Non-criteria Antiphospholipid Antibodies Research Articles

Anti-phosphatidyl-serine/prothrombin (aPS/PT) antibodies are superior predictors of LAC presence and APS diagnoses: A single center study

Background and aimsSeveral non-criteria (NC) anti-phospholipid antibodies (APLA) have been proposed as candidates for antiphospholipid antibody syndrome (APS) diagnosis. The objectives of this study were 1) to determine the association of five different NC-APLA with positivity for Lupus anti-coagulant (LAC) and the criteria antibodies anti-cardiolipin (aCL) and anti-beta glycoprotein (aB2GPI), and 2) to assess the ability of NC-APLA to predict LAC presence and clinical APS diagnoses. Material and methodsResults from 486 patients tested for LAC and APLA were retrieved. Patients were grouped according to LAC and serology positivity into three groups: Single-positives (SP) for LAC, aCL or aB2GPI; Double-positives for aCL and aB2GPI; Triple-positives (TP) for LAC, aCL and aB2GPI. NC-ALPA titers were compared between LAC-positive and negative and APS and non-APS patients. ResultsForty-two of 486 patients were LAC-positive and 28 were diagnosed with APS. All criteria and NC-APLA titers were significantly higher in TP than SP patients. ROC analyses based on LAC status showed highest area under the curve (AUC, 95% CI) for aPS/PT IgG (0.75, 0.65–0.85) and aPS/PT IgM (0.73, 0.63–0.82). Based on APS diagnosis, aPS/PT IgM achieved highest AUC (0.87; 0.79–0.95). ConclusionAnti-phosphatidyl-serine/prothrombin (aPS/PT) antibodies are superior predictors of LAC presence and APS diagnoses.

Antiphospholipid antibodies are enriched post-acute COVID-19 but do not modulate the thrombotic risk

Background and objectivesCOVID-19-associated coagulopathy, shown to increase the risk for the occurrence of thromboses and microthromboses, displays phenotypic features of the antiphospholipid syndrome (APS), a prototype antibody-mediated autoimmune disease. Several groups have reported elevated levels of criteria and non-criteria antiphospholipid antibodies (aPL), assumed to cause APS, during acute or post-acute COVID-19. However, disease heterogeneity of COVID-19 is accompanied by heterogeneity in molecular signatures, including aberrant cytokine profiles and an increased occurrence of autoantibodies. Moreover, little is known about the association between autoantibodies and the clinical events. Here, we first aim to characterise the antiphospholipid antibody, anti-SARS-CoV-2 antibody, and the cytokine profiles in a diverse collective of COVID-19 patients (disease severity: asymptomatic to intensive care), using vaccinated individuals and influenza patients as comparisons. We then aim to assess whether the presence of aPL in COVID-19 is associated with an increased incidence of thrombotic events in COVID-19. Methods and resultsWe conducted anti-SARS-CoV-2 IgG and IgA microELISA and IgG, IgA, and IgM antiphospholipid line immunoassay (LIA) against 10 criteria and non-criteria antigens in 155 plasma samples of 124 individuals, and we measured 16 cytokines and chemokines in 112 plasma samples. We additionally employed clinical and demographic parameters to conduct multivariable regression analyses within multiple paradigms. In line with recent results, we find that IgM autoantibodies against annexin V (AnV), β2-glycoprotein I (β2GPI), and prothrombin (PT) are enriched upon infection with SARS-CoV-2. There was no evidence for seroconversion from IgM to IgG or IgA. PT, β2GPI, and AnV IgM as well as cardiolipin (CL) IgG antiphospholipid levels were significantly elevated in the COVID-19 but not in the influenza or control groups. They were associated predominantly with the strength of the anti-SARS-CoV-2 antibody titres and the major correlate for thromboses was SARS-CoV-2 disease severity. ConclusionWhile we have recapitulated previous findings, we conclude that the presence of the aPL, most notably PT, β2GPI, AnV IgM, and CL IgG in COVID-19 are not associated with a higher incidence of thrombotic events.

16th International congress on antiphospholipid antibodies task force report on antiphospholipid syndrome laboratory diagnostics and trends.

Classification criteria for antiphospholipid syndrome (APS) require IgG or IgM isotypes of the anticardiolipin (aCL) antibodies, anti-β2 glycoprotein I (anti-β2GPI) antibodies, and/or the lupus anticoagulant (LA) to satisfy the laboratory disease definition. Over the past 20 years, non-criteria antiphospholipid antibodies (aPL) directed to other proteins of the coagulation cascade (i.e. prothrombin and/or phosphatidylserine-prothrombin complex) or to some domains of β2GPI have been proposed. This task force concentrated and reviewed the literature on data including aPS/PT, antibodies to domain 4/5 of β2GPI and the newly described antibodies to protein/HLA-DR complex. In addition, we discussed testing of LA in the 'new' oral anticoagulants' era and the value of triple positivity in the risk assessment of aPL. The conclusions were presented at a special session during the 16th International Congress on aPL, Manchester, UK, September 2019.

Preconception Non-criteria Antiphospholipid Antibodies and Risk of Subsequent Early Pregnancy Loss: a Retrospective Study

The aim of this study was to investigate the subsequent early pregnancy outcomes in women positive for non-criteria antiphospholipid antibodies (NC-aPLs) before pregnancy. A total of 273 patients who had experienced sporadic or recurrent pregnancy loss and had been screened for 13 NC-aPLs at preconception were recruited in this study from September 2019 to February 2022. Serum levels of NC-aPLs were measured by ELISA using specific kits. The primary outcome was early pregnancy loss, and the secondary outcomes were biochemical pregnancy, clinically confirmed pregnancy loss, and ongoing pregnancy. Among these subjects, 56 patients had one previous pregnancy loss, and 217 had recurrent pregnancy loss (RPL). The NC-aPLs (+) and NC-aPLs (−) groups had similar rates of early pregnancy loss (EPL) after adjustment, regardless of the number of positive NC-aPLs (aOR = 1.054, 95% CI 0.602–1.846). Other outcomes were comparable in both groups, including the rates of biochemical pregnancy (aOR = 1.344, 95% CI 0.427–4.236), clinically confirmed pregnancy loss (aOR = 0.744, 95% CI 0.236–2.344), and ongoing pregnancy (aOR = 0.949, 95% CI 0.542–1.660). Based on sensitivity analysis, the NC-aPLs (+) were not associated with adverse early pregnancy outcomes in women with RPL. Furthermore, the difference in gestational weeks of pregnancy loss between the two groups was also insignificant. This study found no evidence linking preconception NC-aPL positivity to early pregnancy outcomes but offers a reference for future research to clarify NC-aPLs’ potential clinical impact.

Criteria and Non-Criteria Antiphospholipid Antibodies and Cancer in Patients with Involuntary Weight Loss.

Cancer patients have higher prevalences of antiphospholipid antibodies (aPLs), occasionally associated with thrombotic events. A cross-sectional study regarding the presence of criteria (IgG/IgM anti-cardiolipin-aCL, anti-β2 glycoprotein I-aβ2GPI) and non-criteria (IgG/IgM anti-phosphatidylserine-aPS, anti-phosphatidylethanolamine-aPE, anti-prothrombin-aPT) aPLs in 146 patients with involuntary weight loss was performed. None of the patients had thrombotic events during the study. Out of the 36 cancer patients, 33 had non-hematologic malignancies. In the cancer subgroup, 60% of the patients had at least one positive aPL, with significantly more patients being positive for aβ2GPI IgG compared with the non-cancer subgroup-p = 0.03, OR = 2.23 (1.02-4.88). When evaluating the titres, aCL IgG/IgM, aβ2GPI IgG, aPE IgG, and aPS IgG had significantly higher values in cancer patients, the best cancer predictor being aβ2GPI IgG-AUC 0.642 (0.542-0.742). Gastrointestinal cancer patients were studied separately, and aCL IgM positivity was significantly higher-p = 0.008, OR = 6.69 (1.35-33.02). Both the titres of aCL IgM (p = 0.006) and aPS IgM (p = 0.03) were higher in the gastrointestinal cancer subgroup, with aCL IgM being the best predictor for gastrointestinal cancer development-AUC 0.808 (0.685-0.932). Despite criteria and non-criteria aPLs being frequent in cancer, their connection with thrombosis in these patients is probably dependent on other important risk factors and needs further research.

Thrombotic risk assessment in antiphospholipid syndrome: do noncriteria antibodies contribute?

In this cross-sectional study, it was aimed to test the predictive value of noncriteria antiphospholipid antibodies (aPL) in addition to the global antiphospholipid syndrome score (GAPSS) in predicting vascular thrombosis (VT) in a cohort of patients with APS and aPL (+) systemic lupus erythematosus (SLE). This study included 50 patients with primary APS, 68 with SLE/APS, and 52 with aPL (+) SLE who were classified according to VT as VT ± pregnancy morbidity (PM), PM only or aPL (+) SLE. Antiphospholipid serology consisting of lupus anticoagulant (LA), anticardiolipin (aCL) immunoglobulin G (IgG)/IgM/IgA, antibeta2 glycoprotein I (aβ2GPI) IgG/IgM/IgA, antiphosphatidylserine/prothrombin (aPS/PT) IgG/IgM and antidomain-I (aDI) IgG was determined for each patient. The GAPSS and adjusted GAPSS (aGAPSS) were calculated for each patient, as previously defined. Logistic regression analysis was carried out with thrombosis as the dependent variable and high GAPSS, aCL IgA, aβ2GPI IgA, and aDI IgG as independent variables. The mean GAPSS and aGAPSS of the study population were 11.6 ± 4.4 and 9.6 ± 3.8. Both the VT ± PM APS (n = 105) and PM only APS (n = 13) groups had significantly higher GAPSS and aGAPSS values compared to the aPL (+) SLE (n = 52) group. The patients with recurrent thrombosis had higher aGAPSS but not GAPSS than those with a single thrombotic event. The computed area under the receiver operating characteristic curve demonstrated that a GAPSS ≥13 and aGAPSS ≥10 had the best predictive values for thrombosis. Logistic regression analysis including a GAPSS ≥13, aCL IgA, aβ2GPI IgA, and aDI IgG showed that none of the factors other than a GAPSS ≥13 could predict thrombosis. Both the GAPSS and aGAPSS successfully predict the thrombotic risk in aPL (+) patients and aCL IgA, aβ2GPI IgA, and aDI IgG do not contribute to high a GAPSS or aGAPSS.

B-093 Evaluation of the Association of Non-criteria Antiphospholipid Antibodies with the Presence of Lupus Anticoagulant

Abstract Backrground Laboratory diagnosis of the antiphospholipid antibody syndrome (APS) requires evidence ofpersistently positive lupus anticoagulant (LAC), detected using clot-based assays and/or thepresence of high-titer serum anti-cardiolipin (aCL) and/or anti-beta-2 glycoprotein-1 (aB2GPI)antibodies, measured by semi-quantitative solid-phase immunoassays. Several non-criteria anti-phospholipid antibodies (NC-APLA) have been proposed as candidates for APS diagnosis:phosphatidyl-serine/ prothrombin (aPS/PT; IgM and IgG isotypes), anti-phosphatidyl serine (aPS;IgM and IgG), anti-prothrombin (aPT-IgG). However, their diagnostic relevance in routine APSevaluation is still unclear. The objectives of this study were 1) to determine the prevalence andassociation of NC-APLA in relation to LAC, aCL and aB2GPI antibodies’ positivity,independently and in combination and, 2) to assess the ability of NC-APLA to predict LACactivity, as an indirect measure of their function. Methods Results from 492 patients submitted for antiphospholipid antibody (APLA) panel or standaloneserology testing between January 2016 to January 2023 were retrieved in accordance withinstitutional guidelines. Patients were grouped according to LAC status and serology positivity(using manufacturer-suggested cutoff) into three groups: Single-positives (SP) for LAC, aCL oraB2GPI; Double-positives (DP) for aCL and aB2GPI; Triple-positives (TP) for LAC, aCL andaB2GPI. NC-ALPA titers were compared between LAC-positive and negative patients. Statisticalsignificance was established using unpaired Student’s t-test. Receiver operating curve (ROC)analysis was employed to assess the ability of NC-APLA to predict LAC status. Results Out of the total 492 patients, 1.8% (9/492) were TP, 2.4% (12/492) were DP and 24.7% (122/492)were SP. All NC-APLA titers were significantly higher in TP than in SP patients (P < 0.001).aPS/PT IgG (Mean: 76.3 vs 12.8 Units) and aPS IgG (Mean: 64.8 vs 5.5 GPS) antibodies weresignificantly higher in TP than DP patients (P = 0.008 and <0.0001, respectively). aPS/PT IgM(Mean: 62.5 vs 19.4 Units) and aPS IgM titers (Mean 31.9 vs 7.7 MPS) were significantly higherin DP compared to SP patients (P < 0.0001). When classified by LAC status, 40 patients werepositive and 452 were negative. Levels of all NC-APLA antibody titers (P < 0.0001) followed byaCL (Mean IgG 21.9 vs 7.8 GPL; IgM 20 vs 12.6 MPL; P < 0.01) and aB2GPI (Mean IgG 20.1 vs 4.9 SGU; IgM 13.8 vs 7.6 SMU, P < 0.001) antibodies were significantly higher in LAC-positivepatients compared to the LAC-negative individuals. ROC analyses based on the LAC statusresulted in the highest area under the curve (AUC, 95% CI) for aPS/PT IgM (0.72, 0.62 to 0.81)Private Information and aPS/PT IgG (0.74, 0.65 to 0.83) antibodies relative to aCL (IgM:0.53, 0.43 to 0.64; IgG:0.66, 0.56 to 0.77) or aB2GPI (IgM:0.5, 0.51 to 0.72 and IgG:0.6, 0.51 to 0.72) antibodies; aPS IgMand aPT IgG displayed similar performances (0.65, 0.54 to 0.75 and 0.66, 0.57 to 0.74,respectively). Whereas aPS IgG was of lower AUC (0.58, 0.48 to 0.68). Conclusion Our data demonstrated that at high titers, NC-APLA, display increased association with LACpositivity in comparison to aCL or aB2GPI antibody levels. Particularly, aPS/PT antibodiesdisplayed the superior ability to determine the LAC presence.Private Information

Criteria and Non-Criteria Antiphospholipid Antibodies in Antiphospholipid Syndrome: How Strong Are They Correlated?

The place of non-criteria antiphospholipid antibodies (aPLs) in the diagnosis of antiphospholipid syndrome (APS) is still debatable. The aim of this research was to evaluate the correlations between the titres of non-criteria aPLs (anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine (aPS), and anti-prothrombin (aPT) antibodies), and the ones of the already studied criteria aPLs (anti-cardiolipin (aCL) and anti-β2 glycoprotein I-aβ2GPI antibodies). Altogether, 72 APS (30 primary and 42 secondary) patients were included in our study. High correlation coefficients (rs) were found between aPS IgM and aCL IgM, overall (0.77, p < 0.01), as well as in the primary (0.81, p < 0.01), and secondary (0.75, p < 0.01) APS subgroups. Low or statistically insignificant correlations were observed between IgG/IgM isotypes of aPT and aCL, or aβ2GPI, in the entire study population, and when evaluating the subgroups. Therefore, moderate correlations were mainly identified between the tested non-criteria antibodies and the criteria ones, suggesting little added value for the use of the tested non-criteria aPLs, with the exception of aPT, which seems to have different kinetics and might be a promising APS diagnostic tool.

Profile and clinical relevance of non-criteria antiphospholipid antibodies in patients diagnosed with or highly suspected of APS.

This study investigates the positivity and relevance of non-criteria aPLs with clinical phenotypes in patients highly suspected of or diagnosed with APS. Outpatient cases were included from a prospectively maintained database, and patients were grouped into APS (n = 168), seronegative APS (SNAPS, n = 9), those meeting the diagnostic criteria for clinical events without laboratory results (only-event, n = 15), those that had aPL positivity without clinical manifestations (asymptomatic APA, n = 39), and healthy controls (n = 88). Criteria aPL results and APS-related clinical features were extracted. Sixteen non-criteria aPLs were tested and analysed. LA, aCL and anti-β2 glycoprotein-I were positive in 84.5%, 61.3% and 74.4% of APS patients, and 61.5%, 59.0% and 74.4% of asymptomatic APA patients, respectively. In patients negative for criteria serological tests, 23 out of 24 were positive for at least one non-criteria aPL. Triple-positive patients also had significantly higher tests of some aPLs in comparison with other groups. Stroke was associated with anti-phosphatidyl-inositol (aPI) IgG and anti-phosphatidyl-glycerol (aPG) IgG. Late embryonic loss correlated with aPI IgM, and premature birth/eclampsia was associated with aPI IgG and aPG IgG. There were also positive associations between heart valve lesions and anti-phosphatidylserine-prothrombin (aPS/PT) IgM, APS nephropathy and anti-phosphatidyl-choline IgG or aPS/PT IgG, and livedo reticularis and anti-phosphatidyl-ethanolamine IgM. The prevalence of non-criteria aPLs differed from diagnostic biomarkers in patients diagnosed with or suspected of APS. Detection of aPLs provided additive value in the evaluation of APS-related clinical manifestations.

Prevalence and diagnostic value of non-criteria antiphospholipid antibodies for antiphospholipid syndrome in Chinese patients.

The presence of antiphospholipid antibodies (aPLs) plays a pivotal role in the pathogenesis of antiphospholipid antibody syndrome (APS). This study aimed to examine the diagnostic value of a set of non-criteria aPLs and their relevance with APS-related criteria and extra-criteria manifestations. From a prospectively constructed database, consecutive APS patients consisting of 114 primary APS (PAPS group), 54 with APS secondary to SLE (SAPS group), 9 seronegative APS (SNAPS), as well as 209 patients with systemic lupus erythematosus (SLE) and 88 healthy controls were included in this study. Levels of criteria aPLs, baseline information, and APS-related criteria and extra-criteria features were extracted from the database. Serum levels of non-criteria aPLs including aPC IgG/IgM, aPI IgG/IgM, aPE IgG/IgM/IgA, aPG IgG/IgM/IgA, anti-phosphatidic acid (aPA) IgG/IgM, aSM IgG/IgM, and aPS/PT IgG/IgM were analyzed with AESKULISA® ELISA Test Kits. The addition of aPC IgG/M, aPI IgG/M, aPE IgG/M/A, aSM IgG/M, and aPA IgG/M to aCL or aβ2GPI IgG/M could significantly increase diagnostic sensitivity and accuracy. A significant difference between PAPS or SAPS and HC was presented in all non-criteria aPLs except for aSM IgM and aPG IgA. Eight out of nine SNAPS patients were positive for at least 1 aPL. Pregnancy morbidity was associated with aSM IgM (r = 0.22) and aSM IgG (r = 0.15). Pre-eclampsia or premature birth was associated with aSM IgG (r = 0.16), aPI IgG (r = 0.22), aPC IgG (r = 0.16), and aPG IgG (r = 0.18). Stroke was associated with aPI IgG (r = 0.2). The clinical association was also observed in DVT with aPS/PT IgG (r = 0.17). Valve lesion was positively associated with aSM IgM (Fisher test p = 0.039), APS nephropathy was associated with aPC IgG (OR 3.797), and livedo reticularis was associated with aPE IgM (OR 15.391). Additional detection of non-criteria aPLs including aPC IgG/M, aPE IgG/M/A, aPI IgG/M, aSM IgG/M, and aPA IgG/M could assist in APS diagnosis. The positivity of certain aPLs was statistically associated with both criteria and extra-criteria APS clinical manifestations.

Relevance of non-criteria antiphospholipid antibodies titers among patients with antiphospholipid syndrome and patients with systemic lupus erythematosus

BackgroundThere is an increasing interest in the study of non-criteria antiphospholipid antibodies (aPL) including antibodies targeting domain 1 of the B2 glycoprotein 1 (anti-D1 B2GP1) and antibodies anti phosphatidylserine/ prothrombin (PS/PT). ObjectivesOur aim was to analyze a panel of conventional and non-criteria aPL in a cohort of patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS), to describe if there are differences in aPL titers among groups, to evaluate clinical associations including risk of recurrent events of novel aPL. MethodsObservational study that evaluated at baseline antibodies against anti-D1 B2GP1 and anti PS/PT. Anti-D1 B2GP1 antibodies were tested using a chemiluminescent immunoassay. IgG and IgM anti PS/PT, aCL and anti B2GP1 by ELISA techniques. Therefore, patients were followed in order to identify new thrombotic events. Results133 patients with SLE and 23 with primary APS patients were included. Main APS manifestations were DVT (27%), obstetric morbidity (22%) and arterial thrombosis (10.1%). IgM anti PS/PT antibodies levels were (20.6 - 127) vs 21.9 (11.2 - 39.2) U/ml, p<0.001 in primary APS vs SLE with APS, respectively. Anti-D1 B2GP1, IgG and IgM anti PS/PT were associated with thrombotic and non-thrombotic manifestations. During follow-up, IgG B2GP1 were related with a significant cumulative risk of thrombosis. ConclusionsWe found significant differences in serum titers of non-criteria aPL among patients with primary APS vs SLE with APS. Whether non-criteria aPL antibodies titers are useful to differentiate patients with primary and secondary APS requires further analysis in other populations.

Immune interface of patients with reproductive loss in the North-West region of the Russian Federation

BACKGROUND: Currently, more than a hundred immunological biomarkers are known that are important for fertilization, implantation and placentation.&#x0D; AIM: The aim of this study was to assess the immunological profile for the main allo- and autoantibodies in women with reproductive loss and infertility in the North-West region of the Russian Federation.&#x0D; MATERIALS AND METHODS: This prospective cohort study was conducted at the stage of pregnancy planning in 325 women with reproductive disorders (spontaneous miscarriages, missed abortions, infertility, IVF failures) on the premises of the D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive Medicine (St. Petersburg, Russia) from 2015 to 2022. The study assessed the immune interface of women with a history of reproductive disorders and matching loci of the HLA class II system (DQA1, DQB1, DRB1) among 100 married couples.&#x0D; RESULTS: In couples with reproductive disorders, coincidences of HLA class II allele (DQA1, DQB1, DRB1) loci were diagnosed in 14% (at 2 loci), 31% (at 3 loci), 14% (at 4 loci), 3% (at 5 loci) and 10% (at 6 loci) of couples. In 34.4% of women, we found an elevated number of spontaneously activated NK cells (CD107a). As many as 31.15% of women had a high level of antibodies to human chorionic gonadotropin. We found that 22.34% of women were carriers of at least one criteria antiphospholipid antibody, and 3.16% of women of two antiphospholipid antibodies. The diagnosis of antiphospholipid syndrome was not established in any patient. Non-criteria antiphospholipid antibodies were found in 6.15% of women. In 12.2% of women, we diagnosed a high level of antibodies to thyroperoxidase, while the average antibody value was 30.76 IU/ml. Only one patient had a high level of antisperm antibodies in the blood serum.&#x0D; CONCLUSIONS: In 59% of patients with a history of reproductive disorders, we identified some features of the immunological profile, which can lead to this pathology. Thus, 32% of women had a deviation in one immunological parameter, while 20% of patients had it in two parameters, and 7% in three or more parameters.

Non-criteria antiphospholipid antibodies in antiphospholipid syndrome: Diagnostic value added.

Non-criteria antiphospholipid antibodies (aPLs) increase the diagnostic value for antiphospholipid syndrome (APS) and contribute to better recognition of seronegative APS (SNAPS). However, the clinical utility and the diagnostic value of non-criteria aPLs are inconsistent. This study aimed to investigate the prevalence and clinical significance of 7 non-criteria aPLs in a large APS cohort. Seven non-criteria aPLs, including anti-phosphatidylserine/prothrombin (aPS/PT) antibodies IgG/IgA/IgM, anti-phosphatidylethanolamine antibodies (aPE) IgG/IgA/IgM, anti-Annexin V antibodies (aAnnexinV) IgG/IgA/IgM, anti-phosphatidylserine antibodies (aPS) IgM, aPS IgG, antibodies directed againsta mixture of phospholipids(APhL) IgG, and APhL IgM were tested among 175 patients with APS, 122 patients with other autoimmune diseases (as disease controls), and 50 healthy controls. In the present study, the highest prevalence of non-criteria aPLs was seen in aAnnexinV (58.86%). APhL IgG and aPS IgM showed the highest specificity (95.35%) and aPS/PT showed the highest Youden index (0.3991) for the diagnostic value of APS. The aAnnexinV also showed the highest prevalence in SNAPS (43.3%), followed by APhL IgM (21.7%), aPE (16.7%) and aPS/PT (16.7%). APhL IgG, aPS/PT, and aPS IgG showed positive association with thrombotic events in APS patients [APhL IgG: odds ratio (OR) = 2.26, 95% confidence interval (CI) 1.18-4.34, p = 0.013; aPS/PT: OR = 2.48, 95% CI: 1.32-4.69, p = 0.004; aPS IgG: OR = 1.90, 95% CI 1.01-3.60, p = 0.046; respectively). The inclusion of the non-criteria aPLs increased the accuracy of APS diagnosis from 65.7% to 87.4%. Our data provide evidence that adding the non-criteria aPLs can improve the diagnostic accuracy in APS. APhL IgG, aPS/PT, and aPS IgG may be potential biomarkers to predict the risk of thrombosis in APS.

Non-criteria antiphospholipid antibodies and pediatric rheumatic disease: a case series

BackgroundNon-criteria antiphospholipid antibodies (NC-aPL) are a relatively undefined subgroup of antiphospholipid antibodies (aPL). Knowledge about NC-aPL in adults is limited and even less is known in pediatric patients. Routine tests for antiphospholipid syndrome (APS)—a clinical state marked by the presence of aPL in association with vascular thrombosis—usually include lupus anticoagulant (LAC), anti-cardiolipin (aCL) and -beta-2 glycoprotein I (aβ2GPI). LAC is a functional screen for prothrombotic aPL, while the latter tests identify specific autoantibodies. Specific targets of NC-aPL include, but are not limited to, phosphatidylethanolamine, phosphatidylserine, and prothrombin.Presentation of casesWe present single-center data from eight pediatric patients with NC-aPL identified during a three-year period. All patients had presenting features raising suspicion for APS. Most patients were female with a primary rheumatic disease. One patient had a stroke. Another patient had alveolar hemorrhage and pulmonary hypertension. Raynaud’s phenomenon, rashes involving distal extremities, and headaches were common. Most patients had a positive LAC, yet their routine aPL tests were negative, prompting testing for NC-aPL.ConclusionsOur findings suggest NC-aPL are associated with typical signs and symptoms of APS in pediatric patients. Pediatricians and pediatric subspecialists should consider NC-aPL when clinical suspicion is high and routine aPL tests are negative, particularly when LAC is positive. While guidelines for NC-aPL do not yet exist for children or adults, these autoantibodies have pathogenic potential. Actionable items could include evaluation for the presence of other (primary) rheumatic diseases, and consultation with hematologists and/or obstetricians regarding anticoagulation/platelet inhibition and thrombosis education. Future guidelines regarding NC-aPL will only be generated by gathering more data, ideally prospectively.

'Non-criteria antiphospholipid antibodies': bridging the gap between seropositive and seronegative antiphospholipid syndrome.

We aimed to analyse the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL - anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein I antibodies (aβ2-GPI) and lupus anticoagulant (LA) - named seronegative APS (SN-APS). Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls. We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, three cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS. This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Non-criteria Antiphospholipid Antibodies: a narrative review

The 2006 Revised Sapporo Classification Criteria for Definite Antiphospholipid Syndrome included as laboratory criteria the tests for antiphospholipid antibodies whose accuracy was regarded as satisfactory according to the evidence available at that time. In practice, however, the sensitivity and specificity of these "criteria" of antiphospholipid antibodies are sometimes insufficient for identifying or ruling out antiphospholipid syndrome. It has been studied whether the accuracy of the laboratory diagnosis of the syndrome could be improved by testing for non-criteria antiphospholipid antibodies. In this work, we review evidence on the clinical associations and diagnostic value of the most commonly studied non-criteria antibodies, namely: antiphosphatidylethanolamine, anti-annexin A5, anti-prothrombin, anti-phosphatidylserine/prothrombin complex, IgA anticardiolipin, and IgG anti-domain I of the β2 glycoprotein antibodies.

Non-Criteria Antiphospholipid Antibodies: Risk Factors for Endothelial Dysfunction in Women with Pre-Eclampsia.

The association between unconventional antiphospholipid antibodies and pre-eclampsia in patients without thrombotic manifestations and its relationship with endothelial dysfunction after delivery has been studied poorly. We included 157 pregnant women, 122 of them having developed pre-eclampsia (56 non-severe and 66 severe). The determination of classical and unconventional, as well as pulse wave velocity and ankle-brachial index were performed at three months after delivery. The prevalence of unconventional antiphospholipid antibodies was 22.9% and 54.9% in patients included in control and pre-eclampsia groups, respectively (p = 0.001). The most frequent antiphospholipid antibody was IgM anti-phosphatidylserine/prothrombin in both cohorts. The presence of IgM anti-phosphatidylserine/prothrombin showed an association with the development of pre-eclampsia (OR = 5.4; CI 95% (2.0–14.9), p = 0.001) with an AUC of 0.744 (p < 0.001). Likewise, IgM anti-phosphatidylserine/prothrombin exhibited a positive linear correlation with pulse wave velocity values (rho = 0.830; p < 0.001) and an association with the presence of pulse wave velocity altered values (OR = 1.33; CI95% (1.10–1.59), p = 0.002). With regard to ankle braquial index values, the presence of IgM anti-phosphatidylserine/prothrombin displayed a weak negative correlation (rho = −0.466; p < 0.001) and an association with altered ankle braquial index values (OR = 1.08; CI 95% (1.04–1.13), p < 0.001). In patients who developed preeclampsia, the presence of IgM anti-phosphatidylserine/prothrombin could be associated with endothelial dysfunction, causing alteration of cardiovascular parameters.

The presence of particular criteria and noncriteria antiphospholipid antibodies in patients with uterine malignancies.

Currently, there have been limited data on the presence of antiphospholipid antibodies (aPLs) in patients with uterine malignancies (UMs). We aimed to determine whether criteria and noncriteria aPLs are present in patients with UMs and associated with the thrombotic risk, as compared with patients with noncancerous gynecological diseases (NCGDs). The study involved 151 women scheduled for gynecological surgery. The patients were divided into the UM group (n = 70) and the NCGD group (n = 81). The Antiphospholipid 10 Dot assay was used to detect criteria and noncriteria aPLs before surgery. The study patients were considered positive for thrombosis if they exhibited signs of thrombosis within the 2‑year follow‑up period after surgery. Positive results for aPLs were obtained in 17/70 patients with UMs (24.3%) and in 6/81 patients with NCGDs (7.4%) (P = 0.008). Particular noncriteria aPLs (antiphosphatidic acid, antiphosphatidylserine, anti-annexin V, and antiprothrombin antibodies) yet no criteria aPLs (anticardiolipin and anti-β2‑glycoprotein I antibodies) were more frequently found in patients with UMs than in those with NCGDs. Thrombosis was diagnosed in 9/70 patients (12.9%) in the UM group and in 3/81 patients (3.7%) in the NCGD group (P = 0.03). Antiphospholipid antibodies were present at significant levels in patients with UMs. Noncriteria aPLs yet no criteria aPLs were more frequently found in patients with UMs than in those with NCGDs. The incidence of thrombosis was significantly higher in patients with UMs.

Profiling of non-criteria antiphospholipid antibodies in patients with SLE: differentiation of thrombotic SLE patients and risk of recurrence of thrombosis.

To reveal the clinical significance of criteria and non-criteria antiphospholipid antibodies detected by line immunoassay in comparison with ELISA, systemic lupus erythematosus patients with and without thrombotic events were investigated. Thus, 107 systemic lupus erythematosus patients (48% with deep vein thrombosis or/and arterial thrombosis) and 120 healthy donors were enrolled. Serum antiphospholipid antibodies were detected by ELISA (Orgentec Diagnostika, Germany) and line immunoassay (GA Generic Assays, Germany). Lupus anticoagulant and IgG to cardiolipin and β2GPI but not IgM as well as triple positivity by ELISA and line immunoassay were linked with thrombosis in systemic lupus erythematosus. IgG to phosphatidylinositol and phosphatidylserine by line immunoassay showed significantly higher levels in systemic lupus erythematosus with deep vein thrombosis/arterial thrombosis than without and were independent risk factors for deep vein thrombosis (odds ratio 3.9, 95% confidence interval 1.1, 13.2) and arterial thrombosis (odds ratio 5.1, 95% confidence interval 1.3, 19.8) as well as thrombosis (odds ratio 3.6, 95% confidence interval 1.1, 11.3) and recurrence thereof (odds ratio 6.9, 95% confidence interval 2.1, 22.6), respectively. The occurrence of >4 IgG antiphospholipid antibodies by line immunoassay was an independent risk factor for thrombosis (odds ratio 10.9, 95% confidence interval 1.2, 101.5), arterial thrombosis (odds ratio 14.6, 95% confidence interval 2.5, 86.3), deep vein thrombosis (odds ratio 5.8, 95% confidence interval 1.0, 32.4) and recurrence of thrombosis (odds ratio 35.9, 95% confidence interval 3.8, 342.8). Line immunoassay is a promising multiplex test for the simultaneous detection of criteria and non-criteria antiphospholipid antibodies. Profiling of antiphospholipid antibodies by line immunoassay can differentiate systemic lupus erythematosus patients with thrombosis from systemic lupus erythematosus patients without and assess the risk for thrombosis and recurrence thereof.

\u201cNon-criteria\u201d antiphospholipid antibodies add value to antiphospholipid syndrome diagnoses in a large Chinese cohort

BackgroundDespite expansion in the 2006 Sydney antiphospholipid syndrome (APS) classification criteria to include IgG/IgM anti-β2-glycoprotein (aβ2GPI) antibodies in addition to IgG/IgM anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LAC), some individuals with clinical features of APS remain seronegative (seronegative APS or SNAPS) and are at risk of recurrent thrombosis and pregnancy morbidities. Our aim was to assess the value of “non-criteria” aPL antibodies to detect these SNAPS patients.MethodsOne hundred ninety-two APS patients, 90 SNAPS patients, 193 autoimmune disease controls, and 120 healthy controls were evaluated. Ten antiphospholipid antibodies (aPLs) were tested using commercial kits, including 5 non-criteria aPLs: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, aCL IgA, aβ2GPI IgA, and anti-β2GPI Domain 1 (aβ2GPI-D1) IgG.ResultsUp to 60.9% of the SNAPS and 93.5% of APS patients were detected by at least one non-criteria aPL. aPS/PT IgG had the highest Youden index in classifying APS and SNAPS from controls. aPS/PT IgG and aβ2GPI Domain 1 IgG seem to be the most significant risk factors for thrombotic events and pregnancy morbidity, respectively. aPS/PT IgG/IgM and aβ2GPI-D1 IgG were detected in some SNAPS patients, while IgA isotypes of aCL/aβ2GPI tended to appear together with other biomarkers. The combined analysis showed enhanced diagnostic performance with the inclusion of non-criteria aPLs.ConclusionsRecognition of SNAPS patients is critical for clinical management and prevention of potential thrombotic and obstetric adverse events. The non-criteria antiphospholipid antibodies help to identify a considerable portion (60.9%) of these patients who otherwise may remain untreated and at clinical risk.