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Antiphospholipid syndrome (APS) is characterized by thrombosis (which may be venous, arterial, or microvascular) and/or pregnancy morbidity in association with persistently positive antiphospholipid antibodies. Although thrombosis and pregnancy morbidity are the main clinical criteria for a diagnosis of APS in the revised Sapporo (Sydney) criteria, recently published American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for APS have significantly refined the diagnostic algorithm to include a scoring system clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular thrombosis, obstetric, cardiac valve, and hematologic). Diagnosis of APS is complicated by the fact that significant heterogeneity exists in patients' clinical presentation, underlying vascular risk factors, and methods of detecting antiphospholipid antibodies. Despite the autoimmune nature of APS, anticoagulation remains the main strategy for secondary prevention of thrombosis. Furthermore, optimal antithrombotic treatment in APS patients with arterial thrombosis remains controversial due to a paucity of data from randomized controlled studies. In this paper, we present 2 cases and highlight the diagnostic and therapeutic challenges they pose and how we approach them in the light of current evidence., Competing Interests: Declaration of competing interests J.E.M. has no conflict of interest to declare. D.J.A. received funding from Bayer plc and from LEO Pharma for research outside this project., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Antiphospholipid antibodies (aPL) are known to increase the risk of obstetrical complications. However, aPL significance and prevalence in women with late-onset pregnancy complications (LO-PC) need further clarification., Objectives: To investigate the prevalence of aPL in a cohort of women who experienced LO-PC and to compare it with a cohort of uneventful pregnancies., Methods: One hundred pregnant women who experienced LO-PC, had a low risk for chromosomal abnormalities, and absence of fetal abnormalities were recruited from August 2018 to August 2019. One hundred women with uneventful pregnancy were included as controls. aPL testing was performed on serum samples derived from prenatal screening test and included both criteria and "extra criteria" aPL., Results: Patients with LO-PC had significantly higher aPL prevalence when compared with controls (31/100 [31%] vs 10/100 [10%]; P < .001). More in detail, up to 26% of women with LO-PC were positive for one aPL, with an overall prevalence significantly higher than controls (26% vs 9%; P < .05). Among single aPL positivity, patients had significantly higher rate of positivity and titers of anticardiolipin IgG (10% vs 2%; mean ± standard deviation 11 ± 13 vs 4 ± 9.6 chemoluminescent unit; P < .05) and phosphatidylserine-prothrombin antibodies (aPS/PT) IgM (15% vs 6%; mean ± standard deviation 10.2 ± 21.7 vs 3.7 ± 13.7 U; P < .05). Testing for aPS/PT (IgM/IgG) alone allowed the identification of 17 patients negative for criteria aPL. aPL-positive patients had a significantly higher risk of preterm birth (34-36 + 6 weeks; 10% vs 8%; P < .012)., Conclusions: We report a high prevalence of aPL in our cohort. Testing for both criteria and "extra criteria" aPL in women with previous LO-PC could improve the diagnostic accuracy identifying women at higher risk for recurrent pregnancy complications., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Classification of the antiphospholipid syndrome (APS) relies predominantly on detecting antiphospholipid antibodies (aPLs). Antibodies against a domain I (DI) epitope of anti-β2glycoprotein I (β2GPI) proved to be pathogenic, but are not included in the current classification criteria., Objectives: Investigate the clinical value of detecting anti-DI IgG in APS., Patients/methods: From eight European centers 1005 patients were enrolled. Anti-cardiolipin (CL) and anti-β2GPI were detected by four commercially available solid phase assays; anti-DI IgG by the QUANTA Flash ® β2GPI domain I assay., Results: Odds ratios (ORs) of anti-DI IgG for thrombosis and pregnancy morbidity proved to be higher than those of the conventional assays. Upon restriction to patients positive for anti-β2GPI IgG, anti-DI IgG positivity still resulted in significant ORs. When anti-DI IgG was added to the criteria aPLs or used as a substitute for anti-β2GPI IgG/anti-CL IgG, ORs for clinical symptoms hardly improved. Upon removing anti-DI positive patients, lupus anticoagulant remained significantly correlated with clinical complications. Anti-DI IgG are mainly present in high-risk triple positive patients, showing higher levels. Combined anti-DI and triple positivity confers a higher risk for clinical symptoms compared to only triple positivity., Conclusions: Detection of anti-DI IgG resulted in higher ORs for clinical manifestations than the current APS classification criteria. Regardless of the platform used to detect anti-β2GPI/anti-CL, addition of anti-DI IgG measured by QUANTA Flash ® did not improve the clinical associations, possibly due to reduced exposure of the pathogenic epitope of DI. Our results demonstrate that anti-DI IgG potentially helps in identifying high-risk patients., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of lupus anticoagulant (LAC), anti-cardiolipin (aCL) and/or anti-β2glycoprotein I (aβ2GPI) antibodies of the immunoglobulin G/immunoglobulin M (IgG/IgM) isotype. However, the role of aCL and aβ2GPI IgM as a serologic marker in APS is debated., Objectives: We aimed to assess the diagnostic and clinical value of IgM antiphospholipid antibodies (aPL) in APS within the classification criteria., Patients/methods: Our multicenter study comprised 1008 patients, including APS patients and controls. Anti-CL and aβ2GPI IgG and IgM antibodies were detected with four commercially available solid phase assays., Results: Positivity for aCL and/or aβ2GPI antibodies was significantly correlated with thrombosis and pregnancy morbidity, independent of the isotype and solid phase assay. Higher odds ratios were obtained for IgG compared to IgM positivity. Isolated IgM was rare in thrombotic APS, but more frequent in obstetric APS, ranging from 3.5% to 5.4% and 5.7% to 12.3%, respectively, dependent on the solid phase assay. In a multivariate logistic regression analysis of aPL, IgM positivity was found to be associated with pregnancy morbidity. However, detection of IgM was not independently associated with thrombosis. Combined positivity for LAC, IgG, and IgM was highly associated with thrombosis and pregnancy morbidity., Conclusions: Our data support testing for aCL and aβ2GPI IgM in women suspected of obstetric APS. However, no added value was found for testing IgM in patients suspected of thrombotic APS. Still, IgM aPL might be useful as a second-line test to improve thrombotic risk stratification., (© 2019 International Society on Thrombosis and Haemostasis.)