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1.
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
2.
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
3.
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
5.
Autoimmun Rev ; 18(11): 102395, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520800

RESUMO

BACKGROUND: According to criteria for the classification of Systemic Lupus Erythematosus (SLE), thrombocytopenia is one of the disease-defining hematologic disorders. Since the recognition of Antiphospholipid Syndrome (APS), thrombocytopenia was frequently reported but several studies yielded contradictory results on the association between aPL-positivity and thrombocytopenia. METHODS: We evaluated the role of antiphospholipid antibodies (aPL) and different aPL profiles on the risk of thrombocytopenia in SLE patients by conducting a systematic review and meta-analysis of available literature from 1987 to 2018. MEDLINE, EMBASE, Cochrane Library, congress abstracts, and reference lists of eligible studies were searched. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcomes (thrombocytopenia). Two reviewers extracted study characteristics and outcome data from published reports. Estimates were pooled using random effects models and sensitivity analyses. We followed the PRISMA guidelines for all stages of the meta-analysis. PROSPERO registration number: CRD42015027378. RESULTS: From 3278 articles identified, 53 studies met inclusion criteria amounting to 9019 SLE patients. Twenty-nine percent of aPL-positive SLE patients had thrombocytopenia compared to 15.1% in aPL-negative SLE patients. The overall pooled Odds Ratio (OR) for thrombocytopenia in aPL positive patients was 2.48 (95% CI; 2.10-2.93). Among aPL subtypes, the risk of thrombocytopenia was highest for lupus anticoagulant (OR = 3.56 [95% CI, 2.57-5.25]), IgM anti-ß2-GP1(OR = 2.87 [95% CI; 2.57-5.25]), IgG and IgM anticardiolipin antibodies (OR = 1.87 [95% CI; 1.52-2.31] and OR = 1.73 [95% CI; 1.36-2.19] respectively). CONCLUSIONS: The occurrence of thrombocytopenia was strongly determined by various aPL profiles in SLE patients. While the association between IgM antibodies and other APS manifestations including thrombosis is debated, IgM isotypes are helpful in the risk stratification of thrombocytopenia in SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Lúpus Eritematoso Sistêmico/epidemiologia , Trombocitopenia/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fatores de Risco , Trombocitopenia/imunologia
6.
JNMA J Nepal Med Assoc ; 57(216): 133-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31477950

RESUMO

Anti-phospholipid Antibody Syndrome or Hugh's syndrome is a heterogeneous disorder, first fully described in 1980s. The syndrome is caused by the presence of specific antibodies against phospholipid binding plasma proteins in the serum of the patient, with or without underlying autoimmune diseases, that causes prolongation of tests of coagulation. High index of clinical suspicion is required for diagnosis of Anti-phospholipid Antibody Syndrome. Stroke or myocardial infarction in young, unprovoked recurrent deep vein thrombosis and recurrent pregnancy loss are typical scenarios where Anti-Phospholipid Antibody Syndrome should be suspected. Presence of non-criteria manifestations like livedo reticularis, skin ulcers, nephropathy, valvular heart disease and thrombocytopenia adds to diagnostic clue for presence of Anti-Phospholipid Antibody Syndrome. Treatment of Anti-Phospholipid Antibody Syndrome has preventive and therapeutic aspects that usually focus on thrombotic and obstetric manifestations of the disease. Therapeutic anti-coagulation with heparin followed by warfarin is required for patients presenting with acute thrombosis. Those with venous thrombosis are given moderate intensity warfarin International Normalized Ratio, 2-3), whereas those with arterial thrombosis or recurrent venous thrombosis even on warfarin are treated with high intensity warfarin (International Normalized Ratio, 3-4). Similarly, anticoagulation with heparin is advised in patients with obstetric Anti-Phospholipid Antibody Syndrome throughout pregnancy and up to six weeks postpartum. Treatment recommendations are still not clear for asymptomatic Anti-Phospholipid Antibody Syndrome positive patients and in those with non-criteria manifestations of the disease. Steroids, intravenous immunoglobulin and immunosuppressant are reported to be effective in severe cases of catastrophic antiphospholid syndrome characterized by rapid small vessel thrombotic involvement of multiple organ systems. Studies are evaluating the efficacy of direct thrombin inhibitors in the management of refractory cases. Keywords: anticoagulants; anti-phospholipid syndrome; obstetric APS; thrombotic APS.


Assuntos
Síndrome Antifosfolipídica/terapia , Trombose/etiologia , Anticorpos Antifosfolipídeos/imunologia , Anticoagulantes/administração & dosagem , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/fisiopatologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/terapia , Trombose/tratamento farmacológico
7.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Reumatologia/normas , Adulto , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Proteínas do Sistema Complemento/análise , Técnicas de Apoio para a Decisão , Técnica Delfos , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Sociedades Médicas , Estados Unidos
8.
Blood ; 134(14): 1119-1131, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31434703

RESUMO

Antiphospholipid antibodies (aPLs) with complex lipid and/or protein reactivities cause complement-dependent thrombosis and pregnancy complications. Although cross-reactivities with coagulation regulatory proteins contribute to the risk for developing thrombosis in patients with antiphospholipid syndrome, the majority of pathogenic aPLs retain reactivity with membrane lipid components and rapidly induce reactive oxygen species-dependent proinflammatory signaling and tissue factor (TF) procoagulant activation. Here, we show that lipid-reactive aPLs activate a common species-conserved TF signaling pathway. aPLs dissociate an inhibited TF coagulation initiation complex on the cell surface of monocytes, thereby liberating factor Xa for thrombin generation and protease activated receptor 1/2 heterodimer signaling. In addition to proteolytic signaling, aPLs promote complement- and protein disulfide isomerase-dependent TF-integrin ß1 trafficking that translocates aPLs and NADPH oxidase to the endosome. Cell surface TF pathway inhibitor (TFPI) synthesized by monocytes is required for TF inhibition, and disabling TFPI prevents aPL signaling, indicating a paradoxical prothrombotic role for TFPI. Myeloid cell-specific TFPI inactivation has no effect on models of arterial or venous thrombus development, but remarkably prevents experimental aPL-induced thrombosis in mice. Thus, the physiological control of TF primes monocytes for rapid aPL pathogenic signaling and thrombosis amplification in an unexpected crosstalk between complement activation and coagulation signaling.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Monócitos/imunologia , Tromboplastina/imunologia , Trombose/imunologia , Animais , Coagulação Sanguínea , Células Cultivadas , Feminino , Humanos , Lipoproteínas/imunologia , Masculino , Camundongos Endogâmicos C57BL , Monócitos/patologia , Transdução de Sinais , Trombose/sangue , Trombose/patologia
9.
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
10.
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
11.
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
12.
Thromb Res ; 181: 52-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351266

RESUMO

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) possessing anti-phospholipid antibodies (aPLs) are often complicated by thrombotic vascular events. aPLs commonly associated with the complications are anti-cardiolipin/ß2-glycoprotein I antibodies (aCL/ß2GPI) and anti-phosphatidylserine/prothrombin antibodies (aPS/PT). However, the pathological mechanisms leading to thrombosis remain unclear. We explored clinical features of SLE patients with aCL/ß2GPI and aPS/PT and investigated thrombogenic effects of their IgG fractions. MATERIALS AND METHODS: We enrolled 97 SLE patients and 38 healthy control volunteers and performed activated protein C (APC) resistance screening test using their plasma samples. To detect the direct effect of aPLs IgG on APC, we developed an APC sensitivity ratio assay. Effects of aPLs IgG on monocytes were studied by measuring the surface expression of tissue factor (TF) and excretion of TNF-α from peripheral blood mononuclear cell culture. RESULTS AND CONCLUSION: Thrombotic complications among SLE patients were closely associated with aCL/ß2GPI or aPS/PT, with higher prevalence in patients with both antibodies. Addition of aPLs(+)-IgG to the APC sensitivity ratio assay led to significant suppression of the anticoagulant activity of APC. The suppression was more pronounced in double-positive cases. TF expression on monocytes and concentration of TNF-α in culture medium were increased by aPLs, again more pronounced in double-positive cases. These results indicate that the effects of aCL/ß2GPI and aPS/PT are synergic both for APC anticoagulant activity and for production of TF and TNF-α from mononuclear cells. These modes of thrombogenic action of aPLs could be an important target for developing specific measures to prevent complications of SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Anticoagulantes/uso terapêutico , Genes APC/fisiologia , Leucócitos Mononucleares/metabolismo , Tromboplastina/metabolismo , Trombose/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Expert Opin Drug Saf ; 18(9): 841-852, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31238745

RESUMO

Introduction: Systemic Autoimmune Diseases (SADs) include systemic lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis, systemic sclerosis, Sjogren's syndrome, mixed connective tissue disease, idiopathic inflammatory myopathies and vasculitis. SADs often occur in women of childbearing age and can affect fertility. Both infertility treatments and fertility preservation techniques are thus often indicated. Areas covered: The literature regarding the safety of fertility-related drugs for both fertility preservation and infertility treatment in patients affected by SADs was reviewed. Based on current knowledge, all the options for fertility preservation should be contemplated in patients with SADs who are at risk for fertility loss, including GnRH analogue administration, oocyte/embryo vitrification and ovarian tissue cryopreservation. Similarly, if pregnancy is not contraindicated in a patient with a SAD, neither should be any fertility treatment. Expert opinion: Women with SADs should postpone conception until a stable disease has been achieved for at least 6 months. When infertility treatments are needed, women with antiphospholipid antibodies should receive concomitant anticoagulation. If in vitro fertilization/intra-cytoplasmic sperm injection and embryo transfer is required, ovarian hyperstimulation and the inherent risk of thrombosis should be eliminated by GnRH-agonist trigger and cycle segmentation. Counselling about adherence to anti-rheumatic therapy to prevent disease exacerbations is also critical.


Assuntos
Doenças Autoimunes/complicações , Preservação da Fertilidade/métodos , Infertilidade Feminina/terapia , Anticorpos Antifosfolipídeos/imunologia , Doenças Autoimunes/fisiopatologia , Criopreservação/métodos , Feminino , Fertilização In Vitro/métodos , Humanos , Infertilidade Feminina/etiologia , Gravidez , Técnicas de Reprodução Assistida
14.
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
15.
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
16.
Thromb Res ; 177: 157-160, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30903876

RESUMO

The clinical significance of IgG/IgM antiphosphatidylserine/prothrombin (aPS/PT) antibodies was prospectively evaluated in a cohort of 191 antiphospholipid antibody (aPL) carriers using commercial ELISA assays. IgG aPS/PT antibodies were detected in 40 (20.9%) and IgM aPS/PT in 102 (53.4%) of the carriers. Both IgG and IgM aPS/PT antibodies were significantly associated with triple aPL positivity (Lupus anticoagulants [LAC] plus anti-ß2Glycoprotein I plus anticardiolipin antibodies) (p = 0.0000 for both). There was a significant prevalence of IgM aPS/PT in the individuals with isolated LAC positivity (p = 0.005). Fourteen of the aPL carriers (7.3%) developed a first thrombotic event. There was a significant prevalence of IgG aPS/PT antibodies but not of IgM aPS/PT in the thrombotic patients (p = 0.015). The cumulative incidence rate of thrombotic events was significantly higher in the IgG aPS/PT positive (p = 0.035) but not in the IgM aPS/PT positive carriers. Logistic regression analysis assessing the independent effect of IgG /IgM aPS/PT antibodies, triple aPL positivity, genetic/acquired thrombosis risk factors and autoimmune disorders on thrombosis development uncovered a significant association only for the risk factors (Odds Ratio = OR: 12.451, 95% Confidence Interval = CI: 2.519-61.537, p = 0.002) and for triple aPL positivity (OR: 4.725, 95% CI: 1.135-19.674, p = 0.033). Logistic regression evaluating the independent effect of IgG and IgM aPS/PT on thrombosis development uncovered a significant association only for the former (OR: 3.962, 95% CI: 1.174-13.37, p = 0.026). The risk score for thrombosis in aPL carriers could be more effective if IgG aPS/PT antibodies are added to triple aPL positivity and thrombosis risk factors.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Imunoglobulina G/imunologia , Fosfatidilserinas/imunologia , Protrombina/imunologia , Trombose/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Trombose/etiologia
17.
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
18.
Autoimmun Rev ; 18(4): 406-414, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30772493

RESUMO

AIM: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). METHODS: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. RESULTS: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in IIa, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). CONCLUSION: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.


Assuntos
Síndrome Antifosfolipídica/epidemiologia , Complicações na Gravidez/epidemiologia , Aborto Habitual/tratamento farmacológico , Aborto Habitual/epidemiologia , Aborto Habitual/etiologia , Adulto , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Aspirina/uso terapêutico , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Resultado da Gravidez , Sistema de Registros , Estudos Retrospectivos , Adulto Jovem
19.
Int J Mol Sci ; 20(4)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791371

RESUMO

The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial. The aim of this study is to provide a comprehensive systematic review on the possible complications associated to autoantibodies (AA) impeding the chances of a successful IVF cycle. An Embase, PubMed/Medline and Cochrane Central Database search was performed on 1 December 2018, from 2006 until that date. From the 598 articles yielded in the search only 44 relevant articles ultimately fulfilled the inclusion criteria and were qualitatively analyzed. Five subsets of results were identified, namely, thyroid related AA, anti-phospholipid antibodies, anti-nuclear antibodies, AA affecting the reproductive system and AA related to celiac disease. It may be implied that the majority of auto-antibodies exert a statistically significant effect on miscarriage rates, whereas the effects on clinical pregnancy and live birth rates differ according to the type of auto-antibodies. While significant research is performed in the field, the quality of evidence provided is still low. The conduction of well-designed prospective cohort studies is an absolute necessity in order to define the impact of the different types of autoantibodies on IVF outcome.


Assuntos
Autoanticorpos/imunologia , Fertilização In Vitro , Infertilidade/terapia , Anticorpos Antinucleares/imunologia , Anticorpos Antifosfolipídeos/imunologia , Especificidade de Anticorpos/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Doença Celíaca/complicações , Doença Celíaca/imunologia , Feminino , Fertilização In Vitro/efeitos adversos , Fertilização In Vitro/métodos , Humanos , Infertilidade/etiologia , Gravidez , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Resultado do Tratamento
20.
Thromb Res ; 175: 32-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685523

RESUMO

BACKGROUND: The APS ACTION International Clinical Database and Repository includes a secure web-based data capture system storing patient information including demographics, antiphospholipid antibodies (aPL)-related medical history, and aPL tests. Despite efforts at harmonization, inter-assay variability remains a problem in aPL testing. As a clinical repository open to researchers, ensuring comparability between assays and consistency in results between APS ACTION laboratories is essential to the validity of studies emerging from this network. OBJECTIVE: To assess the level of agreement between an aPL-registry inclusion and core laboratory (core lab) anticardiolipin antibody (aCL) and anti-ß2-glycoprotein-I antibody (aß2GPI) ELISA testing results. METHODS: Patients are recruited from 25 international centers based on positive aPL tests at inclusion. All samples are retested at the corresponding national APS ACTION core lab to confirm aPL positivity based on standard validated protocols. We analysed the categorical agreement, degree of linear association, and correlation between inclusion (local laboratory) and core lab aPL tests. Samples were included in this study only if results of aPL testing with ELISA at baseline were available. RESULTS: 497 registry samples underwent confirmatory aPL tests. Categorical agreement between the inclusion and core lab values, as expressed by Cohen's kappa coefficients, ranged between 0.61 and 0.80 (as substantial agreement). The correlation between quantitative results in the aCL and aß2GPI was better for IgM and IgA compared to IgG (Spearman rho 0.789 and 0.666 vs. 0.600 for aCL and rho 0.892 and 0.744 vs. 0.432 for aß2GPI). CONCLUSIONS: The results of inclusion for aCL and aß2GPI tests used for recruitment into the registry were in agreement to the results obtained by the APS ACTION core laboratories; aCL and aß2GPI results showed very good categorical agreement. This agreement increased when considering high titer (>40 units) samples. APS ACTION is a reliable and useful research resource for APS.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Bases de Dados Factuais , Feminino , Humanos , Masculino
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