Plasma cell-free DNA as a monitoring tool for high-risk pregnancies associated with antiphospholipid syndrome.

INTRODUCTION: Despite thromboprophylaxis, women with antiphospholipid syndrome (APS) face high-risk pregnancies due to proinflammatory and prothrombotic states. This highlights the need for new monitoring and prognostic tools. Recent insights into the pathophysiological role of neutrophil activation and extracellular trap (NET) formation in this syndrome led to the exploration of plasma cell-free DNA (cfDNA), a derivative of NETosis, as a promising biomarker. MATERIALS AND METHODS: cfDNA was isolated and quantified from plasma samples of healthy pregnant women (control group, HC) and women with APS (APS group). We assessed the physiological variability of cfDNA across the three trimesters in HC. Levels of cfDNA were compared between APS and HC by gestational trimester. ROC curve analysis was performed to evaluate the efficacy of cfDNA levels for classifying APS patients. Furthermore, cfDNA levels in pregnant women with APS with obstetric complications were compared to those from uncomplicated pregnancies. RESULTS: Among HC, cfDNA significantly increased in the third trimester compared to the first and second. Elevated cfDNA levels in APS compared to HC were observed in the first and second trimesters. First-trimester cfDNA levels demonstrated the highest classification ability to discriminate between APS and HC patients (AUC: 0.906). Among APS, those with complicated pregnancies (fetal growth restriction, preeclampsia, placenta accreta) exhibited significantly elevated cfDNA levels in the second trimester. CONCLUSIONS: Elevated levels of cfDNA in pregnant women with APS, particularly among those with obstetric complications, supports further investigation into the potential of cfDNA as a valuable tool in the obstetric management of women with APS.

Kidney whole-transcriptome profiling in primary antiphospholipid syndrome reveals complement, interferons and NETs-related gene expression.

OBJECTIVE: Pathogenesis of antiphospholipid syndrome (APS) remains poorly elucidated. We aimed to evaluate for the first time, kidney transcriptome profiles in primary APS vs systemic lupus erythematosus (SLE) and control subjects. METHODS: We performed RNA-sequencing on archival formalin-fixed paraffin-embedded kidney biopsies from APS (n = 4) SLE (n = 5), and control (n = 3) individuals, differential gene expression analysis (DGEA), and enrichment analysis using gene ontology (GO), and CORUM, KEGG and Reactome pathway databases. RESULTS: Two-dimensional projection showed a distinct gene profile in primary APS vs control kidneys samples, but similar to SLE. DGEA in APS vs controls returned 276 upregulated and 217 downregulated genes, while the comparison between APS and SLE identified 75 upregulated and 111 downregulated genes. In 276 upregulated genes, enriched GO terms were (innate) immune response, inflammatory response, leucocyte and lymphocyte activation, cytokine production and T cell activation. CORUM and KEGG revealed complement-related genes (C3, C4A, C4B). Expression levels showed logFC values of 2.25 (p= 1.58e-05) for C3, 2.17 (p= 2.69e-06) for C4A, and 2.135 (p= 3.7e-06) for C4B in APS vs controls, without differences between APS and SLE. Interferon (IFN) alpha/beta signalling was revealed by Reactome. Expression levels of nine IFN-regulated genes found upregulated in APS vs control kidneys (p-values ≤ 0.001 for all). Examining neutrophil-extracellular traps (NETs)-related gene expression, 13 of 15 upregulated NETs-related genes exhibited higher expression in APS vs controls but not vs SLE. CONCLUSION: Complement, interferon and NETs-related genes are highly expressed in APS kidney tissues, similarly to SLE, pointing out the role of innate immunity in APS nephropathy pathogenesis and potential treatment targets.

Interference of lupus anticoagulant causing antiprothrombin and anti-beta-2-glycoprotein I antibodies on international normalized ratio measurements: comparative analysis of international normalized ratio methods.

Background: Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements. Objectives: Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements. Methods: Pooled normal plasma and control plasma from patients on VKA (without LA) were incubated with monoclonal and isolated patient immunoglobulin G antiprothrombin and anti-beta-2-glycoprotein I antibodies that express LA activity. INR was determined before and after addition using 3 laboratory assays (Owren STA-Hepato Prest, Quick STA-NeoPTimal, and Quick STA-Neoplastine R) and 1 point-of-care test device (CoaguChek Pro II). Results: Antiprothrombin and anti-beta-2-glycoprotein I antibodies with LA activity interfered with recombinant human thromboplastin reagents (Quick STA-Neoplastine R and CoaguChek Pro II), particularly when added to plasma of VKA-treated controls. This effect was most evident on point-of-care test INR measurements, while the recombinant Quick reagent exhibited a lesser degree of interference. In contrast, tissue-derived thromboplastin reagents (Owren STA-Hepato Prest and Quick STA-NeoPTimal) remained largely unaffected by these antibodies, both in pooled normal plasma and VKA anticoagulated control plasma. Among these reagents, the Owren INR reagent exhibited the lowest sensitivity to the influence of LA antibodies. This observed difference in sensitivity is independent of the plasma dilution factor or the presence of factor V or fibrinogen in Owren reagent. Conclusion: INR reagents that utilize recombinant human thromboplastin are more sensitive to the presence of monoclonal and patient-derived antibodies with LA activity. Consequently, APS patients positive for LA should be monitored using tissue-derived thromboplastin reagents, given its reduced susceptibility to interference by LA-causing antibodies.

Comparison of clinical and serological features in thrombotic antiphospholipid syndrome patients, with and without associated systemic lupus erythematosus, followed for up to 42 years: A single centre retrospective study.

OBJECTIVE: To assess the impact of concomitant systemic lupus erythematosus (SLE) on the clinicopathological manifestations of thrombotic antiphospholipid syndrome (APS). METHODS: This single-centre, retrospective study compared clinical and antiphospholipid antibody (aPL) data from 118 patients, 58 with SLE-associated APS (SLE-APS), and 60 with primary APS. RESULTS: Median follow-up was 13.9 (IQR 7.7-19.3) and 8.6 years (3.5-10.6) for the SLE-APS cohort and PAPS cohort, respectively. Age at diagnosis of APS was lower in the SLE-APS cohort (mean 35.9 vs PAPS: 46.7 years; p < 0.05). Distribution of aPL subtypes was similar across cohorts. 198 thrombotic events were identified overall (index plus recurrent), with venous thromboembolism (VTE) and arterial thrombosis each occurring in just over half of patients in both cohorts. Microvascular thrombosis (12.1% vs 0%), and a mixed (any combination of venous, arterial and microvascular) thrombotic phenotype (19.0% vs 6.7%, p = 0.05) were more prevalent in SLE-APS patients. Recurrent thrombosis incidence rates (∼0.5 events/10-patient years), and Kaplan-Meier recurrence-free survival after index thrombosis, were similar. In the PAPS cohort, only: (i) triple-aPL-positivity was associated with a significantly higher recurrent thrombosis event rate (incidence rate ratio 2.22, p = 0.03) and lower recurrence-free survival after first thrombosis (log-rank test p = 0.01); (ii) lupus anticoagulant (LA)-positivity was associated with higher prevalance of arterial thrombosis (RR 2.69, p = 0.01), and lower prevlance of VTE (RR 0.48, p < 0.001), versus LA-negativity. CONCLUSION: Concomitant SLE does not appear to modify long-term recurrent thrombosis risk, or aPL phenotypes, in patients with APS. Triple-aPL-positivity and LA-positive status may have less influence on thrombotic outcomes in patients with SLE-APS compared to PAPS.

Biological markers of high risk of thrombotic recurrence in patients with antiphospholipid syndrome: A literature review.

OBJECTIVES: This review aims to identify biological markers of the risk of recurrence of thrombotic and/or obstetric events in patients with antiphospholipid syndrome (APS). METHODS: A comprehensive review of literature was conducted to evaluate established and potential novel biological markers associated with thrombosis in APS. To this end, a PubMed literature search was conducted for the last twenty years using the following keywords or their combinations: thrombotic risk, recurrence of thrombosis, risk stratification, severity, predictive value. RESULTS: Analysis of N-glycosylation of antiphospholipid antibodies (aPL) revealed that low levels of IgG sialylation, fucosylation or galactosylation increases the pro-inflammatory activity of aPL, predisposing to thrombosis. In addition, quantification of neutrophil extracellular traps (NETs) and antibodies directed against NETs (anti-NETs) in serum demonstrates promising prognostic utility in assessing APS severity. Oxidative stress plays a role in the pathogenicity of APS and paraoxonase 1 (PON1) activity emerges as a promising biomarker of thrombotic risk in APS. Furthermore, identification of novel antigenic targets involved in the pathophysiology of APS, such as lysobisphosphatidic acid (LBPA), had led to the discovery of unconventional aPL, antibodies directed against the LBPA (aLBPA), whose clinical value could make it possible to identify APS patients at high risk of thrombotic recurrence. CONCLUSION: The immunological profile of aPL, N-glycosylation of aPL, quantification of NETs and anti-NETs, analysis of biomarkers of oxidative stress and the discovery of aLBPA offer potential prognostic tools for risk stratification in APS patients.

Antiphospholipid syndrome with major arterial thrombosis, presenting as pulmonary thromboembolism, cerebrovascular accident, and coronary artery disease: A case report and literature review.

Antiphospholipid syndrome is an immunopathologic disorder that should be considered in all patients with recurrent and/or unexplained thromboembolic events. Antiphospholipid antibodies are diagnostic markers, and anticoagulation therapy is the therapeutic and preventive strategy. Long-term anticoagulation therapy is necessary, with careful attention to potential bleeding complications.

An Intestinal Microbiome Intervention Affects Biochemical Disease Activity in Patients with Antiphospholipid Syndrome.

Background The origin of autoantibodies in patients with antiphospholipid syndrome (APS) is unknown. The gut microbiome contributes to autoimmunity and contains peptide homologues to the main APS autoantigen, which affect disease activity in animal models. Alteration of the gut microbiota with vancomycin diminishes disease activity in mice but no data on the effect of gut microbiota alteration in APS patients are available to date. Objective To evaluate whether the gut microbiome affects disease activity in human APS. Methods This was a pre-post design intervention study in APS patients with stable disease and no gastrointestinal comorbidity. Subjects received oral vancomycin, 500 mg four times daily for 7 days, previously shown to alter gut microbiota composition without systemic effects. Disease activity was assessed at four time points by measuring a panel of clinical phenotype-related biomarkers: antiphospholipid antibodies (APLAs), complement and inflammation markers, and hemostatic parameters. The primary outcome was the composite of the biomarker panel determined by multilevel principal component analysis. Results A total of 15 subjects completed the study. The primary outcome, the first principal component of the biomarker panel data, was significantly different after 7 days of vancomycin treatment ( p = 0.03), but not at day 42. APLA titers were unaffected. Unexpectedly, 4 out of 15 patients were negative for APLAs at baseline. In a post-hoc analysis, there was a prolonged effect for subjects with positive antibodies at baseline ( p = 0.03). In subjects with negative APLAs at baseline, the intervention showed no effect. Conclusion The intestinal microbiome affects the biochemical disease activity in APS patients. The mechanism is yet unknown but appears to be APS-specific.

Evaluation of an integrated activated partial thromboplastin time (Cephen LS/Cephen) for the detection of lupus anticoagulant.

INTRODUCTION: It is recommended to use two chronometric assays of different principles for the diagnosis of lupus anticoagulant (LA), consisting in diluted Russell Viper Venom Time (dRVVT) and activated Partial Thromboplastin Time (aPTT). Yet, there are only a few integrated aPTT assays; this study aims to evaluate one of them: Cephen LS/Cephen (Hyphen Biomed). METHOD: 249 samples of patients were included in this study. Normal reference ranges were determined with platelet-poor plasma (PPP) from healthy blood donors. Performances were then evaluated by comparing Cephen LS/Cephen test results to the results of the laboratory's reference assay for the diagnosis of LA and to clinical data, both on non-anticoagulated and anticoagulated patients' samples (Unfractioned heparin (UFH), Low Molecular Weight Heparin (LMWH), Vitamin K Antagonists (VKA) and apixaban). Interference of UFH, LMWH and VKA were also evaluated thanks to spiking experiment of increasing heparin concentrations or factor deficiency. RESULTS: Cephen LS/Cephen test had 48.6% sensitivity towards LA. Although UFH and VKA seemed to interfere with this assay and were likely to cause false negative, LMWH and apixaban did not. Finally, combination of Cephen LS/ Cephen with dRVVT had 89.0% sensitivity. CONCLUSION: Cephen LS/Cephen seems relevant for LA diagnosis, in combination with dRVVT, and might be used in patients undergoing LMWH or apixaban therapy.

The association between antiphospholipid syndrome and atrial fibrillation: a single center retrospective case-control study.

Antiphospholipid syndrome (APS) is a systemic autoimmune syndrome characterized by arterial or venous thrombosis, pregnancy complications and thrombocytopenia. The aim of this study is to investigate the association between APS and atrial fibrillation (AF) among patients in Peking University People's Hospital. A single center retrospective study was conducted. Cases were hospitalized patients diagnosed with AF by a cardiologist while the control group patients did not exhibit cardiac diseases. The results of the study revealed that in multivariable logistic regression, APS, anticardiolipin antibody (aCL) positivity and anti-beta-2-glycoprotein antibody (anti-ß2GPI) positivity are independent risk factors of AF. APS, aCL positivity and anti-ß 2GPI positivity are statistically different between AF patients and non-AF patients. Forthcoming studies are needed to clarify the potential link between APS and AF.

[Obstetric Antiphospholipid Syndrome: Insights on the Diagnosis, Treatment, and Hot Issues]. / 产科抗磷脂综合征的诊治原则与热点问题述评.

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder associated with various pathological pregnancies, such as recurrent miscarriage, stillbirth, severe pre-eclampsia and severe placental insufficiency. The persistent presence of antiphospholipid antibodies (aPLs) is the most important laboratory characteristic of OAPS. OAPS severely affects the reproductive health of women of childbearing age in China. Reports indicate that approximately 9.6% stillbirths, 11.5% severe pre-eclampsia, and 54% recurrent miscarriages are associated with OAPS or aPLs. However, the pathogenesis of OAPS remains unclear. Previously, thrombosis at the maternal-fetal interface (MFI) was considered the main mechanism of OAPS-related pathological pregnancies. Consequently, the use of low molecular weight heparin and aspirin throughout pregnancy was recommended to improve outcomes in OAPS patient. In recent years, many studies have found that thrombosis in MFI is uncommon, but various inflammatory factors are significantly increased in the MFI of OAPS patients. Based on these findings, some clinicians have started using anti-inflammatory treatments for OAPS, which have preliminarily improved the pregnancy outcomes. Nevertheless, there is no consensus on these second-line treatments of OAPS. Another troubling issue is the clinical diagnosis of OAPS. Similar to other autoimmune diseases, there are only classification criteria for OAPS, and clinical diagnosis of OAPS depends on the clinicians' experience. The present classification criteria of OAPS were established for clinical and basic research purposes, not for patient clinical management. In clinical practice, many patients with both positive aPLs and pathological pregnancy histories do not meet the strict OAPS criteria. This has led to widespread issues of incorrect diagnosis and treatment. Timely and accurate diagnosis of OAPS is crucial for effective treatment. In this article, we reviewed the epidemiological research progress on OAPS and summarized its classification principles, including: 1) the persistent presence of aPLs in circulation; 2) manifestations of OAPS, excluding other possible causes. For the first point, accurate assessment of aPLs is crucial; for the latter, previous studies regarded only placenta-related pregnancy complications as characteristic manifestations of OAPS. However, recent studies have indicated that adverse pregnancy outcomes related to trophoblast damage, such as recurrent miscarriage and stillbirth, also need to be considered in OAPS. We also discussed several key issues in the diagnosis and treatment of OAPS. First, we addressed the definition of non-standard OAPS and offered our opinion on defining non-standard OAPS within the framework of the 2023 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) APS criteria. Then, we discussed the advantages and disadvantages of different aPL testing methods, emphasizing that harmonizing results across platforms and establishing specific reference values are keys to resolving controversies in aPL testing results. We also introduced the application of non-criteria aPLs, especially anti-phosphatidylserine/prothrombin antibody (aPS/PT) and anti-ß2 glycoprotein Ⅰ domain Ⅰ antibody (aß2GPⅠDⅠ). Additionally, we discussed aPL-based OAPS risk classification strategies. Finally, we proposed potential treatment methods for refractory OAPS. The goal is to provide a reference for the clinical management of OAPS.

Antiphospholipid Syndrome and Patent Foramen Ovale: A Case Report and Literature Review.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial, venous, or microvascular thrombosis, pregnancy morbidity, or non-thrombotic manifestations in patients with persistent antiphospholipid antibodies (aPL). Catastrophic APS is a rare and severe form of APS that is defined by the presence of multiple vascular occlusive events. When a patent foramen ovale (PFO) is present, paradoxical embolization can occur, simultaneously leading to arterial and venous thrombosis. We present a complex clinical case of a patient who presented with multiple arterial and venous thrombotic events with positive aPL. The suspicion of catastrophic APS was removed when a PFO was found in a transesophageal echocardiogram, justifying paradoxical embolization. This emphasizes the importance of searching for PFO in patients with APS presenting with simultaneous venous and arterial thrombosis for management and prognosis purposes.

Atomistic Characterization of ß2-Glycoprotein I Domain V Interaction with Anionic Membranes.

BACKGROUND: Interaction of ß2-glycoprotein I (ß2GPI) with anionic membranes is crucial in antiphospholipid syndrome (APS), implicating the role of its membrane binding domain, Domain V (DV). The mechanism of DV binding to anionic lipids is not fully understood. OBJECTIVES: This study aims to elucidate the molecular details of ß2GPI DV binding to anionic membranes. METHODS: We utilized molecular dynamics (MD) simulations to investigate the structural basis of anionic lipid recognition by DV. To corroborate the membrane-binding mode identified in the HMMM simulations, we conducted additional simulations using a full membrane model. RESULTS: The study identified critical regions in DV, namely the lysine-rich loop and the hydrophobic loop, essential for membrane association via electrostatic and hydrophobic interactions, respectively. A novel lysine pair contributing to membrane binding was also discovered, providing new insights into ß2GPI's membrane interaction. Simulations revealed two distinct binding modes of DV to the membrane, with mode 1 characterized by the insertion of the hydrophobic loop into the lipid bilayer, suggesting a dominant mechanism for membrane association. This interaction is pivotal for the pathogenesis of APS, as it facilitates the recognition of ß2GPI by antiphospholipid antibodies. CONCLUSION: The study advances our understanding of the molecular interactions between ß2GPI's DV and anionic membranes, which are crucial for APS pathogenesis. It highlights the importance of specific regions in DV for membrane binding and reveals a predominant binding mode. These findings have significant implications for APS diagnostics and therapeutics, offering a deeper insight into the molecular basis of the syndrome.

Hematological features and alternate diagnoses in critically ill thrombotic antiphospholipid syndrome patients.

OBJECTIVES: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome. METHODS: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied. RESULTS: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients. CONCLUSION: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated.

[Beyond hypercoagulability in celiac disease]. / Más allá de la hipercoagulabilidad en la enfermedad celíaca.

In celiac disease (CD) there is a state of hypercoagulability and multiple factors have been found that may be involved. Cases of association of CD and antiphospholipid síndrome (APS) have been described and several observational studies have found an increase in antiphospolipid antibodies (AAF) in patients with CD, so both entities may be interrelated, increasing the risk of thrombotic events. A descriptive case of a patient who is simultaneusly diagnosed with CD and APS is presented.

Comparative assessment of the diagnostic performances of particle-based multianalyte technology and commercial ELISA for antiphospholipid autoantibody testing.

BACKGROUND: Diagnosing Antiphospholipid Syndrome (APS) relies heavily on laboratory findings, particularly the detection of specific antibodies like lupus anticoagulant (LA), IgG and/or IgM anti-cardiolipin (aCL), and IgG and/or IgM anti-ß2 glycoprotein 1 (aB2GP1). Although ELISA is widely used in the US for this purpose, standardization between different assay methodologies remains challenging, leading to significant variability across laboratories. Particle-based multi-analyte technology (PMAT) offers a streamlined one-step detection for all six antiphospholipid (aPL) autoantibodies, covering aCL and aB2GP1 of IgA, IgG, and IgM isotypes. METHODS: In this study involving 224 subjects, including 34 clinically diagnosed with APS, alongside 160 non-APS patients and 30 healthy donors, PMAT's performance was evaluated against commercial ELISA in detecting aPL antibodies. RESULTS: At the manufacturer's suggested cutoff, PMAT exhibited sensitivity comparable to ELISA, albeit with a low to moderate decrease in specificity for certain antibodies. With anti-CL IgM alone, PMAT displayed a 17.7% decrease in sensitivity, accompanied by a corresponding 31.1% increase in specificity compared to ELISA. However, applying a stricter cutoff (88-90% specificity), IgA and IgM antibodies yielded 5.9-17.6% higher sensitivities with PMAT, and IgG antibodies displayed similar sensitivity. CONCLUSIONS: In this study cohort, PMAT demonstrated higher or comparable sensitivity to that of commercial ELISA for all six aPL antibodies at a specificity cutoff near 90%. Notably, PMAT demonstrated superior sensitivity and specificity overall in detecting IgA aCL and aB2GP1 antibodies. This study highlights the potential of automated PMAT for detecting aPL antibodies in APS evaluation.

Acute Renal Thrombotic Microangiopathy Caused by Eltrombopag and Romiplostim in a Patient with Myelodysplastic Syndromes (MDS) and Underlying Antiphospholipid Syndrome.

Romiplostim and eltrombopag are synthetic agonists of the thrombopoietin receptor (TPO-R), commonly used for immune thrombocytopenic purpura (ITP) and sometimes in myelodysplastic syndrome (MDS). They are rarely associated with kidney injury. We report a case of acute kidney injury caused by romiplostim and eltrombopag in an 80-year-old male patient with MDS and ITP. He did not have systemic haemolysis syndrome but isolated acute renal thrombotic microangiopathy confirmed by kidney biopsy. He was treated with steroids, plasmapheresis and anticoagulation, with improvement in renal function. Interestingly, the patient had high antiphospholipid (aPL) antibodies noted upon screening, indicating a possible new antiphospholipid syndrome (APS) diagnosis. In the presence of circulating aPL antibodies, eltrombopag may have served as a trigger, causing endothelial injury and subsequent renal microangiopathy; aPL antibodies were still significantly positive at four weeks of outpatient testing. This case and a few others reported in the literature highlight the importance of screening for aPL antibodies before initiating TPO-R agonists in patients with ITP. We suspect that using TPO-R agonists, rather than underlying aPL, caused renal failure. LEARNING POINTS: Synthetic agonists of the thrombopoietin receptor, such as romiplostim or eltrombopag, can cause acute renal failure.Preexisting antiphospholipid (aPL) antibodies may increase the risk of renal failure.Screening for aPL antibodies should be considered before initiating thrombopoietin-receptor agonists (TPO-R agonists) in patients with immune thrombocytopenic purpura (ITP).

A Comparison of Obstetric Outcomes in Antiphospholipid Syndrome Among Pregnant Women With Systemic Lupus Erythematosus.

Objective The aim of this study was to evaluate the maternal and perinatal outcomes in systemic lupus erythematosus (SLE) women with antiphospholipid syndrome (APS). Methods This retrospective case-control study was conducted among pregnant women with SLE with and without APS. Group A included SLE patients with APS, whereas group B included pregnant SLE women without APS. Data were expressed as mean ± standard deviation (SD). Frequency and percentage were computed for categorical data. The chi-square test was used to analyze the difference between categorical data. Results Out of 125 cases of SLE, APS was found in 72 (57.6%) women. Almost 95.8% of patients were on treatment (aspirin and enoxaparin) in group A. Preterm delivery (31.89±7.36 versus 34.46±4.97; p=0.021) and termination of pregnancy (18.1% [13/72] versus 5.7% [3/53]; p=0.04) were statistically significant in group A. Among these terminations, second-trimester intrauterine death is found to be more in group A (SLE with APS) (16.7% [12/72]) as compared to group B (SLE without APS) (5.7% [3/53]) with a p-value of 0.05. Perinatal outcomes including NICU admissions (39% [23/59] versus 24% [12/50]; p=0.071) and neonatal death (12.3% [7/57]; p=0.015) were also found to be statistically significant between the two groups. Conclusion APS with SLE is associated with adverse pregnancy outcomes such as preterm birth, termination of pregnancy due to second-trimester fetal loss, more NICU admission, and neonatal deaths when compared to the control group. Hence, pregnancies with APS with SLE require vigilant monitoring and frequent follow-ups to ensure a positive pregnancy outcome.

Etiology and diagnostic approach of recurrent miscarriage at a reference center in Bucaramanga, Colombia.

OBJECTIVE: The purpose of this study was to determine the etiologies of recurrent miscarriage in our hospital and whether its diagnostic approach followed the recommendations of the American Society of Reproductive Medicine (ASRM) guidelines published in 2012 and the National Institute for Health and Care Excellence (NICE) guidelines published in 2011. METHODS: This was a retrospective study. The medical records of 158 patients diagnosed with recurrent miscarriage between 2013 and 2018 at Santander University Hospital were reviewed. The Institutional Review Board of HUS approved the study in May 2020. RESULTS: The most common etiologies identified were protein S deficiency, thrombophilia, and cervical insufficiency, with incidence rates of 25.9%, 10.7%, and 3.8%, respectively. Moreover, the most frequently requested diagnostic tests were for protein S, protein C, and anti-phospholipid IgG. Abnormal results for protein S were obtained in 49% of the patients, whereas lupus anticoagulant was abnormal in 12.8%, and Factor V Leiden gene mutations in 8.5% of the patients. Three substantial deviations from the recommended diagnostic approach for recurrent miscarriage by international guidelines were identified in our population: the lack of request for cytogenetic analysis of pregnancy tissue, request for cytogenetic analysis for the parents in only 0.6% of the study sample, and the request for imaging tests to assess uterine anatomy in only 6.3% of the studied population. Both the ASRM and NICE guidelines were only partially followed with a combined adherence rate of 66.5%. CONCLUSION: The diagnostic approach for recurrent miscarriage poses important clinical challenges when compared to the recommendations of international guidelines. Therefore, the development of a local recurrent miscarriage assessment protocol is proposed in our institution.

Interaction of antiphospholipid antibodies with endothelial cells in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease with arteriovenous thrombosis and recurrent miscarriages as the main clinical manifestations. Due to the complexity of its mechanisms and the diversity of its manifestations, its diagnosis and treatment remain challenging issues. Antiphospholipid antibodies (aPL) not only serve as crucial "biomarkers" in diagnosing APS but also act as the "culprits" of the disease. Endothelial cells (ECs), as one of the core target cells of aPL, bridge the gap between the molecular level of these antibodies and the tissue and organ level of pathological changes. A more in-depth exploration of the relationship between ECs and the pathogenesis of APS holds the potential for significant advancements in the precise diagnosis, classification, and therapy of APS. Many researchers have highlighted the vital involvement of ECs in APS and the underlying mechanisms governing their functionality. Through extensive in vitro and in vivo experiments, they have identified multiple aPL receptors on the EC membrane and various intracellular pathways. This article furnishes a comprehensive overview and summary of these receptors and signaling pathways, offering prospective targets for APS therapy.

Long COVID Definition, Symptoms, Risk Factors, Epidemiology and Autoimmunity: A Narrative Review.

The virus called SARS-CoV-2 emerged in 2019 and quickly spread worldwide, causing COVID-19. It has greatly impacted on everyday life, healthcare systems, and the global economy. In order to save as many lives as possible, precautions such as social distancing, quarantine, and testing policies were implemented, and effective vaccines were developed. A growing amount of data collected worldwide allowed the characterization of this new disease, which turned out to be more complex than other common respiratory tract infections. An increasing number of convalescents presented with a variety of nonspecific symptoms emerging after the acute infection. This possible new global health problem was identified and labelled as long COVID. Since then, a great effort has been made by clinicians and the scientific community to understand the underlying mechanisms and to develop preventive measures and effective treatment. The role of autoimmunity induced by SARS-CoV-2 infection in the development of long COVID is discussed in this review. We aim to deliver a description of several conditions with an autoimmune background observed in COVID-19 convalescents, including Guillain-Barré syndrome, antiphospholipid syndrome and related thrombosis, and Kawasaki disease highlighting a relationship between SARS-CoV-2 infection and the development of autoimmunity. However, further studies are required to determine its true clinical significance.