Is There an Additional Value in Detecting Anticardiolipin and Anti-β2 glycoprotein I IgA Antibodies in the Antiphospholipid Syndrome?

2020 ◽  
Vol 120 (11) ◽  
pp. 1557-1568
Author(s):  
Walid Chayoua ◽  
Dong-mei Yin ◽  
Hilde Kelchtermans ◽  
Gary W. Moore ◽  
Jean-Christophe Gris ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Immunoglobulin A ◽  
Clinical Manifestations ◽  
Pregnancy Morbidity ◽  
Medical Centers ◽  
Glycoprotein I ◽  
Iga Antibodies ◽  
Obstetric Aps ◽  
Current Criterion ◽  
Additional Value

Abstract Background Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS. Methods We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center. Results Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3–5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity. Conclusion aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.

Pathophysiological insights into the antiphospholipid syndrome

2017 ◽  
Vol 37 (03) ◽  
pp. 202-207 ◽  
Author(s):  
Davit Manukyan ◽  
Nadine Müller-Calleja ◽  
Karl Lackner
Keyword(s):  
Antiphospholipid Syndrome ◽  
Clinical Manifestations ◽  
Future Research ◽  
Scientific Debate ◽  
Pregnancy Morbidity ◽  
Anionic Phospholipids ◽  
The Third ◽  
Glycoprotein I ◽  
Underlying Mechanisms

SummaryThe antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis and severe pregnancy morbidity in presence of antiphospholipid antibodies (aPL). While there is compelling evidence that aPL cause the clinical manifestations of APS, the underlying mechanisms are still a matter of scientific debate. This is mainly related to the broad heterogeneity of aPL. There are three major types of aPL: The first one binds to (anionic) phospholipids, e.g. cardiolipin, in absence of other factors (cofactor independent aPL). The second type binds to phospholipids only in presence of protein cofactors, e.g. ß2-glycoprotein I (ß2GPI) (cofactor dependent aPL). The third type binds to cofactor proteins directly without need for phospholipids. It is widely believed that cofactor independent aPL (type 1) are associated with infections and, more importantly, non-pathogenic, while pathogenic aPL belong to the second and in particular to the third type. This view, in particular with regard to type 1 aPL, has not been undisputed and novel research data have shown that it is in fact untenable. We summarize the available data on the pathogenetic role of aPL and the implications for diagnosis of APS and future research.

Diagnosis and management of non-criteria obstetric antiphospholipid syndrome

2015 ◽  
Vol 113 (01) ◽  
pp. 13-19 ◽  
Author(s):  
Samuel J. Machin ◽  
Ian J. Mackie ◽  
Hannah Cohen ◽  
Deepa R. Jayakody Arachchillage
Keyword(s):  
Antiphospholipid Syndrome ◽  
In Vitro Fertilisation ◽  
International Consensus ◽  
Clinical Criteria ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Retrospective Cohort Studies ◽  
Obstetric Antiphospholipid Syndrome ◽  
Obstetric Aps

SummaryAccurate diagnosis of obstetric antiphospholipid syndrome (APS) is a prerequisite for optimal clinical management. The international consensus (revised Sapporo) criteria for obstetric APS do not include low positive anticardiolipin (aCL) and anti β2 glycoprotein I (aβ2GPI) antibodies (> 99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late preeclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. In this review we examine the available evidence to address the question of whether patients who exhibit non-criteria clinical and/or laboratory manifestations should be included within the spectrum of obstetric APS. Prospective and retrospective cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM aβ2GPI, or low positive positive aCL or aβ2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such prospective and retrospective studies also suggest that women with non-criteria obstetric APS may benefit from standard treatment for obstetric APS with low-molecular-weight heparin plus low-dose aspirin, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches. Women with obstetric APS appear to be at a higher risk than other women of pre-eclampsia, placenta- mediated complications and neonatal mortality, and also at increased long-term risk of thrombotic events. The applicability of these observations to outcomes in women with non-criteria obstetric APS remains to be determined.

scholarly journals IgG Autoantibodies againstβ2-Glycoprotein I Complexed with a Lipid Ligand Derived from Oxidized Low-Density Lipoprotein are Associated with Arterial Thrombosis in Antiphospholipid Syndrome

2003 ◽  
Vol 10 (2-4) ◽  
pp. 203-211 ◽  
Author(s):  
Daniel Lopez ◽  
Kazuko Kobayashi ◽  
Joan T. Merrill ◽  
E. Matsuura ◽  
Luis R. Lopez
Keyword(s):  
Venous Thrombosis ◽  
Antiphospholipid Syndrome ◽  
Arterial Thrombosis ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Clinical Manifestations ◽  
Density Lipoprotein ◽  
Healthy Individuals ◽  
Pregnancy Morbidity ◽  
Glycoprotein I

We recently reported [J. Lipid Res.42(2001), 697;43(2002), 1486;44(2003), 716] thatβ2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship ofβ2GPI/oxLDL complexes and IgG autoantibodies againstβ2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. Theβ2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation withβ2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies againstβ2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome

2017 ◽  
Vol 44 (05) ◽  
pp. 458-465 ◽  
Author(s):  
Walid Chayouâ ◽  
Hilde Kelchtermans ◽  
Bas Laat
Keyword(s):  
Risk Stratification ◽  
Antiphospholipid Syndrome ◽  
Clinical Manifestations ◽  
Detection Methods ◽  
Clinical Value ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Patients At Risk ◽  
Beta 2 ◽  
Domain I

AbstractThe antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (β2GPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of β2GPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required.

scholarly journals Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Manuela Velásquez ◽  
Luisa F. Peláez ◽  
Mauricio Rojas ◽  
Raúl Narváez-Sánchez ◽  
Jesús A. Velásquez ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Clinical Manifestations ◽  
Endothelial Activation ◽  
No Production ◽  
Endothelin 1 ◽  
New Therapies ◽  
Pregnancy Morbidity ◽  
Obstetric Aps

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

scholarly journals Challenges in the Diagnosis of the Antiphospholipid Syndrome

2010 ◽  
Vol 56 (6) ◽  
pp. 930-940 ◽  
Author(s):  
Katrien Devreese ◽  
Marc F Hoylaerts
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Lupus Anticoagulant ◽  
Complex Disease ◽  
Clinical Manifestations ◽  
Clinical Role ◽  
Clinical Criteria ◽  
Pregnancy Morbidity ◽  
Glycoprotein I ◽  
Coagulation Tests

Abstract Background: The antiphospholipid syndrome (APS) is an important cause of acquired thromboembolic complications and pregnancy morbidity. Its diagnosis is based on clinical and laboratory criteria, defined by strict guidelines. The original clinical and laboratory criteria for the identification of APS patients were published in 1999, in the so-called Sapporo criteria. In 2006 these criteria were revised, and recently more precise guidelines for analysis of the lupus anticoagulant have been provided. However, several questions related to the diagnosis of APS remain unanswered. Content: In addition to providing a historical perspective, this review covers several challenges in the diagnosis of APS with respect to clinical and laboratory features, while highlighting pathogenic pathways of the syndrome. We discuss ongoing dilemmas in the diagnosis of this complex disease. Although antiphospholipid antibodies are found in association with various clinical manifestations, the older established clinical criteria were not substantively altered in the 2006 update. Several laboratory tests recommended in the latest criteria, including phospholipid-dependent coagulation tests for the detection of the lupus anticoagulant and ELISAs for measuring anticardiolipin and β2-glycoprotein I antibodies, still show methodological and diagnostic shortcomings. In addition, antiphospholipid antibodies have been described against other antigens, but their clinical role remains uncertain. Conclusions: Despite updated APS criteria, diagnosis of this syndrome remains challenging. Further research on clinically relevant antibodies and standardization of their detection are needed to improve clinical risk assessment in APS.

scholarly journals Anticardiolipin Antibodies in Patients with Chronic Hepatitis C Virus Infection: Characterization in Relation to Antiphospholipid Syndrome

2000 ◽  
Vol 7 (2) ◽  
pp. 241-244 ◽  
Author(s):  
Josep Ordi-Ros ◽  
Julieta Villarreal ◽  
Francesc Monegal ◽  
Silvia Sauleda ◽  
Ignacio Esteban ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Antiphospholipid Syndrome ◽  
Clinical Manifestations ◽  
Cross Reactivity ◽  
Healthy Controls ◽  
Glycoprotein I ◽  
Chronic Hepatitis C Virus

ABSTRACT The antiphospholipid syndrome (APS) is usually defined by the association of clinical manifestations that comprise venous and/or arterial thrombosis, recurrent fetal losses, and thrombocytopenia, along with the presence of anticardiolipin (aCL) antibodies and/or lupus anticoagulant. Various infectious diseases can induce aCL; however, these antibodies are not usually associated with thrombotic events, as happens with autoimmune diseases, in which these antibodies need the presence of β2-glycoprotein I. Levels of immunoglobulin G (IgG) and IgM aCL antibodies were determined by enzyme-linked immunosorbent assay for 243 patients with chronic hepatitis C virus (HCV) infection and 100 healthy controls. Clinical events of APS, the level of β2-glycoprotein dependence of aCL, the presence of cryoglobulins and other autoantibodies, and cross-reactivity between purified aCL and HCV were evaluated. Positive results for aCL antibodies were found more frequently (3.3%) for the patients with HCV infection than for healthy controls (0%). All positive aCL antibodies were β2-glycoprotein I independent. No significant association was found between aCL antibodies and clinical manifestations of APS, neither was one found between the presence of other autoantibodies or cryoglobulins and that of aCL. Finally, no cross-reactivity between aCL antibodies and HCV antigens was observed. As previously reported, aCL antibodies seem to be an epiphenomenon, and they do not have clinical or laboratory significance in HCV patients.

Atherosclerosis and the antiphospholipid syndrome: A link unravelled?

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 140-143 ◽  
Author(s):  
Y Shoenfeld ◽  
D Harats ◽  
J George
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Dominant Role ◽  
Clinical Manifestations ◽  
Humoral Response ◽  
Arterial System ◽  
Glycoprotein I ◽  
Shock Proteins ◽  
Modified Forms ◽  
Progression Of Atherosclerosis

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to β2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

Antiphospholipid syndrome – an update

VASA ◽  
2018 ◽  
Vol 47 (6) ◽  
pp. 451-464 ◽  
Author(s):  
Birgit Linnemann
Keyword(s):  
Antiphospholipid Syndrome ◽  
Lupus Erythematosus ◽  
Clinical Symptoms ◽  
Heart Valve Disease ◽  
Small Vessels ◽  
Glycoprotein I ◽  
Neurologic Disorders ◽  
Cardiolipin Antibodies ◽  
Obstetric Aps ◽  
Beta 2

Abstract. Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called “thrombotic APS”) and pregnancy complications (“obstetric APS”). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option. Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication

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