Harmonizing Motherhood: Navigating Pregnancy Outcomes in Connective Tissue Disorders.

Background Connective tissue disorders encompass a diverse array of autoimmune and hereditary conditions, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and antiphospholipid antibody syndrome. These disorders present unique challenges during pregnancy due to their complex pathophysiology and potential complications. Understanding their impact on pregnancy outcomes is vital for optimizing maternal and fetal health. Objective To investigate the burden, complications, maternal and fetal outcomes, and prognosis of connective tissue disorders in pregnancy. Methods The study was conducted over one year and six months at Saveetha Medical College and Hospital, Chennai, India, involving 45 pregnant women diagnosed with connective tissue disorders. Standard antenatal investigations were conducted, and participants were monitored throughout the antenatal period. Maternal and fetal outcomes were meticulously evaluated. Results Baseline characteristics revealed a heterogeneous distribution of age and parity among participants, reflecting the diverse nature of connective tissue disorders in pregnancy. Maternal medical outcomes, such as gestational hypertension (GHTN) and gestational diabetes mellitus (GDM), were prevalent, highlighting the necessity of close monitoring. Obstetric outcomes included spontaneous abortion and preterm delivery, indicating elevated risks in this population. Fetal outcomes, including fetal growth restriction and admission to the neonatal intensive care unit, underscored the impact of these disorders on fetal health. Conclusion This study examines pregnant connective tissue disorder burden, complications, maternal and fetal outcomes, and prognosis. The complicated relationship between these illnesses, and pregnancy requires specialist care and close monitoring. The participants' baseline features represent connective tissue condition heterogeneity, affecting clinical practice. Among the study subjects, 40% had RA and 20% had SLE, the most common connective tissue illness. Adverse maternal medical outcomes, like GHTN (27.27% of antiphospholipid syndrome (APS) patients and 22.22% of SLE patients) and GDM (18.18% of APS patients and 11.11% of SLE patients), highlight the need for close maternal health monitoring and management during pregnancy. Overall, this study sheds light on connective tissue abnormalities and pregnancy outcomes. Healthcare providers can improve reproductive health and well-being for various illnesses by knowing these relationships.

[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.

Risk factors for thrombotic events in systemic lupus erythematosus patients with antiphospholipid antibodies: insights from morphometric measurements of carotid arteries.

Objective: To identify the correlation between thrombosis and atherosclerosis in systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies (aPLs) (SLE/aPLs) through high-resolution magnetic resonance imaging (HR-MRI) of the carotid artery. Methods: A single-center, cross-sectional study was conducted. We collected consecutive patients with SLE/aPLs and healthy controls who underwent carotid HR-MRI examinations. The morphometric characteristics of the common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA), and carotid bulb (Sinus) were measured, and the differences in morphometric parameters between different groups were analyzed. Results: A total of 144 carotid arteries were analyzed. Compared with the control group, the wall area, wall thickness (WT and WTmax), and normalized wall index of CCA, ICA, ECA, and Sinus were increased in patients with SLE/aPLs, and the total vascular area (TVA) of CCA, ICA, and Sinus, and the bifurcation angle (BIFA) of ICA-ECA were also increased. A negative lupus anticoagulant (LAC) (with or without positive anticardiolipin antibody (aCL) or anti-ß2glycoprotein antibody (aß2GPI)) contributed to illustrating lower increased TVA and thickened vessel walls of CCA and ICA in SLE/aPLs patients without thrombotic events. Logistic regression analysis showed that WTmaxSinus and WTmaxGlobal were independent risk factors for thrombotic events in SLE/aPLs patients. The receiver operator characteristic curve showed that the cut-off value of WTmaxSinus was 2.855 mm, and WTmaxGlobal was 3.370 mm. Conclusion: HR-MRI ensures the complete and accurate measurement of carotid morphometric parameters. Compared with the control group, the carotid artery in patients with SLE/aPLs is mainly characterized by diffusely thickened vessel walls, and the patients with thrombotic events showed additional higher vascular area of CCA and ICA, and BIFA of ICA-ECA without significant change in lumen area. The carotid arteries of SLE/aPLs patients with thrombotic events exhibited significant vessel wall thickening in all segments except ECA compared to those without thrombotic events. LAC-negative and non-thrombotic events distinguish relatively early atherosclerosis in the carotid arteries in patients with SLE/aPLs. Patients with SLE/aPLs that possess circumscribed thickened carotid vessel walls (>3.370 mm), particularly thickened at the Sinus (>2.855 mm), may require management strategies for the risk of thrombotic events.

Impact of antiphospholipid antibodies on cardiac valve lesions in systemic lupus erythematosus: a systematic review and meta-analysis.

This meta-analysis assesses antiphospholipid antibodies' (aPLs) impact on heart valve disease in Systemic Lupus Erythematosus (SLE) patients. We searched PubMed, Embase, Cochrane, and Web of Science up to January 2024 for comparative studies of heart valve disease in aPL-positive versus aPL-negative SLE patients. Fixed-effect or random-effect models were used to synthesize data, with I2 and sensitivity analyses for heterogeneity and the trim-and-fill method for publication bias. Including 25 studies with 8089 patients, of which 919 had valvular changes, aPLs significantly increased the risk of heart valve disease (OR = 2.24, 95% CI: 1.58-3.18, p < 0.001). Lupus anticoagulant (LA) indicated the highest risk (OR = 4.90, 95% CI: 2.26-10.60, p < 0.001), anticardiolipin antibodies (aCL) doubled the risk (OR = 2.69, 95% CI: 1.47-4.93, p = 0.001), and anti-ß2 glycoprotein I (aß2GPI) showed a 70% increase (OR = 1.70, 95% CI: 1.17-2.45, p = 0.005). Valve-specific analysis indicated the mitral valve was most commonly involved (26.89%), with higher occurrences in aPL-positive patients (33.34% vs. 15.92%, p = 0.053). Aortic and tricuspid valve involvements were 13.11% vs. 5.42% (p = 0.147) and 12.03% vs. 8.52% (p = 0.039), respectively. Pulmonary valve disease was rare and similar across groups (1.01% in aPL-positive vs. 1.52% in aPL-negative). Significantly, only tricuspid valve disease showed increased risk in aPL-positive patients (OR = 2.66, 95% CI: 1.05-6.75, p = 0.039). APLs notably increase the risk of heart valve disease in SLE patients, with a pronounced effect on tricuspid valve involvement. Regular cardiac assessments for aPL-positive SLE patients are crucial for timely intervention and improved prognosis.

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.

Criteria and non-criteria antiphospholipid autoantibodies screening in patients with late pregnancy morbidity: A cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is a cause of pregnancy morbidity. We aim to determine the frequency of criteria and non-criteria anti-phospholipid (aPL) autoantibodies in patients admitted for unexplained fetal death (UFD), pre-eclampsia (PE) and/or fetal growth restriction (FGR). METHODS: All consecutive patients with UFD, PE and/or FGR followed in the department of Obstetrics, Bichat Hospital, University of Paris, Paris, between January 2019 and December 2021 were screened. Patients with available serum stored from the index pregnancy were included. Patients with previously known APS or twin pregnancy were excluded. Testing for aPL autoantibodies included anti-cardiolipin (aCL), anti-ß2GPI (aß2GPI), anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine/prothrombin (aPS/PT) IgG/IgM and anti-annexin V IgG. When available, placenta specimens were analyzed by a pathologist blinded to the aPL status. All clinical characteristics, pregnancy features, and comorbidities were extracted from electronic medical records. RESULTS: Overall 167 (32 (28.8-35.7) years) patients with UFD (n = 28; 16.8 %), PE (n = 60; 35.9 %) and/or FGR (n = 105; 62.9 %) were screened for aPL autoantibodies. Moderate titers of aPL autoantibodies were detected in 33 (n = 33/167, 19.8 %) patients. aPL autoantibodies were non-criteria aPE IgG/IgM in most cases (n = 28/33, 84.8 %). aPS/PT IgG/IgM were found in 11 (n = 11/33, 33.3 %) cases and aCL or aß2GP1 IgG/IgM in 4 (n = 4/33, 12.1 %). Multivariable logistic regression showed that aPL autoantibodies were mostly associated with UFD (OR 4.37 [1.72-11.20], p = 0.002), PE ≤ 34th week of gestation (3.22 [0.86-11.90], p = 0.070) and chronic deciduitis (8.03 [0.89-67.2], p = 0.060) DISCUSSION: The frequency of aPL autoantibodies, mostly aPE, is high in patients with late pregnancy morbidity and may qualify obstetrical APS.

The relevance of antiphospholipid antibodies in obstetrics.

AIM AND METHODOLOGY: To provide a comprehensive review on new findings and current recommendations regarding antiphospholipid antibodies with particular emphasis on clinical impact on gestation. CONCLUSION: Antiphospholipid antibodies are an important risk factor for the development of a series of pregnancy-related complications. Early diagnosis and appropriate therapy can reduce the incidence of pregnancy loss and pregnancy-related complications.

The Relentless Recurrence of Diffuse Alveolar Hemorrhage in Catastrophic Antiphospholipid Syndrome and Lupus: A Therapeutic Challenge.

Diffuse alveolar hemorrhage (DAH), a rare complication of coexisting antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), poses significant diagnostic and therapeutic challenges, especially with recurrent episodes. We present a 27-year-old male with catastrophic APS and SLE who experienced acute respiratory failure and hemoptysis due to DAH. Despite aggressive therapy with immunosuppressants, plasma exchange, and anticoagulation, he had recurrent DAH episodes requiring repeated admissions. Early recognition, multidisciplinary management, and utilization of effective targeted therapies, such as intravenous immunoglobulin, in refractory cases are crucial for improving outcomes in this challenging complication.

Antiphospholipid antibodies in patients with antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a rare systemic autoimmune disease characterized by recurrent pregnancy morbidity or thrombosis in combination with the persistent presence of antiphospholipid antibodies (aPLs) in plasma/serum. Antiphospholipid antibodies are a heterogeneous, overlapping group of autoantibodies, of which anti-ß2-glycoprotein I (aß2GPI), anticardiolipin (aCL) antibodies and antibodies that prolong plasma clotting time in tests in vitro known as lupus anticoagulant (LAC) are included in the laboratory criteria for the diagnosis of APS. The presence of LAC antibodies in plasma is indirectly determined by measuring the length of coagulation in two tests - activated partial thromboplastin time (aPTT) and diluted Russell's viper venom time (dRVVT). The concentration of aß2GPI and aCL (immunglobulin G (IgG) and immunoglobulin M (IgM) isotypes) in serum is directly determined by solid-phase immunoassays, either by enzyme-linked immunosorbent assay (ELISA), fluoroimmunoassay (FIA), immunochemiluminescence (CLIA) or multiplex flow immunoassay (MFIA). For patient safety, it is extremely important to control all three phases of laboratory testing, i.e. preanalytical, analytical and postanalytical phase. Specialists in laboratory medicine must be aware of interferences in all three phases of laboratory testing, in order to minimize these interferences. The aim of this review was to show the current pathophysiological aspects of APS, the importance of determining aPLs-a in plasma/serum, with an emphasis on possible interferences that should be taken into account when interpreting laboratory findings.

The Challenge of Neuropsychiatric Systemic Lupus Erythematosus: From Symptoms to Therapeutic Strategies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can seriously impair multiple organs including the nervous system, causing neuropsychiatric SLE (NPSLE), which encompasses a broad range of symptoms. Pathogenesis is not completely understood but is thought to involve inflammatory and vascular pathways. This comprehensive review discusses the complex nature and heterogeneity of NPSLE and the challenges in diagnosis and treatment that result from it. Diagnosis often requires a multidisciplinary approach with multiple assessments, including laboratory testing, imaging, and neuropsychological evaluations. Current treatments focus on managing symptoms through immunosuppressive and anti-thrombotic therapies tailored to the inflammatory or vascular nature of the specific NPSLE manifestations. This paper emphasizes the necessity for interdisciplinary approaches and further research to enhance diagnostic accuracy and treatment effectiveness. It also highlights the importance of understanding the underlying mechanisms of NPSLE to develop more targeted therapies, citing the need for high-quality studies and novel treatment agents.

Positive antiphospholipid antibodies increase the risk of ischemic stroke in patients with atrial fibrillation.

BACKGROUND: Antiphospholipid antibodies (aPL), including lupus anticoagulant (LA), antibodies against ß2 glycoprotein I (anti-ß2GPI) and anticardiolipin antibodies (aCL) are associated with ischemic stroke (IS). Their prevalence and clinical relevance in atrial fibrillation (AF) remain unclear. AIM: To assess whether aPL are associated with increased risk of ischemic stroke (IS) in AF patients despite anticoagulation. MATERIAL AND METHODS: We conducted a post hoc analysis of aPL using blood samples from 243 consecutive AF patients enrolled in the cohort study. Markers of a prothrombotic state, including endogenous thrombin potential (ETP), fibrin clot permeability and lysis time were measured at baseline. During a median follow-up of 52 months, IS/transient ischemic attack (TIA) and major bleeding were recorded. RESULTS: We observed aPL at a moderate or high titer in 51 (21%) patients, including 17 (7%) with anti-ß2GPI, 19 (7.8%) with aCL antibodies, and 37 (15.2%) with LA. aPL-positive patients were more likely to have prior stroke (p=0.01) and be active smokers (p=0.03), along with increased ETP (p=0.02), without any changes in fibrin clot properties. Anti-ß2GPI (HR=4.38, 95% CI 1.58-12.19) and aCL (HR=4.70, 95% CI 1.80-12.30) at a moderate or high titer were associated with IS during follow-up (n=20; 1.9%/year). There were 23 major bleedings (2.1% per year) and 20 deaths (1.9% per year), which were not associated with aPL. CONCLUSION: Our study showed a relatively high prevalence of aPL-positivity in AF patients, which was linked to increased risk of IS/TIA. This suggests that screening for aPL might help optimizing anticoagulant therapy in such patients.

Impact of Inherited Thrombophilia in Women with Obstetric Antiphospholipid Syndrome: A Single-Center Study and Literature Review.

Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal-maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11-79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal-fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

Antiphospholipid Syndrome and Antibodies Associated With Malignancy and Older Age: A Retrospective Study.

BACKGROUND: Antiphospholipid syndrome (APLS) is an established cause of thrombosis and hypercoagulability. However, the clinical characteristics of those with APLS or patients with positive antiphospholipid antibodies (APLA) in the embolic stroke of undetermined source (ESUS) have not been well studied. METHODS: A retrospective analysis was conducted between January 1, 2010, and December 31, 2020, across all three Mayo Clinic sites. Patients who were included in the study were tested for APLA and had a diagnosis of ESUS. Baseline characteristics, radiographic parameters, and outcome data were collected and compared between those who tested positive for APLS or had positive APLA and those who were negative. RESULTS: A total of 206 patients were included in the study. Eight (4%) patients were diagnosed with APLS, and 21 (10%) patients had positive APLA. On comparing those with a diagnosis of APLS and those without, patients with APLS were found to be significantly older (75 years old ± 9 vs. 58 years old ± 14, p = 0.001) and were more likely to have a history of cancer (50% vs. 13%, p = 0.012). Those with positive APLA had similar findings of being older (67 years old ±13 vs. 58 years old ± 14 p = 0.003) and more likely to have a history of cancer (29% vs. 8.4% p = 0.027). Radiographically, those with APLS had a higher white matter disease burden (Fazekas score median 2 (IQR 1.5-3) vs. median 1 (IQR 1-2), p = 0.028). CONCLUSION: Both APLS and positive APLA are associated with older age and a history of malignancy. These findings highlight the importance of considering a hypercoagulable evaluation even in the elderly ESUS population.

Toward harmonized interpretation of anticardiolipin and anti-ß2-glycoprotein I antibody detection for diagnosis of antiphospholipid syndrome using defined level intervals and likelihood ratios: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies.

BACKGROUND: Improving harmonization of the clinical interpretation of anticardiolipin (aCL) and anti-ß2-glycoprotein I (aß2GPI) antibodies immunoglobulin G (IgG)/immunoglobulin M (IgM) in the diagnosis of antiphospholipid syndrome (APS) is desirable. Likelihood ratios (LRs) with corresponding test-result intervals can identify the power of a test to discriminate between a diseased and nondiseased patient and may be useful for the semiquantitative interpretation of aCL/aß2GPI results. OBJECTIVES: To determine moderate and high thresholds for aCL and aß2GPI IgG/IgM measured with chemiluminescent immunoassay, enzyme-linked immunosorbent assay, fluorescence enzyme immunoassay, and multiplex flow immunoassay. METHODS: aCL and aß2GPI antibodies IgG/IgM were determined with 4 solid-phase systems in a case-control study population including 381 APS patients and 727 controls. Interval-specific LRs (IS-LR) were calculated for ranges determined by prespecified specificity and sensitivity levels. Three methods were used for determining thresholds that separated low, moderate, and high positive antibody levels. Interassay agreement was checked with Cohen's kappa statistics. RESULTS: Assay- and antibody-specific thresholds demonstrated increasing IS-LR, reflecting different clinical significance for low, moderate, and high levels, especially for IgG aCL and aß2GPI and in thrombotic APS. IS-LRs per antibody and unit range were comparable across solid-phase platforms resulting in enhanced harmonization of result interpretation. Agreement between assays for identifying high levels was improved by semiquantitative interpretation compared with that by quantitative reporting. CONCLUSION: aCL and aß2GPI IgG/IgM moderate and high thresholds were determined for 4 analytical platforms. Thresholds improve harmonized interpretation of aCL/aß2GPI levels across platforms. The proposed thresholds should be verified in an independent case-control study to check interlaboratory transferability.

D-dimer and fibrinogen indicate ischemic risk in patients with atrial fibrillation after percutaneous coronary intervention.

BACKGROUND: This study aimed to evaluate the association of antiphospholipid antibodies (aPL) and conventional markers of coagulation with ischemic and bleeding risk in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). METHODS: In this prospective two-center observational cohort study, patients with AF and an indication for oral anticoagulation (OAC) were enrolled after PCI. Blood was drawn on day 1-3 after PCI. Dilute Russell's viper venom time was used to determine lupus anticoagulant (LA) in OAC-free plasma. Anti-cardiolipin (aCL) IgG, IgM, and anti-ß2-Glycoprotein 1 (aß2GP1) IgG were analyzed by enzyme-linked immunosorbent assay (ELISA). Fibrinogen (FIB), d-dimer, and prothrombin fragment 1 and 2 (PF 1 + 2) were measured in citrated plasma. The primary ischemic outcome was time to major adverse cardiovascular events (MACE; death, myocardial infarction, or stroke) assessed at 6 months. Bleeding was defined according to International Society on Thrombosis and Haemostasis. RESULTS: 158 patients were enrolled between May 2020 and May 2021 on day 1-3 after PCI. The median age was 78 years (interquartile range [IQR] 72-82), 111 (70%) were male, and 39 (25%) presented with acute coronary syndrome. D-dimer was elevated in 74 (47%) patients, FIB was increased in 40 (25%) and PF1 + 2 in 68 (43%) patients. 32 (20%) patients had ≥ 1 antiphospholipid antibody elevated (aPL; LA: 19 [12%], aCL: 14 [9%], aß2GP1: 2 [1%]). The presence of aPL was neither significantly associated with MACE (HR 1.46, 95% CI [0.39-5.49], p = 0.579), nor bleeding (HR 1.07 [0.30-3.84], p = 0.917). Elevated d-dimer was significantly associated with higher risk for MACE (HR 5.06 [1.09-23.41], p = 0.038) and major bleeding (HR 7.04 [1.58-31.47], p = 0.011). Elevated D-dimer increased the predictive capacity of HAS-BLED for major bleedings (HAS-BLED: AUC 0.71 [0.60-0.83] vs. HAS-BLED + d-dimer: AUC 0.79 [0.70-0.88]; p = 0.025). Increased levels of FIB were associated with higher risk for MACE (HR 3.65 [1.11-11.96], p = 0.033). CONCLUSION: Biomarkers of coagulation might be suitable to assess ischemic and bleeding risk in patients with AF following PCI.

NEUT-RI, a surrogate marker of NETosis is lower in patients with strong IgM antiphospholipid antibodies.

BACKGROUND: Antiphospholipid antibody syndrome (APS) is an acquired autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or pregnancy complications. Recently, thrombotic APS was linked to increased neutrophil extracellular traps (NET) formation, suggesting an association between NETs and the severity of APS-related thrombosis. METHODS: We performed a retrospective study on patients tested for presence of antiphospholipid antibodies (990 negative and 374 positive) to evaluate the association between the neutrophil activation state, estimated by the neutrophil reactive index (NEU-RI), a parameter routinely available from some haematology analysers, and antiphospholipid antibodies. RESULTS: We do not observe a difference in NEU-RI values between positive and negative patients globally. However, interestingly, we highlight an association between high titers of IgM and low NEU-RI values indicating a lower neutrophil activation. CONCLUSION: Our data are in line with the recent questioning about the putative clinical consistency of positive solid-phase aPL IgM.

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.

Dilemmas in the diagnosis and management of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by thrombosis (which may be venous, arterial, or microvascular) and/or pregnancy morbidity in association with persistently positive antiphospholipid antibodies. Although thrombosis and pregnancy morbidity are the main clinical criteria for a diagnosis of APS in the revised Sapporo (Sydney) criteria, recently published American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for APS have significantly refined the diagnostic algorithm to include a scoring system clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular thrombosis, obstetric, cardiac valve, and hematologic). Diagnosis of APS is complicated by the fact that significant heterogeneity exists in patients' clinical presentation, underlying vascular risk factors, and methods of detecting antiphospholipid antibodies. Despite the autoimmune nature of APS, anticoagulation remains the main strategy for secondary prevention of thrombosis. Furthermore, optimal antithrombotic treatment in APS patients with arterial thrombosis remains controversial due to a paucity of data from randomized controlled studies. In this paper, we present 2 cases and highlight the diagnostic and therapeutic challenges they pose and how we approach them in the light of current evidence.

Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review.

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

Current status of testing intervals for antiphospholipid syndrome testing: a 13-year retrospective national data analysis in South Korea.

OBJECTIVE: To assess the appropriateness of laboratory testing intervals and antiphospholipid syndrome (APS) incidence. METHODS: Between January 2010 and August 2022, insurance claims data of patients with disease codes for other thrombophilia (D68.6) and APS (V253) were retrieved in South Korea. Patients who received antiphospholipid antibody tests more than twice were classified as having suspected APS. The interval between the first 2 antiphospholipid antibody tests was evaluated in the patients with suspected APS. Patients with suspected APS who received anticoagulants for >180 days were classified as having APS. RESULTS: Overall, 8656 patients were classified as having suspected APS. The testing interval for the first 2 tests in patients with suspected APS was <6 and <12 weeks in 11.1% and 20.6% of cases, respectively, in 2010, gradually increasing to 21.0% and 35.4%, respectively, in 2021. Subsequently, 4344 patients were classified as having APS, with 65.0% being female. Only 330 patients were diagnosed with APS in 2021, down from 436 in 2020. CONCLUSION: This study showed a gradual increase in patients receiving antiphospholipid antibody testing with an inappropriate short-term interval, underscoring the need for laboratory stewardship to ensure an appropriate interval for APS testing.