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OBJECTIVE:: Antiphospholipid syndrome (APS) and autoimmune rheumatic diseases (ARDs) are known to increase the risk for cardiovascular events (CVEs) in the general population., However, research in pregnancy is limited. We compared the occurrence of acute CVEs in pregnant women with and without ARDs or primary APS using a Californian population-based cohort. STUDY DESIGN:: This was a retrospective cohort study of pregnant individuals who delivered singleton infants in California between 2005 and 2020. Birth certificates were linked by the Study of Outcomes of Mothers and Infants to maternal records. The study was approved by institutional review boards of the State of California and the University of California San Diego. Pregnancies with ARDs were identified by ≥1 International Classification of Diseases (ICD) code for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthritis, Sjogren’s syndrome, and other ARDs (systemic sclerosis, inflammatory myositis, and vasculitides) in maternal hospital discharge, emergency, or ambulatory surgery records. Lupus nephritis (LN) was defined as SLE plus glomerulonephritis, renal failure, nephritic or nephrotic syndrome, or proteinuria. Primary APS included women with APS without concurrent ARDs. Women without ARDs or APS comprised the reference group. Acute CVEs during pregnancy and up to 6 weeks postpartum were identified by ICD codes and compared between groups. CVEs were classified as myocardial infarction, cardiovascular accident, heart failure and peripartum cardiomyopathy, inflammatory heart diseases, cardiac dysrhythmias, and venous thromboembolism (VTE). Covariates identified and adjusted for include age, race and ethnicity, insurance, education, prepregnancy body mass index, preexisting hypertension, diabetes, hyperlipidemia, depression, and substance use disorders. A log linear regression with a Poisson distribution was used to estimate the adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for the associations of ARDs and APS with CVEs. Analyses were performed using Statistical Analysis Software (SAS), version 9.4 (SAS Institute, Cary, NC). Causal mediation analyses were performed for potential mediators, such as gestational diabetes, gestational hypertension, and preeclampsia. RESULTS:: Overall, 19,340 women had ARDs, 7758 had primary APS, and 7,004,334 had neither condition. The ARD and APS groups had more traditional cardiovascular risk factors. Acute CVEs were observed in 2.0% of ARD cases (388/19,340), 7.0% of primary APS cases (540/7,758), and 0.4% of reference group cases (24,402/7,004,334). The aRR for CVEs in the ARD and APS groups in comparison with the reference group was 4.1-fold (95% CI, 3.7–4.5) and 14.7-fold (95% CI, 13.5–16.0), respectively (Table). Of the 388 CVEs that occurred in women with ARDs, 164 (42%) were VTEs, 96 (25%) were heart failure or peripartum cardiomyopathy, and 92 (24%) were cardiac dysrhythmias. In primary APS cases, 453 of 540 (83%) CVEs were VTE. Acute CVEs occurred in 3.1% (159/8,422) of patients with overall SLE, in 10.7% (55/513) of patients with SLE with APS, and in 8.5% (77/903) of patients with SLE with LN (Table). The aRR for CVEs was 6-fold higher among those with SLE (95% CI, 5.3–6.8) and was notably increased with concurrent APS or LN, with aRRs of 18.1 (95% CI, 13.9–23.6) and 12.7 (95% CI, 10.1–15.9), respectively (Figure). The risks for both VTE and non-VTE CVEs was increased among pregnancies affected by ARD and APS (Figure). Five of 6 in-hospital deaths in ARD pregnancies (5/388 or 1.3%) occurred among women with acute CVEs (Table). The risks for CVEs were higher during all perinatal periods. In mediation analyses, 11.2% of the excess risk for CVE in ARD pregnancies was mediated by preeclampsia, whereas

Background: Antiphospholipid syndrome (APS) is a rare systemic autoimmune disease characterized by persistent antiphospholipid antibodies (aPL) in combination with recurrent thrombosis in the veins and/or arteries, obstetric morbidity, and various non-thrombotic associated complications. APS can be primary, as an isolated condition, or secondary in the context of another autoimmune disease, especially systemic lupus erythematosus. This comprehensive clinical review aims to summarize the current understanding of APS pathogenesis, diagnostic approaches, and treatment strategies for this unique clinical entity. Methods: A comprehensive review of the existing literature on APS was conducted, focusing on pathophysiological mechanisms, current diagnostic criteria, and therapeutic approaches. Results: APS pathogenesis involves complex interactions between aPL, phospholipid-binding proteins, and the coagulation cascade. Apart from the cardinal features of thrombosis and APS-related obstetric morbidity, APS is associated with a wide spectrum of clinical manifestations. Diagnosis remains challenging due to overlapping symptoms with other conditions, and clinicians should maintain a high index of suspicion in order to set the diagnosis. The recently published 2023 ACR/EULAR criteria although not definitive for clinical decision-making, these criteria offer clinicians a valuable tool to aid in determining whether further investigation for APS is warranted. Continued refinement of these criteria through ongoing feedback and updates is anticipated. Treatment strategies center on anticoagulation, but individualized approaches are necessary. Conclusions: Early diagnosis and multidisciplinary management of APS are critical to reducing morbidity and improving outcomes. Moreover, familiarization with the 2023 ACR/EULAR criteria is encouraged, recognizing that ongoing feedback and updates will contribute to their ongoing refinement and improvement. While VKAs remain the mainstay of treatment for most APS patients further research is needed to optimize treatment strategies and deepen our understanding of APS's underlying disease mechanisms. [ABSTRACT FROM AUTHOR]

Objectives Patients with antiphospholipid syndrome (APS) carry a substantial burden of cardiovascular disease and subclinical atherosclerosis. We aimed to assess a 7-year follow-up atherosclerotic plaque progression in APS patients versus diabetes mellitus (DM) and healthy controls (HC). Methods Eighty-six patients with thrombotic APS, 86 with DM and 86 HC (all age- and sex-matched) who underwent a baseline ultrasound of carotid and femoral arteries were invited for a 7-year follow-up ultrasonography examination. We compared atherosclerosis progression among the three groups and examined determinants of plaque progression in APS patients. Results Sixty-four APS patients (75% females, 43.8% with primary APS), 58 patients with DM and 66 HC were included in the 7-year ultrasound re-evaluation. New plaque was detected in 51.6%, 36.2% and 25.8% of APS, DM and HC subjects, respectively. After adjusting for traditional cardiovascular risk factors (CVRFs) and baseline plaque presence, APS patients showed a 3-fold (OR = 3.07, P  = 0.007) higher risk for atherosclerosis progression versus HC and 2-fold (OR = 2.25, P  = 0.047) higher risk than DM patients. In multivariate analysis in the APS group, plaque progression was independently associated with systemic lupus erythematosus (SLE) co-existence (OR = 7.78, P  = 0.005) and number of CVRFs (OR = 3.02, P  = 0.002), after adjusting for disease-related parameters and CVRF-related medications. Sustained low-density lipoprotein target attainment reduced plaque progression risk (OR = 0.34, P  = 0.021). Conclusion Half of APS patients develop new atherosclerotic plaques over a 7-year follow-up, having a three-times higher risk versus HC. Concomitant SLE and number of traditional CVRFs are associated with plaque progression, supporting the need for thorough CVRF assessment and control. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can antinuclear antibodies (ANA) affect the subsequent live birth rate (LBR) in patients with unexplained recurrent pregnancy loss (RPL) in the absence of antiphospholipid antibodies (aPL)? SUMMARY ANSWER Women with unexplained RPL have a high probability of live birth following a positive pregnancy test (>70%), being similar between those with positive and negative ANA testing, regardless of the cut-off value. WHAT IS KNOWN ALREADY The RPL guidelines of the ESHRE state that 'ANA testing can be considered for explanatory purposes'. However, there have been a limited number of studies on this issue and sample sizes have been small, and the impact of ANA on the pregnancy prognosis is unclear. STUDY DESIGN, SIZE, DURATION A retrospective cohort study was conducted at Nagoya City University Hospital between 2006 and 2019. The study included 1021 women with RPL without known cause. PARTICIPANTS/MATERIALS, SETTING, METHODS Hysterosalpingography or 3D-ultrasound, chromosome analysis for both partners, blood tests for aPL, ANA, hypothyroidism, and diabetes mellitus were performed before a subsequent pregnancy. ANAs were measured by indirect immunofluorescence on Hep-2 cell slides. The cutoff dilution used was 1:40. In addition, patients were classified according to the ANA pattern on immunofluorescence staining: homogeneous, speckled, nucleolar, centromeric, peripheral, cytoplasmic, and others. LBRs were compared between ANA-positive and ANA-negative patients after excluding patients with antiphospholipid antibody syndrome, an abnormal chromosome in either partner and a uterine anomaly. MAIN RESULTS AND THE ROLE OF CHANCE Considering the cut-off value = 1:40 dilution, the subsequent LBRs were 72.5% (256/353) for the ANA-positive group and 73.2% (489/668) for the ANA-negative group; odds ratio (OR) = 0.97, 95% CI = 0.72–1.29. After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBRs were 92.8% (256/276) for the ANA-positive group and 93.0% (489/526) for the ANA-negative group: OR = 0.97 (95% CI = 0.55–1.70). Considering the cut-off value = 1:80 dilution, the subsequent LBRs were 75.0% (87/116) for the ANA-positive group and 72.7% (658/905) for the ANA-negative group; OR = 1.13 (95% CI = 0.72–1.76). After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBRs were 89.7% (87/97) for the ANA-positive group and 93.3% (658/705) for the ANA-negative group: OR = 0.62 (95% CI = 0.30–1.27). Considering the cut-off value = 1:160 dilution, the subsequent LBRs were 82.4% (28/34) for the ANA-positive group and 72.6% (717/987) for the ANA-negative group; OR = 1.76 (95% CI = 0.72–4.29). After excluding the miscarriages occurring from embryonic aneuploidy, the biochemical pregnancy losses, and the ectopic pregnancies, LBR were 93.3% (28/30) for the ANA-positive group and 92.9% (717/772) for the ANA-negative group: OR = 1.07 (95% CI = 0.25–4.63). There was no difference in LBR between the 2 groups before or after adjustment for age and BMI, but ANA-positive patients were significantly older than ANA-negative patients when using the 1:40 dilution, and ANA-positive patients had significantly lower BMIs than ANA-negative patients when using the 1:80 dilution. LIMITATIONS, REASONS FOR CAUTION A healthy control group was not established, making it impossible to compare ANA positivity rates between healthy controls and RPL patients. There were significant differences in age (1:40 dilution) and BMI (1:160 dilution) between the ANA-positive and ANA-negative groups. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that ANA testing is not useful to predict future pregnancy loss in women with RPL without known cause. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by MEXT Promotion of Distinctive Joint Research Center Program, Grant Number JPMXP0621467963 and used for English proofreading costs. There are no competing interests for all authors. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Background: Acute ischemic stroke (AIS) or transient ischemic attack (TIA) is the most common neurological manifestations of patients with antiphospholipid syndrome (APS). Incidental diffusion-weighted imaging (DWI) positive subcortical and cortical lesions, or acute incidental cerebral microinfarcts (CMI), are microscopic ischemic lesions, detectable on MRI for 10–14 days only. We aimed to look at the prevalence of acute incidental CMI in a cohort of patients with APS and their association with subsequent AIS or TIA. Methods: This is a population-based cohort study of adults with APS diagnosis using International Statistical Classification-9 (ICD-9) and supporting laboratory results between January 2014 and April 2020. We included any patient undergoing brain MRI (index event) during the year prior APS diagnosis or at any time point following diagnosis. Age-matched subjects with negative APS laboratory workup were used as a control group. In the first analysis, we compared acute incidental CMI prevalence in both groups. We then performed a second analysis among APS patients only, comparing patients with and without acute incidental CMI for AIS or TIA as the primary outcome. Cox proportional hazards models used to calculate hazards ratio (HR) and 4 years cumulative risk. Results: 292 patients were included, of which, 207 patients with APS. Thirteen patients with APS had acute incidental CMI on MRI (6.3%), compared with none in the control group (p = 0.013). Following multivariable analysis, APS was the sole factor associated with acute incidental CMI (p = 0.026). During a median follow-up of 4 years (IQR 3.5, 4) in patients with APS, following multivariable analysis, acute incidental CMI was associated with subsequent AIS or TIA (HR 6.73 [(95% CI, 1.96–23.11], p < 0.01). Conclusion: Acute incidental CMI are more common among patients with APS than in patients with negative APS tests, and are associated with subsequent AIS or TIA. Detecting acute incidental CMI in patients with APS may guide etiological workup and reevaluation of antithrombotic regimen. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to evaluate the characteristics of the patients with a rheumatologic disease who underwent TPE. Method: A single‐center, retrospective study was conducted between January 2016 and June 2023. Results: Twenty patients with a median age of 51 years received a median of 6 TPE sessions. Concurrently, immunosuppressive therapy was administered to 18 (90%) of them. During the follow‐up period, 9 patients (45%) died. Creatinine (p = 0.001), C‐reactive protein (p = 0.001), sedimentation rate (p = 0.002), leukocyte (p = 0.003), thrombocyte (p = 0.003), and neutrophil (p = 0.003) counts was decreased after TPE. Similarly, in the ROC analysis of post TPE laboratory parameters, urea, creatinine, CRP, hemoglobin, platelets, and lymphocytes predicted mortality with areas under the curve values ranging from 0.747 to 0.869. In the Cox regression analysis for mortality, creatinine was predictive for mortality (p = 0.030), HR 1.59 (95% CI: 1.05–2.41). Conclusion: In rheumatologic conditions, TPE is beneficial to fill the gap until the effects of immunosuppressants become apparent. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Lupus anticoagulants (LA) can interfere with routine coagulation tests such as the activated partial thromboplastin time (aPTT) and prothrombin time (PT). The international normalized ratio (INR) is derived from PT and is used to monitor warfarin therapy. A positive LA result is one of the laboratory criteria of the 2023 ACR/EULAR antiphospholipid syndrome (APS) classification criteria. We report a case in which LA interfered with INR measurement in an APS patient. Case Report: Our patient was a 45-year-old man who had experienced multiple episodes of thromboembolism. His INR was consistently high, despite not being on any anticoagulant. Our laboratory used a recombinant PT reagent, Siemens Healthineers Dade® Innovin® on a fully automated coagulometer, the Sysmex CS-2500. PT measurements were repeated using 2 different analyzers, the Sysmex CA-104 and Werfen ACL Top 550 CTS. The PT results were 40.5 s (reference range (RR): 9.3-10.8 s) and 56 s, using Sysmex CS2500 and CS104, respectively. However, the PT was 13.4 s (RI: 10.3-12.7 s) using Werfen ACL Top 550 CTS. We retested the sample using Thromborel® S, a tissue-derived PT reagent, and PT was found to be within the reference range. The patient tested positive for LA, anti-cardiolipin, and anti-beta2 glycoprotein I antibodies. Conclusions: LA can falsely prolong the PT when a recombinant PT reagent is used. When we retested the plasma using a tissue-derived PT reagent -- Thromborel® S -- PT was within normal limits. Thus, it is important to acknowledge that LA can react differently with different PT reagents. [ABSTRACT FROM AUTHOR]

A 33-year-old woman with morbid obesity, positive IgM cardiolipin antibody, and recurrent venous thromboembolism on weight-based enoxaparin treatment developed severe headaches during her 9th week of pregnancy and was diagnosed with cerebral vein thrombosis (CVT). She was treated with enoxaparin (1 mg/kg) 240 mg twice daily, after a few days of intravenous heparin. Her complete blood count showed mild pancytopenia, with normal peripheral smear. She had a normal bone marrow biopsy done due to leukocytosis a year ago. She few days later presented to our emergency department (ED) with worsening headache and photophobia. Workup revealed normal anti-Xa activity despite weight-based enoxaparin, CVT, and a new diagnosis of acute promyelocytic leukemia. While it is known that APML predisposes to thrombotic events, there is limited literature that reports enoxaparin-resistant CVT as an initial manifestation of APML. It is important for clinicians to be aware that occurrence of unusual thromboembolism may herald APML. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in ALDH7A1 are associated with pyridoxine-dependent epilepsy (PDE), a rare autosomal recessive disorder characterized by epileptic seizures, unresponsiveness to standard antiseizure medications (ASM), and a response only to pyridoxine. Here, we report two patients (from a consanguineous family) with neonatal seizures and developmental delay. Case presentation: Patient 1 (a 13-year-old girl) was born normally at term. Her pregnancy was complicated by antiphospholipid syndrome, and persistent vomiting was managed with several medications, including pyridoxine (40 mg daily). Seizures occurred 6 h after birth and did not respond to antiseizure medications. However, they ceased 2 days later when pyridoxine (40 mg daily) was administered. She continued her medications and had delayed early milestones. Phenobarbitone was discontinued at 18 months, and pyridoxine was increased to 100 mg daily at 8 years of age. She was able to join a regular school and performed well. Patient 2, a 12-year-old boy, was delivered normally at term. Seizures started 10 h after birth, and he immediately received 40 mg of pyridoxine. Seizures have been controlled since then, and he experienced delayed milestones. Pyridoxine was increased to 100 mg daily at 7 years of age. He is currently in fifth grade and has dyslexia. Whole exome sequencing (WES) revealed that both patients 1 and 2 harbor a novel homozygous missense variant in ALDH7A1 (NM_001202404: exon 12: c.1168G>C; (p.Gly390Arg)). Conclusion: The present study reports a novel ALDH7A1 variant causing PDE and highlights the associated developmental delay and intellectual disability, despite early seizure control treatment. [ABSTRACT FROM AUTHOR]

Purpose: To perform a quantitative multimodal evaluation in 25 patients with primary antiphospholipid syndrome (PAPS) without ocular complaints and to compare them with 25 healthy individuals. Methods: A structural and functional ophthalmological evaluation using optical coherence tomography angiography (OCTA) and microperimetry (MP) exam in 25 patients with PAPS, followed at a tertiary rheumatology outpatient clinic, was performed. All ophthalmologic manifestations were documented and subsequent statistical analysis was performed for comparative purposes, with significance set at p < 0.05. Results: We included 100 eyes of 50 subjects (25 patients with PAPS without ocular complaints and 25 healthy individuals). Quantitative OCTA assessment revealed significant differences between PAPS patients and controls in both the superficial vascular complex (SVC) and deep vascular complex (DVC) using high-speed protocol, as well as in the SVC in the high-resolution protocol. Analysis of the foveal avascular zone (FAZ) parameters showed a larger area of FAZ in the DVC in PAPS patients using the high-speed method compared to the control group (p = 0.047). In MP quantitative analysis, the PAPS group exhibited lower central (p = 0.041) and global (p < 0.001) retinal sensitivity compared to the control group, along with sectoral differences, except in the inferior sector. Conclusions: PAPS patients present lower vascular density and retinal sensitivity compared to the control group, even in patients without paracentral acute middle maculopathy (PAMM). Our findings underscore the significance of ocular evaluation beyond symptomatic assessment in these patients. [ABSTRACT FROM AUTHOR]

Objectives: To determine the number of patients that met classification for antiphospholipid antibody syndrome (APS) after applying the 2023 American College of Rheumatology and the European Alliance for Associations of Rheumatology (ACR/EULAR) classification criteria, to identify reasons patients did not meet the new criteria, and determine the number of patients who were single, double, or triple positive based on laboratory criteria. Methods: A single center, retrospective chart review of patients with APS on anticoagulation managed by ambulatory care clinical pharmacists. Data collected included patient demographics, type of anticoagulation, and clinical and laboratory criteria for APS as defined by the 2023 ACR/EULAR criteria. Data is presented using descriptive statistics. Results: A total of 51 patients previously diagnosed with APS were included. There were 42 patients on warfarin (82.3%), 4 patients on direct oral anticoagulants (19%), 3 patients on low molecular weight heparin (5.8%), and 2 patients on fondaparinux (3.9%). Of the 51 patients, 12 (23.5%) met classification criteria, 33 (64.7%) did not meet classification criteria and 6 (11.7%) had insufficient data. Of the 27 patients that did not meet criteria, 13 patients did not meet the laboratory criteria (39.4%), 6 patients did not meet the clinical criteria (18.2%) and 14 patients did not meet both laboratory and clinical criteria (42.4%). Of the 12 patients that met classification criteria, 2 patients were triple positive (16.7%), 3 were double positive (25%), and 7 were single positive (58.3%). Conclusions: Results from this study indicate that APS continues to be a complex disease state with challenges in diagnosis and classification. Since only a small number of patients in our clinic continued to meet the classification criteria, opportunities for patient re-evaluation of management strategies at our institution could be considered. [ABSTRACT FROM AUTHOR]

Background Activated partial thromboplastin time (APTT) is susceptible to reagent composition. This study aimed to investigate a large number of specimens and determine the cause of discrepancies. Method This study included 18,994 subjects who underwent coagulation tests at our hospital from May 2020 to December 2020. Measuring reagents included HemosIL SynthASil APTT (APTT-SS, Instrumentation Laboratory) and Coagpia APTT-N (APTT-N, Sekisui Medical). Results A total of 451 patients demonstrated APTT-N of >39 seconds and an APTT-N/SS ratio of >1.3. A C-reactive protein (CRP) level of ≥1.4 mg/L demonstrated a significant positive correlation, with a higher APTT-N/SS indicating higher CRP levels. All 28 subjects receiving no anticoagulants and who had remaining specimens underwent a cross-mixing test (CMT). Of them, 17 were suspected for lupus anticoagulant (LA) by both the waveform shape and the index of circulating anticoagulant (ICA) value, 6 by the ICA value, and 5 were difficult to determine. Conclusion This study revealed that the APTT-N prolongation correlated with CRP degree and the transient involvement of LA in CMT results due to CRP. This study indicated various reactivities depending on the assay reagents used. Further testing is warranted if LA is suspected, considering the patient's background. [ABSTRACT FROM AUTHOR]

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. Synopsis: In our institution, the international guidelines for assessing recurrent miscarriage were only partially followed; substantial deviations included the lack of cytogenetic analysis and imaging tests. [ABSTRACT FROM AUTHOR]

Summary We describe a patient with sickle cell disease (SCD) and elevated antiphospholipid antibodies (aPL) who developed multi‐organ failure resembling catastrophic antiphospholipid syndrome. Autoimmune screening revealed several autoantibodies characteristic of systemic lupus erythematosus (SLE). Notably, routinely housed and unmanipulated transgenic sickle mice displayed significantly elevated titres of aPL‐ and SLE‐associated autoantibodies. We hypothesize that SCD may be a risk factor not only for the development of aPL but also more widespread autoimmunity. [ABSTRACT FROM AUTHOR]

Recently published 2023 ACR/EULAR APS classification criteria emphasize the importance of quantifying single-, double-, and triple-antiphospholipid antibody positivity, distinguishing between IgG and IgM isotypes, and delineating moderate/high levels of anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. We aimed to establish clinically important moderate/high thresholds for aCL and anti-β2GPI IgG/IgM chemiluminescent immunoassays (CLIA), in particular QUANTA Flash, comparable to our in-house ELISAs used for over two decades, and to evaluate their diagnostic performance. QUANTA Flash CLIA and in-house ELISAs were used to measure aCL and anti-β2GPI IgG/IgM. Moderate thresholds for QUANTA Flash CLIA were determined using a non-parametric approach, calculating a 99th percentile on serum samples from 139 blood donors, and by mirroring the diagnostic performance of in-house ELISA on 159 patient samples. Thresholds for QUANTA Flash CLIA achieving diagnostic performance equivalent to in-house ELISAs were 40 CU for moderate and 80 CU for high levels for aCL and anti-β2GPI IgG and IgM. The assays showed good qualitative agreement, ranging from 76.10 to 91.19 %. When considering in-house ELISA results, 14 out of 80 (17.5 %) patients did not fulfill the new ACR/EULAR laboratory classification criteria, while 27 out of 80 (33.8 %) did not when considering QUANTA Flash CLIA results. We determined moderate and high thresholds for aCL and anti-β2GPI IgG and IgM detected with QUANTA Flash CLIA, aligning with long-established in-house ELISA thresholds. These thresholds are crucial for seamlessly integrating of the new 2023 ACR/EULAR classification criteria into future observational clinical studies and trials. [ABSTRACT FROM AUTHOR]

Objective. This study examined maternal cardiovascular (CV) events relative to adverse pregnancy outcomes (APOs) among individuals with autoimmune rheumatic diseases (ARDs), primary antiphospholipid syndrome (APS), and those with neither. Methods. Using a California population-based birth cohort (2005-2020), we identified those with CV events (CVEs), ARDs, and APS through International Classification of Diseases, 9th and 10th revisions, Clinical Modification codes in maternal discharge records. Selected APOs identified from birth certifi- cates were preterm birth (PTB; < 37 weeks' gestation), small-for-gestational-age infants (SGA; birth weight < 10th percentile for age and sex), and a composite of either outcome. Adjusted risk ratios (aRRs) for adverse outcomes and their 95% CIs were calculated. Results. CVEs occurred more frequently in individuals with ARDs (265 of 19,340 [1.4%]) and primary APS (428 of 7758 [5.5%]) than those without (17,130 of 7,004,334 [0.3%]). The presence vs absence of CVEs was associated with a greater incidence of adverse outcomes in ARD (53.2% vs 26.6%), APS (30.6% vs 20.7%), and non-ARD/APS pregnancies (28.2% vs 15.2%). CVEs were associated with increased risks of SGA in all groups (aRRs 1.2-1.5) and PTB in ARD (aRR 1.6, 95% CI 1.3-2.0) and non-ARD/APS (aRR 1.7, 95% CI 1.7-1.8) pregnancies. Conclusion. CVEs were associated with modestly increased risks (20-70%) for PTB, SGA, or both across the groups. Notably, > 50% of ARD pregnancies with CVEs experienced APOs. Given that ARD and APS pregnancies have higher (although still low) rates of CVEs and have higher baseline risks of APOs than the general population, the additional burden conferred by CVEs is clinically important. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality. [ABSTRACT FROM AUTHOR]

Introduction: Unfolded Von Willebrand Factor (VWF) is increased in thrombotic pathologies such as myocardial infarction. Unfolded VWF mediates the binding of platelets without the need for collagen. β2-glycoprotein I (β2-GPI) is a natural inhibitor of the platelet-VWF interaction. The antiphospholipid syndrome (APS) is associated with thrombosis, with an important pathophysiological role of auto-antibodies directed against β2-GPI. Methods: (Unfolded) VWF levels were studied in normal controls (n=93), APS patients (n=64), non-APS thrombosis patients (n=39) and non-APS auto-immune disease (AID) patients (n=49. Results: Unfolded VWF levels were respectively, 53%, 50% and 36% higher in APS patients, non-APS thrombosis patients and AID patients, compared to normal controls (p<0.0001). Unfolded VWF levels above the 90th percentile in normal controls were associated with an odds of APS (OR: 8.51; CI:3.26 - 22.2; p<0.001), compared to ORs of non-APS thrombosis (OR:5.87; CI:2.07 - 16.7, p=0.001) and AID (OR:3.71; CI:1.40 – 9.87; p=0.009). Discussion: We found that APS patients have high levels of unfolded VWF in their circulation. In APS, auto-antibodies against-β2-GPI may interfere with the β2-GPI-mediated inhibition of VWF-platelet interaction. Therefore, the higher unfolded VWF levels in APS could in part explain the association of APS and thrombotic complications. [ABSTRACT FROM AUTHOR]