Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome

SummaryThe antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Increased complement activation has been implicated in the pathogenesis of APS in animal models. It was our objective to evaluate complement activation in patients with aPL or primary antiphospholipid syndrome (PAPS). We measured complement activation products, fragments Bb and C3a–desArg by ELISA in 186 aPL/PAPS patients and 30 healthy controls. All patients with aPL had significantly increased levels of complement activation products. Fragment Bb levels (mean, 95% CI); (thrombotic APS 0.54 units/ml, 0.31–0.83, obstetric APS 0.60 units/ml,0.39–1.02, isolated aPL 0.48 units/ml, 0.29–0.85, overall 0.39 units/ml, 0.33–0.47) and C3a–desArg levels (mean, 95% CI): (thrombotic APS 261 ng/ml, 219–311, obstetric APS 308 ng/ml, 243–391, isolated aPL 258 ng/ml, 193–337, overall 225 ng/ml, 202–251) were significantly higher compared to controls (fragment Bb 0.06 units/ml, 0.03–0.11, C3a–desArg 69 ng/ml, 50–92). There were correlations between Fragment Bb and C3a–desArg levels in all patients with aPL. Receiver operator characteristic (ROC) analysis showed increased fragment Bb and C3a–desArg levels had strong associations with the presence of persistent lupus anticoagulant (area under ROC: Bb 0.89, and C3a–desArg 0.90), dual and triple aPL positivity (Bb 0.71–0.82, C3a–desArg 0.71–0.80) but not with high titre anti-cardiolipin antibodies (Bb 0.62, C3a–desArg 0.65), or anti β2-glycoprotein 1 antibodies (Bb 0.66, C3a–desArg 0.67). Complement activation is present in all patient groups within this large cohort of patients aPL. This suggests it may have a major role in the pathogenesis of APS and merits further study.

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

Frontiers in Physiology ◽

10.3389/fphys.2021.764702 ◽

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.

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Complement Activation In Patients with Isolated Antiphospholipid Antibodies (aPL) or Primary Antiphospholipid Syndrome (PAPS)

Blood ◽

10.1182/blood.v116.21.4216.4216 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4216-4216

Author(s):

Karen A Breen ◽

Kiran Parmar ◽

Beverley J Hunt

Keyword(s):

Animal Models ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Complement Activation ◽

Alternative Pathway ◽

Oral Contraceptive Pill ◽

Control Group ◽

P Value ◽

Primary Antiphospholipid Syndrome ◽

Activation Products

Abstract Abstract 4216 Background: Increased complement activation has been implicated in the pathogenesis of APS. Most evidence to date comes from animal models of APS. Studies of murine APS models have demonstrated complement activation to be a mediator of thrombosis (Fischetti et al, 2005, Pierangeli 2007) and foetal loss (Girardi et al, 2003). Increased complement deposition was demonstrated in a study of placentae of APS pregnancies further supporting the findings in mice (Shamonki et al, 2007). Low levels of complement have been demonstrated in patients with APS which may be due to increased complement turnover (Oku et al, 2008). C3a-desArg is a stable product of C3a cleavage generated during complement activation; Bb is an activation fragment of Factor B, an alternative pathway component. Both have been evaluated as reliable markers of complement activation in patients. Objectives: To evaluate levels of complement activation products in patients with antiphospholipid syndrome by measuring the complement activation products Bb and C3a-desArg. Methods: Local ethics committee approval was obtained. Samples were obtained from patients attending clinics at our institution who had PAPS according to International Consensus statement criteria, or had persistent aPL without associated complications. Patients with systemic lupus erythematosus (SLE), intercurrent infection or malignancy were excluded. None of the patients were taking heparin. The control group were recruited from hospital staff who were not known to have aPL, were non smokers and not taking the oral contraceptive pill. Control samples were obtained from 18 healthy non-pregnant women (median age 37.5 (range 20–58) years). Patient blood samples were obtained from 39 women with apL and previous thrombosis, 5 of whom had previous pregnancy morbidity, 3 of whom were smokers and all of whom were on oral vitamin K antagonists (median 47 (23-61)), 15 women with obstetric APS and no history of thrombosis, 2 of whom were smokers (median 41 (32-54)), and 19 women with isolated aPL, 3 of whom were smokers (median 43.5 (19-73)). Blood was drawn by flawless venepuncture into tubes containing EDTA, immediately centrifuged at 3000 rpm for 15 min at 4°C and stored at -80°C until use. ELISA assays measuring complement fragments Bb and C3a-desArg levels were performed on plasma samples in one batch by one technician according to manufacturer's protocol (Quidel, Technoclone Dorking, UK). Intra-assay CV was 2.4% for Bb and 2.8% for C3a-desArg. Statistical analysis: The unpaired t-test was used to compare complement levels between groups. A p-value of <0.05 was considered to be statistically significant. Results: Results are shown below in table 1 and are described as means and standard deviations. Conclusions: Our results demonstrate evidence of increased complement activation in all patient groups with aPL. This supports recent findings in animal models and strongly suggests that all human individuals with aPL have complement activation. The role of complement activation in the pathogenesis of thrombotic and obstetric complications of APS is worthy of further study. Disclosures: Breen: NovoNordisk: Research Funding.

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A brief history of antiphospholipid antibodies and antiphospholipid syndrome

Scientia Medica ◽

10.15448/1980-6108.2018.3.31097 ◽

2018 ◽

Vol 28 (3) ◽

pp. 31097

Author(s):

Henrique Luiz Staub ◽

Lia Portella Staub

Keyword(s):

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Antiphospholipid Antibodies ◽

Anticardiolipin Antibody ◽

Early Years ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

History Of ◽

Obstetric Aps ◽

Definition Of

AIMS: To review the historical reports on antiphospholipid antibodies (aPL) from the early years of the 20th century; to outline the cardinal features of the antiphospholipid syndrome (APS) from 1983 on, including clinical criteria, etiopathogenesis and current therapy.METHODS: Literature review using PubMed. Articles on the history of aPL and APS were selected.RESULTS: The original aPL were described in patients with syphilis yet in 1906 by Wassermann. A first definition of lupus anticoagulant was proposed in 1963,while the anticardiolipin antibody (aCL) test was depicted twenty years later. The APS, initially reported by Hughes in 1985as the “aCL syndrome”, is one of the most prevalent acquired thrombophilia. Venous and arterial thrombosis, associated or not to pregnancy morbidity, comprise the main features. It is a novel disorder firstly associated to systemic lupus erythematosus. A primary form of APS was put forward in 1989, and many APS variants are currently known. Lifelong, full-dose anticoagulation is the mainstream for treatment of thrombotic APS. In obstetric APS, the combination of acetil-salicilic acid and enoxoparin has been a mostly effective therapy.CONCLUSIONS: The sequential characterization of aPL since Wassermann in 1906, and later of the APS in the 1980-thies, is a rather interesting example of how a new entity is sketched step by step. APS is an intriguing novel cause of autoimmune thrombophilia, with a complex pathogenesis and a plethora of clinical and laboratory abnormalities. Treatment is based on life-long anticoagulation.

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POS0712 “EXTRA”- CRITERIA ANTIPHOSPHOLIPID ANTIBODIES IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS (PRELIMINARY DATA)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.818 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 605.2-606

Author(s):

F. Cheldieva ◽

T. Reshetnyak ◽

M. Cherkasova ◽

N. Seredavkina ◽

A. Lila

Keyword(s):

Systemic Lupus Erythematosus ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Preliminary Data ◽

Antiphospholipid Antibodies ◽

Disease Duration ◽

Past History ◽

Igg Antibodies ◽

Systemic Lupus ◽

Pregnancy Morbidity

Background:The study of antiphospholipid antibodies (aPL), not included in the Sydney diagnostic criteria, in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) is poorly understood.Objectives:To determine the frequency of detection of IgA-aCL and IgA-aβ2GP1 and IgG antibodies to β2GP1 domain 1 (IgG-aβ2GP1-D1) in patients with APS with and without SLE.Methods:ELISA and chemiluminescence assays (CMA) were used to test 63 sera of patients: 22 (35%) with primary APS (pAPS) and 41 (65%) patients with APS and with SLE (secondary APS (sAPS)), with mean age 38,0 [33,0 – 43,0] years and disease duration 4,0 [0,1 – 9,9]. Both methods were used to test of IgG/IgM-aCL and IgG/IgM-aβ2GP1. CMA was used for research IgG/IgM/IgA-aCL, IgG/IgM/IgA-aβ2GPI and IgG-aβ2GP1-D1. Of them 49 (78%) (18 – with pAPS; 31 – with sAPS) displayed major thrombotic events and 18 of 22 pregnant women had pregnancy morbidity in past history. Lupus anticoagulant (LA) positivity was in 9 out of 12 patients who had it determined. LA was not investigated due to anticoagulant therapy in the remaining 52 patients.Results:IgG/IgM-aCL and IgG/IgM-aß2GP1 were recorded in 44/18 and 50/17 patients by ELISA and in 55/19 and 59/16 by CMA, respectively.IgA-aCL positivity was found in 35 (56%) of 63 patients. Thirty IgA-positive patients were positive for IgG-aCL by ELISA: 22 – IgG-aCL – highly positive, 6 – medium positive and 2 – low positive patients. IgM-aCL by ELISA was detected in 13 (37%) of 35 IgA-aCL positive patients: 11 – highly positive, 1 – medium positive and 1 – low positive. IgA-aCL was combined with IgG-aCL in 34 patients and with IgM-aCL in 16 patients in the CMA. IgG-aß2GP1 in ELISA was detected in 32 patients with IgA-aCL (24 –highly positive, 5 – medium positive and 3 – low positive) and in 34 – in CMA. IgM-aß2GP1 was combined with IgA-aß2GP1 with the same frequency in both methods (in 13 patients).IgA-aß2GP1 was detected in 30 (48%) of 63 patients. They were combined with both IgG-aCL and IgG-aß2GP1 in all cases in both methods. IgM-aCL and IgM-aß2GP1 were detected in 14 and 11 of 30 patients with IgA-aß2GP1, respectively. The combination of IgA-aß2GP1 with IgG-aCL by ELISA was in 27 (in most cases highly positive – 20) and with IgM-aCL – in 10 (highly positive - 8). IgG-aß2GP1 was detected in 28 patients with IgA-aß2GP1 (high positive – 21) and in 11 patients with IgM-aß2GP1 (high positive –7).IgG-aß2GP1-D1 was revealed in 48 (76%) patients. It was combined with IgG-aCL – in 38, with IgM-aCL – in 15 patients by the ELISA. The combination of IgG-aß2GP1-D1 by CMA was as follows: with IgG-aCL – in 46, with IgM-aCL – in 17, and with IgA-aCL – in 33 patients. In most cases, IgG-aß2gp1-D1 was combined with highly positive aCL levels. IgG-aß2GP1-D1 positivity was associated with IgG-aß2GP1 positivity in 42 – by ELISA and 47 – by CMA, IgМ-aβ2GP1 – in 13 and 14 patients by ELISA and CMA, respectively, and IgA-aß2GP1 – in 29. Isolated IgG-aß2GP1-D1 positivity was not observed.Conclusion:The frequency of IgA-aCL detection was 56% (35 patients out of 63), IgA-aβ2GP1 – 48% (30 patients out of 63), IgG-aβ2GP1-D1 – 76% (48 patients out of 63). There was not isolated positivity of this “extra” criterial antibodies. The presence of IgA-aCL, IgA-aβ2GP1, IgG-aβ2GP1-D1 was associated with highly positivity of IgG/IgM-aCL and IgG/IgM- aβ2GP1.Disclosure of Interests:None declared

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Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia in Association with Antiphospholipid Syndrome

Acta Haematologica ◽

10.1159/000516295 ◽

2021 ◽

pp. 1-4

Author(s):

Ram Gelman ◽

Fadi Kharouf ◽

Yuval Ishay ◽

Alexander Gural

Keyword(s):

Hemolytic Anemia ◽

Antiphospholipid Syndrome ◽

Complement Activation ◽

Autoimmune Hemolytic Anemia ◽

Cold Agglutinin ◽

Primary Antiphospholipid Syndrome ◽

Unique Case ◽

Hematologic Disorders ◽

Clear Association ◽

Immune Mediated

Antiphospholipid syndrome and cold agglutinin-mediated autoimmune hemolytic anemia are 2 distinct immune-mediated hematologic disorders. While no clear association exists between these 2 entities, complement activation is known to occur in both of them. Herein, we report a unique case of cold agglutinin hemolytic anemia in a patient with a known primary antiphospholipid syndrome.

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Central serous chorioretinopathy and antiphospholipid syndrome: Three cases report

Lupus ◽

10.1177/0961203320979736 ◽

2020 ◽

pp. 096120332097973

Author(s):

Paul Billoir ◽

Adrien Michon ◽

Luc Darnige

Keyword(s):

Autoimmune Disease ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Central Serous Chorioretinopathy ◽

Pregnancy Morbidity

Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by recurrent venous or arterial thrombotic events and pregnancy morbidity, with persistently presence of antiphospholipid antibodies (aPL). We report three cases of central serous chorioretinopathy (CSC) associated with APS.

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