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1.
Niger J Clin Pract ; 22(12): 1781-1784, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31793489

RESUMO

The involvement of multiple endocrine organs is rarely identified as initial manifestations of systemic lupus erythematosus (SLE) and autoimmune polyglandular syndrome (APS) in infancy. Childhood SLE tends to present with more severe clinical symptoms at an early age and with a set of unexpected findings. In the literature, the case reports of children presenting with SLE and APS components at the same time are extremely rare. Adrenal insufficiency may be overlooked due to mild clinical findings in later periods, except for neonates characterized by marked salt depletion and ambiguous genitalia signs. Moreover, adrenal insufficiency as an initial symptom in childhood is quite unusual as a component of SLE-associated APS. This report describes the overlap of unexpected, unusual, and severe clinical findings in an infant with APS with a comorbidity of SLE, where the involvement of multiple endocrine organs coexists with multiple serious clinical manifestations from the beginning.


Assuntos
Insuficiência Adrenal/etiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Insuficiência Adrenal/patologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/imunologia , Pré-Escolar , Humanos , Recém-Nascido , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Imagem por Ressonância Magnética , Masculino
2.
Biochemistry (Mosc) ; 84(9): 992-1007, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693459

RESUMO

The review discusses the mechanisms of participation of natural killer T cells (NKT cells) in the induction of antiphospholipid antibodies (APA) that play a major pathogenetic role in the formation of antiphospholipid syndrome (APS), summarizes the data on APS pathogenesis, and presents modern concepts on the antibody formation involving follicular helper type II NK cells.


Assuntos
Síndrome Antifosfolipídica/imunologia , Células T Matadoras Naturais/imunologia , Animais , Anticorpos Antifosfolipídeos/imunologia , Humanos
3.
Presse Med ; 48(11 Pt 2): 347-353, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31694791

RESUMO

Plasma exchange is a well-established therapeutic procedure commonly used in many autoimmune disorders. The beneficial effects of plasma exchange are thought to occur through the elimination of pathogenic mediators found in plasma, including autoantibodies, complement components, and cytokines. The catastrophic antiphsopholipid syndrome (CAPS) is a life-threatening variant of the antiphospholipid syndrome (APS) where several thrombosis take place in a short period of time in patients with circulating antiphospholipid antibodies. The triple therapy with anticoagulation, corticosteroids and plasma exchange or intravenous immunoglobulins has been proposed in CAPS. CAPS is a rare disease precluding the conduction of formal clinical trials. However, the observation of a better clinical course of patients who received this treatment supports their use. Plasma exchange has become an established therapeutic procedure in CAPS but there are no studies regarding the better approach and thus its use relies on the experience of the physicians in charge. The current article aims to review potential mechanisms of action of plasma exchange and the technical aspects of this procedure and will focus on its current role in CAPS, the experience published in treating this condition and the treatment protocol that we use in our institution.


Assuntos
Síndrome Antifosfolipídica/terapia , Troca Plasmática/métodos , Corticosteroides/uso terapêutico , Anticorpos Antifosfolipídeos/sangue , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Terapia Combinada/métodos , Hidratação/métodos , Humanos
4.
Zhonghua Nei Ke Za Zhi ; 58(12): 894-898, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775452

RESUMO

Objective: Portal vein thrombosis (PVT) is a rare and severe clinical manifestation of antiphospholipid syndrome (APS), as well as a predictor of poor prognosis. This study was conducted to explore the clinical features and risk factors of PVT in APS patients. Methods: A total of 123 APS patients diagnosed from 2012 to 2019 were retrospectively enrolled. The diagnosis of PVT was made according to the 2009 American College of Liver Diseases (AASLD) criteria. Clinical and laboratory data were collected. A multivariate (MV) logistic regression model was constructed using a stepwise forward selection procedure among those candidate univariables with P values<0.10. Results: A total of 28 cases with PVT, and 95 control cases without PVT were finally enrolled.The 28 APS-PVT patients included 5 males and 23 females with age range from 17 to 63 years. Clinical manifestations included acute thrombosis in 8 patients, chronic thrombosis in 16, and 4 with portal vein spongiform. As to the involved vessels, single portal vein thrombosis was seen in 20 patients, portal combined with superior mesenteric vein (SMV) and splenic vein in one patient, portal plus SMV in 4 and only SMV in 3 patients. Other manifestations were portal hypertension (16/28), esophageal varices (13/28), spleen infarction (7/28) and gastrointestinal bleeding (4/28). Two antiphospholipid antibodies were positive in 13 cases. Triple positive antibodies were seen in 7 cases. Multivariate logistic regression analysis showed that disease duration less than 0.5 years (OR=72.74, 95%CI 7.50-705.45, P<0.001), hypoalbuminemia (OR=356.45, 95%CI 19.19-6 620.14, P<0.001), and elevated erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) (OR=14.41, 95%CI 1.49-139.20, P<0.001) were independent risk factors for PVT in APS. Conclusion: PVT is usually misdiagnosed due to insidious onset. Short disease duration, hypoalbuminemia and elevated ESR/CRP are risk factors for PVT in APS. Better understanding, early diagnosis and treatment will improve the clinical outcome.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Cirrose Hepática/imunologia , Veia Porta/patologia , Trombose/imunologia , Trombose Venosa/fisiopatologia , Adolescente , Adulto , Síndrome Antifosfolipídica/complicações , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombose/complicações , Trombose Venosa/complicações , Adulto Jovem
5.
Autoimmun Rev ; 18(12): 102407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639518

RESUMO

Antiphospholipid Syndrome (APS) is the commonest treatable cause of recurrent miscarriage and pharmacological treatment of pregnant patients with antiphospholipid antibodies (aPL) should aim at preventing obstetric complications and maternal thrombotic events. Conventional treatment for patients with an established diagnosis of obstetric APS (OAPS), generally resulting in over 70-80% successful pregnancies. Since seropositive (SP)-APS and seronegative (SN)-APS patients had shown similar clinical profiles, patients with SN- OAPS, as well as SP-OAPS, should receive combined treatment in order to improve the pregnancy prognosis; indeed, current standard of care increased good pregnancy outcome in SN-APS, with similar effect to confirmed APS. The above data suggest that there are patients with the clinical manifestations of OAPS but persistently negative to conventional aPL that need to be identified to ensure adequate therapy and therefore a better prognosis. The clinical utility of non-criteria aPL in the diagnosis of SN-APS is still a matter of debate. In the last decade more and more studies have reported the presence of patients suffering from SN-APS in which non-conventional ("non-criteria") aPL might be present or antibodies may be detected using methodological approaches different from the traditional assays. To improve test standardization large prospective, multicenter, and multinational studies are needed. Therefore, when assessing a patient with clinical manifestations consistent with OAPS but aPL negative using the conventional available assays, the clinician should consider the possibility that the patient is affected with SN-APS.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Complicações na Gravidez/sangue , Complicações na Gravidez/diagnóstico , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/imunologia , Estudos Prospectivos
6.
Zhonghua Nei Ke Za Zhi ; 58(7): 496-500, 2019 Jul 01.
Artigo em Chinês | MEDLINE | ID: mdl-31269565

RESUMO

Antiphospholipid antibodies (aPLs) are a group of autoantibodies that target phospholipids and/or phospholipid-binding proteins. aPLs are important serum markers of anti phospholipid syndrome and are also risk factors for thrombosis and pathological pregnancy. Standardization of aPLs detection is critical to its clinical application.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/diagnóstico , Trombose/imunologia , Anticorpos Anticardiolipina/sangue , Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Biomarcadores/sangue , Consenso , Feminino , Humanos , Gravidez , Trombose/prevenção & controle , beta 2-Glicoproteína I
7.
PLoS One ; 14(7): e0220033, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339913

RESUMO

BACKGROUND: Persistent antiphospholipid antibodies (aPL) constitute the serological hallmark of the antiphospholipid syndrome (APS). Recently, various new assay technologies for the detection of aPL better suited to multiplex reaction environments than ELISAs emerged. We evaluated the diagnostic performance of such a novel line immunoassay (LIA) for the simultaneous detection of 10 different aPL. METHODS: Fifty-three APS patients and 34 healthy controls were investigated for criteria (antibodies against cardiolipin [aCL], ß2-glycoprotein I [aß2-GPI]) and non-criteria aPL (antibodies against phosphatidic acid [aPA], phosphatidyl-choline [aPC], -ethanolamine [aPE], -glycerol [aPG], -inositol [aPI], -serine [aPS], annexin V [aAnnV], prothrombin [aPT]) IgG and IgM by LIA. Criteria aPL were additionally determined with the established Alegria (ALE), AcuStar (ACU), UniCap (UNI), and AESKULISA (AES) systems and non-criteria aPL with the AES system. Diagnostic performance was evaluated with a gold standard for criteria aPL derived from the results of the four established assays via latent class analysis and with the clinical diagnosis as gold standard for non-criteria aPL. RESULTS: Assay performance of the LIA for criteria aPL was comparable to that of ALE, ACU, UNI, and AES. For non-criteria aPL, sensitivities of the LIA for aPA-, aPI-, aPS-IgG and aPA-IgM were significantly higher and for aPC-, aPE-, aAnnV-IgG and aPC- and aPE-IgM significantly lower than AES. Specificities did not differ significantly. CONCLUSIONS: The LIA constitutes a valuable diagnostic tool for aPL profiling. It offers increased sensitivity for the detection of aPL against anionic phospholipids. In contrast, ELISAs exhibit strengths for the sensitive detection of aPL against neutral phospholipids.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/diagnóstico , Testes Sorológicos/métodos , Adulto , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Imunoensaio/métodos , Imunoensaio/normas , Masculino , Pessoa de Meia-Idade , Fosfolipídeos/imunologia , Sensibilidade e Especificidade , Testes Sorológicos/normas
8.
Lupus ; 28(10): 1181-1188, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31345117

RESUMO

Antiphospholipid syndrome an autoimmune disease characterized by thrombosis and/or pregnancy morbidity alongside the presence of antiphospholipid antibodies (aPL). This review evaluates primary and secondary thromboprophylaxis in patients with aPL and thrombotic events. In primary thromboprophylaxis a risk-stratified approach is needed based on aPL, comorbidity with other autoimmune conditions and cardiovascular vascular risk factors. In primary thromboprophylaxis, the efficacy of low-dose aspirin is debatable and requires better-designed controlled studies. So far warfarin has not been shown to improve venous and/or arterial thrombosis incidence in aPL carriers and instead increased safety concerns. The benefit of hydroxychloroquine is inconclusive despite promising data, requiring large, controlled trials. For secondary thromboprophylaxis warfarin seems to be the best option with potential in renal transplant recipients and better efficacy at high intensity, although maintenance of target international normalized ratio needs careful monitoring. Aspirin has not shown to be beneficial, and data on rivaroxaban are limited and contradictory. Despite all data being informative, there are limitations that need to be addressed with robust clinical trials.


Assuntos
Anticoagulantes/administração & dosagem , Síndrome Antifosfolipídica/complicações , Trombose/prevenção & controle , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Doenças Autoimunes/complicações , Humanos , Coeficiente Internacional Normatizado , Fatores de Risco , Trombose/etiologia
9.
Autoimmun Rev ; 18(9): 102352, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31323355

RESUMO

Studies on last genetic and epigenetic predisposition to APS are summarized. It is well known that genetic predisposition is in HLA system (DR4 and DRw53) and that lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) are both associated with the same HLA antigens. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia - factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too. The most important discovery of last years is that altered microRNAs' expression is linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in APS.


Assuntos
Síndrome Antifosfolipídica/genética , Epigênese Genética/fisiologia , Antígenos HLA/genética , Resistência à Proteína C Ativada/sangue , Resistência à Proteína C Ativada/genética , Resistência à Proteína C Ativada/imunologia , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Predisposição Genética para Doença , Genótipo , Humanos , Inibidor de Coagulação do Lúpus/sangue , Polimorfismo Genético , Trombose/complicações , Trombose/genética , Trombose/imunologia , beta 2-Glicoproteína I/imunologia
10.
Semin Thromb Hemost ; 45(5): 458-467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31234212

RESUMO

Prothrombin fragment F1 + 2 (F1 + 2) and thrombin-antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case-control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-ß2-glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL -ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL -ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL -ve SLE patients and between aPL -ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS (p < 0.0001), inversely correlated with IgG aCL, IgM aPT, and LA (p = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted F1 + 2 (p = 0.01). IgG aCL inversely predicts F1 + 2. IgG aCL positivity introduces heterogeneity in the F1 + 2 ES, whereas the lack of heterogeneity in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements may be unfounded as already demonstrated for TAT in the 1990s.


Assuntos
Síndrome Antifosfolipídica/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Lupus ; 28(6): 783-785, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31042125

RESUMO

Neonatal thrombosis is considered a rare manifestation with unclear aetiology. We reported a neonatal lupus of a Sjogren's syndrome mother with recurrent miscarriage secondary to antiphospholipid syndrome; seronegative to anticardiolipin antibodies, lupus anticoagulant and B2GP1. She was serologically positive to antiphosphatidylethanolamine and antiprothrombin antibodies, anti-SSA/Ro and anti-SSB/La. The neonate developed neonatal lupus complicated with right ventricular thrombus assumed to be induced by maternal transmission of antiphosphatidylethanolamine and antiprothrombin antibodies, treated successfully with tissue plasminogen activator and warfarin.


Assuntos
Ventrículos do Coração/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/congênito , Complicações na Gravidez/imunologia , Trombose/diagnóstico por imagem , Adulto , Anticorpos Antinucleares/imunologia , Síndrome Antifosfolipídica/imunologia , Ecocardiografia , Feminino , Humanos , Recém-Nascido , Lúpus Eritematoso Sistêmico/complicações , Masculino , Gravidez , Complicações na Gravidez/diagnóstico , Síndrome de Sjogren , Trombose/etiologia
12.
Lupus ; 28(7): 893-897, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31126213

RESUMO

OBJECTIVES: This study aims to inhibit antiphospholipid syndrome (APS) serum derived IgA anti-beta-2-glycoprotein I (aß2GPI) binding using Domain I (DI). METHODS: Serum from 13 APS patients was tested for IgA aß2GPI and Anti-Domain I. Whole IgA was purified by peptide M affinity chromatography from positive serum samples. Serum was tested for IgA aß2GPI binding in the presence and absence of either DI or of two biochemically modified variants containing either 20 kDa of poly(ethylene glycol) (PEG) or 40 kDa of PEG. RESULTS: Significant inhibition with DI was possible with average inhibition of 23% (N = 13). Further inhibitions using 20 kDa PEG-DI and 40 kDa PEG-DI variants showed significant inhibition (p = 0.0001) with both the 40 kDa PEG-DI and 20 kDa PEG-DI variants showing increased inhibition compared with DI alone (p = 0.0001 and p = 0.001, n = 10). CONCLUSIONS: Inhibition of IgA aß2GPI by DI is possible and can be enhanced by biochemical modification in a subset of patients.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Imunoglobulina A/imunologia , Inibidor de Coagulação do Lúpus/imunologia , beta 2-Glicoproteína I/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Londres , Lúpus Eritematoso Sistêmico/complicações , Masculino , Oxirredução , Turquia
13.
Thromb Res ; 179: 15-19, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059997

RESUMO

INTRODUCTION: Annexin A2 (ANXA2), an endothelial cell receptor for plasminogen and tissue plasminogen activator, has been identified as a new autoantigen in antiphospholipid syndrome (APS). ANXA2 can exist as a monomer or a heterotetrameric complex with S100A10 protein. This S100A10 subunit also plays a pivotal role in the regulation of fibrinolysis. The aim of this study was to evaluate the prevalence of autoantibodies directed against S100A10 protein in patients with APS. METHODS: Patients with primary antiphospholipid syndrome (PAPS), patients with systemic lupus erythematosus (SLE) and patients with unexplained thrombosis were retrospectively included in this study. Patients were followed in the department of Internal Medicine of Amiens University Hospital, Amiens, France. IgG and IgM anti-S100A10 antibodies were detected in the serum of patients by enzyme-linked immunosorbent assay. The cut-off value for positivity was defined as 3 standard deviations above the mean optical density (OD) obtained in the sera of 116 healthy blood donors. RESULTS: The study group consisted of 116 healthy individuals and 106 patients: 42 APS patients (26 patients with PAPS and 16 patients with secondary SLE-related APS), 43 SLE patients without APS and 21 patients with unexplained thrombosis. The median age of APS patients, SLE patients without APS, patients with unexplained thrombosis and healthy individuals was 47, 38, 53 and 42 years, respectively. Anti-S100A10 antibodies were detected in 11.9% of APS patients and this prevalence was statistically higher than that observed in healthy individuals (1.7%) (p = 0.0148). Highest levels of anti-S100A10 were observed in the serum of one PAPS patient with venous thrombosis and one SLE patient with APS with a history of stroke and recurrent miscarriage. CONCLUSION: S100A10 protein, the binding partner of ANXA2, was identified as a target of autoantibodies in sera from patients with APS. Further studies involving a large cohort of APS patients are required to determine whether these antibodies could play a role in thrombogenic mechanisms of APS and to determine their diagnostic value in discriminating clinical subgroups of patients with APS, particularly those with seronegative APS.


Assuntos
Anexina A2/imunologia , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/imunologia , Proteínas S100/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
14.
Arthritis Rheumatol ; 71(9): 1545-1552, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30957430

RESUMO

OBJECTIVE: To estimate the annual incidence and prevalence of and frequency of mortality associated with antiphospholipid syndrome (APS). METHODS: An inception cohort of patients with incident APS in 2000-2015 from a geographically well-defined population was identified based on comprehensive individual medical records review. All cases met the 2006 Sydney criteria for APS (primary definition) or had a diagnosis of APS confirmed by physician consensus (secondary definition). Levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies, and anti-ß2-glycoprotein I antibodies were tested in a centralized laboratory. Incidence rates were age- and sex-adjusted to the 2010 US white population. Prevalence estimates were obtained from the incidence rates, assuming that there was no increased mortality associated with APS and that migration in or out of the area was independent of disease status. RESULTS: Among this cohort in 2000-2015, 33 cases of incident APS, as defined by the Sydney criteria, were identified (mean age of patients 54.2 years; 55% female, 97% white). The annual incidence of APS in adults ages ≥18 years was 2.1 (95% confidence interval [95% CI] 1.4-2.8) per 100,000 population. Incidence rates were similar in both sexes. The estimated prevalence of APS was 50 (95% CI 42-58) per 100,000 population, and was similar in both sexes. Six patients (18%) had a concurrent diagnosis of systemic lupus erythematosus. The most frequent clinical manifestation was deep vein thrombosis. The overall frequency of mortality among patients with APS was not significantly different from that in the general population (standardized mortality ratio 1.61, 95% CI 0.74-3.05). CONCLUSION: APS occurred in ~2 persons per 100,000 population per year. The estimated prevalence was 50 per 100,000 population. Overall mortality was not notably different from that observed in the general population.


Assuntos
Síndrome Antifosfolipídica/epidemiologia , Adulto , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Austrália/epidemiologia , Autoanticorpos/sangue , Feminino , Humanos , Imunoglobulina M/sangue , Incidência , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Prevalência , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Trombose Venosa/imunologia , Adulto Jovem , beta 2-Glicoproteína I/imunologia
15.
Nat Commun ; 10(1): 1916, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015489

RESUMO

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.


Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/análogos & derivados , Síndrome Antifosfolipídica/tratamento farmacológico , Armadilhas Extracelulares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Fenetilaminas/farmacologia , Trombose Venosa/tratamento farmacológico , Adenosina/imunologia , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Dipiridamol/farmacologia , Modelos Animais de Doenças , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Fibrinolíticos/farmacologia , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/imunologia , Transdução de Sinais , Veia Cava Inferior/efeitos dos fármacos , Veia Cava Inferior/imunologia , Veia Cava Inferior/metabolismo , Trombose Venosa/genética , Trombose Venosa/imunologia , Trombose Venosa/patologia
16.
Thromb Haemost ; 119(7): 1147-1153, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31018220

RESUMO

Antiphospholipid antibodies (aPL) have been reported to activate platelets. This is considered to be one of the pathogenic properties of aPL. Even though aPL heterogeneity is quite well established, little is known, if the ability to activate platelets is common to all aPL or depends on antigen specificity. To further study this issue, we analyzed the ability of three human monoclonal aPL with distinctly different antigenic specificities to activate platelets in vitro. The results obtained with human monoclonal aPL were validated with immunoglobulin G (IgG) fractions obtained from patients with antiphospholipid syndrome (APS). A co-factor-independent human monoclonal anticardiolipin aPL had no discernible effect on human platelets. Two monoclonal aPL reactive against ß2 glycoprotein I (ß2GPI) induced platelet aggregation, integrin αIIbß3 activation and P-selectin surface expression. These data could be confirmed with patient IgG fractions which could only induce aggregation, if they had anti-ß2GPI activity. Anti-ß2GPI aPL-induced platelet activation depended on interaction of aPL with the low affinity Fcγ-receptor IIa on the platelet surface. It was completely abolished by pretreatment of platelet-rich plasma with the mechanistic target of rapamycin (mTOR) inhibitors rapamycin or everolimus. This extends previous data showing that mTOR is involved in signaling of anti-ß2GPI in monocytes and endothelial cells. In conclusion, anti-ß2GPI aPL activate platelets while co-factor-independent anticardiolipin aPL have no effect. mTOR is involved in this signaling process which has implications beyond APS, because so far the role of mTOR signaling in platelets is incompletely explored and requires further study.


Assuntos
Síndrome Antifosfolipídica/imunologia , Plaquetas/fisiologia , Epitopos de Linfócito B/metabolismo , Epitopos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Anticorpos Antifosfolipídeos/metabolismo , Síndrome Antifosfolipídica/tratamento farmacológico , Autoanticorpos/metabolismo , Células Cultivadas , Everolimo/farmacologia , Everolimo/uso terapêutico , Humanos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , beta 2-Glicoproteína I/imunologia
17.
PLoS One ; 14(3): e0212614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870459

RESUMO

Antiphospholipid antibodies (aPL) promote endothelial dysfunction, inflammation and procoagulant state. We investigated the effect of hydroxychloroquine (HCQ) on prothrombotic state and endothelial function in mice and in human aortic endothelial cells (HAEC). Human aPL were injected to C57BL/6 mice treated or not with HCQ. Vascular endothelial function and eNOS were assessed in isolated mesenteric arteries. Thrombosis was assessed both in vitro by measuring thrombin generation time (TGT) and tissue factor (TF) expression and in vivo by the measurement of the time to occlusion in carotid and the total thrombosis area in mesenteric arteries. TGT, TF, and VCAM1 expression were evaluated in HAEC. aPL increased VCAM-1 expression and reduced endothelium dependent relaxation to acetylcholine. In parallel, aPL shortened the time to occlusion and extended thrombus area in mice. This was associated with an overexpression of TF and an increased TGT in mice and in HAEC. HCQ reduced clot formation as well as TGT, and improved endothelial-dependent relaxations. Finally, HCQ increased the p-eNOS/eNOS ratio. This study provides new evidence that HCQ improves procoagulant status and vascular function in APS by modulating eNOS, leading to an improvement in the production of NO.


Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Hidroxicloroquina/farmacologia , Trombose/prevenção & controle , Animais , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III/imunologia , Trombina/imunologia , Tromboplastina/imunologia , Trombose/imunologia , Trombose/patologia , Molécula 1 de Adesão de Célula Vascular/imunologia
18.
Rev Med Interne ; 40(6): 351-354, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-30905593

RESUMO

PURPOSE: Antiphospholipid syndrome (APS) is a clinico-biological syndrome, which associates vascular injury and persisting antiphospholipid antibodies (aPL). Patients with clinical symptoms of APS but without aPL are defined as "seronegative APS" (SNAPS). The aim of this study was to evaluate antiphosphatidylethanolamine antibody (aPE) investigation in patients with SNAPS suspicion. METHODS: This retrospective study was conducted in patients with SNAPS suspicion. A homemade enzyme-linked immunosorbent assay (ELISA) was used to search for aPE. The results of this homemade method were compared with those from a global screening ELISA. RESULTS: Two hundred twenty-eight patients with SNAPS suspicion were included. Among them, 58.3% had a thrombotic event. The homemade ELISA found positive persisting aPE in 23 patients (10%): 15 with a thrombotic event, 6 with obstetrical morbidity and 2 with a combined event. The global screening ELISA was positive in only 11 of these 23 patients (47.8%). CONCLUSION: These results suggest the implication of aPE in SNAPS.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Fosfatidiletanolaminas/imunologia , Adulto , Idoso , Síndrome Antifosfolipídica/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
Hum Antibodies ; 27(2): 135-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30856108

RESUMO

BACKGROUND: Extractable nuclear antigen (ENA) and anti-double stranded DNA (anti-dsDNA) positivity and related diseases like systemic lupus erythematosus, Sjögren syndrome, and other autoimmune diseases are known to be associated with obstetrical complications and poor perinatal outcomes. OBJECTIVE: To demonstrate the importance of ENA, anti-dsDNA, antiphospholipid (APL), and anticardiolipin (ACL) antibody positivity on pregnancy outcomes. METHODS: Ninety one pregnant women with known ENA, anti-dsDNA, APL IgG and IgM, and ACL IgG and IgM antibody positivity were retrospectively compared with 91 randomly selected pregnant woman in terms of obstetrical complications and pregnancy outcomes. Beksac Obstetrics Index-pregnancy (BOIp), calculated as (number of children + (π/10))/gravidity in the current pregnancy, was used to compare the risk level between groups. RESULTS: Significant differences were found in the median maternal age, gravidity, number of previous miscarriages, and BOIp between the groups (p= 0.04, p< 0.001, p< 0.001, and p< 0.001, respectively). Significant differences were also found between the study and control groups in the median gestational age at birth, birth weight, and APGAR1 score (p< 0.001 for all). Similarly, significant differences were found between groups in the rates of intra-uterine growth restriction, oligohydramnios, and gestational hypertension (p< 0.001, p= 0.05, and p= 0.05, respectively). There were 3 (3.3%) stillbirths in the study group and none in the control group (p= 0.123). CONCLUSION: We evaluated the impact of anti-dsDNA, ENA, APL, and ACL antibody positivity, which may cause immunologic inflammation at placenta and thereby affect pregnancy outcomes.


Assuntos
Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Antígenos Nucleares/imunologia , Complicações na Gravidez/imunologia , RNA de Cadeia Dupla/imunologia , Aborto Espontâneo/imunologia , Adulto , Síndrome Antifosfolipídica/imunologia , Doenças Autoimunes/imunologia , Feminino , Retardo do Crescimento Fetal/imunologia , Idade Gestacional , Humanos , Imunoglobulinas/imunologia , Inibidor de Coagulação do Lúpus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Placenta/imunologia , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Fatores de Risco , Natimorto , Adulto Jovem
20.
Autoimmun Rev ; 18(5): 519-525, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844560

RESUMO

BACKGROUND: Anticardiolipin antibodies of the immunoglobulin G isotype (IgG aCL) have been suggested as risk factor for arterial and venous thrombosis. No conclusive data in patients with coronary artery disease (CAD) do exist. We investigate the risk of recurrent CAD according to the presence of IgG aCL. METHODS: We performed a systematic review and meta-analysis to evaluate the risk of recurrent major adverse cardiac events (MACE) associated with the presence of IgG aCL in patients with CAD. MEDLINE and Cochrane databases were searched. We conducted a meta-analysis of the relative risk (RR) both at 12 and 24 months. RESULTS: We included 11 eligible studies with a total of 2425 patients, 283 IgG aCL+ and 2142 IgG aCL-. The prevalence of IgG aCL+ ranged from 6.1% to 43.3%. A total of 341 cardiac events were reported: 71 (25.1%) in IgG aCL+ and 270 (12.6%) in IgG aCL- patients. We found an increased risk of recurrent MACE in patients with high IgG aCL both at 12 (RR 2.17, 2.5-97.5%CI, 1.54-3.00) and 24 months (RR 2.11, 2.5-97.5%CI, 1.62-2.66). This association was even stronger in patients with juvenile CAD (i.e. <50 years) at both 12 (RR 3.21, 2.5-97.5%CI, 1.74-5.41) and 24 months (RR 3.24, 2.5-97.5%CI, 1.84-5.21). CONCLUSION: Patients with CAD and elevated IgG aCL have a doubled risk of recurrent MACE at 12 and 24 months. The presence of aCL should be suspected in patients with recurrent CAD events or in patients with juvenile CAD.


Assuntos
Anticorpos Anticardiolipina/efeitos adversos , Síndrome Antifosfolipídica/imunologia , Doenças Cardiovasculares/etiologia , Imunoglobulina G/efeitos adversos , Adolescente , Adulto , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/epidemiologia , Teorema de Bayes , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Recidiva , Análise de Regressão , Fatores de Risco , Adulto Jovem
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