Beyond thrombosis: Anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome.
TL;DR: The data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positiveAnti-D4/5 antibodies are not predictive of thromBosis or PM.
About: This article is published in Journal of Autoimmunity.The article was published on 2018-06-01. It has received 53 citations till now. The article focuses on the topics: Autoantibody.
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TL;DR: APL in COVID-19 patients are mainly directed against β2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome, which shows a low prevalence and is not associated with major thrombotic events.
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.
137 citations
TL;DR: There are two main clinical variants of antiphospholipid syndrome (APS): vascular and obstetric APS; non-thrombotic mechanisms might be more important than placental infarction in the pathogenesis of obstetrical APS.
Abstract: Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid syndrome (APS). Although most patients display both clinical signs, some patients can have isolated vascular or obstetric variants. Emerging data raise the question of whether obstetric and vascular APS are the same or different diseases. An important difference between the two conditions is that a thrombophilic state is a common feature in vascular APS, whereas clot occlusions of the decidual spiral arteries are seldom observed in obstetric APS, and infarctions are found in only one-third of APS placentae. Conversely, inflammation, which is undetectable in vascular APS, is frequently observed in the placentae of patients with obstetric APS and has been documented in the placentae of pregnant mice with fetal loss mediated by antiphospholipid antibodies. Attempts to identify different antibodies or epitopes responsible for the two clinical manifestations of APS have so far been unsuccessful. Possible mechanisms exist that might explain the development of the two clinical presentations, including the tissue distribution and expression level of the main target antigen of antiphospholipid antibodies, β2 glycoprotein I (β2GPI). The identification of the factors that promote the onset of either obstetric or vascular APS has important diagnostic and therapeutic implications.
80 citations
TL;DR: Beta-2-Glycoprotein I is a unique protein with a key role in haemostasis, homeostasis and immunity and how these factors may influence its contribution to disease pathogenesis is examined.
76 citations
TL;DR: New autoantibodies and antibody complexes of different immunoglobulin subtypes (IgA, IgG, IgM) are now recognised as significant contributors to the pathogenesis of antiphospholipid syndrome.
Abstract: Antiphospholipid syndrome, also known as 'Hughes Syndrome', is an autoimmune disease characterised by a set of clinical manifestations, almost all of which are direct or indirect sequelae of a hypercoagulable state involving the venous, and to a lesser extent the arterial vasculature. The incidence and prevalence of antiphospholipid syndrome are estimated at approximately 5 de novo cases per 100 000 per year and 40-50 cases per 100 000 individuals, respectively. The clinical spectrum of antiphospholipid syndrome involves haematological (thrombocytopaenia, venous thrombosis), obstetrical (recurrent pregnancy loss), neurological (stroke, transient ischaemic attack, migraine, seizures, cognitive dysfunction, chorea, transverse myelitis, multiple sclerosis), cardiovascular (cardiac valve disease), dermatological (livedo reticularis and racemosa, skin ulceration and necrosis), renal (glomerulonephritis, renal thrombotic microangiopathy) and orthopaedic (avascular necrosis of bones, non-traumatic fractures) manifestations, among others. In addition to the classical antiphospholipid antibodies, namely anticardiolipin antibodies and lupus anticoagulant, new autoantibodies and antibody complexes of different immunoglobulin subtypes (IgA, IgG, IgM) are now recognised as significant contributors to the pathogenesis of antiphospholipid syndrome. Anticoagulation remains the cornerstone in the management of antiphospholipid syndrome; nevertheless, new drugs and therapeutic strategies are being tested, and some have been found effective for the primary and secondary thromboprophylaxis in antiphospholipid syndrome.
72 citations
TL;DR: A management envisaging multiple drugs (anticoagulation, steroids, plasma exchange and/or intravenous immunoglobulins) is the most effective approach in catastrophic APS.
54 citations
References
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University of New South Wales1, Hospital for Special Surgery2, Hokkaido University3, University of Utah4, University of Texas Health Science Center at San Antonio5, Utrecht University6, University of Milan7, Geneva College8, Sheba Medical Center9, University of Brescia10, National and Kapodistrian University of Athens11
TL;DR: This document appraise the existing evidence on clinical and laboratory features of APS addressed during the forum and proposes amendments to the Sapporo criteria, including definitions on features ofAPS that were not included in the updated criteria.
5,699 citations
TL;DR: In this article, the authors generalize the concept of variance inflation as a measure of collinearity to a subset of parameters in a linear model and examine the impact on the precision of estimation of less-than-optimal selection of other columns of the design matrix.
Abstract: Working in the context of the linear model y = Xβ + e, we generalize the concept of variance inflation as a measure of collinearity to a subset of parameters in β (denoted by β 1, with the associated columns of X given by X 1). The essential idea underlying this generalization is to examine the impact on the precision of estimation—in particular, the size of an ellipsoidal joint confidence region for β 1—of less-than-optimal selection of other columns of the design matrix (X 2), treating still other columns (X 0) as unalterable, even hypothetically. In typical applications, X 1 contains a set of dummy regressors coding categories of a qualitative variable or a set of polynomial regressors in a quantitative variable; X 2 contains all other regressors in the model, save the constant, which is in X 0. If σ 2 V denotes the realized variance of , and σ 2 U is the variance associated with an optimal selection of X 2, then the corresponding scaled dispersion ellipsoids to be compared are ℰ v = {x : x′V ...
1,100 citations
TL;DR: Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT and the interpretation of the results in general and in particular situations is reported.
1,068 citations
TL;DR: Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
Abstract: Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β(2) glycoprotein I (β(2)GPI)-dependent aPL, the most important subset of these antibodies, mediate several--not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with β(2)GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β(2)GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
497 citations
TL;DR: The occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE.
361 citations