aPL Tests Research Articles

Thrombosis in Antiphospholipid Syndrome: Current Perspectives and Challenges in Laboratory Testing for Antiphospholipid Antibodies.

Antiphospholipid syndrome (APS) diagnosis hinges on identifying antiphospholipid antibodies (aPL). Currently, laboratory testing encompasses lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I antibodies (aβ2GPI) IgG or IgM, which are included in the APS classification criteria. All the assays needed to detect aPL antibodies have methodological concerns. LA testing remains challenging due to its complexity and susceptibility to interference from anticoagulant therapy. Solid phase assays for aCL and aβ2GPI exhibit discrepancies between different assays. Antibody profiles aid in identifying the patients at risk for thrombosis through integrated interpretation of all positive aPL tests. Antibodies targeting domain I of β2-glycoprotein and antiphosphatidylserine-prothrombin antibodies have been evaluated for their role in thrombotic APS but are not yet included in the APS criteria. Detecting these antibodies may help patients with incomplete antibody profiles and stratify the risk of APS patients. The added diagnostic value of other methodologies and measurements of other APS-associated antibodies are inconsistent. This manuscript describes laboratory parameters useful in the diagnosis of thrombotic APS and will concentrate on the laboratory aspects, clinical significance of assays, and interpretation of aPL results in the diagnosis of thrombotic APS.

Antiphospholipid Antibody Testing in a Maximum Care Hospital: Method-Dependent Differences.

Background: Antiphospholipid antibody (aPL) testing is critical for the classification of antiphospholipid syndrome. The 2023 ACR/EULAR classification criteria recommend the use of enzyme-linked immunosorbent assays (ELISAs) and specific thresholds for aPL positivity. Since non-ELISA methods are increasingly used, we compared and evaluated ELISA and non-ELISA aPL assays in a real-world maximum care hospital setting. Methods: Between January 2021 and June 2024, anticardiolipin (aCL; IgG and IgM) and anti-beta2 glycoprotein I (aß2GPI; IgG and IgM) antibodies were measured using ELISA (n = 5115) and a chemiluminescence-based automated immunoassay (CLIA) (n = 3820). Results of parallel testing were compared, and associations with clinical and laboratory characteristics were evaluated. Results: A total of 946 samples were tested using ELISA and CLIA in parallel. A total of 136 (14%) specimens were positive for at least one aPL, and 55 (6%) specimens were from patients diagnosed with APS. Among the latter, 47 (85%) and 41 (75%) patients were positive when ELISA- or CLIA-based aPL assays were used, respectively. After applying the >40 units threshold of the new classification criteria, the number of aPL-positive specimens was significantly lower. In the entire cohort, the agreement between ELISA and CLIA aPL assays was acceptable only for aß2GPI IgG; the results from the two methods did not agree for aCL IgG/IgM and aß2GPI IgM. In APS patients, the agreement between ELISA and CLIA aPL assays was acceptable for aß2GPI IgG and IgM but poor for aCL IgG and IgM. Antibody levels in APS patients were significantly higher using CLIA compared to ELISA. Conclusions: The method-dependent discrepancies between ELISA- and CLIA-based aPL assays regarding the quantitative and qualitative results are substantial. Both methods are suitable for APS classification, but the choice of aPL assay may influence the classification, and therefore, aPL results should be interpreted carefully in the clinical context.

Obstetric Antiphospholipid Syndrome: Insights on the Diagnosis, Treatment, and Hot Issues

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-β2 glycoprotein Ⅰ domain Ⅰ antibody (aβ2GPⅠDⅠ). 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.

Laboratory assessment of antiphospholipid syndrome: Laboratory data.

Thorough assessment of the antiphospholipid syndrome (APS) includes retesting of positive antiphospholipid antibody (aPL) tests after at least 12 weeks, and a full antiphospholipid antibody profile. To what extent this work-up is done in clinical practice is unknown. Data on 25 116 in- and out-hospital patients tested for the presence of lupus anticoagulant (LA), the aPL which most strongly correlates with thrombosis, was extracted from the laboratory information system of the only laboratory that performs LA tests in the Capital Region, Denmark. We estimated fraction of repeated tests, tests repeated within the recommended time span, and fraction with a full aPL profile. Out of 25 116 patients, 843 were positive for LA (3.3%), and 3948 results were inconclusive (16%). Only 51% (95% CI of the proportion: 48%-54%) (n = 431) of positive tests were repeated. The proportion of inconclusive LA test results increased from 13% (12%-15%) in 2009 to 20% (19%-22%) in 2020. Out of the positive tests repeated within the first year, only 60/353 (17%; 13%-21%) were repeated within 12-16 weeks; 177/353 (50%; 45%-55%) were re-tested within the first 12 weeks of first positive test result. The proportion of patients with a full antiphospholipid antibody profile increased from 161/1978 (8%) in 2010 to 1041/1978 (43%) in 2020. We found several issues with the laboratory workup of APS. This indicates a need for increased awareness of comprehensive laboratory assessment of possible APS as well as a closer collaboration between the laboratory and clinicians.

Antiphospholipid Antibody Testing: An Audit on Testing Practices in a Public Tertiary Care Center.

Antiphospholipid antibodies (aPLs) are antibodies directed against cell membrane components and can be associated with clinical features or be asymptomatic. Testing and interpreting these antibodies is associated with many challenges and pitfalls in clinical practice. To review all antiphospholipid antibody testing and describe the testing practices, indications for testing and interpretation of results to infer local challenges with aPL testing and subsequently address ways to overcome those challenges. This is a retrospective analysis of all aPL testing done in a tertiary center between 2014 and 2018. Characteristics of study patients collected through chart review were described using the mean and standard deviation for continuous variables and proportion for categorical variables. Group differences were compared between patients with any aPL-positive result and those with no positive result using chi-square or Fisher's exact test as appropriate for categorical variables and a simple regression model for numerical variables. Among 414 patients undergoing aPL testing, mainly adult females, 62 (14.9%) patients had at least one positive antibody, of those, 26 (42%) had repeat testing done. Testing was mostly done for obstetric indication (107, 25.8%), with 36 patients having one or two early pregnancy losses <10 weeks as their testing indication. A total of 27 (6.5%) patients were labeled with APS/possible APS based on chart review, but on review of the testing of those patients according to classification criteria, only nine patients satisfied the criteria for APS. This study highlights the clinical challenges associated with aPL testing, including the controversies around indication for testing, the low rates of repeat testing to confirm persistence, and the common misinterpretation of results. Having an aPL testing profile, explicit reference ranges, results commentary, and close interaction between ordering physicians and laboratory staff might be starting points to overcome these challenges.

Surviving Multiple Cardiac Arrests Secondary to Catastrophic Sero-Negative Antiphospholipid Syndrome: A Case Report

Antiphospholipid syndrome (APS) is an autoimmune disorder which predisposes to venous and arterial thrombosis due to the autoantibodies targeting phospholipids in cell membranes contributing to a pro-thrombotic state. The appropriately named catastrophic anti-phospholipid syndrome (CAPS) is distinguished from classical APS by the rapid involvement of 3+ organs, evidence of areas of small vessel occlusions, and significantly elevated anti-phospholipid titers (Cervera, 2018). To further complicate the matter, there is a growing body of evidence of the existence of sero-negative APS (SNAPS) that are negative for the classical lupus anticoagulant, anticardiolipin antibody (aCL), and anti-beta2 glycoprotein-I but may be positive for non-criteria APS antibodies. Presented below is a patient with SNAPS who responded to the therapy for CAPS despite negative classical autoantibodies. A 34 year old man with a past medical history of chronic alcohol use presented to the ED with a two day history of worsening shortness of breath. The patient was found to have an spO2 of 45-50% on room air and was quickly transitioned to a non-rebreather and subsequently BIPAP. Initial CBC was significant for WBC 22.1, Hg 19.3, Hct 58.5, MCV 100.8, and platelets of 166 consistent with neutrophilic leukocytosis and macrocytic polycythemia. D-dimer &amp;gt;20 was suggestive recent/on-going coagulation and/or fibrinolysis. Due to worsening respiratory failure, he was intubated and admitted to the ICU. While on 3 vasopressors he became bradycardic and a code blue was called for pulseless electrical activity (PEA). After 3 rounds of CPR he achieved return of spontaneous circulation (ROSC) and was taken for urgent CT imaging. After arriving in the radiology department he went into cardiac arrest for two rounds of CPR before achieving ROSC and being scanned and returning to the ICU. Polycythemia tests were drawn which revealed elevated erythropoietin of 52.1 (2.6-18.5) and ultimately negative JAK2. Chest CTA was significant for a PE with a heavy clot burden involving the entire right lung and the left upper and lower lobes. CT C/A/P showed findings of bilateral lower lobe pneumonia, severe gastritis, pancolitis, proctitis, pancreatitis with a 4.6cm pseudocyst, and fatty liver with congestive enhancement. Tissue-type plasminogen activator (tPA) bolus and infusion was initiated based on the imaging findings with the third cardiac arrest occurring 7 minutes later early in the morning. Repeat CBC revealed an Hgb/Hct of 22.2 g/dL and 71.5%, respectively, with a significant drop in platelets down to 103 with occasional large platelets consistent with peripheral destruction of platelets was noted on peripheral blood smear (PBS). Therapeutic phlebotomy of 300mL was subsequently performed with two additional cardiac arrests within 2 hours of each other before vascular surgery was able to perform thrombectomies of the involved pulmonary arteries and initiate catheter-directed thrombolysis. Platelet count dropped while on heparin to 25,000 so a HIT panel was ordered and he was transitioned to argatroban. At this point hematology was consulted who was concerned for CAPS and ordered aPL (anti-phospholipid) tests along with an appropriate panel of labs to rule out alternative causes. Peripheral blood smear did not reveal fragmentation of RBC to suspect TTP. Tests for ACL IgG/IgM and anti-beta2GPI IgG/IgM antibodies, COVID, HIV, ADAMTS deficiency, hereditary thrombophilia, and ANA were negative. High-dose steroids and daily plasma exchanges via vascath was initiated and within 12 hours there was significant improvement. He was extubated and off pressors in 24 hours with improved platelets. Lupus anticoagulant test results were reported after discharge with dVVT mix and PTT LA mix both being prolonged, however, repeat lupus anticoagulant 3 months later was negative. Given the potentially catastrophic effects of a missed CAPS diagnosis, a high level of clinical suspicion is needed as plasma exchange can quickly alleviate an otherwise disastrous condition. Further research into non-criteria APS autoantibodies (IgA)may be able to help guide future SNAPS diagnoses.

Cytokine Profiling in Antiphospholipid Syndrome Demonstrates Persistent Immune Dysregulation and a Procoagulant Phenotype

Background: The antiphospholipid syndrome (APS) is an autoimmune thromboinflammatory disease characterized by thrombosis and the persistent detection of antiphospholipid antibodies (aPL). The rate of recurrent thrombosis in APS is between 3 and 24% despite standard of care anticoagulation with a vitamin K antagonist, suggesting a persistent prothrombotic milieu in APS which may be driven by altered cytokine signaling. Objective: To test the hypothesis that cytokine signaling is dysregulated in APS and contributes to thrombotic risk, we profiled cytokine levels in patients with thrombotic APS and healthy individuals. Methods: We measured a panel of 46 serum cytokines using the Meso Scale Discovery electrochemiluminescent platform, a validated measurement system that provides linear readouts of analytes over several logs of concentration, in 21 APS patients and 12 healthy individuals. All APS patients met the Revised Sapporo Criteria for thrombotic APS. Measurements were performed in triplicate and the log2 transformed averages were analyzed, setting significance at a FDP-adjusted p value of &amp;lt;0.05, while controlling for age and sex. Cytokine values were correlated with clinical history and antibody isotype profile. Results: Our cohort was 67% female and 85% identified as white. All APS patients had thrombotic disease: 57% with history of VTE, 19% with ATE, and 24% with both VTE and ATE. 14% had catastrophic APS. 67% were triple-positive for anti-cardiolipin (aCL), anti-β2 glycoprotein 1 (aβ2GP1), and lupus anticoagulant (LAC). 10% had isolated IgM isotypes of aCL or aβ2GP1. We found significantly elevated levels of TNF-α, IL-6, IL-7, IL-8, IL-10, IL-16, IL-12/IL-23p40, soluble VCAM-1, soluble ICAM-1, PIGF, SAA and CRP and significantly decreased levels of IL-17genB, IL-22 and IL-31 in APS compared with healthy controls (Figure 1). Cytokine levels were measured a median of 5 months (1-240) from the last thrombotic event, demonstrating persistence of the inflammatory response. To determine if cytokine levels were predictive of thrombotic risk, we correlated the number and pattern of positive aPL isotypes and LAC with cytokine levels. We found that TNF-α, IL-8, IL-10, sVCAM-1, sICAM-1, VEGF, IL-7, IL-12/IL-23p40, IL-4, IL-6, IL-16, PIGF, IL-23 and IL-17A each correlated with aPL positivity, with higher levels in triple-positive APS, and the highest levels observed in patients positive for all five measured antibody isotypes (aCL IgG, IgM, IgA; aβ2GP1 IgG, IgM) plus the functional LAC (Figure 2). IL-31 level inversely correlated to the number of positive aPL tests. A sub-analysis of cytokines in patients with isolated IgM aCL or aβ2GP1 antibodies with or without LAC showed significantly increased levels of TNF-α compared to healthy controls, and did not differ from APS patients with other patterns of aPL positivity. This suggests that a similar proinflammatory or procoagulant background is present in patients with isolated antiphospholipid IgM antibodies as those with IgG. Discussion: The sustained differences in cytokine levels measured in APS patients suggests a picture of ongoing immune dysregulation and compensation capable of driving vascular cell activation, and tipping the hemostasis balance into thrombosis. We find upregulation of proinflammatory cytokines, such as TNF-α and IL-6, capable of activating endothelial cells and triggering amplification loops leading to chemokine and acute phase reactant release, cell adhesion molecule expression, recruitment of leukocytes, and accumulation of complement and coagulation proteins, with the net effect of driving inflammation and thrombosis. Decreased levels of IL-17, IL-22 and IL-31 are indicative of dysregulation of the Th17 CD4+ T cell response, which has been implicated in autoimmune pathogenesis. The correlation of cytokine levels with triple or greater aPL positivity suggests a model for advancing risk stratification and has utility as a biomarker of thrombosis. Our study, although limited by size, represents one of the most extensive profiling of cytokines in thrombotic APS.

Descriptive analysis of patients positive for anti-phospholipid antibodies included in two Italian registries

The definite diagnosis of antiphospholipid syndrome (APS) depends on the laboratory performance and clinicians’ interpre- tation. Results from two Italian inception cohort studies of anti- phospholipid antibodies (aPL)-positive subjects, the Italian Survey on ANtiphoSpholipid antibody Positive Individuals Reg- istry (INSPIRE) and the Survey on AnTicoagulated Patients- Reg- isTry (START) have been compared. Data from INSPIRE were collected by rheumatologists of the FIRMA group while those of START by physicians working in Italian thrombosis centers. Ev- idence on several, still unraveled, clinical and methodological as- pects of ‘real life’ aPL testing and APS diagnosis was collected. In this paper, we report the characteristics of 123 cases enrolled in INSPIRE and 229 in START registries, with particular refer- ence to the reasons why these tests were requested, the obtained aPL profile, and consequent treatment. Laboratory testing for aPL in the absence of clinical criteria defining APS was more frequent in INSPIRE (p&lt;0.0001). The rate of patients in classification cat- egory I (more than one aPL test positive) was significantly higher in START (p&lt;0.0001) as well as the use of warfarin. A wide va- riety of treatments has been observed in patients in classification category II (single aPL positivity). These data indicate that there is a need to harmonize many aspects among the various specialists dealing with APS.

Beyond the classics: The emerging value of anti-phosphatidylserine/prothrombin antibodies in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy complications. Within the diverse range of aPLs, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have gained significance in clinical practice. The detection of aPS/PT has proven valuable in identifying APS patients and stratifying their risk, especially when combined with other aPL tests like lupus anticoagulant (LA) and anti-β2-glycoprotein I (aβ2GPI). Multivariate analyses have confirmed aPS/PT as an independent risk factor for vascular thrombosis and obstetric complications, with its inclusion in the aPL score and the Global Anti-Phospholipid Syndrome Score (GAPSS) aiding in risk evaluation. However, challenges remain in the laboratory testing of aPS/PT, including the need for assay standardization and its lower sensitivity in certain patient populations. Further research is necessary to validate the clinical utility of aPS/PT antibodies in APS diagnosis, risk stratification, and management.

Current status and value of testing antiphospholipid antibody in patients with acute ischemic stroke: a retrospective single-center study in China.

Testing for antiphospholipid antibodies (aPL) is useful to determine the cause of ischemic stroke in young and female patients. However, the clinical relevance of aPL in older patients with ischemic stroke remains unclear. We aimed to explore the status and diagnostic value of initial aPL testing in all patients with acute ischemic stroke. We retrospectively analyzed patients with acute ischemic stroke who were consecutively hospitalized in our hospital between June 2012 and January 2022 and investigated the factors associated with performing aPL screening in real-world clinical practice. Furthermore, factors associated with initial aPL positivity were evaluated by comparing the demographic, etiological, and therapeutic characteristics. Of 1209 patients, 287 (23.7%) were tested for aPL and 58 (20.2%) tested positive. Physicians tended to conduct aPL testing on female patients (P<0.001), younger patients (P<0.001), patients with fewer vascular risk factors (P<0.001), and multiple infarctions in the multivascular blood supply area (P<0.001). Multivariate logistic regression analysis showed that only stroke of other determined etiology type was a significant influencing factor for positive aPL results (OR 2.97, 95% CI 1.137, 7.774, P=0.026), adjusting for sex, age, and causes of stroke, etc. CONCLUSION: Approximately one-quarter of the patients with acute ischemic stroke were tested for aPL. Age, sex, number of vascular risk factors, and neuroimaging features affected the discretion in performing aPL testing. aPL testing may be appropriate in older patients with no identified cause of ischemic stroke and may provide additional diagnostic opportunities for acute ischemic stroke.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Influence of Antiphospholipid Antibody-Associated Thrombophilia on the Risk of Preterm Birth: A Systematic Review.

Antiphospholipid antibody (aPL)-associated thrombophilia has been implicated in various adverse pregnancy outcomes, including preterm birth and impaired fetal development. This systematic review aimed to elucidate the relationship between aPL-associated thrombophilia and these outcomes, as well as to identify potential modifiers of this relationship such as maternal age, coexisting maternal medical conditions, type of aPL antibodies involved, and the timing of thrombophilia diagnosis during gestation. We conducted a comprehensive literature search in PubMed, Web of Science, Cochrane, and Scopus in May 2023, covering literature published within the last 10 years. Eight articles, involving 2935 patients, were eligible for inclusion in the review. Single aCL was the most common type of aPL found in patients, with rates up to 61.0% in some studies, followed by single LA and single ab2GPI. Multiple aPL antibody positivity was found to be associated with a higher risk of preterm birth, with odds ratios ranging from 1.29 to 9.61. Patient characteristics and previous pregnancy history varied significantly across the studies. Risk factors such as diabetes mellitus, thrombosis, and systemic lupus erythematosus were also variable across the studies, but presence of these risk factors did not consistently affect the risk of preterm birth. Furthermore, although a triple positive aPL test was the most important risk factor for preterm birth, it was observed that thrombophilia treatment during pregnancy significantly reduced the risk by 2.44 times (95% CI = 1.18-6.20). This review supports the evidence for aPL-associated thrombophilia being a significant contributor to preterm birth and fetal developmental abnormalities. Further research is required to investigate the exact mechanisms and to determine the best clinical management for patients with aPL-associated thrombophilia during pregnancy.

Is a Higher Body Mass Index a Risk Factor for Developing Antiphospholipid Antibody Syndrome?

Antiphospholipid antibodies (aPLs) are antibodies directed against components of the cell membraneand can be associated with clinical features or be asymptomatic in 1-5% of the population. The objective of this study is to investigate the frequency of aPL positivity based on body mass index (BMI). This is a retrospective analysis of all aPL testing done in a tertiary center between 2010 and 2020. The difference between patients with BMI<25, BMI 25-30, and BMI>30 is calculated using chi-square or Fisher's exact test as appropriate for categorical variables and a two-sample t-test for numerical variables. Unadjusted then multivariable logistic regression models were conducted to evaluate the effect of BMI on aPLpositivity adjusting for age, thrombosis history, pregnancy complications history, and presence of autoimmune disease. Sex was included as an effect modifier. Among 312 patients, the outcome (any positive aPL) was detected in 26 (20.8%), 13 (13.0%), and 16 (18.4%) patients with BMI groups: BMI <25, BMI 25-30, and BMI > 30, respectively. A multivariable logistic regression showed that those with BMI 25-30 had a lower risk of aPL positivity when compared to patients with BMI <25 (OR of 0.55 CI 0.25 - 1.14, p=0.116), and patients with BMI >30 also carried a lower risk compared with patients with BMI<25 (OR of 0.76, 95% CI 0.36 - 1.56, p=0.46); these results were not statistically significant. The results suggest that a higher BMI was not a risk factor for aPL positivity. A better understanding of the complex interactions between antiphospholipid antibodies and obesity should be further investigated.

Survey on antiphospholipid syndrome diagnosis and antithrombotic treatment in patients with ischemic stroke, other brain ischemic injury, or arterial thromboembolism in other sites: communication from ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies

BackgroundThe optimal strategy for diagnosis and antithrombotic treatment of patients with antiphospholipid syndrome (APS)–associated acute ischemic stroke (AIS), transient ischemic attack (TIA), or other brain ischemic injury is poorly defined. ObjectivesThe survey goal was to capture variations in diagnosis and antithrombotic treatment of APS-associated ischemic stroke and related disorders to inform guidance and clinical trials to define optimal management. MethodsProfessional colleagues, including key opinion leaders, were invited to complete a REDCap survey questionnaire initiated by the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. The survey data were tallied using simple descriptive statistics. ResultsThere was generally good agreement on several aspects, including which patients to test for antiphospholipid antibodies (aPL), use of a lifelong vitamin K antagonist for AIS or recurrent TIA, and formal cognitive assessment for suspected cognitive impairment. There was less agreement on other aspects, including aPL testing for brain ischemic injury other than AIS/TIA or if an alternative cause for AIS or TIA exists; choice of aPL tests, their timing, and age cutoff; the aPL phenotype to trigger antithrombotic treatment; management for patent foramen ovale; antithrombotic treatment for first TIA or white matter hyperintensities; head magnetic resonance imaging specifications; and low-molecular-weight heparin dosing/anti-Xa monitoring in pregnancy. The survey highlighted that approximately 25% practice at dedicated APS clinics and <50% have a multidisciplinary team structure for patients with APS. ConclusionMuch of the variation in practice reflects the lack of evidence-based recommendations. The survey results should inform the development of a more uniform multidisciplinary consensus approach to diagnosis and antithrombotic treatment.

Non-Criteria Antiphospholipid in Seronegative Antiphospholipid Syndrome: A Systematic Review

Background: Given the catastrophic results of antiphospholipid syndrome (APS) left untreated, the possible role of non-criteria antiphospholipid (aPL) in the diagnosis of seronegative (SN)-APS patients, and its impact on the timely treatment of people with SN-APS, the present review aimed to gather the available literature up to 2022 focusing on the role of non-criteria aPL in the diagnosis of SN cases suspected of APS using non-criteria aPL.&#x0D; Methods: All published papers focusing mainly on the diagnosis of the SN-APS patients by non-criteria aPL were searched in four databases of PubMed, Scopus, Medline, and Web of Sciences, followed by manual search up to 20 February 2022 using such keywords as “Antiphospholipid Syndrome”, “Seronegative”, and “Non-Criteria”. Finally, 15 studies were selected after the detailed evaluation of the full-text versions.&#x0D; Results: Based on the obtained results of our study, 24% to 81.9% of the SN-APS cases were positive for at least one isotype of non-criteria aPL. Thrombophilia events were more frequent in the APS population, compared to SN-APS; however, obstetric manifestations were more frequent in the SN-APS population, compared to seropositive-APS. Antivimentin/cardiolipin and antiphosphatidylserine/prothrombin IgG/IgM were introduced as the best non-criteria aPL to detect seronegative cases that were correlated with clinical manifestations.&#x0D; Conclusion: It seems that a combination of testing for non-criteria aPL should be performed for cases suspected of APS with negative criteria markers.

Post-viral idiopathic purpura fulminans is associated with inherited thrombophilia and anti-cardiolipin antibodies.

Idiopathic purpura fulminans (IPF) is a rare and severe coagulation disorder, associated with transient anti-protein S (anti-PS) antibodies in the context of post-viral infection such as varicella. Anti-protein S antibodies are frequently found in the context of varicella, in contrast with the rarity of IPF. Other factors such as anti-phospholipid antibodies (APL) and inherited thrombophilia may be associated with severe vascular complication. This is an ancillary study of a French multicenter retrospective series and systematic review of literature. We analyzed patients who were tested for inherited thrombophilia, namely antithrombin, protein C, protein S deficiency; prothrombin gene G20210A polymorphism (FII:G20210A),Factor V R506Q polymorphism (FV:R506Q); and/or for APL (lupus anticoagulant (LA), anti-cardiolipin antibodies (ACL), or anti-beta 2-GPI antibodies (Aβ2GP1). Among the 25 patients tested for inherited thrombophilia, 7 (28%) had positive results. Three had FV R506Q, two FII:G20210A, one compound heterozygote FV:R506Q associated to FII:G20210A, and one protein C deficiency. APL testing was performed in 32 patients. It was positive in 19 patients (59%): 17 ACL (53%), 5 LA (16%), 4 Aβ2GP1 (13%). The risk of severe complications was not associated with presence of inherited thrombophilia or APL presence, with RR: 0.8 [95% CI: 0.37-1.71], p = 1 and RR: 0.7 [95% CI: 0.33-1.51], p = 0.39, respectively. We found a high prevalence of inherited thrombophilia or APL in a population of patients with IPF. However, we do not find an association with the occurrence of severe vascular complications or venous thromboembolism.

Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study

Several antiphospholipid antibody (aPL) profiles (“triple” and lupus anticoagulant [LA] positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-β2 glycoprotein-I antibody (aβ2GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aβ2GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aβ2GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aβ2GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.

Fluctuation of Anti-Domain 1 and Anti-β2 -Glycoprotein I Antibody Titers Over Time in Patients With Persistently Positive Antiphospholipid Antibodies.

The present study was undertaken to longitudinally evaluate titers of antibodies against β2 -glycoprotein I (anti-β2 GPI) and domain 1 (anti-D1), to identify predictors of variations in anti-β2 GPI and anti-D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry. Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2-4 of follow-up) were included. Detection of anti-β2 GPI and anti-D1 IgG antibodies was performed using chemiluminescence (BIO-FLASH; INOVA Diagnostics). Among 230 patients in the study cohort, anti-D1 and anti-β2 GPI titers decreased significantly over time (P < 0.0001 and P=0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti-D1 and anti-β2 GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3-fold and 1.4-fold decreases in anti-D1 and anti-β2 GPI titers, respectively. Incident vascular events were associated with 1.9-fold and 2.1-fold increases in anti-D1 and anti-β2 GPI titers, respectively. Anti-D1 and anti-β2 GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6-fold decrease in anti-D1 titers and a 2-fold decrease in anti-β2 GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62-59.3) and 9.4 (95% CI 1.1-80.2), respectively. Treatment with HCQ and incident vascular events in aPL-positive patients predicted significant anti-D1 and anti-β2 GPI titer fluctuations over time. Both anti-D1 and anti-β2 GPI titers decreased around the time of thrombosis, with potential clinical relevance.

TeleRehabilitation of Social-Pragmatic Skills in Children with Autism Spectrum Disorder: A Principal Component Analysis.

In many therapeutic settings, remote health services are becoming increasingly a viable strategy for behavior management interventions in children with autism spectrum disorder (ASD). However, there is a paucity of tools for recovering social-pragmatic skills. In this study, we sought to demonstrate the effectiveness of a new online behavioral training, comparing the performance of an ASD group carrying out an online treatment (n°8) with respect to a control group of demographically-/clinically matched ASD children (n°8) engaged in a traditional in-presence intervention (face-to-face). After a 4-month behavioral treatment, the pragmatic skills language (APL test) abilities detected in the experimental group were almost similar to the control group. However, principal component analysis (PCA) demonstrated that the overall improvement in socio-pragmatic skills was higher for ASD children who underwent in-presence training. In fact, dimensions defined by merging APL subscale scores are clearly separated in ASD children who underwent in-presence training with respect to those performing the online approach. Our findings support the effectiveness of remote healthcare systems in managing the social skills of children with ASD, but more approaches and resources are required to enhance remote services.

Predictors and clinical complications associated with antiphospholipid antibodies in sickle cell disease.

Although a higher prevalence of antiphospholipid autoantibodies (aPL) has been observed in some cohorts of sickle cell disease (SCD) patients, the clinical risk factors for the development of aPL and its associated complications remain unclear. In a retrospective study of 63 SCD patients, a lower hemoglobin concentration and higher white blood cell count were independently associated with an elevated aPL. SCD patients with elevated aPL had increased pregnancy complications (≥3 miscarriages, preterm delivery, pre-eclampsia) and venous thrombotic events. Our findings suggest that SCD may predispose to the generation of aPL and that aPL itself may contribute to the vasculopathy of SCD. Prospective testing for aPL is warranted in patients with SCD.