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In pregnant individuals with antiphospholipid antibodies, anti-β2 glycoprotein-I domain 1 and antiphosphatidylserine–prothrombin antibodies are significant independent predictors of adverse pregnancy outcome. OBJECTIVE: To investigate the value of anti-β2 glycoprotein-I domain 1 (aD1) and antiphosphatidylserine–prothrombin antibodies for predicting adverse pregnancy outcomes in an at-risk population and to describe the relationship among aD1, antiphosphatidylserine–prothrombin, lupus anticoagulant, and other antiphospholipid antibodies (aPL). METHODS: Data were obtained from a prospective cohort of pregnant patients with aPL, with systemic lupus erythematosus (SLE) (n=59) or without SLE (n=106), or SLE without aPL (n=100) (PROMISSE [Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus and Antiphospholipid Syndrome] study; NCT00198068). Levels of aD1 and antiphosphatidylserine–prothrombin were quantified with the QUANTA Flash and QUANTA Lite systems, respectively, in sera collected at less than 18 weeks of gestation. Adverse pregnancy outcome was defined as delivery at before 34 weeks of gestation for preeclampsia or placental insufficiency or fetal death after 12 weeks of gestation. Receiver operating characteristic (ROC) analysis assessed the diagnostic properties of aD1 and antiphosphatidylserine–prothrombin for adverse pregnancy outcomes. Bivariate comparisons were made between each biomarker. Multivariable regression modeling of adverse pregnancy outcomes was performed, and backward selection determined variables for a final model for adverse pregnancy outcomes. Logistic regression of lupus anticoagulant quantified the association with aD1 and antiphosphatidylserine–prothrombin. The rate of adverse pregnancy outcomes was described by combined results of lupus anticoagulant, aD1, and antiphosphatidylserine–prothrombin immunoglobulin G (IgG). RESULTS: Of 265 individuals, 45 (17.0%) experienced adverse pregnancy outcomes. Area under the curve from ROC analysis for aD1 was 0.734 (95% CI, 0.664–0.805), for antiphosphatidylserine–prothrombin IgG was 0.83 (95% CI, 0.751–0.899), and for antiphosphatidylserine–prothrombin immunoglobulin M (IgM) was 0.612 (95% CI, 0.520–0.703). Markers associated with adverse pregnancy outcomes were aD1 (P <.001), anticardiolipin IgG (P <.001), β2-glycoprotein I IgG (P =.003), antiphosphatidylserine–prothrombin IgG (P <.001), antiphosphatidylserine–prothrombin IgM (P =.03), and lupus anticoagulant (P <.001). Backward selection identified lupus anticoagulant, aD1, and antiphosphatidylserine–prothrombin IgG for final adverse pregnancy outcome modeling: lupus anticoagulant odds ratio (OR) 7.0 (95% CI, 3.4–14.4), aD1 OR 12.1 (95% CI, 3.64–40.2), and antiphosphatidylserine–prothrombin IgG OR 11.4 (95% CI, 5.2–25.2). Both aD1 and antiphosphatidylserine–prothrombin IgG remained significant when lupus anticoagulant was removed from the model. Both aD1 and antiphosphatidylserine–prothrombin IgG performed the best in ruling in adverse pregnancy outcomes. With a likelihood ratio less than 0.1, aD1 or antiphosphatidylserine–prothrombin IgG performed well for ruling out adverse pregnancy outcomes. Both aD1 and antiphosphatidylserine–prothrombin IgG were associated with lupus anticoagulant positivity: OR 27.9 (95% CI, 12.1–64.0) if both were positive. Adverse pregnancy outcomes were highest in those with positive lupus anticoagulant, aD1, and antiphosphatidylserine–prothrombin IgG (47.6%). CONCLUSION: In pregnant individuals with aPL, with or without SLE, aD1 and antiphosphatidylserine–prothrombin IgG are significant independent predictors of adverse pregnancy outcomes and are strongly associated with lupus anticoagulant. Combined use may identify patients at greatest risk for severe obstetric complications. [ABSTRACT FROM AUTHOR]

Objective: The 2023 American College of Rheumatology/EULAR antiphospholipid syndrome (APS) classification criteria development, which aimed to identify patients with high likelihood of APS for research, employed a four‐phase methodology. Phase I and II resulted in 27 proposed candidate criteria, which are organized into laboratory and clinical domains. Here, we summarize the last stage of phase III efforts, employing a consensus‐based multicriteria decision analysis (MCDA) to weigh candidate criteria and identify an APS classification threshold score. Methods: We evaluated 192 unique, international real‐world patients referred for "suspected APS" with a wide range of APS manifestations. Using proposed candidate criteria, subcommittee members rank ordered 20 representative patients from highly unlikely to highly likely to have APS. During an in‐person meeting, the subcommittee refined definitions and participated in an MCDA exercise to identify relative weights of candidate criteria. Using consensus decisions and pairwise criteria comparisons, 1000Minds software assigned criteria weights, and we rank ordered 192 patients by their additive scores. A consensus‐based threshold score for APS classification was set. Results: Premeeting evaluation of 20 representative patients demonstrated variability in APS assessment. MCDA resolved 81 pairwise decisions; relative weights identified domain item hierarchy. After assessing 192 patients by weights and additive scores, the Steering Committee reached consensus that APS classification should require separate clinical and laboratory scores, rather than a single‐aggregate score, to ensure high specificity. Conclusion: Using MCDA, candidate criteria preliminary weights were determined. Unlike other disease classification systems using a single‐aggregate threshold score, separate clinical and laboratory domain thresholds were incorporated into the new APS classification criteria. [ABSTRACT FROM AUTHOR]

BackgroundWe recently suggested that many anticardiolipin antibodies bind only to oxidized cardiolipin (OxCL) and/or to OxCL-beta(2)-glycoprotein 1 (beta(2)GP1) adducts but not to a "reduced" cardiolipin that is unable to undergo oxidation. To test this hypothesis, we investigated 24 sera, 4 protein A-purified IgG fractions, and 3 human monoclonal antibodies that were all isolated from patients with antiphospholipid antibody syndrome (APS); testing was also performed in 7 controls. Two monoclonal antibodies (IS3 and IS4) were selected for binding to CL and one was selected for binding to beta(2)GP1 (LJB8).Methods and resultsBy chemiluminescent immunoassay, all APS sera samples bound only to OxCL and not to reduced CL, and the binding was inhibited >95% by OxCL but not reduced CL. All purified IgG fractions bound to beta(2)GP1 but only when the beta(2)GP1 was plated on microtiter wells coated with OxCL. All 3 monoclonal antibodies bound only to OxCL. On Western blots, IS4 and LJB8 bound to beta(2)GP1 as well as to delipidated apoB of oxidized LDL but not to native apoB. IS3 also bound to oxidized apoB on Western blot. Covalent modification of beta(2)GP1 with oxidation products of CL made it more antigenic for APS serum samples, for purified IgG fractions, and for the monoclonal antibodies.ConclusionsThese data support the hypothesis that oxidation of CL is needed to generate epitopes for many anticardiolipin antibodies and that some of these epitopes are covalent adducts of OxCL with beta(2)GP1 or apoB.

Circulating autoantibodies to phospholipids (aPLs), such as cardiolipin (CL), are found in patients with antiphospholipid antibody syndrome (APS). We recently demonstrated that many aPLs bound to CL only after it had been oxidized (OxCL), but not to a reduced CL analogue that could not undergo oxidation. We now show that the neoepitopes recognized by some aPLs consist of adducts formed between breakdown products of oxidized phospholipid and associated proteins, such as beta2 glycoprotein 1 (beta2GP1). Addition of human beta2GP1, polylysine, native low-density lipoprotein, or apolipoprotein AI to OxCL-coated wells increased the anticardiolipin antibody (aCL) binding from APS sera that first had been diluted so that no aCL binding to OxCL could be detected. No increase in aCL binding was observed when these proteins were added to wells coated with reduced CL. The ability of beta2GP1, polylysine, or low-density lipoprotein to be a "cofactor" for aCL binding to OxCL was greatly reduced when the proteins were methylated. Incubation of beta2GP1 with oxidized 1-palmitoyl-2-linoleyl-[1-14C]-phosphatidylcholine (PC), but not with dipalmitoyl-[1-14C]-PC, led to formation of covalent adducts with beta2GP1 recognized by APS sera. These data suggest that the reactive groups of OxCL, such as aldehydes generated during the decomposition of oxidized polyunsaturated fatty acids, form covalent adducts with beta2GP1 (and other proteins) and that these are epitopes for aCLs. Knowledge that the epitopes recognized by many aPLs are adducts of oxidized phospholipid and associated proteins, including beta2GP1, may give new insights into the pathogenic events underlying the clinical manifestations of APS.

Objectives Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. Methods In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. Results Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P  = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P  = 0.007), aβ2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P  = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P  < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P  = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P  = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P  = 0.016). Conclusions DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden. [ABSTRACT FROM AUTHOR]

Introduction: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels. Aims: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre. Methods: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected. Results: Forty‐seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty‐one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self‐reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported. Conclusion: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery‐associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non‐VWD population. [ABSTRACT FROM AUTHOR]

Objective This study aimed to evaluate the "off-hour effect" on maternal and neonatal adverse events in a large cohort representing U.S. population. Study Design A secondary analysis of the Consortium on Safe Labor (CSL) dataset with 208,695 women and 229,385 deliveries was performed. The study included the deliveries of ≥23 gestational weeks from 19 hospitals in the United States from 2002 to 2008. Babies with congenital anomalies were excluded from neonatal outcomes. We compared maternal and neonatal outcomes of patients delivered during weekdays versus off hours (nights and weekends). The primary outcomes of the study were composite maternal and composite neonatal adverse events. The secondary outcomes were delivery type and individual maternal and neonatal adverse events including maternal death and perinatal mortality rate. Associations between off hours and all the outcomes were analyzed in bivariable and multivariable analyses. The same analyses were performed in strata by indication for admission (spontaneous labor or induction of labor). Results Composite maternal adverse events (6.19 vs. 6.06%, p = 0.41) and maternal death (0.01 vs. 0.01%, p = 0.19) were not significantly different between off hours and weekday groups. In contrast, composite neonatal adverse events (6.91 vs. 5.84%, p < 0.001) and perinatal mortality rate (1.03 vs. 0.77%, p < 0.001) were higher in the off-hour group. After adjusting for confounding variables, only the composite neonatal outcome continued to be associated with off hours (adjusted odds ratio [aOR] = 1.10, 95% confidence interval [CI]: 1.04–1.16). Stratified analyses showed that the off-hour effect for the neonatal composite outcome was not present in those presenting in spontaneous labor (6.1 vs. 5.9%, p = 0.40). Conclusion Off-hour delivery was not associated with severe maternal morbidity and was only modestly associated with severe neonatal morbidity. This association was observed in women undergoing induction, not in those presenting in spontaneous labor. These data draw into question the existence of a clinically meaningful and correctable "off-hour effect" in obstetrics. Key Points The presence of a significant off-hour effect in obstetrics is still questionable. If the off-hour effect exists, it seems that not to be related with staffing issues. There is not a big difference for adverse events at off hours in spontaneously laboring patients. [ABSTRACT FROM AUTHOR]