aPL Titers Research Articles

Recurrent miscarriage and low-titer antiphospholipid antibodies

ObjectiveTo evaluate the clinical features and pregnancy outcomes in patients experiencing recurrent miscarriage (RM) with either low-titer or medium-high titer positivity of antiphospholipid antibodies (aPL).MethodsA retrospective review of medical records was conducted for patients with aPL positivity and recurrent miscarriage between 2018 and 2022. The clinical features, treatment strategies, outcomes were compared between the patients with low (n = 92) and medium (n = 32) titer of aPL.ResultsA total of 118 patients, resulting in 124 obstetric episodes (pregnancies), with a mean age of 33. 15 ± 4.56 and 31.47 ± 4.41 years between the two groups. The low-titer group exhibited a higher frequency of anti-cardiolipin antibodies IgM (P < 0.001), whereas the medium-high titer group demonstrated a higher frequency of anti-β2-glycoprotein 1 antibodies IgG (P < 0.001) and IgM (P = 0.032). Moreover, the medium-high titer group displayed a significantly elevated erythrocyte sedimentation rate compared to the low-titer group (P < 0.05). In the low-titer group, 71 patients (77.2%) received appropriate treatment, resulting in 48 live births (67.6%) and 23 repeat abortions (32.4%). In the medium-high titer group, 29 patients (90.6%) received relevant treatment, leading to 23 live births (79.3%) and 6 repeat abortions (20.7%). No significant differences were observed in live births or maternal-fetal complications between the two groups (all P > 0.05).ConclusionNoteworthy distinctions in laboratory parameters were identified between the low-titer and medium-high titer groups. However, when appropriately treated, the fetal-maternal outcomes were comparable in both groups. Timely intervention by clinicians is imperative to enhance pregnancy outcomes in patients experiencing recurrent miscarriage with low levels of aPL.Key Points• This study challenges the conventional belief that only the higher antiphospholipid antibodies (aPL) titers directly correlated with worse pregnancy outcomes, which emphasized the importance of patients with low titer positive aPL-positive RM.• The results underscore the need for timely intervention in women with low titer aPL-positive RM, as it leads to favorable maternal–fetal outcomes.

Angiology and hemostasis: what's new in 2023

We discuss four topics among the angiology and hemostasis studies of importance in 2023. The BASIL-2 study provides new data for the management of chronic limb-threatening ischemia by comparing surgical and endovascular treatment. The new classification of antiphospholipid antibody (aPL) syndrome integrates new clinical elements and gives a different weight among the isotype and titer of aPL. Concizumab, an antibody targeting the tissue factor pathway inhibitor, broadens the therapeutic arsenal for hemophilia A and B as evidenced by the results of the EXPLORER 7 study. The PREVENT-CLOT and CASTING study focus on the prevention of thrombosis after trauma, by testing the role of aspirin or the lack of thromboprophylaxis, respectively.

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.

The impact of antiphospholipid antibodies in Takayasu arteritis.

The significance of antiphospholipid antibodies (aPL) is controversial in Takayasu arteritis (TA). This study was conducted to explore the frequency of aPL and their association with disease-related complications in TA. : This cross-sectional study was conducted to investigate the presence of anti-cardiolipin (aCL), anti-beta 2 glycoprotein- 1(aβ2G1) antibodies, and lupus anticoagulant (LA) in TA patients. TA patients admitted to the Department of Rheumatology of Hacettepe University Faculty of Medicine between December 2015 and September 2016 who fulfilled the American College of Rheumatology (ACR) classification criteria for TA were consecutively enrolled in the study. Patients were grouped according to aPL positivity and compared in terms of disease manifestations, type of vascular involvement at diagnosis, and vascular complications/interventions attributable to TA. Fifty-three TA (49 female) patients were enrolled in the study. We detected 9 (16.9%) patients with IgM and/or IgG aβ2G1 and/or LA positivity. There were no patients with positive aCL. All aβ2G1 titers were low. There were no differences in terms of symptoms, signs, type of vascular involvement, the number of patients with disease-related complications or vascular interventions/surgery between aPL (+) and aPL(-) groups (p > 0.05 for all). The number of patients with thrombotic lesions was similar between the groups (p > 0.05). There were no patients with a history of venous thrombosis or on anticoagulant treatment in the aPL(+) group. Only 1 patient with IgM aβ2G1 (+) had a history of pregnancy loss. Our results indicate that aPL positivity is not rare in TA. On the other hand, all aPL titers were low and no differences were found in the frequency of disease-related complications between aPL(+) and aPL(-) patient groups. Only TA patients with atypical manifestations with high suspicion of aPL-related complications should be considered to be investigated for aPL.

Prevalence of Anti-nuclear and Anti-phospholipid Antibodies in an Egyptian Cohort with Schizophrenia: A Case-control Study.

Psychiatric disorders, including schizophrenia, could herald other manifestation( s) of systemic lupus erythematosus (SLE) potentially hindering timely and optimal management. Moreover, schizophrenia is among the described 'extra-criteria' manifestations of anti-phospholipid syndrome (APS). Hence, screening schizophrenia patients for SLE and APS may pose diagnostic and therapeutic implications. Examine schizophrenia patients with no overt connective tissue disease(s) manifestation( s) for clinical and/or serologic evidence of SLE and/or APS. The study included 92 schizophrenia patients (61 (66.3%) males) and 100 age- and gender- matched healthy controls. Both groups were tested for anti-nuclear antibodies (ANAs), antidouble stranded deoxyribonucleic acid (anti-dsDNA) antibodies, complement 3 (C3) and C4, and criteria anti-phospholipid antibodies (aPL) (anticardiolipin Immunoglobulin (Ig) G and IgM, antibeta- 2-glycoprotein I IgG and IgM, and lupus anticoagulant (LAC)). The patients' mean age and disease duration were 28.8 ± 8.1 and 5.7 ± 2.2 years, respectively. The prevalence of ANA positivity, height of titre, and pattern was comparable between patients and controls (p = 0.9, p = 0.8 and p = 0.1, respectively). Anti-dsDNA antibodies and hypocomplementemia were absent in both groups. A significantly higher frequency of positive LAC was observed among patients compared with controls (7.6% vs. 1%, p = 0.02), whereas other aPL were comparable between both groups. None of the patients or controls demonstrated clinically meaningful (medium or high) aPL titres. In our study, schizophrenia was solely associated with LAC. Thus, in the absence of findings suggestive of SLE or APS, routine screening for both diseases is questionable.

Anti-Phospholipid Antibodies and Coronavirus Disease 2019: Vaccination Does Not Trigger Early Autoantibody Production in Healthcare Workers.

A molecular mimicry between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human proteins supports the possibility that autoimmunity takes place during coronavirus disease 2019 (COVID-19) contributing to tissue damage. For example, anti-phospholipid antibodies (aPL) have been reported in COVID-19 as a result of such mimicry and thought to contribute to the immunothrombosis characteristic of the disease. Consistently, active immunization with the virus spike protein may elicit the production of cross-reactive autoantibodies, including aPL. We prospectively looked at the aPL production in healthcare workers vaccinated with RNA- (BNT162b2, n. 100) or adenovirus-based vaccines (ChAdOx1, n. 50). Anti-cardiolipin, anti-beta2 glycoprotein I, anti-phosphatidylserine/prothrombin immunoglobulin G (IgG), IgA, and IgM before and after vaccination were investigated. Anti-platelet factor 4 immunoglobulins were also investigated as autoantibodies associated with COVID-19 vaccination. Additional organ (anti-thyroid) and non-organ (anti-nuclear) autoantibodies and IgG against human proteome were tested as further post-vaccination autoimmunity markers. The antibodies were tested one or three months after the first injection of ChAdOx1 and BNT162b2, respectively; a 12-month clinical follow-up was also performed. Vaccination occasionally induced low titers of aPL and other autoantibodies but did not affect the titer of pre-existing autoantibodies. No significant reactivities against a microarray of approximately 20,000 human proteins were found in a subgroup of ChAdOx1-vaccinees. Consistently, we did not record any clinical manifestation theoretically associated with an underlying autoimmune disorder. The data obtained after the vaccination (two doses for the RNA-based and one dose for the adenovirus-based vaccines), and the clinical follow-up are not supporting the occurrence of an early autoimmune response in this cohort of healthcare workers.

Abstract 461: Antiphospholipid Antibodies In Covid-19 Convalescent Plasma

Background: Although convalescent plasma has historically yielded significant benefits in the treatment of infectious diseases, numerous clinical trials have not shown a consistent benefit in treating either moderately or severely ill COVID-19 patients with plasma from convalescent patients. We previously reported increased levels of antiphospholipid antibodies (aPL) in acutely ill COVID patients, with high aPL titers correlating with more neutrophil extracellular traps (NETs) and poorer patient outcomes. We hypothesized that persistence of potentially deleterious autoantibodies in previously hospitalized, convalescent plasma donors may activate immune cells and add context for the lack of clinical efficacy in COVID. Methods: 116 samples of convalescent plasma from donors previously hospitalized with COVID were obtained from Vitalant. Antibody titers (IgG, IgM, IgA) of anti-2-glycoprotein 1 (a2GP1) and anti-cardiolipin (aCL) and anti-phosphatidylserine/prothrombin (IgG, IgM) were quantified. NET formation by healthy human neutrophils treated with convalescent plasma was evaluated in vitro. Results: High aPL titers &gt;40 U/mL) were observed in 10/116 (8.6%) convalescent samples, and 6/10 were positive for either IgG or IgM aCL. The aPL positivity rate exceeded the expected background population rate of ~3%. Six of 116 convalescent samples increased NET-associated MPO activity in purified, primary neutrophils from healthy donors compared with control plasma (mean increase of 23% +/- 11, p&lt;0.01), where only 2 of these were aPL-positive samples. Conclusion: aPL were elevated in a larger proportion of surveyed convalescent plasma samples than reported in the healthy population. aPL positivity did not correlate with purified neutrophil activation, suggesting aPL in donor plasma does not have a direct, activating effect on healthy neutrophils. Considering the complex interactions among circulating blood cells, ongoing experiments are examining the impact of convalescent plasma on platelet and endothelial cell function to further elucidate potential autoantibody-mediated vascular perturbations. The results of these studies will be important in informing the vascular implications and safety of convalescent plasma in COVID.

Cardiac manifestations in primary antiphospholipid syndrome and their association to antiphospholipid antibodies' types and titers-cross-sectional study of Serbian cohort.

Antiphospholipid syndrome (APS) is multisystem autoimmune coagulopathy with antiphospholipid antibodies (aPL) in its ground, manifested as a primary disease (PAPS) or in the setting of other conditions, most commonly systemic lupus erythematosus. The objective of this cross-sectional study was to investigate various cardiac manifestations and their possible relation to aPL type and titer in a Serbian cohort of PAPS patients. A total of 360 PAPS patients were analyzed and aPL analysis included detection of anticardiolipin antibodies (aCL: IgG/IgM), anti-ß2glycoprotein I (ß2GPI: IgG/IgM), and lupus anticoagulant (LA). Cardiac manifestations investigated were valvular lesions (comprehending valvular thickening and dysfunction not related to age and pseudoinfective endocarditis), coronary artery disease (CAD) with specific insight for myocardial infarction (MI), chronic cardiomyopathy (CMP), and acute decompensated heart failure (ADHF) as well as pulmonary hypertension (PH) and intracardiac thrombus presence. The prevalence of cardiac manifestations overall was 19.6%. There was a strong association between age and the majority of cardiac manifestations, as well as standard atherosclerotic risk factors. aCL IgG-positive patients had a higher prevalence of valvular lesions (p = 0.042). LA presence was significantly related to MI (p = 0.031) and PH (p = 0.044). CMP and ADHF were significantly related to higher titers of aCl IgG (p = 0.033, p = 0.025 respectively). Age and smoking were independent risk predictors for MI in PAPS with meaningful risk for LA positivity (OR 2.567 CI 0.671-9.820 p = 0.168). Certain cardiac manifestations in PAPS were related to certain aPL type and/or titer levels, imposing confirmation in prospective studies. Preventive actions, comprehending proper anticoagulant/antithrombotic therapy, and intense action against standard atherosclerotic risk factors are of utmost importance in this group of patients. Key Points • In Serbian patients with primary antiphospholipid syndrome (PAPS), prevalence of non-criteria cardiac manifestations was 19.6% and they were significantly related to certain antiphospholipid antibodies and titers. • Lupus anticoagulant was a meaningful predictor of myocardial infarction, enabling possible risk stratification and proper preventive and therapeutical strategies in this subgroup of PAPS patients. • Patients with high titers of aCL IgG are more prone to acute decompensated heart failure occurence, imposing careful follow-up of these patients • Based on the analysis of the Serbian PAPS cohort, even being non-criterial, cardiology manifestations are significantly present and inclusion of cardiologists in treatment and follow-up of these patients should be implied from the diagnosis establishment.

Assessment of antiphospholipid antibodies profiles based on severity of COVID-19 pneumonia.

Introductionthrombotic events are the most severe complications of the coronavirus disease 2019 (COVID-19). It is known that anti-phospholipid antibodies (APL) could be involved in thrombosis mechanism. Thus, APL profiles were studied particularly in patients with severe and critical COVID-19, and their clinical impact.Methodsa retrospective study of 54 COVID-19 hospitalized patients (34 in intensive care unit (ICU) and 20 in non-ICU) was conducted. These COVID-19 patients were tested for the presence of LAC (lupus anticoagulant) using the ACLTOP750®, anti-cardiolipine (ACL) and anti-β2glycoprotéine I (anti-β2GPI) IgG/IgM/IgA by enzyme-linked immunosorbent assay (ELISA). IgA isotype was tested in only 25 patients.Resultsanti-phospholipid antibodies were present in 74.1% of tested patients. LAC positivity was the highest (60.8%) among all patients, followed by IgM aCL (18.5%) and IgM anti-β2GPI (14.8%). Besides, LAC and anti-β2GPI IgA were the most predominant APL regarding the 25 patients tested for IgA isotype (52% and 24% respectively). Nine patients had thrombotic events, among them 6 were positive in APL and 5 were positive in LAC. However, there was any significant association between APL positivity or titers and thrombosis. There was also no significant difference between the two COVID-19 groups regarding APL profiles.Conclusiongiven the relatively high frequency of APL and especially LAC, and given the multitude of thrombotic risk factors in these severely and critically ill COVID-19 patients, a prophylactic anticoagulation remains essential.

Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries.

Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and β2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-β2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.

Antiphospholipid Antibody Assays in 2021: Looking for a Predictive Value in Addition to a Diagnostic One.

Antiphospholipid antibodies (aPL) are mandatory for the diagnosis but are also a risk factor for the antiphospholipid syndrome (APS) clinical manifestations. Lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2 glycoprotein I (β2GPI) assays are the formal laboratory classification/diagnostic criteria. Additional nonclassification assays have been suggested; among them, antiphosphatidylserine-prothrombin (aPS/PT) and antidomain 1 β2GPI antibodies are the most promising ones although not yet formally accepted. aPL represent the example of a laboratory test that moved from dichotomous to quantitative results consistent with the idea that reporting quantitative data offers more diagnostic/prognostic information for both vascular and obstetric manifestations. Although the general rule is that the higher the aPL titer, the higher the test likelihood ratio, there is growing evidence that this is not the case for persistent low titers and obstetric events. LA displays the highest diagnostic/prognostic power, although some isolated LAs are apparently not associated with APS manifestations. Moreover, isotype characterization is also critical since IgG aPL are more diagnostic/prognostic than IgA or IgM. aPL are directed against two main autoantigens: β2GPI and PT. However, anti-β2GPI antibodies are more associated with the APS clinical spectrum. In addition, there is evidence that anti-β2GPI domain 1 antibodies display a stronger diagnostic/prognostic value. This finding supports the view that antigen and even epitope characterization represents a further step for improving the assay value. The strategy to improve aPL laboratory characterization is a lesson that can be translated to other autoantibody assays in order to improve our diagnostic and prognostic power.

Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice.

ObjectivesLupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice.MethodsIn this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018.ResultsDuring the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-β2 glycoprotein I (β2GPI) IgG compared with patients with other indications.ConclusionThe prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-β2GPI IgG and aCL IgG, which should be confirmed in future studies.

Poor Agreement between Commercially Available Anti-Cardiolipin and Anti-β2glycoprotein I IgG and IgM Solid Phase Assays Hampers Uniformity in the Classification of Antiphospholipid Syndrome Patients

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or specific pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPL). Given the high frequency of clinical symptoms irrespective of APS, laboratory tests are of utmost importance for the diagnosis of the disease. Laboratory criteria include aPL detection by a functional assay referred to as lupus anticoagulant (LAC) or by semi-quantitative solid phase assays measuring anti-β2glycoprotein I (aβ2GPI) or anti-cardiolipin (aCL) IgG/IgM antibodies. Reports from external quality control programs illustrate that commercially available aPL assays produce variable results, probably originating from differences in assay design, epitope exposure and a lack of standardization. In a large multicentre study, we aimed to assess the agreement between four solid phase assays measuring IgG and IgM aCL and aβ2GPI aPL.1168 patients were included from eight European centers. Patients were classified by the local centers resulting in 259 thrombotic APS patients, 204 diseased controls for thrombosis, 122 obstetric APS patients, 33 diseased controls for pregnancy complications, 196 patients with autoimmune disease other than APS, 100 pregnant women without complications, 194 patients without clinical and laboratory criteria for APS and 60 APS patients without specification of the clinical condition. Four platforms were selected based on frequency of use and the willingness of manufacturers to provide their assays (Table 1). All samples with all assays were tested at one location by a single technician.To assess the agreement between the four platforms in the detection of IgG/IgM aCL and aβ2GPI aPL Kappa statistics was performed. A Kappa agreement value of 0.40-0.59 implies that only 15-35% of the data are reliable. Low levels of reliability affect diagnosis and treatment of APS patients and are unacceptable for clinical laboratories. In this study a Kappa agreement value of ≥0.8 (“good agreement”) was considered as acceptable. The manufacturer's recommended cut-off value was used upon confirmation in at least 20 healthy donors.Apart from Bioplex versus AcuStar and ImmunoCap EliA versus AcuStar (good agreement) all the other tested platforms did not reach a Kappa value ≥0.80 for aCL IgG and aβ2GPI IgM positivity (Table 2). Only two assays were in good agreement for aβ2GPI IgG positivity (AcuStar versus Bioplex and Quanta Lite ELISA versus ImmunoCap EliA), while all other tested platforms did not reach the threshold value. aCL IgM reactivity showed the lowest level of agreement, resulting in Kappa values <0.80 between the platforms.Additionally, we determined the aPL titer correlation using a Spearman's rank test to be independent of differences in cut-off values. Values below the detection limit were replaced by the lower detection limit value. Apart from AcuStar and Bioplex all the other tested platforms had a Spearman's rank correlation coefficient <0.80 for aβ2GPI IgG, aCL and aβ2GPI IgM positivity (Table 3). None of the tested platforms resulted in a correlation coefficient ≥0.80 for aCL IgG.To assess the clinical implications of the observed (dis)agreements, we investigated the number of patients that would be reclassified from thrombotic APS to non-APS thrombosis and vice versa based on our results. From the 259 thrombotic APS patients, 35 were negative for LAC (determined by the center). From these 35 patients, 18 up to 26 patients tested negative for any aPL in the four included platforms. Additionally, from the 204 non-APS thrombotic patients 1 up to 11 patients were positive for at least one aPL. In case of repetitive positivity, these patients in our hands would be classified as APS patients. Similar data were obtained for obstetric patients, resulting in a possible reclassification of 17 up to 21 patients.Our study clearly indicates that diagnosis of APS is strongly platform dependent. Since APS patients have an increased risk for thrombosis recurrence, misclassification of patients has major implications. Falsely diagnosed patients may be given indefinite oral anticoagulant treatment, thus being exposed to a high risk of bleeding without having any benefit of such treatment. False-negative results have serious consequences as they need long-term anticoagulation to prevent recurrence. Standardization/uniformity of laboratory assays for the diagnosis of APS is therefore urgently warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thrombotic Risk Factors, Antithrombotic Therapy, and Outcomes of Asymptomatic Carriers of Antiphospholipid Antibodies and Patients with Antiphospholipid Syndrome

Background: There is marked heterogeneity in the clinical presentation of patients with antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) and a variable thrombotic risk. Putative thrombotic risk factors include male gender, high titer aPL serology with IgG isotype, triple positivity and concomitant autoimmune disease. However, the evidence is conflicting for some, and the patient heterogeneity makes risk stratification challenging. Thus, long-term antithrombotic management decisions remain primarily driven by clinical judgment. Decisions such as discontinuation of therapy, use of direct oral anticoagulants (DOAC), and the role of hydroxychloroquine (HCQ) and immunosuppressive therapy remain areas of ongoing research.Objectives: To outline clinical risk factors of thrombotic events in antiphospholipid patients and describe outcomes of different antithrombotic strategies in this heterogeneous cohort.Methods: We retrospectively identified all adult patients followed at Weill Cornell Hematology with aPL or APS. Patients were included if they met laboratory criteria for APS. Data on patient demographics, concomitant thrombophilia, autoimmune disease, and family history of thrombosis, aPL isotype and titer, thrombotic events prior to and during follow-up, and antithrombotic therapies were collected. Time to event analysis was used to identify clinical risk factors for thrombosis. The time varying effects of antithrombotic therapies were also evaluated.Results: A total of 122 patients were identified with a median age of 43 (range 19-86 yrs.). Ninety-three (76%) were female and 29 (24%) were male. Eighty-four patients (69%) were diagnosed with APS prior to their initial visit and the remaining 38 (31%) were aPL positive. Of the 84 APS patients, 63 (74%) had a history of a single thrombotic event and 22 (20%) had recurring events. Those were venous thromboembolic events (VTE) in 45 patients (53%), Arterial (AT) in 19 (22%), pregnancy morbidity (PM) in 12 (14%), and combinations of VTE, AT, and PM in the remaining 9 patients (11%). Of the 38 aPL positive carriers, 25 (66%) were asymptomatic, tested mainly for prolonged aPTT (68%), and 13 (44%) had non-criteria events that prompted testing. Autoimmune disease was present in 37 (30%), of which 16 (43%) were SLE. Hereditary thrombophilia was identified in 7 (6%) and a family history of thrombosis, aPL positivity, or APS was noted in 15 (12%).During a median follow-up duration of 47 months, 19 patients had an event (16%). A significantly higher rate of thrombosis was observed in patients with autoimmune disease (HR 4.64, p<0.01), and in Blacks vs. Whites (HR 8.37 p<0.01). Triple positivity, found in 45 patients (37%), was not associated with an increased thrombotic risk. The risk of thrombosis was significantly lowest among patients on therapeutic dose anticoagulant therapy (ac) with low-molecular weight heparin (LMWH) or vitamin K antagonist (VKA) (Figure 1). In comparison, patients on antiplatelet therapy (apt) alone had 5.4 times the risk (HR 5.432, p=0.01). DOACs were used in 9 (10%) of the APS patients, with a median follow-up of 19 months (2-37) and a single event occurring in a young male without the aforementioned risk factors. Thirteen patients (11%) were on HCQ, 8 (7%) with autoimmune disease and 5 (4%) without, for a median duration of 20 months, with a single event occurring in a patient on HCQ alone.Conclusions: In this study, concomitant autoimmune disease and Black race were risk factors for thrombotic events in antiphospholipid patients. Anticoagulation with LMWH or VKA remains the most effective therapy. Deciding on who can safely discontinue anticoagulation and who may benefit from additional antithrombotic and immunosuppressive therapies remains a matter of clinical judgment until multicenter, prospective studies are carried out. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is Lupus Anticoagulant a Significant Feature of COVID-19? A Critical Appraisal of the Literature.

The term "lupus anticoagulant (LA)" identifies a form of antiphospholipid antibodies (aPLs) causing prolongation of clotting tests in a phospholipid concentration-dependent manner. LA is one of the laboratory criteria identified in patients with antiphospholipid (antibody) syndrome (APS). The presence of LA in patients with APS represents a significant risk factor for both thrombosis and pregnancy morbidity. There have been several reports of similarities between some of the pathophysiological features of COVID-19 and APS, in particular the most severe form, catastrophic APS. There have also been many reports identifying various aPLs, including LA, in COVID-19 patients. Accordingly, a very pertinent question arises: "Is LA a feature of COVID-19 pathology?" In this review, we critically appraise the literature to help answer this question. We conclude that LA positivity is a feature of COVID-19, at least in some patients, and potentially those who are the sickest or have the most severe infection. However, many publications have failed to appropriately consider the many confounders to LA identification, being assessed using clot-based assays such as the dilute Russell viper venom time, the activated partial thromboplastin time (aPTT), and the silica clotting time. First, most patients hospitalized with COVID-19 are placed on anticoagulant therapy, and those with prior histories of thrombosis would possibly present to hospital already on anticoagulant therapy. All anticoagulants, including vitamin K antagonists, heparin (both unfractionated heparin and low-molecular-weight heparin), and direct oral anticoagulants affect these clot-based assays. Second, C-reactive protein (CRP) is highly elevated in COVID-19 patients, and also associated with severity. CRP can also lead to false-positive LA, particularly with the aPTT assay. Third, persistence of aPL positivity (including LA) is required to identify APS. Fourth, those at greatest risk of thrombosis due to aPL are those with highest titers or multiple positivity. Most publications either did not identify anticoagulation and/or CRP in their COVID-19 cohorts or did not seem to account for these as possible confounders for LA detection. Most publications did not assess for aPL persistence, and where persistence was checked, LA appeared to represent transient aPL. Finally, high titer aPL or multiple aPL positivity were in the minority of COVID-19 presentations. Thus, at least some of the reported LAs associated with COVID-19 are likely to be false positives, and the relationship between the detected aPL/LA and COVID-19-associated coagulopathy remains to be resolved using larger and better studies.

Antiphospholipid antibodies and cerebrovascular thrombosis in the pediatric population: Few answers to many questions.

Most of the knowledge in pediatric antiphospholipid syndrome (APS) is derived from studies performed on the adult population. As in adults, antiphospholipid antibodies (aPL) can contribute to thrombosis, especially cerebrovascular thrombosis, in neonates and children. Since aPL have the potential to cross the placental barrier, and since the pediatric population is prone to infections, re-testing for their positivity is essential to specify their role in cerebrovascular thrombosis.In this review, we aimed at assessing the prevalence of aPL, criteria or non-criteria, in neonatal and childhood ischemic stroke and sinovenous thrombosis trying to find an association between aPL and cerebrovascular thrombosis in the neonatal and pediatric population. Also, we looked into the effect of aPL and anticoagulants/antiplatelets on the long term neurological outcomes of affected neonates or children. The questions regarding the prevalence of aPL among pediatric patients with cerebrovascular thrombosis, the relationship between the titers of aPL and incidence and recurrence of cerebrovascular events, the predictability of the long term neurological outcomes, and the most optimal anticoagulation plan are still to be answered. However, it is crucial for clinicians to screen neonates and children with cerebrovascular thrombosis for aPL and confirm their presence if positive.

AB0696 ANTI-PHOSPHOLIPID AUTOANTIBODIES IN COVID-19 PATIENTS

Background:Because of the inflammation boosting cytokines, Coronavirus disease 2019 (COVID-19) has demonstrated thrombotic consequences that have increased its morbidity and mortality. There is evidence that mechanisms that contribute in thrombosis in COVID-19 patients are similar to those in anti-phospholipid syndrome (aPS). In fact, there is a possibility that anti-phospholipid autoantibodies (aPLs) might impulse thrombosis in patients with COVID-19, as literature suggests2.Objectives:The aim of our study was to evaluate the anti-phospholipid autoantibody titre in patients with COVID-19 during and after the infection.Methods:This is an observational study which included 71 patients with a recent COVID-19 up to 4 weeks after. Every patient was completed with aPL titre about IgG and IgM anti-cardiolipine (ACA) and lupus anticoagulant (LAC) autoantibodies. According to titre results, the patients were divided into groups in order to better show the immunologic results.Results:After gathering and analysing the data, it was estimated that 21 patients (29.6%) were positive for at least one type of aPL antibody: 12 patients were found positive for lupus anticoagulant autoantibodies (57.1%), 6 patients were double positive for LAC and ACA (28.6%), and 3 patients were positive for anti-cardiolipin antibodies (14.3%). Seven patients were IgM positive for any aPL (33.3%), 6 patients were found to have positive IgM and IgG (28.6%) and 8 patients had only IgG antibodies (38.1%).Conclusion:From this study it was observed that a significant proportion of patients with recent COVID-19 infection had positive anti-phospholipid antibodies, compared to the general population prevalence. This suggests that the impact of aPLs in COVID-19 might be of great importance. It should be carefully evaluated in order to better understand the mechanisms of thrombotic complications.

Thrombosis and thrombocytopenia in antiphospholipid syndrome: their association with mean platelet volume and hematological ratios

ObjectiveTo assess the mean platelet volume (MPV), platelet-to-lymphocyte ratio (PLR), the neutrophil-to-lymphocyte ratio (NLR) and the MPV-to-lymphocyte ratio, and to test them according to the clinical/serological status, shift through time and other comorbidities in APS. MethodsWe included 96 primary APS patients according to the Sydney classification criteria and/or patients with thrombocytopenia and/or autoimmune hemolytic anemia who also fulfilled the serological criteria. We tested aCL, anti-β2GP-I and aPS/PT antibodies and LA. We first registered the MPV and the aforementioned ratios within at least 6 months after an event of thrombosis or thrombocytopenia/AIHA (baseline determination), and during thrombosis/thrombocytopenia/AIHA onset when available (acute event). ResultsA lower baseline MPV and a higher PLR characterized the thrombotic group (n = 74). The AUC for baseline PLR was 0.82 (p < 0.001): SE of 69%, SP 91%, PPV 96%, NPV 74%, LR+ 13.67 and LR- 0.19. During the acute event, both variables increased. The thrombocytopenic group (n = 66) had a higher baseline MPV and a lower PLR, and during an acute event the PLR decreased more deeply. The AUC for MPV was 0.64 (p = 0.02): SE 44%, SP 92%, PPV 86%, NPV 40%, LR+ 3.3 and LR- 0.85. These findings were not related with the aPL antibody profile status, titers or comorbidities. ConclusionBasal MPV and PLR might help to identify APS patients according to their thrombotic or thrombocytopenic phenotype. These variables change during the acute events and might be the reflex of physiopathological or compensatory mechanisms in APS.

Identifying additional risk factors for arterial and venous thrombosis among pediatric antiphospholipid antibodies carriers.

Antiphospholipid antibodies (aPL) have been extensively reported in children, but investigations into thrombotic risks associated with aPL positivity in pediatric patients is scarce. Positive aPL are not uncommon in pediatric connective tissue diseases (CTD), but identification and management of these patients is challenging due to lack of validated criteria and a paucity of data. In this study, we identify potential additional risk factors for thrombosis in a unique cohort of pediatric aPL positive carriers. Retrospective chart review was performed on 491 pediatric patients with CTD seen in our institution from 2001 to 2019. Patients without persistently moderate to high titer aPL at least 12 weeks apart were excluded. Univariate analysis was performed to evaluate correlation between different risk factors and thrombotic events. Seventy-one aPL positive children with underlying CTD are included in this cohort. The majority (87%) are female and of Hispanic ethnicity (56%). Mean age of the cohort at the diagnosis of connective tissue disease is 12.7 (SD 2.6) years, and mean age of first positive aPL is 13.3 (SD 2.5) years. Average length of follow-up is 4.3 (SD 2.5) years. Four (5.6%) patients experienced arterial thrombosis, and 11 (15.5%) had venous thrombosis. Fifty-seven (80.3%) patients did not have any thromboembolic events. Among traditional risk factors and signs of endothelial injury, only Raynaud's phenomena demonstrated significant association with arterial thrombosis (OR = 8.4, 95%CI 1.13-111, P = 0.039), and hypertension or anti-hypertensive use demonstrated significant association with venous thrombosis (OR = 8.387, 95%CI 1.2 - 94, P = 0.02). Data from our cohort suggest that Raynaud's phenomenon is a potential predictor of arterial thrombosis while the presence of hypertension or anti-hypertensive medication use is a potential predictor of venous thrombosis in aPL positive pediatric carriers. Further studies investigating pediatric aPL profiles and risk factors for development of thrombosis are needed to help guide clinicians in caring for these challenging patients.

Case of catastrophic antiphospholipid syndrome presenting as neuroretinitis and vaso-occlusive retinopathy

BackgroundOcular involvement in catastrophic antiphospholipid syndrome (CAPS), a rare, life-threatening form of antiphospholipid syndrome (APS) that results in multiorgan failure and a high mortality rate, has rarely been reported.Case presentationA 15-year-old girl presented with sudden vision blurring in both eyes. She had marked optic disc swelling and macular exudates in the right eye and intra-arterial white plaques, a few retinal blot hemorrhages, and a white ischemic retina in the left eye. Systemic examination revealed she had acute kidney injury with thrombotic microangiopathy (TMA), multiple cerebral infarcts, valvular dysfunction, and a high titer of triple aPL. Thus, she was diagnosed with CAPS involving the brain, eyes, heart, and kidneys. Plasma exchange and the administration of glucocorticoids, immunoglobulin, warfarin, and rituximab brought a sustained recovery of the TMA, visual symptoms, and echocardiographic findings.ConclusionsOcular involvement of both vaso-occlusive retinopathy, an APS-related thrombotic microangiopathy, and neuroretinitis, a non-thrombotic microangiopathy, can occur as an initial presentation of CAPS.