Preconception antiphospholipid antibodies and risk of subsequent early pregnancy loss.

Objectives To prospectively estimate the association of preconception antiphospholipid antibodies (aPL) with subsequent pregnancy loss using a cohort design. aPL have been associated with recurrent early pregnancy loss (EPL) prior to 10 weeks in previous case-control studies. Prospective ascertainment of pregnancy loss is challenging, as most women do not seek care prior to EPL. Methods Secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial of preconception low-dose aspirin. Preconception anticardiolipin (aCL) and anti-ß2-glycoprotein-I (a-ß2-I) were assessed in 1208 women with one or two prior pregnancy losses and no more than two prior live births. Comparison cohorts were defined by positive aPL (+aPL) or negative aPL (-aPL) status. All women were followed for six menstrual cycles while trying to conceive; if successful, they underwent an ultrasound at 6-7 weeks' gestation. EPL was defined as loss prior to 10 weeks' gestation; embryonic loss was loss after visualization of an embryo but prior to 10 weeks; clinical loss was any loss after visualization of an embryo (with or without fetal cardiac activity detected). Results In total, 14/1208 (1%) tested positive for +aPL. 786/1208 (65%) women had positive human chorionic gonadotropin during the study period, of which 9/786 (1%) had +aPL. Of the 786 pregnant women, 589 (75%) had live births and 24% had pregnancy losses. Women with +aPL experienced EPL at similar rates as women with -aPL, 44% vs 21% (aRR 2.4, 95% confidence interval (CI) 0.5-10.9). Embryonic loss was more common in women with +aCL IgM (aRR 4.8, 95% CI 1.0-23.0) and in women with two positive aPL. Clinical pregnancy loss was more common in women with positive a-ß2-I IgM (50% vs 16.5%, aRR 3.7, 95% CI 1.3-10.8). Conclusion Positive levels of aPL are rare in women with one or two prior pregnancy losses and are not clearly associated with an increased rate of subsequent loss. Clinical trial registration The original source study was registered at ClinicalTrials.gov (#NCT00467363).

Presencia de anticuerpos antifosfolípidos en niños con fiebre y petequias / Presence of antiphospholipid antibodies in children with fever and petechiae

Introducción: La presencia de un tiempo de cefalina (APTT) alargado en niños con fiebre y petequias es un hallazgo descrito en la bibliografía. La causa de esta alteración se desconoce, pero se postula que puede deberse a la formación de anticuerpos antifosfolípidos (Ac AFL). El objetivo de este estudio es determinar si el alargamiento del APTT se asocia con la formación Ac AFL. Pacientes y métodos: Estudio observacional, prospectivo, de casos y controles, realizado en niños que consultaron por fiebre y petequias en el servicio de urgencias de un hospital de tercer nivel durante un periodo de 13 meses. Se recogieron variables epidemiológicas, clínicas y analíticas. Se describieron las características de los grupos con APTT alargado y normal, y se comparó la asociación entre las concentraciones de los diferentes anticuerpos y el APTT. Resultados: Se incluyeron 36 pacientes, 12 casos y 24 controles. No se encontraron diferencias significativas respecto a la positividad de Ac AFL entre los casos y los controles (odds ratio [OR]= 1,67; intervalo de confianza [IC] del 95%: 0,31-9,04). No se observó ninguna asociación entre los diferentes tipos de anticuerpos y el APTT, cuyos coeficientes de regresión fueron de 0,04 seg (IC del 95%: -0,31 a 0,40) para anticardiolipina IgG, de 1,11 seg (IC del 95%: -1,24 a 3,46) para la IgM, y de -0,02 seg (IC del 95%: -0,35 a 0,31) y 0,64 seg (IC del 95%: -1,40 a 2,68) para antibeta 2 GPI, IgG e IgM, respectivamente. Conclusión: Ante los resultados de nuestro estudio, no podemos concluir que el alargamiento de APTT se relacione con la presencia de Ac AFL (AU)

Introduction: The presence of a longer time of cephalin (APTT) extended in children who come to emergency department with fever and petechiae is a result previously described in the literature. The cause of this alteration in coagulation is unknown, it is presumed that may be due to the formation of antiphospholipids antibodies. The aim of this study is to determine if the length of APTT is associated to the formation of antiphospholipids antibodies. Patients and methods: Observational, prospective case-control study in children who consulted for fever and petechiae in the emergency department of a tertiary hospital over a 13-month period epidemiological; clinical and laboratory variables were collected. The characteristics of groups with elongated and normal APTT were described and the association between concentrations of different antibodies and APTT were compared. Results: 36 patients, 12 cases and 24 controls, were included. No significant differences were found regarding the positivity of antiphospholipid antibodies between cases and controls (OR= 1.67; 95%CI: 0.31 to 9.04). No association was observed between the different types of antibodies and APTT, resulting regression coefficients in 0.04 s (95%CI: -0.31 to 0.40) for cardiolipin IgG, 1.11 s (95%CI: -1.24 to 3.46) for IgM and -0.02 s (95%CI: -0.35 to 0.31) and 0,64 s (95%CI: -1.40 to 2.68) for antibeta 2 GPI, IgG and IgM, respectively. Conclusion: Given the results of our study we can not conclude that the elongation of APTT is related with the presence of antiphospholipids antibodies (AU)

Trombocitopenia como factor de riesgo trombótico en pacientes con anticuerpos antifosfolipídicos sin criterios de enfermedad / Thrombocytopenia as a thrombotic risk factor in patients with antiphospholipid antibodies without disease criteria

Introducción: El síndrome antifosfolípido (SAF) es un trastorno inmunitario adquirido, definido por la presencia de trombosis (arterial y/o venosa) y/o morbilidad del embarazo junto con la presencia de anticuerpos antifosfolipídicos (aFL) positivos. Existe una relación clara entre los aFL y algunas manifestaciones no incluidas en los criterios clínicos, entre ellas, las hematológicas. Objetivos: a) estudiar la probabilidad de desarrollar SAF clínico en pacientes con aFL positivos y trombocitopenia; b) identificar posibles factores de riesgo para trombosis, y c) estudiar la asociación entre trombocitopenia y aFL. Métodos: Estudio retrospectivo de 138 pacientes con aFL positivos sin cumplir criterios clínicos de SAF. Se definió trombocitopenia como una cifra de plaquetas≤100.000/μl. Se excluyeron los pacientes con otras causas de trombocitopenia. Resultados: Diecisiete de los 138 (12%) pacientes incluidos en el estudio presentaban trombocitopenia. La cifra media de plaquetas fue de 60.000/μl. El riesgo para desarrollar trombocitopenia fue mayor en los pacientes fumadores (OR 2,8; p=0,044), en aquellos con anticoagulante lúpico (OR 13,5; p<0,001) y en los que tenían una mayor carga de aFL (OR 50,8; p<0,001). Tras un seguimiento medio de 146±60,3 meses, 5 pacientes con trombocitopenia (29,4%) desarrollaron trombosis. Conclusiones: En nuestra serie, la incidencia de trombocitopenia es del 12%. Los pacientes con aFL positivos que desarrollan trombocitopenia tienen un riesgo potencial de desarrollar trombosis. El tabaco podría ser un factor de riesgo para trombocitopenia. La carga de autoanticuerpos es un factor de riesgo para el desarrollo de trombocitopenia (AU)

Introduction: The antiphospholipid syndrome (APS) is an acquired immune disorder defined by the presence of thrombosis (arterial and/or venous) and/or pregnancy morbidity along with the presence of positive antiphospholipid antibodies (aPL). There is a clear relationship between aPL and some events not included in the clinical criteria, including haematologic. Objectives: a) to study the probability of developing clinical APS in patients with positive aPL and thrombopenia; b) to identify potential risk factors for thrombosis, and c) to study the association between thrombocytopenia and aPL. Methods: A retrospective study of 138 patients with positive aPL without fulfilling clinical criteria for APS. Thrombocytopenia was defined as a platelet count≤100,000/μl. Patients with other causes of thrombocytopenia were excluded. Results: Seventeen of the 138 (12%) patients in the study had thrombocytopenia. The mean platelet count was 60,000/μl. The risk of developing thrombocytopenia was higher in smokers (OR 2.8; P=.044), in those with lupus anticoagulant (OR 13.5; P<.001) and those with higher burden of aPL (OR 50.8; P<.001). After a mean follow-up of 146±60.3 months, 5 patients with thrombocytopenia (29.4%) developed thrombosis. Conclusions: In our series, the incidence of thrombocytopenia is 12%. aPL-positive patients who develop thrombocytopenia have a potential risk of developing thrombosis. Tobacco could be a risk factor for thrombocytopenia. Autoantibodies load is a risk factor for the development of thrombocytopenia (AU)

Measuring IgA Anti-ß2-Glycoprotein I and IgG/IgA Anti-Domain I Antibodies Adds Value to Current Serological Assays for the Antiphospholipid Syndrome.

INTRODUCTION: Currently available clinical assays to detect antiphospholipid antibodies (aPL) test for IgG and IgM antibodies to cardiolipin (aCL) and ß2-glycoprotein I (aß2GPI). It has been suggested that testing for IgA aPL and for antibodies to Domain I (DI), which carries the key antigenic epitopes of ß2GPI, could add value to these current tests. We performed an observational, multicenter cohort study to evaluate the utility of IgG, IgM and IgA assays to each of CL, ß2GPI and DI in APS. METHODS: Serum from 230 patients with APS (n = 111), SLE but not APS (n = 119), and 200 healthy controls were tested for IgG, IgM and IgA aCL, aß2GPI and aDI activity. Patients with APS were further classified into thrombotic or obstetric APS. Logistic regression and receiver operator characteristic analyses were employed to compare results from the nine different assays. RESULTS: All assays displayed good specificity for APS; IgG aCL and IgG aß2GPI assays however, had the highest sensitivity. Testing positive for IgA aß2GPI resulted in a higher hazard ratio for APS compared to IgM aß2GPI. Positive IgG, IgM or IgA aDI were all associated with APS, and in subjects positive for aCL and/or aß2GPI, the presence of aDI raised the hazard ratio for APS by 3-5 fold. IgG aCL, aß2GPI, aDI and IgA aDI were associated with thrombotic but not obstetric complications in patients with APS. CONCLUSION: Measuring IgG aDI and IgA aß2GPI and aDI may be useful in the management of patients with APS, particularly thrombotic APS.

Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion.

PROBLEM: Some patients with antiphospholipid syndrome (APS) suffer pregnancy morbidity (PM) but not vascular thrombosis (VT), whilst others suffer VT only. Therefore, we compared the effects of IgG from VT+/PM- and VT-/PM+ subjects on human first-trimester trophoblast (HTR8) cells. METHOD OF STUDY: HTR-8 cells were incubated with APS VT+/PM-, APS VT-/PM+ or healthy control (HC) IgG. We measured trophoblast invasion by cell invasion assay; mRNA expression of TLR4 and adaptor proteins; phosphorylation of p38 MAPK, NFκB and ERK; and expression of interleukin (IL)-8 and IL-6. RESULTS: VT-/PM+ IgG, but not VT+/PM- IgG significantly reduced HTR-8 invasion. The effects on invasion were blocked by TLR-4 inhibition. Neither VT+/PM- nor VT-/PM+ IgG altered MyD88 mRNA expression, phosphorylation of signalling molecules or cytokine expression. CONCLUSIONS: VT-/PM+ IgG exert functionally relevant effects on human trophoblast cells but VT+/PM- IgG do not.

Evolución del título de anticuerpos contra el receptor tipo M de la fosfolipasa A2 y respuesta clínica en pacientes con nefropatía membranosa idiopática tratados con tacrolimus / Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus

Introducción y objetivos: Se ha descrito que el nivel de anticuerpos circulantes contra el receptor tipo M de la fosfolipasa A2 tiene correlación significativa con la actividad clínica de la enfermedad en la nefropatía membranosa idiopática (NMI). Sin embargo, la utilidad de la monitorización del título de anticuerpos como predictor de respuesta clínica tras el inicio del tratamiento no ha sido formalmente analizada. En el siguiente estudio se analiza el valor predictivo de la evolución del título de anticuerpos anti-PLA2R sobre la respuesta clínica en enfermos con NMI tratados con tacrolimus. Pacientes y métodos: 36 enfermos con síndrome nefrótico secundario a NMI, con criterios de indicación de tratamiento inmunosupresor, fueron tratados con tacrolimus en monoterapia. Se determinó el nivel de anticuerpos anti-PLA2R antes del tratamiento y a los 3, 6, 9 y 12 meses tras su inicio. Se analizó el valor predictivo de la pendiente de reducción en el título de anticuerpos y de la reducción absoluta y relativa en el título de anticuerpos a los 3 y 6 meses sobre el tiempo hasta la remisión y sobre la probabilidad de remisión a los 6, 9 y 12 meses. Resultados: La reducción relativa en el título de anticuerpos anti-PLA2R fue significativamente mayor en los enfermos que presentaron remisión y precedió a la respuesta clínica. No se apreció asociación entre el título de anticuerpos previo al tratamiento con el tiempo medio de respuesta o la respuesta a los 12 meses. La pendiente de reducción en el título de anticuerpos se asoció significativamente con el tiempo hasta la evidencia de remisión. La reducción relativa en el título de anticuerpos anti-PLA2R a los 3 meses tuvo una elevada sensibilidad y especificidad para predecir la respuesta a los 6 y 9 meses, pero no a los 12 meses, mientras que la reducción relativa en el título de anticuerpos a los 6 meses tuvo una elevada sensibilidad y especificidad para predecir la respuesta a los 12 meses. Conclusión: En enfermos con NMI asociada a anticuerpos anti-PLA2R, la monitorización del título de anticuerpos tras el inicio del tratamiento es útil para estimar el período de tiempo hasta la remisión y para predecir la probabilidad de remisión a los 12 meses (AU)

Introduction and objectives: The level of circulating antibodies against M-type phospolipase A2 receptor has been reported as having a significant correlation with clinical activity in idiopathic membranous nephropathy. However, the usefulness of monitoring antibody titre as a predictor of clinical response following the onset of treatment has not been formally analysed. The predictive value of the evolution of anti-PLA2R antibody titre on the clinical response of idiopathic membranous nephropathy patients treated with tacrolimus is analysed in the following study. Patients and method: 36 patients with nephrotic syndrome secondary to idiopathic membranous nephropathy with immunosuppressive treatment indication criteria were treated with tacrolimus in monotherapy. The level of anti-PLA2R antibodies was determined before treatment and at 3, 6, 9 and 12 months after the onset of treatment. The study analysed the predictive value of the reduction in antibody titre and the relative and absolute reduction in antibody titre at 3 and 6 months over the period until remission and on the probability of remission at 6, 9 and 12 months. Results: The relative reduction in the anti-PLA2R antibody titre was significantly greater in those patients with remission and it preceded the clinical response. No association was observed between the antibody titre prior to treatment and the mean response time or the response at 12 months. Reduction in antibody titre is significantly associated with the time until signs of remission. Relative reduction in anti-PLA2R antibody titre at 3 months had a high sensitivity and specificity to predict the response at 6 and 9 months, but not at 12 months; however the relative reduction in the antibody titre at 6 months had a high sensitivity and specificity for predicting the response at 12 months. Conclusion: In patients with IMN associated with anti-PLA2R antibodies, the monitoring of antibody titre following the onset of treatment is useful for estimating the time period until remission and predicting the probability of remission at 12 months (AU)

Una causa inusual de hematomas / An unusual cause of bruising

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Respuesta a: «Comprender el concepto de inmunogenicidad» / Reply to: «Understanding the immunogenicity concept»

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Antiphospholipid antibodies in Mexican HIV-positive patients

Several studies have shown that HIV patients tend to develop autoimmune diseases, and have numerous antibodies, such as antiphospholipid antibodies. Antiphospholipid antibodies are the serological markers used in the diagnosis of the antiphospholipid syndrome. However, antiphospholipid antibodies also appear to exist in infectious diseases. Objective: TomeasurethetitersofantiphospholipidantibodiesinhealthyandinHIVpositiveMexican mestizo patients, and correlate them with the patient clinical manifestations to identify possible findings compatible with an autoimmune disease. Material and methods: A case control study was conducted on 50 healthy mixed race Mexican subjects andin50 randomly selectedHIV-positive patients from the (..) (AU)

Varios estudios han demostrado que los pacientes con VIH tienden a desarrollar enfermedades autoinmunes, presentando diversos anticuerpos como los anticuerpos antifosfolípidos. Los anticuerpos antifosfolípido son los marcadores serológicos que se emplean en el diagnóstico del síndrome antifosfolípido. Sin embargo los anticuerpos antifosfolípido también suelen existir en enfermedades infecciosas específicas. Objetivo: Medir los títulos de anticuerpos antifosfolípido en pacientes mexicanos mestizos sanos y VIH positivos y correlacionarlos con las manifestaciones clínicas de los pacientes para identificar posibles hallazgos compatibles con alguna enfermedad autoinmune. Material y métodos: Se trata de un estudio de casos y controles en el que se evaluaron (..) (AU)

Anticoagulante lúpico en Pediatría. Experiencia en nuestro centro / Lupus anticoagulant in Pediatrics. Experience in our center

Objetivo. Estudio descriptivo de las formas de presentación, características biológicas y evolución de los pacientes pediátricos diagnosticados de anticoagulante lúpico en nuestro Hospital. Pacientes y métodos. Revisión retrospectiva de todos los pacientes que cumplieron los criterios establecidos por la Sociedad Internacional de Trombosis y Hemostasia para diagnóstico de anticoagulante lúpico. Resultados. Cumplieron los criterios establecidos 16 niños, 9 varones (53,6%) y 7 mujeres, con una mediana de edad decimal al diagnóstico de 6,25 años (rango: 1,1-13). Los motivos del estudio de coagulación fueron: preoperatorio (n: 6, 37,5%), estudio por trombosis (n: 4, 25%), infección (n:3, 18,8%), hemorragia (n: 2, 12,5%) e ingesta de raticida (n:1, 6,3%). Diez casos (62,5%) permanecieron asintomáticos y correspondieron a los casos de preoperatorio, infecciones e ingesta de raticida. Cuatro de los pacientes presentaron trombosis (25%), en dos de ellos se encontraron además trombofilia primaria y patología inmunitaria o tumoral y en otro caso se cumplieron criterios de síndrome antifosfolípido primario, único de los casos en que el anticoagulante lúpico fue persistente. Dos casos (12,5%) presentaron hemorragias asociadas a disminución de algún factor de coagulación (déficits transitorios de FII y FVIII).Conclusiones. El anticoagulante lúpico es un hallazgo poco frecuente en Pediatría. Se encuentra con más frecuencia en preoperatorio de procesos ORL y/o infecciones. La gran mayoría son transitorios y sin relevancia clínica. Cuando se asocia trombosis frecuentemente se asocia a trombofilia primaria y patología inmunitaria o tumoral y cuando lo hace a hemorragias, a déficit de factores procoagulantes (AU)

Objective. A descriptive study of the presentation forms, biological and evolution characteristics of the pediatric patients diagnosed of lupus anticoagulant in our hospital. Patients and methods. Retrospective review of all the patient who met the criteria established by the International Society of Thrombosis and Hemostasis for diagnosis of lupus anticoagulant. Results. The established criteria were met by 16 children, 9 males (53.6%) and 7 women, with a mean decimal age on diagnosis of 6.25 years (range: 1.1-13). The reasons for the coagulation study were: preoperative (n: 6, 37.5%), thrombosis study (n: 4, 25%), infection (n: 3, 8.8%), hemorrhaging (n: 2, 12.5%) and taking of rodenticide (n: 1, 6.3%). Ten cases (62.5%) remained asymptomatic and corresponded to pre-operative cases, infections and intake of rodenticide. Four of the patients had thrombosis (25%). In two of the latter, primary thrombophilia and immune or tumor pathology were also found and another case fulfilled the criteria of primary antiphospholipid syndrome, this being the only case in which the lupus anticoagulant was persistent. Two cases (12.5%) presented hemorrhages associated to decrease of a coagulation factor (transient deficits of FII and FVIII).Conclusions. Lupus anticoagulant is an uncommon finding in Pediatrics. It is more frequently found in the preoperative of ENT and/or infectious processes. The vast majority are transient and do not show clinical significance. When thrombosis is associated, it is frequently associated to primary thrombophilia and immune or tumor disorder and when it is associated to hemorrhages, it is associated to a deficit of procoagulant factors (AU)

Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome.

Conventional therapy with aspirin and/or heparin is at times incapable of preventing complications in high risk pregnancies of patients with antiphospholipid syndrome (APS). In those cases, a so-called second-line treatment protocol is used in addition to conventional therapy strategies. This manuscript is a report on three APS pregnant patients who were successfully treated with plasma exchange (PE) (two cases) or with immunoadsorption (IA) (one case) as a second-line treatment strategy. The efficacy of these procedures in removing anticardiolipin (aCL) and anti-ß(2)glycoprotein I (aß(2)GPI) antibodies from blood was evaluated. Serum samples were collected before and after 87 apheretic treatment sessions. Serum IgG/M aCL and IgG/M aß(2)GPI antibodies were determined using an "in-house" enzyme-linked immunosorbent assay and showed that all three patients had medium/high IgG aCL and aß(2)GPI titers. All three women had a successful pregnancy. A significant decrease in IgG aCL (P = 0.0001) and aß(2)GPI (P = 0.0001) antibody titers was observed after PE and IA sessions. There was moreover a significant, steady fall in serum IgG aCL pretreatment levels during the course of all three pregnancies (P = 0.0001, P = 0.0001, P = 0.001). The fall in IgG aß(2)GPI was significant in two of the patients (P = 0.0001, P = 0.0001) both with high antibody titers, but not in one with medium antibody titers, who was treated with PE (P = 0.17).

Effects of antiphospholipid antibodies on in vitro platelet aggregation.

Antiphospholipid antibodies contribute to the development of thrombosis, although precise mechanisms remain to be elucidated. We determined the effects of affinity-purified anti-beta(2)-glycoprotein 1 (anti-ß(2)GP1) and anti-prothrombin (anti-PT) antibodies on in vitro platelet aggregation. Adenosine diphosphate (ADP) and collagen-induced platelet aggregation were performed using platelet-rich plasma ([PRP] 250 × 10(9)/L). Antiphospholipid antibodies (1.25-10 µg/mL) were preincubated with PRP for 10 minutes at 37°C prior to the addition of agonist. Anti-ß(2)GP1 antibodies significantly reduced platelet aggregation (percentage area under the curve; %AUC) in a concentration-dependent manner using both 5 µmol/L (P < .001) and 2.5 µmol/L (P = .038) ADP but did not significantly affect the rate of aggregation. Anti-PT antibodies significantly enhanced 5 µg/mL collagen-induced platelet aggregation (%AUC; P = .034) but did not affect ADP-induced platelet aggregation. These results suggest (1) interactions and effects of antiphospholipid antibodies on platelets are agonist and concentration dependent and (2) anti-ß(2)GP1 antibodies may inhibit dense granule release and/or inhibition of the arachidonic acid pathway.

Anticuerpos antifosfolipídicos y fracaso implantatorio recurrente en fertilización in vitro. El debate continúa / Antiphospholipid antibodies and recurrent implantation failure in in-vitro fertilization. The debate goes on

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Células endoteliales y micropartículas circulantes en pacientes portadores de anticuerpos antifosfolípidos / Circulating endothelial cells and microparticles in patients with antiphospholipid antibodies

Fundamento y objetivo: Determinar si los valores de células endoteliales circulantes (CEC), micropartículas circulantes (MP) y factor von Willebrand (FvW), marcadores establecidos de disfunción/daño endotelial, están elevados en pacientes portadores de anticuerpos antifosfolípidos (AAF) y si existe correlación con marcadores de inflamación y coagulación. Pacientes y método: Se estudian 12 pacientes portadores de AAF y 12 sujetos sanos. Se determinaron CEC, MP, FvW, proteína C reactiva (PCR), fibrinógeno (Fg), ácido siálico (AS), interleucina 6, factor tisular (FT), generación de trombina (GT) y fragmentos de protrombina (F1+2) y de fibrina (DD). Resultados: En los pacientes están significativamente elevados los valores de los marcadores de: disfunción/daño endotelial (CEC, MP y FvW), inflamación (Fg y PCR) y coagulación (FT y DD). El análisis bivariante muestra correlación significativa entre CEC y Fg, AS, PCR y DD, así como entre CEC y FvW y MP. Conclusión: Los pacientes portadores de AAF presentan una disfunción endotelial asociada a un proceso inflamatorio, que, unido a los valores elevados de Fg, FT y DD, puede inducir un estado de hipercoagulabilidad (AU)

Background and objective: To determine whether circulating endothelial cells (CECs), circulatingmicroparticles (MPs) and von Willebrand factor (vWF), established markers of endothelial dysfunction/ damage, are elevated in patients with antiphospholipid antibodies (aPL) and its possible correlation with inflammation and coagulation. Patients and methods: Twelve atients with aPL and 12 healthy subjects were studied. Levels of CECs, MPs, vWF, C reactive protein (CRP), fibrinogen (Fg), sialic acid (SA), interleukin 6 (IL-6), tissue factor (TF), thrombin generation (TG) and prothrombin (F1 + 2) and fibrin (DD) fragments were determined. Results: In patients, markers of dysfunction/damage endothelial, CECs, MPs and vWF; inflammation, Fgand CRP and coagulation, TF and DD were significantly elevated. The bivariate analysis showedsignificant correlation among CECs and Fg, AS, CRP and DD, as well as between CECs and vWF and MPs.Conclusion: Patients with aPL had endothelial dysfunction associated with an inflammatory process,which, together with high levels of Fg, TF and DD, may be responsible for the hypercoagulable state (AU)

Mecanismos patogénicos de los anticuerpos antifosfolípidos / Pathogenic mechanisms of the anti-phospholipid antibodies

El síndrome de antifosfolípidos (SaF) es una enfermedad autoinmune caracterizada por abortos recurrentes, eventos trombóticos (arteriales o venosos) y hemocitopenias asociadas con títulos altos de aFL séricos. Se han descrito dos presentaciones de SaF: el SaF primario, que se presenta como entidad única y el SaF secundario o asociado principalmente a LEG. Los aFL son un grupo heterogéneo de inmunoglobulinas dirigidas contra diversos componentes o factores proteicos. En 1990, tres grupos de investigadores identificaron a la Beta2GP-I como el principal blanco antigénico de los aFL presentes en los pacientes con SaF. Diversos trabajos han mostrado que existe más de un mecanismo patogénico involucrado en el desarrollo del SaF. Las manifestaciones clínicas mejor documentadas son los abortos recurrentes y las alteraciones trombóticas. Lo anterior se fundamenta en las evidencias observadas in vivo en modelos animales e in vitro causadas por los anticuerpos anti-Beta2GP-I (aBeta2GP-I) de pacientes con SaF o de origen animal. La presente revisión tiene como objetivo mostrar los mecanismos patogénicos que participan en el desarrollo del SaF. Presentamos, además, las evidencias que muestran que los aBeta2GP-I inducen un estado proinflamatorio, proadhesivo y procoagulante (AU)

The antiphospolipid syndrome (APS) is an autoimmune disease characterized by recurrent fetal loss, thrombotic events (arterial or venous) and hemocytopenic disorders associated to high titers of circulating aPL. Two variants of the APS have been described. Primary APS is a clinical entity without evidence of any other autoimmune disease and secondary APS is a clinical disorder mainly associated with Systemic Lupus Erithematosus (SLE). aPL are a widely group of immunoglobulins directed against different components or proteins factors. In 1990 three groups of researchers identified that Beta2GP-I is the mainly antigenic target of aPL in APS patients. There are evidences that show that more than one pathogenic mechanism is involved in the development of the APS. The best documented clinical manifestations associated with the APS are recurrent fetal loss and thrombotic disorders. The latter is based on observations in vivo in animal models and in vitro on the effects caused by aBeta2GP-I antibodies from patients with APS or from animals which cause experimental APS. The objective of the present paper is to show the pathogenic mechanisms that participate in the development of the APS. We also presented evidence that shows that aBeta2GP-I induces pro-inflammatory, pro-adhesive and pro-coagulant disorder (AU)

Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome.

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies in blood of patients with thrombosis or fetal loss. There is ample evidence that beta(2)-glycoprotein I (beta(2)GPI) is the major antigen for antiphospholipid antibodies. The autoantibodies recognize beta(2)GPI when bound to anionic surfaces and not in solution. We showed that beta(2)GPI can exist in at least 2 different conformations: a circular plasma conformation and an "activated" open conformation. We also showed that the closed, circular conformation is maintained by interaction between the first and fifth domain of beta(2)GPI. By changing pH and salt concentration, we were able to convert the conformation of beta(2)GPI from the closed to the open conformation and back. In the activated open conformation, a cryptic epitope in the first domain becomes exposed that enables patient antibodies to bind and form an antibody-beta(2)GPI complex. We also demonstrate that the open conformation of beta(2)GPI prolonged the activated partial thromboplastin time when added to normal plasma, whereas the activated partial thromboplastin time is further prolonged by addition of anti-beta(2)GPI antibodies. The conformational change of beta(2)GPI, and the influence of the autoantibodies may have important consequences for our understanding of the antiphospholipid syndrome.

Estrategias terapéuticas en el síndrome antifosfolipídico / Therapeutic strategies in antiphospholipid syndrome

El síndrome antifosfolipídico (SAF) se caracteriza por la asociación de los anticuerpos antifosfolipídicos (AAF) con trombosis de repetición, abortos o pérdidas fetales recurrentes y trombocitopenia. Los AAF más estudiados son los anticuerpos anticardiolipina, el anticoagulante lúpico y los anticuerpos anti-ß2-glucoproteína I. El SAF puede presentarse de forma aislada, denominándose SAF primario, o bien asociado a otras enfermedades autoinmunes sistémicas, fundamentalmente a lupus eritematoso sistémico. Más recientemente, se ha descrito un subgrupo de SAF en el que los pacientes desarrollan múltiples trombosis durante un corto espacio de tiempo, que se ha denominado SAF catastrófico. Aunque parece clara la asociación entre la presencia de AAF y trombosis, la actitud terapéutica no debe ir dirigida primariamente a la eliminación o a la reducción de los niveles de estos anticuerpos mediante recambios plasmáticos, gammaglobulinas intravenosas o inmunodepresores (excepto en el SAF catastrófico), ya que no existe una clara correlación entre los niveles de los AAF y los episodios trombóticos. El tratamiento de estos pacientes debe basarse en el uso de antiagregantes plaquetarios o anticoagulantes(AU)

The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous or arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant, anticardiolipin antibodies or antibodies directed to various proteins, mainly â2 glycoprotein I, or all three. Apart from being “primary” (without any discernable underlying systemic autoimmune disease), or associated to another disease (usually to systemic lupus erythematosus), it may also occur rapidly over days or weeks when it has been termed “catastrophic” APS. Therapy should not primarily be directed at effectively reducing the aPL levels and the use of immunotherapy (including high dose steroid administration, immunosuppression or plasma exchange) is generally not indicated, unless in the catastrophic APS. Treatment of APS patients should be based on the use of antiaggregant and anticoagulant therapy(AU)

Clinical significance of antiphospholipid syndrome nephropathy (APSN) in patients with systemic lupus erythematosus (SLE) / Significado clínico de la nefropatía del síndrome antifosfolípido en pacientes con lupus eritematoso sistémico (LES)

La nefropatía del síndrome anti fosfolípido (NSAF) es actualmente una alteración patológica bien definida, caracterizada por la presencia de lesiones renales vaso-oclusivas, trombosis aguda arterial y arteriolar, y que ocasiona zonas de atrofia isquémica cortical. El objetivo del presente trabajo fue analizar la prevalencia y el significado clínico de la NSAF en pacientes con glomerulonefritis (GN) secundaria a Lupus Eritematoso Sistémico (LES). Se analizaron retrospectivamente las biopsias renales de 162 pacientes con GN secundaria a LES, buscando intencionadamente los datos histopatológicos de la NSAF. Se registraron los datos clínicos y serológicos al momento de la biopsia renal y durante el período de seguimiento promedio de 7 años. En los casos en que se obtuvo una biopsia renal subsecuente se analizó el desarrollo de la NASF. Resultados: Encontramos datos de NSAF en 17 pacientes (10.4%); 12 de ellos tenían lesiones proliferativas focales o difusas. Los índices histopatológicos de actividad y de cronicidad fueron más altos en los pacientes con la NSAF cuando se compararon con los pacientes sin NSAF. Los pacientes con nefropatía anti fosfolípido tuvieron con mayor frecuencia hipertensión arterial, creatinina sérica elevada, síndrome nefrótico, GN rápidamente progresiva y muerte, en comparación con los pacientes con GN lúpica sin NSAF. Se detectaron anticuerpos anticardiolipina en 52% de los pacientes con NSAF en quienes se realizó el examen al momento de la biopsia, en comparación con 27% de los pacientes sin NSAF. Se realizó biopsia renal subsecuente en 18 pacientes; quienes tuvieron NSAF en la primera biopsia tuvieron mayor incremento en la esclerosis glomerular en la segunda biopsia, al compararlo con quienes no tuvieron NSAF en la biopsia inicial. Conclusiones: La nefropatía del antifosfolípido es un factor de riesgo para hipertensión arterial, síndrome nefrótico y GN rápidamente progresiva en los pacientes con GN lúpica. La NSAF debiera considerarse en los criterios de clasificación del síndrome anti fosfolípido, y sería recomendable realizar estudios con tratamiento anticoagulante en estos pacientes (AU)

Antiphospholipid syndrome nephropathy (APSN) is now a well-recognized vaso-occlusive renal lesion associated with acute thrombosis and chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. Our objective was to evaluate the prevalence and clinical significance of APSN in patients with Systemic Lupus Erythematosus (SLE). Methods Kidney biopsy specimens obtained from 162 patients with lupus glomerulonephritis were retrospectively examined for the presence of APSN. Clinical and laboratory data obtained at the time of kidney biopsy and during a mean follow-up of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APSN was examined. Results We found APSN in 17 (10.4%) patients with lupus glomerulonephritis (GN), 12 with focal or proliferative lesions. Both activity and chronicity indexes were higher in patients with APSN when compared with lupus nephritis without APSN. Patients with APSN had a higher frequency of hypertension and elevated serum creatinine levels at the time or kidney biopsy, as well as a higher frequency of rapidly progressive GN, nephrotic syndrome and death at the end of the follow-up. Anticardiolipin antibodies were found in 52% of those with APSN and in 27% of those without APSN. Serial kidney biopsy specimens were available from 18 patients. An increase of glomerular sclerosis was found in the second biopsy particularly in those patients with APSN in the first biopsy. Conclusions APSN is a risk factor that contributes to an elevated prevalence of hypertension, elevated serum creatinine, nephrotic syndrome and increased glomerular sclerosis. APSN should be included in the classification criteria of APS, and the use of appropriate anticoagulant therapy should be tested (AU)

Síndrome antifosfolípido primario: dormido, no curado / No disponible

No disponible