RESUMO
OBJECTIVE: The objective of this study was to clarify the efficacy and safety of factor Xa inhibitors for antiphospholipid syndrome patients in real world utilization. METHODS: This is a retrospective cohort study comprised of all consecutive patients with antiphospholipid syndrome in our department over a period of 28 years. Patients treated with factor Xa inhibitors were extracted from the cohort. As a control group, patients treated with warfarin were selected from the same cohort with matched age, gender, coexistence of systemic lupus erythematosus, and the presence of antiplatelet therapy, after which we used a propensity score for each of the risk factors as an additional covariate in multivariate Cox proportional hazard regression. The primary endpoint was set as thrombotic and hemorrhagic event-free survival for five years. RESULTS: Among 206 patients with antiphospholipid syndrome, 18 had a history of anti-Xa therapy (five rivaroxaban, 12 edoxaban, one apixaban). Fourteen out of 18 patients on anti-Xa therapy had switched to factor Xa inhibitors from warfarin. Event-free survival was significantly shorter during anti-Xa therapy than that during warfarin therapy (hazard ratio: 12.1, 95% confidence interval: 1.73-248, p = 0.01) ( Figure 1(a) ). Similarly, event-free survival in patients treated with factor Xa inhibitors was significantly shorter compared with controls (hazard ratio: 4.62, 95% confidence interval: 1.54-13.6, p = 0.0075). In the multivariate Cox proportional hazard model, event-free survival in patients with anti-Xa therapy remained significantly shorter (hazard ratio: 11.9, 95% confidence interval: 2.93-56.0, p = 0.0005). CONCLUSIONS: Factor Xa inhibitors may not be recommended for antiphospholipid syndrome.
Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Trombose/prevenção & controle , Adulto , Síndrome Antifosfolipídica/complicações , Estudos de Coortes , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombose/etiologiaRESUMO
The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lúpus Eritematoso Sistêmico/complicações , Trombose/tratamento farmacológico , Trombose/etiologia , Adulto , Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Japão/epidemiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombose/diagnóstico por imagem , Trombose/prevenção & controleRESUMO
Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p < 0.0001. Sensitivity, specificity, LR + and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Fosfatidilserinas/imunologia , Complicações na Gravidez/diagnóstico , Trombose/diagnóstico , Adolescente , Adulto , Idoso , Síndrome Antifosfolipídica/sangue , Estudos Transversais , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações na Gravidez/sangue , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: The objective of this paper is to elucidate the not yet known plasma molecule candidates involved in the induction of tissue factor (TF) expression mediated by ß2GPI-dependent anticardiolipin antibody (aCL/ß2GPI) on monocytes. METHODS: Human serum incubated with FLAG-ß2GPI was applied for affinity chromatography with anti- FLAG antibody. Immunopurified proteins were analyzed by a liquid chromatography coupled with mass spectrometry (LC-MS). TF mRNA induced by the identified molecules on monocytes was also analyzed. RESULTS: Apolipoprotein B100 (APOB) was the only identified serum molecule in the MS search. Oxidized LDL, containing APOB as well as ox-Lig1 (a known ligand of ß2GPI), was revealed as a ß2GPI-binding molecule in the immunoprecipitation assay. TF mRNA was markedly induced by oxidized LDL/ß2GPI complexes with either WBCAL-1 (monoclonal aCL/ß2GPI) or purified IgG from APS patients. The activities of lipoprotein-associated phospholipase A2, one of the component molecules of oxidized LDL, were significantly higher in serum from APS patients than in those from controls. CONCLUSION: APOB (or oxidized LDL) was detected as a major ß2GPI binding serum molecule by LC-MS search. Oxidized LDL/aCL/ß2GPI complexes significantly induced TF expressions on monocytes. These data suggest that complexes of oxidized LDL and aCL/ß2GPI may have a crucial role in the pathophysiology of APS.
Assuntos
Anticorpos Anticardiolipina/metabolismo , Síndrome Antifosfolipídica/sangue , Apolipoproteína B-100/sangue , Lipoproteínas LDL/sangue , Tromboplastina/biossíntese , beta 2-Glicoproteína I/imunologia , Animais , Células HEK293 , Humanos , Camundongos , Células RAW 264.7RESUMO
Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DM-associated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported.
Assuntos
Inibidores de Calcineurina/uso terapêutico , Dermatomiosite/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Tacrolimo/uso terapêutico , Corticosteroides/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Humanos , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/patologia , Prognóstico , Estudos RetrospectivosRESUMO
OBJECTIVE: Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. METHODS: Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3. RESULTS: Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. CONCLUSION: This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.
Assuntos
Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/fisiopatologia , Complicações na Gravidez/prevenção & controle , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Resultado da Gravidez , Prevenção Primária/métodosRESUMO
Recently our group introduced the "antiphospholipid score" (aPL-S), a quantitative marker that represents aPL profile. We have validated its efficacy for the diagnosis of antiphospholipid syndrome (APS) and predictive value for thrombosis. The study comprised two independent sets of patients with autoimmune diseases. In the first set of patients (n=233), the aPL-S was established by analyzing aPL profiles. In the second set of patients (n=411), the predictive value of the aPL-S for thrombosis was evaluated. To define aPL-S, we calculated the relative risks (approximated by odds ratios (ORs)) of having APS manifestations (thrombosis and/or pregnancy morbidity) for each of the aPL tests and devised an original formula in which aPL-S was determined by OR: aPL-S=5 × exp ([OR] -5)/4. The receiver operating characteristic (ROC) curve showed a hyperbolic pattern and the area under the ROC curve value was 0.752 (0.686 for revised Sapporo criteria), implying that aPL-S is a potential quantitative marker for APS diagnosis. The OR for thrombosis in patients with a high aPL-S (≥ 30) was 5.27 (95% confidence interval (95% CI) 2.32-11.95, p<0.0001). By multivariate analysis, an aPL-S of ≥ 30 appeared to be an independent risk factor for thrombosis (hazard ratio 3.144 (95% CI 1.383-7.150), p=0.006). The aPL-S is a useful quantitative index for diagnosing APS and may be a predictive marker for thrombosis in autoimmune diseases.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/complicações , Feminino , Humanos , Gravidez , Prognóstico , Modelos de Riscos Proporcionais , Trombose/etiologiaAssuntos
Anticorpos Antifosfolipídeos/imunologia , Apresentação de Antígeno , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Dobramento de Proteína , beta 2-Glicoproteína I/imunologiaRESUMO
BACKGROUND: CD36, known as a scavenger receptor, is a transmembrane glycoprotein expressed on monocytes, platelets and endothelial cells, recognizes multiple ligands, including phosphatidylserine, and regulates atherogenesis and thrombosis. The objective of this study is to investigate the possible involvement of CD36 in the pathophysiology of thrombosis in patients with antiphospholipid syndrome (APS). METHODS: First, rs3765187, a missense mutation linked to CD36 deficiency, was investigated by TaqMan polymerase chain reaction (PCR) genotyping method in 819 Japanese, including 132 patients with APS, 265 with systemic lupus erythematosus (SLE) in the absence of APS, and 422 healthy subjects. Then, the involvement of CD36 in antiphospholipid antibody (aPL)-induced tissue factor (TF) expression was examined using CD36-null mice or anti-CD36. Purified IgG from patients with APS and a monoclonal phosphatidylserine-dependent antiprothrombin antibody were used in these experiments. TF expression was tested by real-time PCR and flow cytometry. RESULTS: Minor allele carrier of rs3765187 was less frequent in patients with APS (3.8% p=0.032), but not in patients with SLE in the absence of APS (7.9% p=0.32), compared with healthy subjects (10.2%). The aPL-induced TF expression was significantly suppressed on peritoneal macrophages from CD36-null mice compared to wild type and significantly inhibited by anti-CD36 on human monocytes. CONCLUSIONS: The gene mutation linked to CD36 deficiency was less frequent in patients with APS. The deficient or suppressed CD36 function significantly reduced aPL-induced TF expression in vitro. Taken together, in a susceptible background CD36 scavenger receptor function may be involved in the thrombotic pathophysiology in patients with APS.
Assuntos
Anticorpos Antifosfolipídeos/metabolismo , Síndrome Antifosfolipídica/fisiopatologia , Antígenos CD36/genética , Trombose/fisiopatologia , Adolescente , Adulto , Idoso , Animais , Síndrome Antifosfolipídica/genética , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Genótipo , Humanos , Japão , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/metabolismo , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase em Tempo Real , Tromboplastina/genética , Adulto JovemRESUMO
OBJECTIVE: To study the clinical and immunological manifestations of antiphospholipid syndrome (APS) in the Japanese population by a single-centre registration. METHODS: In this retrospective cohort study, 141 consecutive patients with APS, fulfilling the Sydney revised Sapporo criteria for definite APS, who visited our autoimmune clinic from 1988 to 2010, were recruited and followed up. All the patients were interviewed and underwent a general physical examination by qualified rheumatologists on the day of blood sampling. RESULTS: The population comprised 119 woman and 22 men with a mean age at diagnosis of 44 years (range 9-79 years). Seventy patients (49.6%) had primary APS, and 71 (50.4%) had systemic lupus erythematosus. The prevalence of thrombosis was 85.8 per cent, arterial thrombosis was found in 93 patients (66.0%) and venous thrombosis was found in 46 patients (32.6%). The most common thrombosis was cerebral infarction [86/141 (61.0%)] followed by deep vein thrombosis [33/141 (23.4%)]. Among 70 pregnant women, 45 (64.3%) had obstetric complications. Lupus anticoagulant was detected in 116 patients (82.3%), anticardiolipin antibodies in 83 (58.9%), anti-ß2 glycoprotein I antibodies in 73 (51.8%) and phosphatidylserine-dependent antiprothrombin antibodies in 98 (69.5%). CONCLUSION: High prevalence of arterial thrombosis was noted in Japanese patients with APS. The profile of heterogeneous and complex clinical manifestations was substantiated in Japanese patients with APS.
Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Trombose/epidemiologia , Adolescente , Adulto , Idoso , Síndrome Antifosfolipídica/complicações , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Japão , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações na Gravidez/imunologia , Prevalência , Estudos Retrospectivos , Trombose/etiologia , Trombose/patologia , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Trombose Venosa/patologia , Adulto JovemRESUMO
Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to ß(2)glycoprotein I (anti-ß(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force.
Assuntos
Comitês Consultivos , Anticorpos Antifosfolipídeos/análise , Síndrome Antifosfolipídica/diagnóstico , Congressos como Assunto , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/normas , Feminino , Guias como Assunto , Humanos , Gravidez , Protrombina/imunologia , TexasRESUMO
OBJECTIVE: To investigate the significance of complement activation in patients with primary antiphospholipid syndrome (APS). METHODS: Thirty-six patients with primary APS, 42 control patients with non-systemic lupus erythematosus (SLE) connective tissue diseases, and 36 healthy volunteers were analysed retrospectively. Serum complement levels (C3, C4, CH(50)) and anaphylatoxins (C3a, C4a, C5a) were examined in all subjects, and serum complement regulatory factors (factor H and factor I) were measured in patients with primary APS. Plasma anticoagulant activity was determined in a mixing test using the activated partial thromboplastin time. RESULTS: Serum complement levels were significantly lower in patients with primary APS than in patients with non-SLE connective tissue diseases (mean (SD) C3: 81.07 (17.86) vs 109.80 (22.76) mg/dl, p<0.001; C4: 13.04 (8.49) vs 21.70 (6.96) mg/dl, p<0.001; CH(50): 31.32 (8.76) vs 41.40 (7.70) U/ml, p<0.001) or healthy volunteers. Only two healthy subjects with low serum C4 levels showed hypocomplementaemia, whereas most patients with primary APS showed raised serum C3a and C4a. No subjects showed raised C5a. Patients with primary APS with low serum C3 or C4 had significantly higher levels of C3a or C4a than healthy controls. No patients had low serum complement regulatory factors. Among patients with primary APS, hypocomplementaemia was significantly more common in those with high anticoagulant activity than in those with low or normal activity. CONCLUSION: Hypocomplementaemia is common in patients with primary APS, reflecting complement activation and consumption, and was correlated with anticoagulant activity, suggesting that antiphospholipid antibodies may activate monocytes and macrophages via anaphylatoxins produced in complement activation.
Assuntos
Síndrome Antifosfolipídica/imunologia , Ativação do Complemento/imunologia , Adolescente , Adulto , Idoso , Complexo Antígeno-Anticorpo/análise , Síndrome Antifosfolipídica/sangue , Coagulação Sanguínea , Estudos de Casos e Controles , Complemento C3/análise , Complemento C3a/análise , Complemento C4/análise , Complemento C4a/análise , Doenças do Tecido Conjuntivo/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular thrombosis. TMA has been reported in patients with antiphospholipid antibodies and/or antiphospholipid syndrome but its pathogenesis is not clarified. We present two patients with TMA associated with IgG phosphatidylserine dependent antiprothrombin antibodies (aPS/PT). CASE 1: A 44-year-old Japanese female with systemic lupus erythematosus (SLE) and positive lupus anticoagulant (LA) was started on ticlopidine after having stroke. Four weeks later she developed TMA. IgG/M/A anticardiolipin antibodies (aCL) were negative, but strong positive IgG aPS/PT were detected. CASE 2: A 32-year-old Russian female with SLE was admitted because of hypertension, renal insufficiency and proteinuria at 14 weeks of pregnancy. She developed TMA after surgical abortion. IgG aPS/PT and LA were strongly positive but IgG/M/A aCL were negative. Neither case had von Willebrand factor cleaving protease (ADAMTS-13), suggesting that TMA in those patients was associated with thrombophilia rather than insufficient ADAMTS-13. Both patients were successfully treated with a series of plasma exchange.
Assuntos
Síndrome Antifosfolipídica/complicações , Autoanticorpos/sangue , Fosfatidilserinas/fisiologia , Trombose/complicações , Doenças Vasculares/complicações , Adulto , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/terapia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Troca Plasmática , Gravidez , Complicações na Gravidez , Trombose/imunologia , Trombose/terapia , Doenças Vasculares/imunologia , Doenças Vasculares/terapiaRESUMO
Essentials Thrombotic risk stratification is an unmet need in antiphospholipid antibody carriers. Platelet count and antiphospholipid score (aPL-S) were combined to predict thrombotic events. Patients with high aPL-S are at high thrombotic risk regardless of platelet count. If platelet count is low, patients with low aPL-S are also on high thrombotic risk. SUMMARY: Background Thrombocytopenia is a non-criteria clinical manifestation of antiphospholipid syndrome. However, it remains to be elucidated whether thrombocytopenia increases thrombotic risk in antiphospholipid antibody (aPL) carriers. Objectives To investigate the impact of platelet count in terms of predicting thrombotic events in aPL carriers, and to stratify the thrombotic risk by combining platelet count and antiphospholipid score (aPL-S), which represents a quantification of aPL varieties and titers. Patients/methods A single-center, retrospective, longitudinal study comprising 953 consecutive patients who were suspected of having autoimmune disease between January 2002 and December 2006 was performed. Low platelet count was defined as a count of < 150 × 103 µL-1 at the time of aPL testing. Results A negative correlation was observed between aPL-S and platelet count (r = - 0.2477). Among aPL-positive patients, those with a low platelet count developed thrombosis more frequently than those without (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.11-7.88). Among aPL-negative patients, no difference was found in the predictive value of thrombosis regardless of platelet count. Patients with aPLs were further divided into two subgroups according to aPL-S. Among low-aPL-S patients, those with low platelet counts developed thrombosis more frequently than those without (HR 3.44, 95% CI 1.05-11.2). In contrast, high-aPL-S patients developed thrombosis frequently regardless of platelet count. Conclusions aPL carriers with low platelet counts are at high risk of developing thrombosis. In particular, 'low-aPL-S carriers' may be stratified by platelet count in terms of predicting future thrombotic events.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Plaquetas , Contagem de Plaquetas , Trombocitopenia/sangue , Trombose/epidemiologia , Adulto , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/epidemiologia , Biomarcadores/sangue , Técnicas de Apoio para a Decisão , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Trombose/sangue , Trombose/diagnósticoRESUMO
The antiphospholipid syndrome (APS) is characterised by both arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopaenia in association with antiphospholipid antibodies (aPL). To explore further the pathogenesis of thrombosis in APS, we evaluated the behaviour of tissue factor (TF) pathway in patients with APS. Plasma antigen levels of soluble TF and tissue factor pathway inhibitor (TFPI), a physiological regulator of TF dependent coagulation activation, were measured in 57 APS patients (36 primary and 21 secondary to systemic lupus erythematosus). Significantly elevated levels of both TF and TFPI were found in APS patients compared with 25 healthy controls (279 +/- 15 vs. 217 +/- 17 pg/ml, p = 0.01; 56.24 +/- 2.00 vs. 47.92 +/- 2.22 ng/ml, p = 0.01, respectively), suggesting in vivo upregulation of TF pathway in patients with APS. By flow-cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of APS plasmas than in control plasmas (24.23 +/- 3.11 vs. 12.78 +/- 1.57%, p = 0.002). Peripheral blood mononuclear cells (PBMC) also expressed more procoagulant activity (PCA) when incubated in the presence of APS plasmas than in control plasmas (1.80 +/- 0.12 vs. 1.35 +/- 0.054, p = 0.001) implying that TF up-regulation in APS was reproducible in vitro. Human monoclonal anticardiolipin antibodies induced PCA on PBMC and also TF mRNA on both PBMC and human umbilical vein endothelial cells shown by reverse-transcription polymerase chain reaction. These data strongly suggest that the TF pathway is implicated in the pathogenesis of aPL related thrombosis.
Assuntos
Síndrome Antifosfolipídica/sangue , Coagulação Sanguínea , Lipoproteínas/sangue , Tromboplastina/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Regulação para CimaRESUMO
A role for Fcgamma receptor in the pathophysiology of thrombosis in APS has been hypothesized. The polymorphism of this receptor, FcgammaRIIA H/R131, is associated with the binding affinity for human IgG2 (i.e. FcgammaRIIA-H131 isoform has a higher affinity than FcgammaRIIA-R131). Since anti-beta2 glycoprotein I antibodies (anti beta2GPI), which play a major pathogenic role in APS, show IgG2 dominant distribution, we investigated the prevalence of receptor isoforms in patients with antiphospholipid antibodies (aPL) by a PCR-RFLP method. We studied 100 Caucasian patients with aPL (57 primary APS, 32 secondary APS to SLE and 11 other diseases with aPL) and 41 healthy controls. H131/H131, H131/R131 and R131/R131 genotypes were found in 21 (21%), 50 (50%) and 29 (29%) in the patient group, and 9 (22%), 23 (56%) and 9 (22%) in control group, respectively. Thus there was no statistically significant difference in the prevalence of each genotype in these groups. None of the clinical manifestations of primary APS (arterial/venous thrombosis, recurrent pregnancy loss and thrombocytopenia) was significantly correlated with any FcgammaRIIA genotype. In conclusion, FcgammaRIIA polymorphism did not correlate with the manifestations of APS, and FcgammaRIIA genotype is not a genetic marker of APS.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/genética , Anticorpos Antifosfolipídeos/imunologia , Antígenos CD/genética , Polimorfismo Genético , Receptores de IgG/genética , Adolescente , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , GravidezRESUMO
OBJECTIVES: Previous studies showed that antiphospholipid antibodies (aPL) are frequent in the sera of leprosy patients and are most probably directed against body tissue cardiolipins. Some groups have demonstrated differences between the binding specificity of "autoimmune-aPL" and "non-autoimmune-aPL". It is widely accepted that a plasma protein, beta 2-Glycoprotein I (beta 2-GPI), is required for the binding of autoimmune anticardiolipin antibodies (aCL) to cardiolipin. However, some reports suggested heterogeneity of leprosy aCL with respect to their beta 2-Glycoprotein I (beta 2GPI) dependency, although no thromboembolic complications have been reported. This study was designed to assess the specificity of aPL by investigating the prevalence of aCL, anti-phosphatidylserine (aPS), anti-phosphatidylinositol (aPI), anti-beta 2GPI and antiprothrombin (aPT) antibodies, and evaluate their clinical significance in a group of patients with lepromatous leprosy. PATIENTS AND METHODS: 35 lepromatous leprosy patients were selected randomly from an Egyptian leprosarium as a study group. 35 normal household contact controls were selected matching the study group for both sex and age. aCL, aPS, aPI, aPT, anti-beta 2GPI and beta 2-dependent aCL antibodies were investigated by ELISA in all patients and controls. RESULTS: aCL antibodies were more frequent in leprosy patients than in controls [13/35 (37%) vs. 3/35 (9%), respectively, p = 0.02] and significantly correlated with Raynaud's phenomenon, skin nodules, chronic skin ulcers and urticarial skin rash. No association was found with hypopigmentation, hyperpigmentation and saddle nose. None of the patients presented aPS nor aPI. Only 1 subject from the control group presented aPI along with aCL. aPT were present in 2/35 (5.7%) and anti-beta 2GPI in 1/35 (2.9%) leprotic patients. None of the individuals from the control group presented aPT nor anti-beta 2GPI. CONCLUSIONS: An association was found between the presence of aCL and certain dermatological manifestations of leprosy, such as Raynaud's phenomenon, skin nodules, chronic skin ulcers and urticarial skin rash. As in other infectious diseases, there was a lack of beta 2GPI-dependency and an absence of thrombotic complications.