of telitacicept (a TACI-Fc fusion protein)- induced remission in cSLE related antiphospholipid syndrome (cSLE-APS), where targeted dual BAFF(B cell-activating factor)/APRIL(a proliferation-inducing ligand) inhibition resolved life-threatening infarctions and achieved sustained disease control. During treatment, corticosteroids were successfully discontinued within six months, and a lupus low disease activity state (LLDAS) was maintained. Our findings indicate that telitacicept's unique ability to regulate B-cell activity could target the dual pathology of cSLE-APS, offering a new therapeutic approach for this serious condition.
2026-01-28 | Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)-like Syndrome: A Case Report and Some Considerations on a Novel Diagnostic and Therapeutic Challenge.
Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient's clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis.
2026-01-04 | The regulatory roles of Beta-2 glycoprotein I (β2GPI) in thrombosis and hemostasis and abnormal disease conditions developed by autoantibodies against β2GPI.
Beta-2 glycoprotein I (β2GPI) as a core target antigen of antiphospholipid antibodies (aPLs), is a multifunctional plasma protein with phospholipid-binding properties. Under physiological conditions, β2GPI not only binds to negatively charged phospholipids via its domain V but also interacts with various molecules, such as angiostatin4.5 (AS4.5) and annexin II. These interactions play key roles in maintaining the balance between procoagulant and anticoagulant processes and in promoting angiogenesis. β2GPI binds to pathophysiological ligands, such as apoptotic cells, oxidized low-density lipoprotein (oxLDL) and neutrophil extracellular traps (NETs). These complexes can trigger the production of anti-β2GPI autoantibodies in autoimmune patients, leading to antiphospholipid syndrome (APS). The resulting IgG immune complexes activate and impair endothelial cells, resulting in aberrant activation of the coagulation cascade, disruption of lipid metabolic homeostasis, and breakdown of immune tolerance. Together, these processes promote thrombotic events in APS and accelerate the progression of atherosclerotic plaques. This review paper summarizes the dynamic conformational transitions of β2GPI's functional domains that elucidates the dual regulatory role of β2GPI-mediated molecular interactions in thrombosis and atherosclerosis (AS) and reveals the mechanism by which anti-β2GPI autoantibodies mediate endothelial injury, thrombosis, and inflammatory amplification. These findings may provide a theoretical molecular basis for the development of novel diagnostic and therapeutic strategies targeting β2GPI. TAKE HOME MESSAGE.
cell therapies
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-04-09 | Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
2025-09-08 | Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
CAR-T cell therapy has been proven effective in various autoimmune diseases, with most studies utilizing lentiviral-transduced CAR-T cells. In recent years, retroviral vector-transduced CAR-T cells-characterized by a high positivity rate, stable cell lines, and lower plasmid requirements-have attracted increasing attention. This article presents a complex case of a patient with SLE combined with APS and TBIRS. For four years following the diagnosis, the patient underwent conventional steroid therapy and immunotherapy, which yielded unsatisfactory and relapse-prone results. After receiving anti-CD19 CAR-T cells transduced with a retroviral vector, the patient experienced an excellent postoperative recovery without any infusion-related adverse reactions. Post-treatment, the patient's creatinine, anti-dsDNA antibodies, albumin, and glycated hemoglobin levels returned to normal, eliminating the need for ongoing glucocorticoids or hypoglycemic agents. Although there are some available reports of CAR-T cells treating SLE, it is still very rare and significant for successfully treating such a complicated case, especially after proving the unavailability of traditional therapy. Furthermore, this is the first reported case of treating TBIRS syndrome with retroviral vector-transduced CAR-T therapy.
2025-03-06 | Plasmapheresis for lowering the risks of placenta-associated complications in antiphospholipid syndrome
Aim : to study plasmapheresis (PP) effect on antiphospholipid syndrome (APS) treatment during preconception preparation and pregnancy. Materials and Methods . A single-center, prospective, randomized, uncontrolled study was conducted. A total of 137 women aged 22 to 32 years diagnosed with APS-related habitual miscarriage were examined. The patients were stratified as follows: main group consisted of 73 patients underwent a PF course (7 procedures at preconception preparation stage); comparison group – 64 patients not underwent efferent therapy. Antiphospholipid antibodies (APA) circulation was determined by solid-phase immunofluorescence. PР was performed using an intermittent technique. The laboratory study included assessing titers of lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein 1 antibodies (anti-β2-GP1) and anti-annexin V antibodies (anti-ANX). Antibody titers were measured before and after pregravid preparation. Results . After PР, anti-β2-GР1 titers decreased by 66.6 % (p = 0.00001) in main group. In patients who underwent standard therapy without PР, no significant changes in circulation level of anti-β2-GР1 were noted. LA frequency in main and comparison group decreased by 57.3 % (p = 0.042) and 10.9 % (p = 0.69), respectively. Conclusion . The frequency of detecting elevated AРA levels in women after a course of efferent therapy decreased significantly, whereas standard therapy showed no such effects. PР as part of complex therapy is more appropriate for achieving maximum effect.
2025-02-19 | In-hospital outcomes of patients with antiphospholipid syndrome undergoing transcatheter and surgical aortic valve replacement: A population-based analysis of national inpatient sample from 2015-2021.
BackgroundValvular abnormalities are common in antiphospholipid syndrome (APS). For patients who undergo aortic valve replacement (AVR), previous single institutional studies or case reports reported higher risks of mortality and thromboembolic complications among APS patients. This study aimed to investigate in-hospital outcomes of APS patients undergoing transcatheter (TAVR) and surgical aortic valve replacement (SAVR) using the largest all-payer database in the United States.MethodsPatients who underwent TAVR and SAVR were selected from National Inpatient Sample from Q4 2015-2021. Exclusion criteria were age under 18 years and concomitant procedures. Preoperative characteristics were matched between APS and non-APA patients using a 1:5 propensity-score matching in TAVR and SAVR, separately. In-hospital outcomes were examined.ResultsAfter propensity-score matching, 504 non-APS patients were matched to 100 APS patients in TAVR, while 581 non-APS patients were matched to 119 APS patients in SAVR. All outcomes between APS and non-APS patients were comparable after TAVR. In contrast, APS patients undergoing SAVR had higher risks of pulmonary embolism (PE; 5.13% vs 0.86%, p < .01) and acute kidney injury (AKI; 35.04% vs 22.55%, p = .01).ConclusionThis study represents one of the first large-scale, population-based analyses of AVR outcomes for APS patients using a national registry. APS patients had all comparable outcomes after TAVR, while they had higher risks of PE and AKI after SAVR. This highlights the necessity for close perioperative antithrombotic management and careful monitoring of renal function in APS patients. TAVR may offer a safer alternative to SAVR for appropriately selected patients, including those with APS.
antibodies
2026-08-13 | Reported Prevalence of Inherited Thrombophilia in Pregnancy: Impact of Cohort Selection on Screening Implications-A Systematic Review.
Background/Objectives: Inherited thrombophilia (IT) has been extensively investigated as a potential contributor to adverse pregnancy outcomes; however, reported prevalence varies widely across studies. This systematic review aimed to evaluate how cohort selection influences the reported prevalence of inherited thrombophilia in pregnancy and to explore the implications of this variability for clinical interpretation and screening practices. Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, and Google Scholar were searched. A total of 5480 records were identified, and 7 observational studies (cohort and case-control) met inclusion criteria. Data were synthesized qualitatively due to heterogeneity. Results: Prevalence ranged from 0% to 14%, depending on population characteristics. The largest cohort study reported an inherited thrombophilia prevalence of 8.1%, comparable to the general population. Higher rates were observed in referral-based and antiphospholipid Syndrome (APS)-associated cohorts, while case-control studies showed no significant differences between affected individuals and controls. Ethnic variability was also observed. Conclusions: These findings should be interpreted as patterns observed across heterogeneous study designs rather than as definitive evidence of causality. Current evidence does not clearly support universal screening in pregnancy; however, the findings should be interpreted cautiously because several included studies were limited by small sample sizes and methodological heterogeneity.
2026-08-12 | Case Report: IVIG as a bridging strategy in high-risk antiphospholipid syndrome with infected cutaneous ulceration and thrombocytopenia.
Severe cutaneous ulceration in antiphospholipid syndrome (APS) with concurrent infection and thrombocytopenia presents a therapeutic dilemma: standard immunosuppression risks worsening infection, while anticoagulation risks hemorrhage. We present a high-risk case successfully managed using intravenous immunoglobulin (IVIG) as a bridging immunomodulatory strategy. A 73-year-old man with triple-positive APS and immune thrombocytopenic purpura (ITP) developed rapidly progressive leg ulcers with clinical features consistent with pyoderma gangrenosum-like disease, complicated by active MRSA and Pseudomonas aeruginosa infection and severe thrombocytopenia (12 × 109/L). Standard therapies were contraindicated: corticosteroids risked worsening infection; anticoagulation risked hemorrhage. The patient received IVIG (0.4 g/kg per dose, every 3 weeks) as primary immunomodulation, concurrent targeted antimicrobial therapy, temporary anticoagulation interruption, and discontinuation of baseline mycophenolate mofetil. Following platelet recovery above 70 × 109/L, therapeutic anticoagulation was resumed with enoxaparin (80 mg subcutaneously twice daily) and aspirin (75 mg daily). Over five months, progressive re-epithelialization culminated in complete healing with platelet recovery. This case supports the feasibility of IVIG as a bridging immunomodulatory strategy in high-risk APS cutaneous disease where standard therapies are contraindicated by concurrent infection and thrombocytopenia. The sequential management approach successfully resolved a clinically challenging scenario. This case illustrates how risk-adapted immunomodulation may enable safe management of complex APS manifestations.
2026-08-10 | Monoclonal Gammopathy of Thrombotic Significance.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.
2026-07-30 | Neutrophil extracellular traps induced by a monoclonal anti-phosphatidylserine/prothrombin antibody activate platelets in vitro.
Antiphospholipid syndrome (APS) is an autoimmune thrombotic disorder characterized by the presence of antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (aPS/PT). While neutrophil extracellular traps (NETs) are implicated in the pathogenesis of APS, the role of aPS/PT in NET induction and its contribution to thrombosis remain unclear. This study aimed to clarify the effects of NETs induced by a monoclonal aPS/PT antibody on platelet activation and their potential contribution to thrombo-inflammatory responses. NETs were induced by stimulating peripheral blood neutrophils from healthy donors with aPS/PT. Their morphology and platelet-activating capacity were compared with NETs induced by anti-neutrophil cytoplasmic antibodies (ANCAs). Proteomic analyses were conducted to comprehensively compare protein compositions of these NETs, and candidate proteins associated with platelet activation in aPS/PT-induced NETs were identified. Functional inhibition assays were then conducted to assess whether blocking these candidates would suppress aPS/PT-induced NET-mediated platelet activation. We found that binding of aPS/PT to neutrophils induced NET formation, with a larger and more fibrous morphology compared to ANCA-induced NETs. Platelets trapped in aPS/PT-induced NETs showed significantly higher activation compared to those trapped in ANCA-induced NETs. Proteomic analyses identified histone H3 as a potential mediator of platelet activation in aPS/PT-induced NETs. Correspondingly, plasma concentrations of H3.1 nucleosome were significantly higher in patients with APS than in healthy controls. Blockade of histone H3 using a neutralizing antibody significantly suppressed platelet activation mediated by aPS/PT-induced NETs. These findings suggest that aPS/PT-induced NETs contribute to platelet activation and may promote thrombo-inflammatory responses in APS. Targeting histone H3 within aPS/PT-induced NETs may provide a potential therapeutic strategy for thrombo-inflammatory processes in APS.
2026-07-19 | Perioperative Use of Efgartigimod Alfa, a Neonatal Fc Receptor Antagonist, to Reduce Antiphospholipid Antibody Titers and Thrombotic Risk in a Kidney Transplant Recipient.
Antiphospholipid syndrome (APS) is associated with an increased risk of thrombotic complications after kidney transplantation, particularly in patients with persistently elevated and triple-positive antiphospholipid antibodies (aPLs). Management of APS in kidney transplantation relies primarily on perioperative anticoagulation; however, thrombotic events may still occur despite appropriate therapy in patients with high-risk aPLs. We report the case of a 49-year-old woman with systemic lupus erythematosus-associated APS and persistently triple-positive aPLs who underwent living donor kidney transplantation. Because of her high thrombotic risk, perioperative immunoglobulin G--lowering therapy with the neonatal Fc receptor antagonist efgartigimod alfa was administered in addition to therapeutic anticoagulation. Treatment with efgartigimod alfa was associated with marked reductions in anticardiolipin and anti-β2-glycoprotein I antibody levels before transplantation, conversion of lupus anticoagulant to negative after transplantation, and sustained suppression of aPLs during the early posttransplant period. Kidney transplantation was successful with stable graft function during follow-up. To our knowledge, this represents the first reported use of efgartigimod alfa to reduce aPLs in the perioperative management of APS in kidney transplantation.
other
2024-07-25 | Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.
Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.
2023-05-17 | Metastasis-associated lung adenocarcinoma transcript 1 induces methyl-CpG-binding domain protein 4 in mice with recurrent spontaneous abortion caused by anti-phospholipid antibody positivity.
Antiphospholipid syndrome is an autoimmune disease characterized by pregnancy-related morbidity, related to persistent positivity of antiphospholipid antibodies (APL). One of the characteristics of pregnancy-related morbidity in patients with antiphospholipid syndrome is recurrent spontaneous abortion (RSA). This study aimed to examine the mechanism through which metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates methyl-CpG-binding domain protein 4 (MBD4) expression in APL-positive RSA. Clinical samples were subjected to microarray analysis to filter differentially expressed genes. RSA mice with APL positivity were generated, followed by adenoviral vector injection to artificially upregulate MALAT1. The effects of MALAT1 on the biological behavior of trophoblast cells were assessed. The downstream mechanism of MALAT1 was analyzed using subcellular fractionation and bioinformatics prediction, and the relationship between MALAT1 and CREB binding protein (CREBBP) or MBD4 was investigated in trophoblast cells. MALAT1 was downregulated in APL-positive RSA patients. MALAT1 was predominantly localized in the nucleus and recruited CREBBP to mediate the MBD4 transcription. In the APL-positive RSA mice overexpressing MALAT1, the expression of soluble Fms-related tyrosine kinase 1 and anticardiolipin antibody and the embryonic resorption rate were decreased, indicating that MALAT1 reduced the occurrence of RSA in mice. Moreover, MALAT1 enhanced proliferation, migration, and invasion of trophoblast cells through recruiting CREBBP to promote MBD4 expression. Silencing of CREBBP or MBD4 increased embryonic resorption rate in RSA mice overexpressing MALAT1. MALAT1 suppresses APL-positive RSA by promoting MBD4 transcription through recruitment of CREBBP to the MBD4 promoter region.
2023-04-24 | Antisense oligonuleotides influences trophoblasts behaviors by changing LncNR_040117 expression in antiphospholipid antibody syndrome-induced recurrent pregnancy loss.
The primary objective of this study was to explore whether antisense oligonucleotides (ASOs) that reduce LncNR_040117 expression in patients with antiphospholipid antibody syndrome (APS)-induced recurrent pregnancy loss (RPL), and further decrease apoptosis and improve trophoblasts invasion through mitogen-activated protein kinase (MAPK) pathways. This paper aimed to provide a new strategy to treat APS-induced RPL. In this study, we used quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to analyze the expression level of LncNR 040117 in HTR-8/SVneo cells following transfection with ASOs. Then we utilized Western blotting to test the expression levels of interleukin-1β (IL-1β), intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and key molecules of MAPK pathways, including the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38. In addition, we examined the HTR-8/SVneo cells apoptosis by cell apoptosis assay, and migration and invasion by transwell antibody assay. Each experiment was repeated three times. The data are presented as the means ± SDs, and statistical comparisons were performed using Student's t-test. p < 0.05 was considered significant. Transfected with ASOs, LncNR_040117 was downregulated in trophoblasts compared with APS-induced RPL patients. And LncNR_040117 low expression induced IL-1β and downstream adhesion molecules ICAM-1 and VCAM-1expression level decreased, as well as MAPK pathways downregulation, including the ERK pathway, JNK pathway and p38/MAPK pathway. Furthermore, all these changes resulted in decreased apoptosis and increased migration and invasion of trophoblasts. This study indicated that ASOs that decrease LncNR_040117 expression can reduce apoptosis and enhance the invasion and migration of trophoblasts by regulating the MAPK pathway.
2023-02-10 | Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome.
Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.
2022-06-14 | Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome.
Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19. This prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed. We included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG (p=0.058) and IgM (p=0.091); anti-beta-2 glycoprotein I (aβ2GPI) IgG (p=0.513) and IgM (p=0.468). We provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.
small molecules
2026-08-08 | Enhanced type I interferon signature in primary APS patients is associated with thrombocytopenia.
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and/or obstetric complications due to persistent antiphospholipid antibodies. Type I interferon (IFN) upregulation has been identified as a potential contributor to the pathophysiology of APS, however, the relationship between type I IFN and clinical manifestations of APS still needs to be delineated. The objective of this study was the evaluation of the potential role of type I IFN regarding different APS manifestations. We conducted a retrospective analysis of APS patients who presented to our clinic between 2017 and 2024, focusing on clinical manifestations, recurring events and serological profiles in relation to Siglec-1 expression on monocytes, as a surrogate marker of type I IFN signature. Out of the 218 APS patients included in the study, 123 were diagnosed with primary APS (pAPS) and 95 with secondary APS (sAPS), the latter mostly SLE associated, showing a general higher type I IFN signature as the pAPS cohort. While no significant differences in Siglec-1 expression were observed across most APS manifestations (venous, arterial, mixed and obstetric events), significantly higher type I IFN activity was detected in APS patients with thrombocytopenia compared to those without (p = 0.0061). Moreover, we found an inverse correlation between platelet numbers and Siglec-1 values. Interestingly, the difference in type I IFN signature was confirmed in the pAPS cohort with thrombocytopenia (p = 0.0242). In sAPS, Siglec-1 expression did not differ significantly between patients with and without thrombocytopenia (p = 0.4664). With regard to serological and clinical characteristics, patients with thrombocytopenia exhibited a higher prevalence of triple positivity, elevated levels of anti-cardiolipin IgG antibodies and an increased incidence of recurrent and mixed (arterial/venous) thromboembolic events. To conclude, the data indicate that type I IFN may be a relevant factor for the occurrence of thrombocytopenia in pAPS. Moreover, thrombocytopenia in APS was linked to increased prevalence of triple positivity, higher anti-cardiolipin IgG titres, and higher disease severity, underscoring the importance of closer monitoring in this subgroup. These results warrant validation in prospective studies and could support potential therapeutic targeting of type I IFN in a subset of APS patients.
2026-08-02 | The Dual Role of Uric Acid: Pathological Implications Across Chronic Diseases and Current Approaches to Hyperuricemia Management.
Uric acid is the end product of purine metabolism and plays a dichotomous role in the human body. On one hand, it exerts antioxidant and neuroprotective effects; on the other hand, chronic hyperuricemia has been strongly associated with diseases beyond gout, affecting the cardiovascular, renal, metabolic, autoimmune, and central nervous systems (CNS). Excess uric acid promotes oxidative stress, endothelial damage, neurodegeneration, inflammasome activation, and impairs energy metabolism. It exacerbates autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and antiphospholipid syndrome (APS), by increasing inflammatory and oxidative damage, leading to greater end-organ damage. The British Society for Rheumatology, European League Against Rheumatism, American College of Rheumatology, and National Institute for Health and Care Excellence (NICE) have all established a "treat-to-target" approach for hyperuricemia with serum urate levels below 6 mg/dL and below 5 mg/dL in severe cases. Allopurinol and Febuxostat, xanthine oxidase inhibitors, are used as first-line pharmacological therapies for the treatment of hyperuricemia, whereas uricosurics and Interleukin-1 (IL-1) inhibitors are preferred in cases of refractory hyperuricemia. Lifestyle modifications, such as the Dietary Approaches to Stop Hypertension (DASH) diet, weight reduction, and smoking cessation, are also recommended for the long-term management of the disease. Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, selective urate transport inhibitors, and plant-derived anti-inflammatory compounds have emerged as new treatments with promising responses. This review synthesizes the current literature on the multifaceted role of uric acid and emphasizes its systemic implications in chronic diseases. It also outlines the already established management options and new innovative therapies for managing this disease. Understanding this dichotomous role is essential for adopting a precise management approach that balances the protective and pathological effects of uric acid.
2026-07-30 | Hydroxychloroquine in pregnancy: therapeutic applications, mechanisms of action, and safety - a narrative review.
Hydroxychloroquine (HCQ), a 4-aminoquinoline originally developed as an antimalarial, is widely used as an immunomodulatory therapy in rheumatic diseases during pregnancy. It is recommended for women with Systemic lupus erythematosus (SLE) and Antiphospholipid syndrome (APS), with emerging interest in broader obstetric applications. To synthesise current evidence on the pharmacology, mechanisms of action, clinical applications, and safety of HCQ in pregnancy and lactation, and to appraise its place in contemporary obstetric practice. We conducted a structured narrative review of peer-reviewed literature indexed in PubMed, Embase, and the Cochrane Library (January 2005 to March 2026), and consultation of major international guidelines. Randomised controlled trials, cohort studies, systematic reviews, meta-analyses, mechanistic studies, and authoritative clinical guidelines were prioritised. Current data support the safety of HCQ at doses ≤ 400 mg/day, with no consistent increase in major congenital malformations or adverse birth outcomes. HCQ reduces disease flares in SLE pregnancies, lowers the risk of preeclampsia, and improves live-birth rates in obstetric APS. Emerging but lower-certainty evidence suggests a possible benefit in antinuclear antibody-positive recurrent pregnancy loss and recurrent implantation failure. HCQ is compatible with breastfeeding. Evidence for use in recurrent pregnancy loss and implantation failure remains limited. Current evidence affirms HCQ as a safe and effective pharmacotherapy in rheumatic disease pregnancies, with potential benefits in selected obstetric indications. Ongoing randomised trials are required.
2026-07-29 | OFDI-Guided Stentless PCI for Erosion-Related STEMI Unmasking Antiphospholipid Syndrome.
Antiphospholipid syndrome (APS) accounts for 2.8% to 5.5% of acute myocardial infarctions in young adults, yet it is often unrecognized at presentation. A 25-year-old man presented with anterior ST-segment elevation myocardial infarction, ventricular fibrillation, and cardiogenic shock. Angiography revealed a 99% proximal left anterior descending artery stenosis. Intracoronary imaging revealed an organized thrombus-dominant lesion without plaque rupture, suggestive of plaque erosion. Given his young age and large diagonal branch at risk, a prolonged perfusion-balloon inflation was used to achieve TIMI flow grade 3. Persistent antiphospholipid antibody positivity at ≥12 weeks confirmed definite APS; warfarin monotherapy was initiated. Post hoc confirmation of APS guided long-term vitamin K antagonist therapy, underscoring the value of thrombophilia screening in young-onset myocardial infarction. Stentless revascularization is a reasonable option in young patients with myocardial infarction and imaging features of plaque erosion. APS should be screened to guide appropriate anticoagulation therapy.
2026-07-28 | Nasal Mucosal Necrosis in a Patient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A Case Report and Literature Review.
Background: The clinical presentation of nasal mucosal necrosis, an exceedingly rare manifestation of secondary antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus, often mimics invasive fungal sinusitis (IFS), causing diagnostic challenges and potentially unnecessary surgical interventions. Here, we report a unique case of nasal necrosis exacerbation by thrombopoietin receptor agonist (TPO-RA) therapy. Case Description: A 54-year-old woman with systemic lupus erythematosus and APS developed rapid nasal mucosal necrosis after receiving TPO-RA. An initial clinical suspicion of IFS led to emergency surgical debridement, and histopathology revealed fibrin-rich intraluminal microthrombi without fungal elements. After replacing eltrombopag with fostamatinib (a Syk inhibitor), the nasal lesions improved markedly, with complete mucosal healing. Conclusions: Nasal mucosal necrosis, a rare but serious symptom of secondary APS, requires careful differential diagnosis from IFS or other necrotizing diseases. APS-related vasculopathy should be considered following TPO-RA therapy, particularly if repeat debridement fails to identify an infectious cause.
proteins
2026-04-09 | β2-Glycoprotein I: structure, mechanisms of autoantibody recognition, and polymorphisms.
Identified in the 1990s as the primary target of antiphospholipid antibodies (aPL) in antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) remains a central focus in hematology and immunology. Anti-β2GPI antibodies are important not only for diagnosing APS but also play a key role in causing thrombosis and pregnancy complications in these patients. Elucidating the molecular basis of antibody-β2GPI interactions is therefore critical for advancing APS research and has broad implications for understanding related thrombotic autoimmune disorders. In this review, we summarize recent progress on the structural biology of β2GPI, discuss mechanisms of autoantibody recognition, and provide an update on genetic polymorphisms. By resolving longstanding controversies and uncovering new regulatory principles, structural insights are paving the way for targeted approaches aimed at selectively neutralizing pathogenic autoantibodies without broadly impairing coagulation or immune function, offering promising paths toward transformative APS therapies.
2026-03-12 | Autoimmunity beyond antibodies: alternative roles of beta-2-glycoprotein I in and out of antiphospholipid syndrome?
The term autoimmune disease refers to autoantibody-dependent pathophysiological conditions, in which characterising the autoantibodies is essential, as is studying their target(s), the (auto)antigen(s), which represent the other side of the coin. In this review, we aimed to go further inside the ultimate experimental works on the pathophysiology of Beta-2-Glycoprotein I (B2GPI), the main target of the antiphospholipid antibodies (aPL) in Antiphospholipid Syndrome (APS). This protein is almost unique in the body. It is able to up and down regulate the complement and the coagulative cascade and displays pleiotropic functions that are still to be fully understood. Many recent omics-based experimental approaches have found B2GPI among the proteins involved in both acute and chronic disease conditions. These range from inflammatory diseases to cancer. The protein's ability to modulate biological processes like apoptosis, redox impairment, cardiolipin binding, lipopolysacharide, and circulating mitochondria scavenging suggests its role in homeostasis, both as an acute phase modulator and a tolerogenic spark. We imagined B2GPI as a sentinel protein, patrolling tissues as part of a complex system of interacting molecules: the fine-tuning regulation of its threshold in circulation and on solid-target tissues may hold the key to its reactivity. The aPL might represent the prototypical way of this threshold dysfunction. The change in focus towards the antigen might help APS therapeutic approaches and aid in understanding different clinical outcomes. Moreover, it reveals a fascinating protein, acting like a safety net in the body, whose disruption can lead to a wide range of pathophysiological conditions.
2026-02-23 | Case Report: Telitacicept in the treatment of cSLE-APS: novel therapeutic perspectives on autoimmune thrombotic diseases in children.
Thrombotic antiphospholipid syndrome (APS) in Childhood-onset systemic lupus erythematosus (cSLE) remains a therapeutic frontier. Here, we report the first case of telitacicept (a TACI-Fc fusion protein)- induced remission in cSLE related antiphospholipid syndrome (cSLE-APS), where targeted dual BAFF(B cell-activating factor)/APRIL(a proliferation-inducing ligand) inhibition resolved life-threatening infarctions and achieved sustained disease control. During treatment, corticosteroids were successfully discontinued within six months, and a lupus low disease activity state (LLDAS) was maintained. Our findings indicate that telitacicept's unique ability to regulate B-cell activity could target the dual pathology of cSLE-APS, offering a new therapeutic approach for this serious condition.
2026-01-28 | Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)-like Syndrome: A Case Report and Some Considerations on a Novel Diagnostic and Therapeutic Challenge.
Background and Clinical Significance: Disorders caused by platelet-activating antibodies targeting platelet factor 4 (PF4) are recognized as the cause of severe thrombotic events and are not restricted to heparin-induced thrombocytopenia (HIT). Case Presentation: We report a 67-year-old man with thrombocytopenia and extensive portal-splenic-mesenteric vein thrombosis complicated by intestinal ischemia. Despite intravenous unfractionated heparin (UFH), his condition worsened toward pulmonary embolism, septic shock, and multi-organ failure. Thrombolysis with alteplase was also ineffective. Both thrombophilia testing and autoimmune panels were negative, including those for antiphospholipid syndrome. An anti-PF4 immune thrombotic disorder was hypothesized. Therefore, argatroban was initiated instead of UFH therapy and intravenous immune globulin (IVIG) was administered. The platelet count increased and the patient's clinical condition progressively improved. An anti-PF4/heparin assay on a blood sample collected before IVIG was highly positive. Platelet activation assays did not demonstrate an increased activation after the addition of heparin (the Heparin-Induced Platelet Activation [HIPA] assay was negative) though increased activation was observed with the addition of PF4 (the PF4-Induced Platelet Activation [PIPA] assay was positive), thus defining a VITT-like syndrome. Conclusions: This case report highlights the crucial function of having adequate laboratory facilities available to disentangle different anti-PF4 disorders for an accurate definition of a specific diagnosis, such as VITT-like syndrome, thereby allowing for the most appropriate therapeutic management of these complex pathological conditions. The clinical suspicion of an anti-PF4 immune disorder should be considered in cases of severe, otherwise unexplained, thrombotic events associated with thrombocytopenia. Specific tests like HIPA and PIPA are essential for definitive diagnosis.
2026-01-04 | The regulatory roles of Beta-2 glycoprotein I (β2GPI) in thrombosis and hemostasis and abnormal disease conditions developed by autoantibodies against β2GPI.
Beta-2 glycoprotein I (β2GPI) as a core target antigen of antiphospholipid antibodies (aPLs), is a multifunctional plasma protein with phospholipid-binding properties. Under physiological conditions, β2GPI not only binds to negatively charged phospholipids via its domain V but also interacts with various molecules, such as angiostatin4.5 (AS4.5) and annexin II. These interactions play key roles in maintaining the balance between procoagulant and anticoagulant processes and in promoting angiogenesis. β2GPI binds to pathophysiological ligands, such as apoptotic cells, oxidized low-density lipoprotein (oxLDL) and neutrophil extracellular traps (NETs). These complexes can trigger the production of anti-β2GPI autoantibodies in autoimmune patients, leading to antiphospholipid syndrome (APS). The resulting IgG immune complexes activate and impair endothelial cells, resulting in aberrant activation of the coagulation cascade, disruption of lipid metabolic homeostasis, and breakdown of immune tolerance. Together, these processes promote thrombotic events in APS and accelerate the progression of atherosclerotic plaques. This review paper summarizes the dynamic conformational transitions of β2GPI's functional domains that elucidates the dual regulatory role of β2GPI-mediated molecular interactions in thrombosis and atherosclerosis (AS) and reveals the mechanism by which anti-β2GPI autoantibodies mediate endothelial injury, thrombosis, and inflammatory amplification. These findings may provide a theoretical molecular basis for the development of novel diagnostic and therapeutic strategies targeting β2GPI. TAKE HOME MESSAGE.
cell therapies
2026-04-11 | CD19 CAR-T therapy induces remission in refractory autoimmune hemolytic anemia with ITP and antiphospholipid syndrome.
Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.
2026-04-09 | Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
2025-09-08 | Case Report: Remission of a patient with complex combination of autoimmune diseases by anti-CD19 CAR-T cell therapy.
CAR-T cell therapy has been proven effective in various autoimmune diseases, with most studies utilizing lentiviral-transduced CAR-T cells. In recent years, retroviral vector-transduced CAR-T cells-characterized by a high positivity rate, stable cell lines, and lower plasmid requirements-have attracted increasing attention. This article presents a complex case of a patient with SLE combined with APS and TBIRS. For four years following the diagnosis, the patient underwent conventional steroid therapy and immunotherapy, which yielded unsatisfactory and relapse-prone results. After receiving anti-CD19 CAR-T cells transduced with a retroviral vector, the patient experienced an excellent postoperative recovery without any infusion-related adverse reactions. Post-treatment, the patient's creatinine, anti-dsDNA antibodies, albumin, and glycated hemoglobin levels returned to normal, eliminating the need for ongoing glucocorticoids or hypoglycemic agents. Although there are some available reports of CAR-T cells treating SLE, it is still very rare and significant for successfully treating such a complicated case, especially after proving the unavailability of traditional therapy. Furthermore, this is the first reported case of treating TBIRS syndrome with retroviral vector-transduced CAR-T therapy.
2025-03-06 | Plasmapheresis for lowering the risks of placenta-associated complications in antiphospholipid syndrome
Aim : to study plasmapheresis (PP) effect on antiphospholipid syndrome (APS) treatment during preconception preparation and pregnancy. Materials and Methods . A single-center, prospective, randomized, uncontrolled study was conducted. A total of 137 women aged 22 to 32 years diagnosed with APS-related habitual miscarriage were examined. The patients were stratified as follows: main group consisted of 73 patients underwent a PF course (7 procedures at preconception preparation stage); comparison group – 64 patients not underwent efferent therapy. Antiphospholipid antibodies (APA) circulation was determined by solid-phase immunofluorescence. PР was performed using an intermittent technique. The laboratory study included assessing titers of lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein 1 antibodies (anti-β2-GP1) and anti-annexin V antibodies (anti-ANX). Antibody titers were measured before and after pregravid preparation. Results . After PР, anti-β2-GР1 titers decreased by 66.6 % (p = 0.00001) in main group. In patients who underwent standard therapy without PР, no significant changes in circulation level of anti-β2-GР1 were noted. LA frequency in main and comparison group decreased by 57.3 % (p = 0.042) and 10.9 % (p = 0.69), respectively. Conclusion . The frequency of detecting elevated AРA levels in women after a course of efferent therapy decreased significantly, whereas standard therapy showed no such effects. PР as part of complex therapy is more appropriate for achieving maximum effect.
2025-02-19 | In-hospital outcomes of patients with antiphospholipid syndrome undergoing transcatheter and surgical aortic valve replacement: A population-based analysis of national inpatient sample from 2015-2021.
BackgroundValvular abnormalities are common in antiphospholipid syndrome (APS). For patients who undergo aortic valve replacement (AVR), previous single institutional studies or case reports reported higher risks of mortality and thromboembolic complications among APS patients. This study aimed to investigate in-hospital outcomes of APS patients undergoing transcatheter (TAVR) and surgical aortic valve replacement (SAVR) using the largest all-payer database in the United States.MethodsPatients who underwent TAVR and SAVR were selected from National Inpatient Sample from Q4 2015-2021. Exclusion criteria were age under 18 years and concomitant procedures. Preoperative characteristics were matched between APS and non-APA patients using a 1:5 propensity-score matching in TAVR and SAVR, separately. In-hospital outcomes were examined.ResultsAfter propensity-score matching, 504 non-APS patients were matched to 100 APS patients in TAVR, while 581 non-APS patients were matched to 119 APS patients in SAVR. All outcomes between APS and non-APS patients were comparable after TAVR. In contrast, APS patients undergoing SAVR had higher risks of pulmonary embolism (PE; 5.13% vs 0.86%, p < .01) and acute kidney injury (AKI; 35.04% vs 22.55%, p = .01).ConclusionThis study represents one of the first large-scale, population-based analyses of AVR outcomes for APS patients using a national registry. APS patients had all comparable outcomes after TAVR, while they had higher risks of PE and AKI after SAVR. This highlights the necessity for close perioperative antithrombotic management and careful monitoring of renal function in APS patients. TAVR may offer a safer alternative to SAVR for appropriately selected patients, including those with APS.
antibodies
2026-08-13 | Reported Prevalence of Inherited Thrombophilia in Pregnancy: Impact of Cohort Selection on Screening Implications-A Systematic Review.
Background/Objectives: Inherited thrombophilia (IT) has been extensively investigated as a potential contributor to adverse pregnancy outcomes; however, reported prevalence varies widely across studies. This systematic review aimed to evaluate how cohort selection influences the reported prevalence of inherited thrombophilia in pregnancy and to explore the implications of this variability for clinical interpretation and screening practices. Methods: A systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, and Google Scholar were searched. A total of 5480 records were identified, and 7 observational studies (cohort and case-control) met inclusion criteria. Data were synthesized qualitatively due to heterogeneity. Results: Prevalence ranged from 0% to 14%, depending on population characteristics. The largest cohort study reported an inherited thrombophilia prevalence of 8.1%, comparable to the general population. Higher rates were observed in referral-based and antiphospholipid Syndrome (APS)-associated cohorts, while case-control studies showed no significant differences between affected individuals and controls. Ethnic variability was also observed. Conclusions: These findings should be interpreted as patterns observed across heterogeneous study designs rather than as definitive evidence of causality. Current evidence does not clearly support universal screening in pregnancy; however, the findings should be interpreted cautiously because several included studies were limited by small sample sizes and methodological heterogeneity.
2026-08-12 | Case Report: IVIG as a bridging strategy in high-risk antiphospholipid syndrome with infected cutaneous ulceration and thrombocytopenia.
Severe cutaneous ulceration in antiphospholipid syndrome (APS) with concurrent infection and thrombocytopenia presents a therapeutic dilemma: standard immunosuppression risks worsening infection, while anticoagulation risks hemorrhage. We present a high-risk case successfully managed using intravenous immunoglobulin (IVIG) as a bridging immunomodulatory strategy. A 73-year-old man with triple-positive APS and immune thrombocytopenic purpura (ITP) developed rapidly progressive leg ulcers with clinical features consistent with pyoderma gangrenosum-like disease, complicated by active MRSA and Pseudomonas aeruginosa infection and severe thrombocytopenia (12 × 109/L). Standard therapies were contraindicated: corticosteroids risked worsening infection; anticoagulation risked hemorrhage. The patient received IVIG (0.4 g/kg per dose, every 3 weeks) as primary immunomodulation, concurrent targeted antimicrobial therapy, temporary anticoagulation interruption, and discontinuation of baseline mycophenolate mofetil. Following platelet recovery above 70 × 109/L, therapeutic anticoagulation was resumed with enoxaparin (80 mg subcutaneously twice daily) and aspirin (75 mg daily). Over five months, progressive re-epithelialization culminated in complete healing with platelet recovery. This case supports the feasibility of IVIG as a bridging immunomodulatory strategy in high-risk APS cutaneous disease where standard therapies are contraindicated by concurrent infection and thrombocytopenia. The sequential management approach successfully resolved a clinically challenging scenario. This case illustrates how risk-adapted immunomodulation may enable safe management of complex APS manifestations.
2026-08-10 | Monoclonal Gammopathy of Thrombotic Significance.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.
2026-07-30 | Neutrophil extracellular traps induced by a monoclonal anti-phosphatidylserine/prothrombin antibody activate platelets in vitro.
Antiphospholipid syndrome (APS) is an autoimmune thrombotic disorder characterized by the presence of antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (aPS/PT). While neutrophil extracellular traps (NETs) are implicated in the pathogenesis of APS, the role of aPS/PT in NET induction and its contribution to thrombosis remain unclear. This study aimed to clarify the effects of NETs induced by a monoclonal aPS/PT antibody on platelet activation and their potential contribution to thrombo-inflammatory responses. NETs were induced by stimulating peripheral blood neutrophils from healthy donors with aPS/PT. Their morphology and platelet-activating capacity were compared with NETs induced by anti-neutrophil cytoplasmic antibodies (ANCAs). Proteomic analyses were conducted to comprehensively compare protein compositions of these NETs, and candidate proteins associated with platelet activation in aPS/PT-induced NETs were identified. Functional inhibition assays were then conducted to assess whether blocking these candidates would suppress aPS/PT-induced NET-mediated platelet activation. We found that binding of aPS/PT to neutrophils induced NET formation, with a larger and more fibrous morphology compared to ANCA-induced NETs. Platelets trapped in aPS/PT-induced NETs showed significantly higher activation compared to those trapped in ANCA-induced NETs. Proteomic analyses identified histone H3 as a potential mediator of platelet activation in aPS/PT-induced NETs. Correspondingly, plasma concentrations of H3.1 nucleosome were significantly higher in patients with APS than in healthy controls. Blockade of histone H3 using a neutralizing antibody significantly suppressed platelet activation mediated by aPS/PT-induced NETs. These findings suggest that aPS/PT-induced NETs contribute to platelet activation and may promote thrombo-inflammatory responses in APS. Targeting histone H3 within aPS/PT-induced NETs may provide a potential therapeutic strategy for thrombo-inflammatory processes in APS.
2026-07-19 | Perioperative Use of Efgartigimod Alfa, a Neonatal Fc Receptor Antagonist, to Reduce Antiphospholipid Antibody Titers and Thrombotic Risk in a Kidney Transplant Recipient.
Antiphospholipid syndrome (APS) is associated with an increased risk of thrombotic complications after kidney transplantation, particularly in patients with persistently elevated and triple-positive antiphospholipid antibodies (aPLs). Management of APS in kidney transplantation relies primarily on perioperative anticoagulation; however, thrombotic events may still occur despite appropriate therapy in patients with high-risk aPLs. We report the case of a 49-year-old woman with systemic lupus erythematosus-associated APS and persistently triple-positive aPLs who underwent living donor kidney transplantation. Because of her high thrombotic risk, perioperative immunoglobulin G--lowering therapy with the neonatal Fc receptor antagonist efgartigimod alfa was administered in addition to therapeutic anticoagulation. Treatment with efgartigimod alfa was associated with marked reductions in anticardiolipin and anti-β2-glycoprotein I antibody levels before transplantation, conversion of lupus anticoagulant to negative after transplantation, and sustained suppression of aPLs during the early posttransplant period. Kidney transplantation was successful with stable graft function during follow-up. To our knowledge, this represents the first reported use of efgartigimod alfa to reduce aPLs in the perioperative management of APS in kidney transplantation.
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2024-07-25 | Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.
Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.
2023-05-17 | Metastasis-associated lung adenocarcinoma transcript 1 induces methyl-CpG-binding domain protein 4 in mice with recurrent spontaneous abortion caused by anti-phospholipid antibody positivity.
Antiphospholipid syndrome is an autoimmune disease characterized by pregnancy-related morbidity, related to persistent positivity of antiphospholipid antibodies (APL). One of the characteristics of pregnancy-related morbidity in patients with antiphospholipid syndrome is recurrent spontaneous abortion (RSA). This study aimed to examine the mechanism through which metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates methyl-CpG-binding domain protein 4 (MBD4) expression in APL-positive RSA. Clinical samples were subjected to microarray analysis to filter differentially expressed genes. RSA mice with APL positivity were generated, followed by adenoviral vector injection to artificially upregulate MALAT1. The effects of MALAT1 on the biological behavior of trophoblast cells were assessed. The downstream mechanism of MALAT1 was analyzed using subcellular fractionation and bioinformatics prediction, and the relationship between MALAT1 and CREB binding protein (CREBBP) or MBD4 was investigated in trophoblast cells. MALAT1 was downregulated in APL-positive RSA patients. MALAT1 was predominantly localized in the nucleus and recruited CREBBP to mediate the MBD4 transcription. In the APL-positive RSA mice overexpressing MALAT1, the expression of soluble Fms-related tyrosine kinase 1 and anticardiolipin antibody and the embryonic resorption rate were decreased, indicating that MALAT1 reduced the occurrence of RSA in mice. Moreover, MALAT1 enhanced proliferation, migration, and invasion of trophoblast cells through recruiting CREBBP to promote MBD4 expression. Silencing of CREBBP or MBD4 increased embryonic resorption rate in RSA mice overexpressing MALAT1. MALAT1 suppresses APL-positive RSA by promoting MBD4 transcription through recruitment of CREBBP to the MBD4 promoter region.
2023-04-24 | Antisense oligonuleotides influences trophoblasts behaviors by changing LncNR_040117 expression in antiphospholipid antibody syndrome-induced recurrent pregnancy loss.
The primary objective of this study was to explore whether antisense oligonucleotides (ASOs) that reduce LncNR_040117 expression in patients with antiphospholipid antibody syndrome (APS)-induced recurrent pregnancy loss (RPL), and further decrease apoptosis and improve trophoblasts invasion through mitogen-activated protein kinase (MAPK) pathways. This paper aimed to provide a new strategy to treat APS-induced RPL. In this study, we used quantitative reverse transcription-polymerase chain reaction (RT-qPCR) to analyze the expression level of LncNR 040117 in HTR-8/SVneo cells following transfection with ASOs. Then we utilized Western blotting to test the expression levels of interleukin-1β (IL-1β), intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and key molecules of MAPK pathways, including the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38. In addition, we examined the HTR-8/SVneo cells apoptosis by cell apoptosis assay, and migration and invasion by transwell antibody assay. Each experiment was repeated three times. The data are presented as the means ± SDs, and statistical comparisons were performed using Student's t-test. p < 0.05 was considered significant. Transfected with ASOs, LncNR_040117 was downregulated in trophoblasts compared with APS-induced RPL patients. And LncNR_040117 low expression induced IL-1β and downstream adhesion molecules ICAM-1 and VCAM-1expression level decreased, as well as MAPK pathways downregulation, including the ERK pathway, JNK pathway and p38/MAPK pathway. Furthermore, all these changes resulted in decreased apoptosis and increased migration and invasion of trophoblasts. This study indicated that ASOs that decrease LncNR_040117 expression can reduce apoptosis and enhance the invasion and migration of trophoblasts by regulating the MAPK pathway.
2023-02-10 | Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome.
Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.
2022-06-14 | Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome.
Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19. This prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed. We included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG (p=0.058) and IgM (p=0.091); anti-beta-2 glycoprotein I (aβ2GPI) IgG (p=0.513) and IgM (p=0.468). We provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.
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Drug Discovery Landscape
2 orphan drug designations for Antiphospholipid syndrome.
2 orphan drug designations for Antiphospholipid syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
certolizumab pegol | antibodies | FDA | 2026-03-02 | — | UCB, Inc. |
Hydroxychloroquine | small molecules | EMA | 2017-01-12 | — | Cristina Belizna |
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