Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.

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ANTIPHOSPHOLIPID SYNDROME

Health and Ecology Issues ◽

10.51523/2708-6011.2017-14-4-1 ◽

2017 ◽

pp. 4-11

Author(s):

E. V. Makarenko

Keyword(s):

Blood Plasma ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Lupus Anticoagulant ◽

Pregnancy Complication ◽

Classification Criteria ◽

Clinical Criteria ◽

Glycoprotein I ◽

Acquired Thrombophilia

Antiphospholipid syndrome is autoimmune acquired thrombophilia associated with the formation of antibodies to phospholipids, which is manifested by recurrent venous or arterial thrombosis and/or pathology of pregnancy. Antiphospholipid antibodies are a heterogeneous group of autoantibodies interacting with phospholipids, which are components of cell membranes and phospholipid-binding proteins of blood plasma. Antiphospholipid syndrome can affect vessels of any caliber and localization, with thrombosis accompanied by no morphological signs of inflammation in the wall of the vessel. Obstetrical pathology is manifested by loss of the fetus, which can occur at any time of pregnancy, as well as other complications of pregnancy, such as preeclampsia and placental insufficiency. Based on the classification criteria, antiphospholipid syndrome is diagnosed if one of the clinical criteria (thrombosis or pregnancy complication) and one of the laboratory criteria including the lupus anticoagulant, antibodies to cardiolipin or β2-glycoprotein I, are revealed. The main tactic of the treatment of patients with antiphospholipid syndrome is to prevent thrombosis. For this purpose, the traditional therapy with anticoagulants and antiaggregants is applied. In addition, new medicines are being developed and evaluated

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Challenges in the Diagnosis of the Antiphospholipid Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2009.133678 ◽

2010 ◽

Vol 56 (6) ◽

pp. 930-940 ◽

Cited By ~ 55

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.

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Atherosclerosis and the antiphospholipid syndrome: A link unravelled?

Lupus ◽

10.1177/096120339800700231 ◽

1998 ◽

Vol 7 (2_suppl) ◽

pp. 140-143 ◽

Cited By ~ 46

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.

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The significance of autoantibodies against β2-glycoprotein I

Blood ◽

10.1182/blood-2012-03-378646 ◽

2012 ◽

Vol 120 (2) ◽

pp. 266-274 ◽

Cited By ~ 85

Author(s):

Philip G. de Groot ◽

Rolf T. Urbanus

Keyword(s):

Autoimmune Disease ◽

Infectious Diseases ◽

Antiphospholipid Syndrome ◽

Plasma Protein ◽

Antiphospholipid Antibodies ◽

Fetal Loss ◽

Thrombotic Risk ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

History Of

AbstractThe antiphospholipid syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with a history of thrombosis and/or pregnancy morbidity, including fetal loss. APS is an autoimmune disease with a confusing name because the pathologic auto-antibodies are shown to be directed against the plasma protein β2-glycoprotein I and not against phospholipids. In fact, auto-antibodies that recognize phospholipids themselves are not associated with thrombosis but with infectious diseases. One of the intriguing questions is why autoantibodies against β2-glycoprotein I are so commonly found in both patients and the healthy. Several potential mechanisms have been suggested to explain the increased thrombotic risk in patients with these autoantibodies. In this overview, we will summarize our knowledge on the etiology of the autoantibodies, and we will discuss the evidence that identify autoantibodies against β2-glycoprotein I as the culprit of APS.

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Non β2-Glycoprotein I Cofactors for Antiphospholipid Antibodies

Lupus ◽

10.1177/096120339600500511 ◽

1996 ◽

Vol 5 (5) ◽

pp. 388-392 ◽

Cited By ~ 32

Author(s):

M Galli

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Protein C ◽

Activated Protein C ◽

Clinical Manifestations ◽

Annexin V ◽

Protein S ◽

Thromboembolic Events ◽

Glycoprotein I ◽

Recurrent Abortions

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, β2-glycoprotein I is the best known and characterized antiphospholipid ‘cofactor’ ( this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. ‘Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.

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

Clinical and Developmental Immunology ◽

10.1080/10446670310001642113 ◽

2003 ◽

Vol 10 (2-4) ◽

pp. 203-211 ◽

Cited By ~ 40

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.

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Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-1129 ◽

2015 ◽

Vol 53 (8) ◽

Cited By ~ 19

Author(s):

Ariela Hoxha ◽

Amelia Ruffatti ◽

Elena Mattia ◽

Lauro Meneghel ◽

Marta Tonello ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Primary Antiphospholipid Syndrome ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Coagulation Tests ◽

Healthy Control ◽

Independent Risk Factors ◽

Ig G

AbstractAntiphosphatidylserine/prothrombin complex (aPS/PT) antibodies are emerging as an important marker for antiphospholipid syndrome (APS). We aimed to compare their performance with that of conventional antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2GPI) in APS and to assess their frequency in APS-negative (APS-ne) patients.We considered 160 APS patients and 128 APS-ne patients with clinical criteria for APS but tested negative for conventional aPL. Immunoglobulin (Ig)G/IgM aPS/PT, IgG/IgM aCL, and IgG/IgM anti-β2GPI were detected using ELISA assay and LA with a series of coagulation tests.IgG aPS/PT were significantly associated with IgG aCL, IgG anti-β2GPI, and LA (p<0.0001 for all). IgM aPS/PT were significantly associated only with LA (p<0.0001) instead. There was a significant correlation between IgG aPS/PT and both IgG aCL and IgG anti-β2GPI levels (ρ=0.42 and ρ=0.40, respectively). Both IgG aPS/PT and IgM aPS/PT positivity significantly correlated with LA (ρ=0.44 and ρ=0.5, respectively). IgG and IgM aPS/PT were significantly more frequent in triple than in double and in single positivity (p<0.0001). According to multivariate analysis, IgG and/or IgM aPS/PT were independent risk factors for LA. APS/PT antibodies were found in 9.4% of the APS-ne patients vs. 2% of healthy control (p=0.043); those antibodies were significantly more frequent in the thrombosis with respect to the pregnancy morbidity subset (p=0.01).Our data attribute a clinical relevance to both IgG and IgM aPS/PT antibodies. In particular, the significant prevalence of aPS/PT in APS-ne patients suggests including them as additional laboratory criterion for APS.

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Recent advances in understanding antiphospholipid syndrome

F1000Research ◽

10.12688/f1000research.9717.1 ◽

2016 ◽

Vol 5 ◽

pp. 2908 ◽

Cited By ~ 12

Author(s):

Maria Laura Bertolaccini ◽

Giovanni Sanna

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Anticardiolipin Antibodies ◽

Coagulation Cascade ◽

Systemic Autoimmune Disease ◽

Vascular Thrombosis ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Hughes Syndrome

Antiphospholipid syndrome (APS), also known as Hughes Syndrome, is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. A patient with APS must meet at least one of two clinical criteria (vascular thrombosis or complications of pregnancy) and at least one of two laboratory criteria including the persistent presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and/or anti-b2 glycoprotein I (anti-b2GPI) antibodies of IgG or IgM isotype at medium to high titres in patient’s plasma. However, several other autoantibodies targeting other coagulation cascade proteins (i.e. prothrombin) or their complex with phospholipids (i.e. phosphatidylserine/prothrombin complex), or to some domains of β2GPI, have been proposed to be also relevant to APS. In fact, the value of testing for new aPL specificities in the identification of APS in thrombosis and/or pregnancy morbidity patients is currently being investigated.

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Current concepts on the pathogenesis of the antiphospholipid syndrome

Blood ◽

10.1182/blood-2006-04-001206 ◽

2006 ◽

Vol 109 (2) ◽

pp. 422-430 ◽

Cited By ~ 148

Author(s):

Bill Giannakopoulos ◽

Freda Passam ◽

Soheila Rahgozar ◽

Steven A. Krilis

Keyword(s):

Experimental Evidence ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Clinical Manifestations ◽

Fetal Loss ◽

Peripheral Tolerance ◽

The Core ◽

Glycoprotein I ◽

Antigenic Targets ◽

Acquired Thrombophilia

Abstract The antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia. It is characterized by the core clinical manifestations of thrombosis, either venous or arterial, and in women it can also be associated with recurrent fetal loss. The detection of persistently elevated levels of antiphospholipid antibodies (aPL Abs) is a requisite laboratory feature for the diagnosis to be made. The dominant antigenic targets in APS are beta 2-glycoprotein I (β2-GPI) and prothrombin. There is an accumulating body of experimental evidence that suggests that specific subgroups of aPL Abs may directly contribute to disease pathogenesis. This review critically examines the experimental evidence underlying the various propositions made to explain how these antibodies may predispose to disease in humans. Furthermore, it also examines the evidence relating to the immunologic mechanisms that may contribute to the breakage of peripheral tolerance in this disorder. Delineating the strengths and limitations of the experimental evidence accumulated thus far will hopefully stimulate further experimentation toward achieving the ultimate goal of precisely defining the dominant pathogenic mechanisms operational in APS. This may pave the way for the development of improved therapies.

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The spectrum of clinical manifestations of antiphospholipid syndrome

Romanian Medical Journal ◽

10.37897/rmj.2015.1.11 ◽

2015 ◽

Vol 62 (1) ◽

pp. 59-63

Author(s):

Camelia C. Diaconu ◽

◽

Giorgiana Dediu ◽

Bianca Paraschiv ◽

◽

...

Keyword(s):

Autoimmune Disease ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Clinical Manifestations ◽

Lung Damage ◽

Clinical Spectrum ◽

Gastrointestinal Complications ◽

Immune Mediated ◽

Organ Specific ◽

Systemic Symptoms

Antiphospholipid syndrome is an acquired autoimmune disease characterized by the appearance of thrombosis (venous, arterial and microvascular) and/or complications during pregnancy, in the presence of antiphospholipid antibodies. The clinical spectrum of the disease is now more complex and include organ-specific and systemic symptoms induced not only by thrombotic mechanisms, but also immune-mediated. Patients diagnosed with antiphospholipid syndrome should be evaluated clinically and laboratory periodically to detect lung damage, cardiac, neurological, skin, eye, hematological, gastrointestinal complications.

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