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Journal ArticleDOI: 10.1093/RHEUMATOLOGY/KEAA203

EUREKA algorithm predicts obstetric risk and response to treatment in women with different subsets of anti-phospholipid antibodies.

02 Mar 2021-Rheumatology (Oxford University Press (OUP))-Vol. 60, Iss: 3, pp 1114-1124
Abstract: Objectives aPL, the serum biomarkers of APS, are the most common acquired causes of pregnancy morbidity (PM). This study investigates the impact of aPL positivity fulfilling classification criteria ('criteria aPL') and at titres lower than thresholds considered by classification criteria ('low-titre aPL') on PM and assesses the effectiveness of low-dose aspirin (LDASA), low molecular weight heparin (LMWH) and HCQ in reducing the probability of PM (PPM). Methods Longitudinal data on 847 pregnancies in 155 women with persistent aPL at any titre and 226 women with autoimmune diseases and negative aPL were retrospectively collected. A generalized estimating equations model for repeated measures was applied to quantify PPM under different clinical situations. Results EUREKA is a novel algorithm that accurately predicts the risk of aPL-associated PM by considering aPL titres and profiles. aPL significantly impact PPM when at low titres and when fulfilling classification criteria. PPM was further stratified upon the aPL tests: aCL IgG/IgM and anti-β2-glycoprotein I (β2GPI) IgM, alone or combined, do not affect the basal risks of PPM, an increase occurs in case of positive LA or anti-β2GPI IgG. LDASA significantly affects PPM exclusively in women with low-titre aPL without anti-β2GPI IgG. The LDASA + LMWH combination significantly reduces PPM in all women with low-titre aPL and women with criteria aPL, except those carrying LA and anti-β2GPI IgG. In this group, the addition of HCQ further reduces PPM, although not significantly. Conclusion EUREKA allows a tailored therapeutic approach, impacting everyday clinical management of aPL-positive pregnant women.

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Open accessJournal ArticleDOI: 10.3389/FIMMU.2020.584241
Abstract: Background Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPLs) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-β2GPI), and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-β2GPI antibodies was not reported. Objective To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β2GPI antibodies. Methods ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. Results Anti-β2GPI IgG/IgA/IgM was the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM was detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of β2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-β2GPI nor with thrombosis. Conclusions aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against β2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.

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Topics: Lupus anticoagulant (58%), Antiphospholipid syndrome (55%), Beta 2-Glycoprotein I (54%) ... read more

69 Citations


Open accessPosted ContentDOI: 10.1101/2020.06.17.20134114
16 Jul 2020-medRxiv
Abstract: Background Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPL) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-β2GPI) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-β2GPI antibodies was not reported. Objective To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-β2GPI antibodies. Methods ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. Results Anti-β2GPI IgG/IgA/IgM were the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM were detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of β2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-β2GPI nor with thrombosis. Conclusions aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against β2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.

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15 Citations


Journal ArticleDOI: 10.1111/AJI.13258
Abstract: Anti-phospholipid syndrome (APS) recapitulates the link between autoimmunity and pregnancy failure: Acquired anti-phospholipid antibodies (aPL) play a pathogenic role in pregnancy complications. The diagnosis of obstetric APS can easily be pursued when women present with laboratory and clinical features fulfilling the international classification criteria. Standard therapeutic approach to obstetric APS consists in the association of anti-platelet agents and anticoagulants. Most patients achieve a live birth thanks to conventional treatment; however, approximately 20% fail to respond and are managed with additional therapeutic tools added on the top of conventional treatment. Surely, a refinement of risk stratification tools would allow early identification of high-risk pregnancies that warrant tailored treatment. In real life, obstetricians and rheumatologists face complex diagnostic scenarios including women with pregnancy morbidities other than those mentioned in classification criteria such as one or two early losses and premature birth after 34 weeks due to preeclampsia or placental insufficiency, women with low-titer aPL not fulfilling criteria laboratory requirements, women with positive non-criteria aPL, asymptomatic aPL carriers, and infertile women found to be aPL-positive. This review focuses on some of the several unanswered questions related to diagnostic, prognostic, and therapeutic aspects in obstetric APS.

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6 Citations


Open accessJournal ArticleDOI: 10.1002/JHA2.228
Jecko Thachil1Institutions (1)
17 May 2021-
Abstract: The coronavirus disease 2019 (COVID-19) pandemic has already left an indelible mark in human lives. Despite the havoc it created, this pandemic also saw significant advances in the management of an infectious disease wherein worldwide collaborative efforts from health care professionals have been unprecedented. One of the commonest complications recognised early in the pandemic is the development of coagulopathy. In this review, the lessons learnt from COVID-19 coagulopathy are summarised with some perspectives on future clinical and research strategies. These include how local versus systemic coagulopathy can matter, how we can put D-dimers to effective use, exhort more input into identifying a simple platelet activation marker, rethink the role of fibrinogen, look differently at lupus anticoagulant and heparin-induced thrombocytopenia, bring back disseminated intravascular coagulation into our differential diagnosis slate and most importantly channel more funding into haemostasis and thrombosis research.

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Topics: Platelet activation (53%)

2 Citations


Open accessJournal ArticleDOI: 10.1136/ANNRHEUMDIS-2021-220520
Abstract: The high morbidity and mortality of COVID-19 have been associated with the thrombotic microangiopathy described in the patients in addition to the increased prevalence of thrombosis affecting medium/large arterial and venous vessels.1 2 Initial reports demonstrating prolonged activated partial thromboplastin times (aPTT) and positivity for antiphospholipid antibody (aPL) assays raised the issue of whether common pathogenic mechanisms were shared by the antiphospholipid antibody syndrome (APS) and COVID-19.3 4 In particular, the systemic thrombotic microangiopathy and the increased circulating levels of proinflammatory cytokines underlined the similarity between catastrophic APS (CAPS) and COVID-19.5 6 The similarities between APS/CAPS and COVID-19 are even more complex and intriguing as summarised in table 1. A proinflammatory environment that includes the activation of the complement system has been reported in all these conditions, although at different degrees. The involvement of several cell types playing a role in the coagulation cascade, such as platelets, monocytes and neutrophils, has been described which is closely associated with the proinflammatory and prothrombotic phenotypes.7 8 In particular, an endothelial perturbation is generally thought to be a common denominator in these diseases and several authors described it with the term ‘endothelitis’ in the COVID-19.9–11 View this table: Table 1 Pathogenic pathways reported in APS, CAPS and COVID-19 Both proinflammatory cytokine (eg, interleukin-6) and complement activation products (ie, C5a and C5b9) were thought to play a role in mediating the endothelitis together with a direct effect of SARS-CoV-2 on the endothelium.10–12 However, the SARS-CoV-2 endothelial tropism is still a matter of debate despite the presence of the entry molecule (ie, ACE2) on the endothelial surfaces.13 So, it is not surprising that additional potential mediators of endothelial perturbation have been suggested. In particular, aPL came into the limelight because of their well-known …

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1 Citations


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Open accessJournal ArticleDOI: 10.1093/BIOMET/73.1.13
Kung Yee Liang1, Scott L. Zeger1Institutions (1)
01 Apr 1986-Biometrika
Abstract: SUMMARY This paper proposes an extension of generalized linear models to the analysis of longitudinal data. We introduce a class of estimating equations that give consistent estimates of the regression parameters and of their variance under mild assumptions about the time dependence. The estimating equations are derived without specifying the joint distribution of a subject's observations yet they reduce to the score equations for multivariate Gaussian outcomes. Asymptotic theory is presented for the general class of estimators. Specific cases in which we assume independence, m-dependence and exchangeable correlation structures from each subject are discussed. Efficiency of the proposed estimators in two simple situations is considered. The approach is closely related to quasi-likelih ood. Some key ironh: Estimating equation; Generalized linear model; Longitudinal data; Quasi-likelihood; Repeated measures.

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16,152 Citations


MonographDOI: 10.1017/CBO9780511803161
Judea Pearl1Institutions (1)
Abstract: 1. Introduction to probabilities, graphs, and causal models 2. A theory of inferred causation 3. Causal diagrams and the identification of causal effects 4. Actions, plans, and direct effects 5. Causality and structural models in the social sciences 6. Simpson's paradox, confounding, and collapsibility 7. Structural and counterfactual models 8. Imperfect experiments: bounds and counterfactuals 9. Probability of causation: interpretation and identification Epilogue: the art and science of cause and effect.

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Topics: Causal model (66%), Causal inference (64%), Causal reasoning (63%) ... read more

11,220 Citations


Open accessJournal ArticleDOI: 10.1111/J.1538-7836.2006.01753.X
Spiros Miyakis1, Michael D. Lockshin2, Tatsuya Atsumi3, D W Branch4  +11 moreInstitutions (11)
Abstract: New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum Based on this, we propose amendments to the Sapporo criteria We also provide definitions on features of APS that were not included in the updated criteria

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Topics: Beta 2-Glycoprotein I (54%)

5,039 Citations


Open accessBook
01 Jul 2004-
Abstract: Preface.Acknowledgments.PART I: INTRODUCTION TO LONGITUDINAL AND CLUSTERED DATA.1. Longitudinal and Clustered Data.2. Longitudinal Data: Basic Concepts.PART II: LINEAR MODELS FOR LONGITUDINAL CONTINUOUS DATA.3. Overview of Linear Models for Longitudinal Data.4. Estimation and Statistical Inference.5. Modelling the Mean: Analyzing Response Profiles.6. Modelling the Mean: Parametric Curves.7. Modelling the Covariance.8. Linear Mixed Effects Models.9. Residual Analyses and Diagnostics.PART III: GENERALIZED LINEAR MODELS FOR LONGITUDINAL DATA.10. Review of Generalized Linear Models.11. Marginal Models: Generalized Estimating Equations (GEE).12. Generalized Linear Mixed Effects Models.13. Contrasting Marginal and Mixed Effects Models.PART IV: ADVANCED TOPICS FOR LONGITUDINAL AND CLUSTERED DATA.14. Missing Data and Dropout.15. Some Aspects of the Design of Longitudinal Studies.16. Repeated Measures and Related Designs.17. Multilevel Models.Appendix A: Gentle Introduction to Vectors and Matrices.Appendix B: Properties of Expectations and Variances.Appendix C: Critical Points for a 50:50 Mixture of Chi-Squared Distributions.References.Index.

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3,555 Citations


Journal ArticleDOI: 10.1111/J.0006-341X.2001.00120.X
Wei Pan1Institutions (1)
01 Mar 2001-Biometrics
Abstract: Correlated response data are common in biomedical studies. Regression analysis based on the generalized estimating equations (GEE) is an increasingly important method for such data. However, there seem to be few model-selection criteria available in GEE. The well-known Akaike Information Criterion (AIC) cannot be directly applied since AIC is based on maximum likelihood estimation while GEE is nonlikelihood based. We propose a modification to AIC, where the likelihood is replaced by the quasi-likelihood and a proper adjustment is made for the penalty term. Its performance is investigated through simulation studies. For illustration, the method is applied to a real data set.

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1,990 Citations