Utilización de un dispositivo portátil para monitorear la relación internacional normalizada en pacientes con anticoagulante lúpico positivo / Use of a portable device to monitor the international normalized ratio in patients with positive lupus anticoagulant

La certeza del valor de la relación internacional normalizada (RIN), ensayo para controlar la anticoagulación con dicumarínicos, en pacientes con anticoagulante lúpico positivo (AL) es desconocida especialmente para los dispositivos al lado del paciente (POCT). El objetivo de este trabajo fue investigar si existe correlación entre el valor del RIN obtenido por el método tradicional y el obtenido con un dispositivo portátil en pacientes con AL positivo. Se estudiaron 35 pacientes anticoagulados por enfermedad tromboembólica con diagnóstico de AL positivo persistente a los que se les determinó al mismo tiempo el RIN por el método tradicional y con CoaguChek durante 4 controles consecutivos. El rango del RIN fue 1,9 a 5,60 y el RIN-POCT estuvo entre 2,0 y 4,92. La comparación del RIN vs RIN-POCT mostró r=0,98, pendiente: 1,56 (0,98-1,12) y una ordenada al origen de -0,088 (-0,282-0,007). El sesgo fue 2,1%. Para un nivel del RIN menor de 3,5 (n=136 controles) la diferencia del RIN promedio fue de 0,17 con un rango de 0,01-0,56. Un paciente, con triple positividad, mostró una diferencia entre ambos métodos mayor de 0,4 en dos controles. Para un RIN mayor de 4,5 el grado de concordancia fue menor pero no tiene implicancia clínica. Los resultados del RIN obtenidos por CoaguChek en los pacientes estudiados con AL positivo son útiles para la práctica clínica. Los datos obtenidos demuestran que hay una buena correlación entre el RIN tradicional y el CoaguChek. Por la gran diversidad de los equipos POCT los resultados no son extrapolables a otros dispositivos. Dada la heterogeneidad de los anticuerpos antifosfolípidos, es recomendable probar en cada paciente si hay una buena concordancia entre el RIN tradicional y el RIN-POCT.

The certainty of the value of the international normalized relation (INR) assay to control dicoumarin anticoagulation in patients with positive lupus anticoagulant (LA) is unknown especially for the point of care testing (POCT). The aim of this work was to investigate if there was a correlation between the INR values obtained by the traditional method and those obtained with a POCT in patients with positive LA. The population under study were 35 patients anticoagulated by thromboembolic disease with a persistent positive LA, whose INR was determined at the same time by the traditional method and with CoaguChek during 4 consecutive controls. The INR range was 1.9 to 5.60 and the RIN-POCT was between 2.0-4.92. The comparison of INR vs. INR - POCT showed r=0.98, slope: 1.56 (0.98-1.12) and ordered to the origin -0.088 (-0.282-0.007). The bias was 2.1%. For an INR level lower than 3.5 (n=136 controls) the average INR difference was 0.17 with a range of 0.01-0.56. One patient, with triple positivity showed a difference between both methods greater than 0.4. in two controls. For INR greater than 4.5, the degree of concordance is lower but has no clinical implications. The data obtained show that there is a good correlation between the traditional INR and the CoaguChek. The results of INR obtained by CoaguChek in patients studied with positive LA are useful for clinical practice. Due to the large diversity of POCT, the results cannot be extrapolated to other devices. Given the heterogeneity of antiphospholipid antibodies, it is advisable to test in each patient whether there is a good agreement between the traditional INR and INR-POCT.

A certeza do valor da razão internacional normalizada (RIN ou IIN), ensaio que controla a anticoagulação com dicumarínicos, em pacientes com anticoagulante lúpico positivo (AL) é desconhecida especialmente para os dispositivos de teste do tipo point-of-care (POCT). Este trabalho teve como objetivo pesquisar se existe correlação entre o valor de RIN obtido pelo método tradicional e aquele obtido com um dispositivo portátil em pacientes com AL positivo. Foram estudados 35 pacientes anticoagulados por doença tromboembólica com diagnóstico de AL positivo persistente aos quais lhes determinaram, ao mesmo tempo, a RIN pelo método tradicional e com CoaguChek durante 4 controles consecutivos. O intervalo de RIN foi de 1,9 a 5,60 e o de RIN-POCT ficou entre 2,0 e 4,92. A comparação de RIN vs RIN-POCT mostrou r=0,98, pendente: 1,56 (0,98-1,12) e uma ordenada à origem de -0,088 (-0,282-0,007). O viés foi 2,1%. Para um nível de RIN menor a 3,5 (n=136 controles) a diferença de RIN em média foi de 0,17 com um intervalo de 0,01-0,56. Um paciente, com tríplice positividade, mostrou uma diferença entre ambos os métodos maior a 0,4 em dois controles. Para um RIN de mais de 4,5, o grau de concordância foi menor, mas não tem consequências clínicas. Nos pacientes estudados com AL positivo, os resultados da RIN obtidos por CoaguChek são úteis para a prática clínica. Os dados obtidos demonstram que existe uma boa correlação entre a RIN tradicional e o CoaguChek. Devido à grande diversidade dos equipamentos POCT, os resultados não são extrapoláveis a outros dispositivos. É recomendável, visto a heterogeneidade dos anticorpos antifosfolípídes, provar em cada paciente a existência de uma boa concordância entre a RIN tradicional e a RIN-POCT.

Inhibidor lúpico en situaciones clínicas diferentes al síndrome antifosfolipídico / Lupus inhibitor in clinical situations other than antiphospholipid syndrome

El inhibidor lúpico (IL) es uno de los criterios de laboratorio para Síndrome Antifosfolipídico (SAF); sin embargo, puede detectarse en individuos asintomáticos o estar asociado a otras situaciones clínicas. Presentamos un análisis retrospectivo de 1000 exámenes consecutivos para IL (TTPA, DRVVT) de los cuales 249 casos no presentaban criterios clínicos de SAF. Aplicando los criterios SSC-ISTH, hallamos IL+ en 27,30% (205/751) y 43,37% (108/249) de los casos con y sin criterios clínicos de SAF respectivamente; analizándose en estos últimos casos las características clínicas y de laboratorio. Contexto clínico de casos IL+ sin SAF: 18,52% asintomáticos, 34,26% síntomas de sangrado y 47,22% otras manifestaciones. Otras alteraciones de laboratorio en casos IL+ sin SAF, con síntomas de sangrado: detectamos alteraciones plaquetarias, descenso de VWF:RCo y/o VWF:Ag, disminución de FVIII, FV, FVII, FXI o fibrinógeno e hiperfibrinolisis en el 54,05% de los casos. El análisis mostró detección de IL+ en un número importante de estudios (108/1000) sin criterios SAF. Los casos con IL+ y sangrado representan un desafío particular, al requerir evaluar otros posibles defectos subyacentes, que pudiesen justificar el comportamiento clínico. La detección e identificación de defectos combinados requiriere de un análisis minucioso, a fin de alcanzar un diagnóstico correcto, esencial para tomar decisiones terapéuticas adecuadas. (AU)

Despite lupus anticoagulant (LA) is one of the laboratory criteria for antiphospholipid syndrome (APS), it can be present in asymptomatic subjects or it can be associated with other clinical settings. We present a retrospective analysis of 1000 consecutive LA assays (APTT, DRVVT), 249 of them were performed in patients without clinical criteria for APS. According to ISTH criteria, positive LA was found in 27.30% (205/751) and 43.37% (108/249) of cases with or without APS criteria respectively; in the last group, the analysis of clinical background and laboratory characteristics was done. Clinical background of LA+ cases without APS: 18.52% asymptomatic, 34.26% bleeding symptoms and 47.22% other clinical settings. Other abnormal laboratory tests in LA+ cases without APS and bleeding symptoms: platelet dysfunction; low VWF:RCo and/or VWF:Ag; decrease of FVIII, FV, FVII, FXI or fibrinogen and hyperfibrinolysis were found in the 54.05% of the cases. The analysis showed positive LA in an important number of cases (108/1000) without criteria of APS. Those LA+ cases with bleeding symptoms represent a particular challenge because other possible underlying defects have to be analysed in order to explain the clinical behaviour. The detection and identifications of combined defects required a careful analysis in order to achieve accurate diagnosis, essential for therapeutic decisions. (AU)

Placental histomorphology in unexplained foetal loss with thrombophilia.

BACKGROUND & OBJECTIVES: Acquired and genetic thrombotic conditions, both organ and non organ specific, are associated with increased foetal wastage. This study was carried out to examine the placenta from women with abnormal pregnancies and a history of unexplained foetal loss, and to associate with maternal thrombophilia status. METHODS: Placentas from eight women with history of unexplained foetal loss were analyzed for histopathological characteristics. All the women were simultaneously screened for the common acquired and genetic thrombophilia markers i.e., lupus anticoagulants ( LA), IgG / IgM antibodies for anticardiolipin (ACA), beta2 glycoprotein 1 (beta2GPI) and annexin V, protein C (PC), protein S (PS), antithrombin III (AT III), factor V Leiden ( FVL) mutation, prothrombin (PT) gene G20210A, methylene tetrahydrofolate reductase (MTHFR) C 677T, endothelial protein C receptor (EPCR) 23 bp insertion and plasminogen activator inhibitor ( PAI-1 4G/5G) polymorphisms RESULTS: Six of eight women were positive for one or more thrombophilia markers. The placenta in all the cases except one, showed the characteristic features of infarct fibrin deposition and calcification. Among two women who were negative for thrombophilia, one showed clear evidence of thrombus in the placental sections while the other did not show any characteristic infarcts in the placental sections. INTERPRETATION & CONCLUSION: Our findings showed that the histopathological examination of the placentas confirmed thrombophilia as the aetiological cause of thrombosis in 6 of the 8 women. The presence of thrombus in a negative thrombophilia woman suggests yet unidentified thrombophilia markers or probably non-haemostatic factors causing thrombosis.

Trombofilia primaria: 41 nuevos casos / Primary thrombophilias: 41 new cases

Se presentan 37 casos de trombosis, en su mayoría jóvenes, con antecedentes trombóticos familiares y con diagnóstico de trombofilia primaria o hereditaria además de cuatro familiares de primer grado de estos pacientes en los cuales se confirmó la portación familiar de trombofilia. La anamnesis reveló que el 82 por ciento presentó la primera trombosis antes de los 45 años; tuvo más de una trombosis en un 59 por ciento y tenía antecedentes familiares en 49 por ciento. Los defectos trombofílicos determinantes encontrados fueron: deficiencia de proteína S (27 por ciento); resistencia a proteína C activada por factor V Leiden (24,3 por ciento); deficiencia proteína C (21,6 por ciento) y antotrombina III (16,2 por ciento); mutación G20210 A del gen protrombina (8,1 por ciento). Entre los defectos adquiridos estudiados simultáneamente, un 27,2 por ciento de los casos presentaron anticoagulante lupico y ninguno hiperhomocisteína. La existencia de mas de un factor de riesgo trombofílico se observó en el 24.3 por ciento de los pacientes. En el estudio de los 4 parientes de primer grado se encontró factor V Leiden en uno; factor V Leiden mas anticoagulante lupico en uno y deficiencia proteína S en dos. El trabajo anterior publicado en 2004 motivó a los pacientes que no se hicieron el estudio a tomar conciencia de su situación y de la necesidad de controlarse, lo que demuestra la importancia de difundir esta patología aún poco conocida.

Significance of antiphospholipid antibodies in lupus nephritis.

BACKGROUND: Some autoantibodies have been associated with lupus nephritis but the role of antiphospholipid antibodies (APA) is controversial. OBJECTIVE: The present study was to explore the role of APA by comparing demographic profiles and the presence of anticardiolipin antibody (aCL) and lupus anticoagulant (LA) in systemiclupus erythematosus 1 (SLE) patients with and without nephritis. MATERIAL AND METHOD: The cross-sectional study in a tertiary center was conducted in 77 SLE patients. All patients attended our renal or rheumatology clinics between June 2002 and December 2003. RESULTS: Sixty-three (82%) of the 77 SLE patients had nephritis. The prevalence of antiphospholipid syndrome (APS) was 10% (8 patients), positive aCL (IgG) was 26% (20 patients) and positive LA was 26% (20 patients). The receiver operating characteristic (ROC) method was applied to assess the significance of aCL in both nephritis and non-nephritis groups. Area under the ROC curve was 0.538 (95%CI 0.312-0.765), a cutoff value of 20.5 GPL had a sensitivity of 75% and a specificity of 53%. In univariate analysis, neither positivity for anticardiolipin antibody nor lupus anticoagulant was associated with lupus nephritis. Analyzed in only the lupus nephritis group, LA-positive lupus nephritis patients had higher systolic blood pressure (SBP) (133.7 vs 121.9 mmHg, p = 0.005), lower platelet count (209.8 vs 264.4 x 10(3)/microL, p = 0.02) and higher 24-hr urine protein excretion (2.6 vs 1.4 g, p = 0.02) than LA-negative lupus nephritis patients. Serum creatinine was higher in LA-positive lupus nephritis than LA-negative (233.0 vs 94.9 micromol/L), but did not reach statistical significance. CONCLUSION: APA are frequently seen in SLE patients, but not associated with lupus nephritis. However lupus anticoagulant tends to associate with lupus nephritis. Detection of LA in lupus nephritis patients could identify patients who had increased risk to develop bad renal outcomes (elevated SBP and 24-hr urine protein excretion).

Anticardiolipin antibodies in young Iraqi adults with deep venous thrombosis

To determine the prevalence and clinical significance of anticardiolipin antibodies [ACA] in young Iraqis with Deep venous thrombosis [DVT]. A total of 50 unselected young Iraqi adults [<45 years] with Doppler confirmed DVT were evaluated. The evaluation included full relevant history, Prothrombin Time, Partial Thromboplastin Time, Kaolin Clotting time [KCT], KCT index [to screen for Lupus Anticoagulant [LA] in patients not on oral anticoagulants], and lgG and IgM ACA titres [by ELISA]. The median age of the DVT patients was 32.5 years with a M:F ratio of 1:2.6. The overall prevalence of Antiphopholipid Antibodies [APA] [those with elevated ACA and/or LA] was 16%, while it was 9.5% in the subcategory with single DVT attack. The subcategory of patients with recurrent DVT [8 patients] had significantly higher frequency of APA [OR 9.5] and lgG ACA titres compared to those with a single episode [p=0.01583 and 0.01 respectively]. Higher frequencies of APA were also encountered in the subcategories with history of Pulmonary embolism, Stroke and recurrent fetal loss, compared to those without such histories [OR of 3.2, 6.7 and 7.7 respectively]. The findings of this study are consistent with worldwide reports on prevalence and significance of APA. The high frequency of these antibodies in young Iraqi patients and their association with recurrent thrombotic events, in addition to the bulk of the literature suggesting higher recurrence rates and mortality in those with the antibodies on cessations of therapy, warrants pursuing the policy of evaluating all Iraqi young adults at diagnosis or just prior stopping therapy for APA, and considering long term appropriate anticoagulation in those with the antibodies, to reduce recurrence and mortality

Antiphospholipid antibody positive young stroke: an analysis of 12 cases.

AIMS AND OBJECTIVES: To study clinico-investigative profile of 12 young (<45 years) patients with stroke who tested positive for anti phospholipid antibodies (APLA). SUBJECTS AND METHODS: The diagnostic, clinical, laboratory and radiologic features in 12 APLA positive young patients who presented with stroke were studied. The APLA analysis included estimation of anticardiolipin (aCL) antibodies and lupus anticoagulant (LA). Other relevant tests included anti-nuclear antibody, human immunodeficiency virus, Venereal Diseases Research Laboratory, platelet count, echocardiography and carotid Doppler. APLA positive strokes were those cases where either the immunoglobulin G (IgG) and immunoglobulin M (IgM) were raised or LA was positive, and other known causes were excluded. RESULTS: Levels of IgG (aCL) was raised in 11 cases (mild 7, moderate 1, high 3), IgM was elevated in all the 12 cases (moderate 2, high 10). Of the two LA positive cases both were IgM positive but in one IgG was negative. Five patients showed small multiple bilateral cerebral infarcts on computerised tomography (CT) scan. 5 patients had history of recurrent strokes. Hemiparesis was more frequent than hemiplegia. None presented with dense hemiplegia. All patients recovered to normal functional capacity and did not have recurrence on drugs. CONCLUSION: A preliminary study on APLA positive young strokes showed certain clinical and radiological features, mild to moderate stroke, pre-treatment recurrences, multiple smaller infarcts on CT, which could be clustered in a subgroup of stroke in young. Incidentally these patients showed a good prognosis in terms of long term outcome.

Pioderma gangrenosum asociado a anticuerpos antifosfolípidos: a propósito de 4 casos / Pyoderma gangrenosum associated with antiphospholipid antibodies: a 4 case presentation

El pioderma gangrenosum es una afección poco frecuente, de naturaleza inflamatoria, que se caracteriza por lesiones pápulo-pustulosas, nodulares y extensas ulceraciones necróticas, asociada frecuentemente a afecciones sistémicas. Su fisiopatología es muy compleja pues se describen diversos mecanismos inmunológicos. En la histología se observa una intensa infiltración de neutrófilos y una necrosis localizada en todo el espesor de la piel. Es de evolución crónica y recidivante y rebelde a distintos tratamientos. Forma parte del complejo de las enfermedades neutrofílicas. Presentamos 4 casos de pioderma gangrenosum asociados a distintas afecciones sistémicas: 3 con enfermedad de Crohn y 2 de ellos con artritis reumatoidea sero-negativa. Los síntomas cutáneos se localizaban fundamentalmente en los sitios de injuria, por lo que presentaban el fenómeno de patergia. Tratados con ciclosporina A se obtuvo una evidente mejoría. El caso 4 presentaba una colitis ulcerosa crónica y una mielofibrosis sin patergia. En todos ellos se estudiaron los anticuerpos antifosfolípidos y lupus anticoagulante, proteína C y S de la coagulación, la fracción funcional e inmunológica de antitrombina III, alfa-1 antitripsina y de alfa-2 macroglobulina, PAI, kininógeno de alto peso molecular y todos los factores de la coagulación. Los resultados muestran en un caso la presencia de anticuerpos antifosfolípidos y en tres lupus anticoagulante. Todos los factores de la coagulación fueron normales, lo que podría explicar que ninguno de los pacientes presentaba las manifestaciones sistémicas trombóticas que caracterizan el síndrome antifosfolípido. Es probable que la lesión se inicie a nivel de los capilares y arteriolas, dado que el trauma lesionaría sus endotelios, exponiendo los fosfolípidos de sus membranas a los que se unirían los anticuerpos antifosfolípidos circulantes. De esa manera se desencadena un fenómeno inmune a nivel local, con expresión de moléculas de adhesión, especialmente las selectinas E y P, liberación de citoquinas y mediadores proinflamatorios, activación del sistema de la coagulación y del complemento y activa participación de los linfocitos T y B. Sugerimos que todos estos elementos provocan una diversidad de patologías a nivel vascular y celular con liberación de factores quimiotácticos para los neutrófilos. Es muy posible que el pioderma gangrenosum comprenda un síndrome con características clínicas e histológicas monomorfas, pero desencadenado por múltiples mecanismos fisiopatológicos, todos ellos de naturaleza inmunológica. Uno de ellos estaría dado por la presencia de autoanticuerpos tipo antifosfolípidos. Estos anticuerpos estarían presentes por una disregulación de los linfocitos T y B, que estarían en la base de los mecanismos fisiopatológicos de esta afección.

Diagnóstico de anticuerpos antifosfolípidos / Diagnosis of antiphospholipid antibodies

Los anticuerpos antifosfolípidos (Ac aFL) han sido definidos como autoanticuerpos que reaccionan como fosfolípidos. Pueden ser identificados como anticoagulante lúpico (AL) mediante ensayos de coagulación y como anticuerpos anticardiolipina (Ac aCL), utilizando el método de ELISA. Generalmente ambas actividades están asociadas, pero en algunos pacientes el AL y los Ac aCL pueden ser separados por técnicas cromatográficas como anticuerpos con diferentes actividades. La heterogeneidad de los Ac aFL ha sido recientemente confirmada y principalmente en los estudios que evalúan el requerimiento de cofactores proteicos en su interacción con los fosfolípidos. Los ensayos para detectar los Ac aCL están bien estandarizados, pero aún existe cierta dificultad en el diagnóstico del AL por las diferencias en la sensibilidad de los reactivos y ensayos que se utilizan

Lupus anticoagulant and anticardiolipin antibodies in systemic lupus erythematosus.

BACKGROUND. Lupus anticoagulant and anticardiolipin antibodies are antiphospholipid antibodies which have been independently associated with a high incidence of thrombotic diseases. However, the importance of their combined occurrence has not yet been examined. METHODS. We investigated 70 patients with systemic lupus erythematosus for the presence of anticardiolipin antibodies paying particular attention to a history of thrombosis and abortion. Lupus anticoagulant was detected using the kaolin clotting time, its mixing tests with normal plasma and the inosithin neutralization test. Anticardiolipin antibodies were detected using the ELISA technique. RESULTS. Lupus anticoagulant was detected in 11 patients (16%) and anticardiolipin antibodies in 13 (19%). Six patients were positive for both lupus anticoagulant and anticardiolipin antibodies. These patients had a higher incidence of thrombosis or recurrent abortion (5 of 6) compared to those with lupus anticoagulant (2 of 5) or anticardiolipin antibodies alone (1 of 7). The amount of inosithin required to neutralize lupus anticoagulant was greater [mean (SD) 27.5 (20.5) micrograms] in patients with both lupus anticoagulant and anticardiolipin antibodies than in patients with lupus anticoagulant alone [mean (SD) 4.0 (5.4) micrograms]. CONCLUSION. The presence of lupus anticoagulant is associated with thrombosis and recurrent abortion which are more frequent when both lupus anticoagulant and anticardiolipin antibodies are present and these patients probably have more severe disease as the amount of inosithin required to neutralize the lupus anticoagulant was greater.

Spontaneous left ventricle cavity thrombus in a patient of systemic lupus erythematosus.

A 32 year old female with systemic lupus erythematosus having circulating lupus anticoagulant developed a thrombus in the left ventricle cavity, an unusual site. She responded to standard anticoagulant regime.

Absence of lupus anticoagulants in Behcet's disease

The presence of a lupus anticoagulant was evaluated in patients with Bechet's disease by the kaolin clotting time method. Four percents (three patients) of 69 patients analyzed were found positive for the lupus anticoagulant. However, no statistically significant association existed between the presence of this antibody and the presence of thrombosis, clinical activity, clinical type, antinuclear antibodies and the positive VDRL test.

Anticoagulante lúpico: análisis clínico y de laboratorio de 45 pacientes

El anticoagulante lúpico (ACL) es un anticuerpo antifosfolipídico que prolonga las pruebas de coagulación dependientes de fosfolípidos como el tiempo de tromboplastina parcial activado (TTPa). El objetivo del presente estudio es informar la experiencia clínica y de laboratorio con 45 pacientes portadores de esta anomalía que clásicamente se manifiesta por trombosis, abortos a repetición y trombocitopenia. Los 45 pacientes se estudiaron en un período de 67 meses y represetan el 1.76 por ciento de todos los pacientes evaluados hemostáticamente en este tiempo. Cuarenta por ciento de los casos de ACL se presentó en pacientes con lupus eritematoso sistemico (LES); 25 por ciento en pacientes con neoplasia hematológica y 35 por ciento restante en pacientes con enfermedades benignas. Hubo 15 episodios de trombosis en 13 pacientes (28.8 por ciento de la muestra), ocho de estos tenian LES (44.4 por ciento). Dos pacientes con LES dieron historia de abortos a repetición (4.5 por ciento) y cuatro casos presentaron fenómenos hemorragiparos (9 por ciento). El estudio sugiere como grupo de riesgo elevado para trombosis a los pacientes con LES y VDRL falso positivo.