Recomendaciones de manejo de los anticoagulantes orales directos (DOACs) anti Xa y anti IIa / Recommendations for the practical management of the direct oral anticoagulants anti Xa and anti IIa

Resumen Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas pro piedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Abstract Direct oral anticoagulants have emerged as the drugs that have changed the man agement of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagu lants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

[MANAGEMENT RECOMMENDATIONS FOR DIRECT ORAL ANTICOAGULANTS (DOACs) ANTI Xa AND ANTI IIa]. / RECOMENDACIONES DE MANEJO DE LOS ANTICOAGULANTES ORALES DIRECTOS (DOACS) ANTI Xa Y ANTI IIa.

Direct oral anticoagulants have emerged as the drugs that have changed the management of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagulants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas propiedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Acquired factor XIII deficiency in patients under therapeutic plasma exchange: A poorly explored etiology.

INTRODUCTION: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency. OBJECTIVES: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE. METHODS: We respectively studied a cohort of consecutive patients from 2014 to 2019 who were treated with TPE with FXIII levels <50%. The FXIII was measured after the start of the TPE course, on days between the TPE sessions, due to suspected acquired deficiency. All TPE were performed using continuous flow cell separator. In all cases, the initial replacement fluid applied was albumin. Apheresis procedures were held at 24to 48 hours intervals. RESULTS: Eighteen patients were included, 13 of them were recipients of kidney transplants. The main TPE prescription was humoral rejection. Median FXIII at diagnosis (measured on days between sessions of the TPE course) was 19%(IQR17-25). The median of apheresis procedures before measurement of FXIII was 3(IQR2-4). Among the total cohort, 10 patients suffered hemorrhages. None of the patients without history of kidney transplants had bleeding (n = 5), however, 10/13 with kidney transplants did. Five kidney transplant patients received therapy with FXIII concentrate because of life-threatening bleeding. In all cases, the bleeding stopped within the first 24 hours. All patients had their FXIII levels measured again after finishing the TPE course, with normal results. CONCLUSIONS: TPE is an under-diagnosed cause of acquired FXIII deficiency since routine coagulation tests remain unaltered. It might cause major bleeding, particularly in patients with a recent history of surgery like kidney transplants.

[Argentine Consensus in effective management of anticoagulation clinics for the use of vitamin k antagonists]. / Consenso Argentino en gestión efectiva de clínicas de anticoagulación para el uso de antagonistas de la vitamina k.

Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly. In this Argentine consensus we propose a series of guidelines for the effective management of the anticoagulation clinics. The goal is to achieve the excellence in both the clinical healthcare and the hemostasis laboratory for the anticoagulated patient. The criteria developed in the document were agreed upon by a large group of expert specialists in hematology and biochemistry from all over the country. The criteria presented here must always be considered when indicating VKA although they had to be adapted to the unequal reality of each center. Taking these premises into consideration will allow us to optimize the management of the anticoagulated patient with VKA and thus minimize thrombotic and hemorrhagic intercurrences, in order to honor our promise not to harm the patient.

El tratamiento de un paciente anticoagulado con antagonistas de la vitamina K (AVK) sigue siendo un desafío, especialmente en regiones donde, por el costo, los dicumarínicos son todavía la alternativa más buscada a la hora de elegir un anticoagulante oral. Las clínicas de anticoagulación han demostrado ser la forma más eficiente y segura de evitar complicaciones trombóticas y hemorrágicas y de mantener al paciente en rango óptimo de tratamiento. Sin embargo, requieren de una adecuada infraestructura y personal capacitado para que funcionen eficientemente. En este consenso argentino se propone una serie de parámetros para la gestión efectiva de una clínica de anticoagulación. El objetivo es lograr una elevada calidad desde el punto de vista clínico-asistencial a través de un laboratorio de hemostasia de excelencia. Los criterios desarrollados en el documento fueron consensuados por un amplio grupo de expertos especialistas en hematología y en bioquímica de todo el país. Estos criterios deben adaptarse a la irregular disponibilidad de recursos de cada centro, pero siempre se los debe tener en cuenta a la hora de indicar el tratamiento anticoagulante con estas drogas. Tener en consideración estas premisas nos permitirá optimizar la atención del enfermo anticoagulado con AVK y de esta forma minimizar las intercurrencias trombóticas y hemorrágicas a las que está expuesto, para así honrar nuestra promesa de no dañar al paciente.

Consenso argentino en gestión efectiva de clínicas de anticoagulación para uso de antagonistas de la vitamina K / Argentine consensus in effective management of anticoagulation clinics for the use of vitamin K antagonists

Resumen El tratamiento de un paciente anticoagulado con antagonistas de la vitamina K (AVK) sigue siendo un desafío, especialmente en regiones donde, por el costo, los dicumarínicos son todavía la alternativa más buscada a la hora de elegir un anticoagulante oral. Las clínicas de anticoagulación han demostrado ser la forma más eficiente y segura de evitar complicaciones trombóticas y hemorrágicas y de mantener al paciente en rango óptimo de tratamiento. Sin embargo, requieren de una adecuada infraestructura y personal capacitado para que funcionen eficientemente. En este consenso argentino se propone una serie de parámetros para la gestión efectiva de una clínica de anticoagulación. El objetivo es lograr una elevada calidad desde el punto de vista clínico-asistencial a través de un laboratorio de hemostasia de excelencia. Los criterios desarrollados en el documento fueron consensuados por un amplio grupo de expertos especialistas en hematología y en bioquímica de todo el país. Estos criterios deben adaptarse a la irregular disponibilidad de recursos de cada centro, pero siempre se los debe tener en cuenta a la hora de indicar el tratamiento anticoagulante con estas drogas. Tener en consideración estas premisas nos permitirá optimizar la atención del enfermo anticoagulado con AVK y de esta forma minimizar las intercurrencias trombóticas y hemorrágicas a las que está expuesto, para así honrar nuestra promesa de no dañar al paciente.

Abstract Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly. In this Argentine consensus we propose a series of guidelines for the effective management of the anticoagulation clinics. The goal is to achieve the excellence in both the clinical healthcare and the hemostasis laboratory for the anticoagulated patient. The criteria developed in the document were agreed upon by a large group of expert specialists in hematology and biochemistry from all over the country. The criteria presented here must always be considered when indicating VKA although they had to be adapted to the unequal reality of each center. Taking these premises into consideration will allow us to optimize the management of the anticoagulated patient with VKA and thus minimize thrombotic and hemorrhagic intercurrences, in order to honor our promise not to harm the patient.

Nonimmune-acquired factor XIII deficiency: a cause of high volume and delayed postoperative hemorrhage.

: Factor XIII (FXIII) levels may decrease because of surgical consumption. Acquired FXIII deficiency could be a cause of postoperative hemorrhage usually underdiagnosed in clinical practice. To determine the diagnosis confirmation rate of acquired FXIII deficiency in postsurgical patients with clinical suspicion and to compare the characteristics and evolution of patients with or without FXIII deficiency. We performed a retrospective cohort study, which included 49 inpatients who were attended at our university hospital from 2014 to 2018 with suspicion of acquired FXIII deficiency because of disproportionate postoperative hemorrhage. FXIIIA levels less than 50% was considered a deficiency. Persistence of bleeding for more than 48 h, drop in hematocrit points, red blood cells transfused units, hemoglobin levels 12-36 h after bleeding, and time elapsed from the procedure to the bleeding were assessed as outcome variables. Logistic regression was employed for both univariate and multivariate analyses. Of the 49 patients included, 27(55%) had FXIII deficiency, with a median level of 34% [interquartile range (IQR) 19-42]. Abdominal surgery was the most common [n = 21 (43%)]. All patients had routine coagulation tests within the hemostatic range. FXIII deficiency was associated with a drop of more than 4 points in hematocrit [OR 59.69 (95% CI 4.71-755.30)], red blood transfused units >2 [OR 45.38 (95% CI 3.48-590.65)], and delayed bleeding >36 h after surgery [OR 100.90 (95% CI 3.78-2695.40)]. Plasma-derived FXIII concentrate was administered to eight patients with life-threatening bleeding with resolution within 24 h. Only one deficient patient died from bleeding. FXIII levels were measured 15 days after diagnosis or more in 20 out of 27 deficient patients, with normal results. Acquired FXIII deficiency may be a frequent underdiagnosed entity that should be considered when high-volume and delayed postoperative hemorrhage is present in patients with hemostatic routine coagulation test results.

[Recommendations for the use of thromboprophylaxis in hospitalized patients with COVID-19 in Argentina]. / Recomendaciones para el uso de tromboprofilaxis en pacientes hospitalizados por COVID-19 en la Argentina.

Although the incidence is uncertain, some case reports suggest that COVID 19 infection is associated with an increased risk of venous thromboembolism. We suggest starting prophylactic anticoagulant therapy for all patients hospitalized with a symptomatic infection with COVID-19, unless contraindicated, with enoxaparin 40 mg SC daily if creatinine clearance is greater than 30 ml/min.

Si bien la incidencia es incierta, algunos reportes de caso sugieren que la infección por COVID 19 se asocia con un aumento del riesgo de tromboembolismo venoso. Sugerimos iniciar tromboprofilaxis a todos los pacientes hospitalizados por síntomas asociados con una infección por COVID-19, a menos que esté contraindicado, con enoxaparina 40 mg SC diariamente si el clearance de creatinina es mayor a 30 ml/min.

Recomendaciones para el uso de tromboprofilaxis en pacientes hospitalizados por COVID-19 en la Argentina / Recommendations for the use of thromboprophylaxis in hospitalized patients with COVID-19 in Argentina

Si bien la incidencia es incierta, algunos reportes de caso sugieren que la infección por COVID 19 se asocia con un aumento del riesgo de tromboembolismo venoso. Sugerimos iniciar tromboprofilaxis a todos los pacientes hospitalizados por síntomas asociados con una infección por COVID-19, a menos que esté contraindicado, con enoxaparina 40 mg SC diariamente si el clearance de creatinina es mayor a 30 ml/min.

Although the incidence is uncertain, some case reports suggest that COVID 19 infection is associated with an increased risk of venous thromboembolism. We suggest starting prophylactic anticoagulant therapy for all patients hospitalized with a symptomatic infection with COVID-19, unless contraindicated, with enoxaparin 40 mg SC daily if creatinine clearance is greater than 30 ml/min.

[Updated recommendations for venous thromboembolic prophylaxis in Argentina]. / Recomendaciones actualizadas para profilaxis de la enfermedad tromboembólica venosa en Argentina.

Venous thromboembolic disease (VTE) in hospitalized adults has high morbidity and mortality, is the origin of chronic complications and increased cost for the health system. Since the publication of recommendations for thromboprophylaxis in hospitalized patients in 2013, new alternatives and strategies have emerged, which motivated us to update our recommendations. Although there are different consensus and clinical practice guidelines, adherence to them is suboptimal. The different therapeutic alternatives for hospitalized adult patients (non-surgical, surgical non-orthopedic, with and without cancer, orthopedic an d pregnant) have been updated, paying particular attention to the drugs available in Argentina.

La enfermedad tromboembólica venosa (ETV) en adultos hospitalizados posee elevada morbimortalidad, es origen de complicaciones crónicas y determina incrementos de costos para el sistema de salud. Desde la publicación de recomendaciones de tromboprofilaxis en pacientes internados en 2013, han surgido nuevas alternativas y estrategias, que nos motivaron a actualizar nuestras recomendaciones. A pesar de que existen diferentes consensos y guías de práctica clínica la adherencia a las mismas es subóptima. Se han actualizado las diferentes alternativas terapéuticas para los adultos hospitalizados (clínicos no quirúrgicos, quirúrgicos no ortopédicos, con y sin cáncer, ortopédicos y embarazadas), poniendo particular atención en los fármacos disponibles en Argentina.

Recomendaciones actualizadas para profilaxis de la enfermedad tromboembólica venosa en Argentina / Updated recommendations for venous thromboembolic prophylaxis in Argentina

La enfermedad tromboembólica venosa (ETV) en adultos hospitalizados posee elevada morbimortalidad, es origen de complicaciones crónicas y determina incrementos de costos para el sistema de salud. Desde la publicación de recomendaciones de tromboprofilaxis en pacientes internados en 2013, han surgido nuevas alternativas y estrategias, que nos motivaron a actualizar nuestras recomendaciones. A pesar de que existen diferentes consensos y guías de práctica clínica la adherencia a las mismas es subóptima. Se han actualizado las diferentes alternativas terapéuticas para los adultos hospitalizados (clínicos no quirúrgicos, quirúrgicos no ortopédicos, con y sin cáncer, ortopédicos y embarazadas), poniendo particular atención en los fármacos disponibles en Argentina.

Venous thromboembolic disease (VTE) in hospitalized adults has high morbidity and mortality, is the origin of chronic complications and increased cost for the health system. Since the publication of recommendations for thromboprophylaxis in hospitalized patients in 2013, new alternatives and strategies have emerged, which motivated us to update our recommendations. Although there are different consensus and clinical practice guidelines, adherence to them is suboptimal. The different therapeutic alternatives for hospitalized adult patients (non-surgical, surgical non-orthopedic, with and without cancer, orthopedic an d pregnant) have been updated, paying particular attention to the drugs available in Argentina.

[Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay]. / Función renal y nivel plasmático de dabigatrán en el valle, medido por un ensayo de trombina diluida.

Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients' cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

Función renal y nivel plasmático de dabigatrán en el valle, medido por un ensayo de trombina diluida / Renal function and plasma dabigatran level measured at trough by diluted thrombin time assay

El dabigatrán etexilato (inhibidor directo de trombina) es eficaz en la prevención tromboembólica en pacientes con fibrilación auricular. No requiere control rutinario de laboratorio, pero dada su eliminación renal, sería importante medirlo ante el deterioro de la función renal. Los objetivos del trabajo fueron verificar la calidad analítica del ensayo tiempo de trombina diluido para medición de la concentración plasmática (cc) de dabigatrán, correlacionar las cc con las pruebas básicas de coagulación tiempo de protrombina (TP) y tiempo de tromboplastina parcial activada (APTT) y evaluarlas de acuerdo al clearance de creatinina (CLCr). Se utilizaron muestras de plasma de 40 pacientes que recibían dabigatrán 150 (n = 19) o 110 (n = 21) mg/12 horas, colectadas 10-14 horas después de la última toma. Los ensayos de trombina diluida HemosIL DTI para la medición de dabigatrán, TP y APTT (IL), fueron realizados en coagulómetros fotoópticos ACL TOP 300 y 500 (IL). El DTI presentó coeficiente de variación intraensayo < 5.4% e interensayo < 6.0%, rango de linealidad 0-493 ng/ml; cc medidas en pacientes: mediana 83 (4-945) ng/ml. Individuos con CLCr en tercil inferior (< 46.1 ml/min) presentaron cc significativamente más elevadas, 308 (49-945), que los de tercilos medio, 72 (12-190), y superior, 60 (4-118) ng/ml. Las correlaciones cc vs. APTT o TP fueron moderadas, r2 = 0.59, -0.66, p < 0.0001, respectivamente. La prueba ensayada permitió cuantificar el nivel de dabigatrán plasmático tanto en pacientes con función renal normal como deteriorada, representando una herramienta útil en situaciones clínicas como deterioro de la función renal, pre cirugía o emergencias.

Dabigatran etexilate (direct thrombin inhibitor) is effective in preventing embolic stroke in patients with atrial fibrillation. It does not require laboratory control, but given the high renal elimination, its measurement in plasma is important in renal failure. The objectives of the study were to verify the analytical quality of the diluted thrombin time assay for measurement of dabigatran plasma concentration (cc), correlate cc with classic coagulation assays, prothrombin time (PT) and activated partial thromboplastin time (APTT), and evaluate them according to the creatinine clearance (CLCr). Forty plasma samples of patients (34 consecutive and 6 suspected of drug accumulation) receiving dabigatran at 150 (n = 19) or 110 (n = 21) mg/12 hours were collected. Blood samples were drawn at 10-14 hours of the last intake. Dabigatran concentration was determined by diluted thrombin time (HemosIl DTI, Instrumentation Laboratory (IL). PT and APTT (IL) were performed on two fotooptical coagulometers, ACL TOP 300 and 500 (IL). DTI presented intra-assay coefficient of variation < 5.4% and inter-assay < 6%, linearity range 0-493 ng/ml. Patients´ cc: median 83 (4-945) ng/ml. Individuals with CLCr in the lowest tertile (22.6-46.1 ml/min) showed significantly higher median cc: 308 (49-945), compared to the average 72 (12-190) and highest tertile, 60 (4-118) ng/ml. Correlation between cc and APTT or PT were moderate, r2 = 0.59 and -0.66, p < 0.0001, respectively. DTI test allowed us to quantify plasma dabigatran levels, both in patients with normal or altered renal function, representing a useful tool in clinical situations such as renal failure, pre surgery or emergencies.

Dabigatran en plasma: tiempos de trombina diluido, Ecarin y veneno de víbora de Russell diluido / Plasma dabigatran: diluted thrombin time, Ecarin and diluted Russell Viper Venom Time / Dabigatrana em plasma: tempos de trombina diluído, Ecarin e veneno de víbora de Russell diluído

Los objetivos del trabajo fueron verificar la calidad analítica del ensayo tiempo de trombina diluido (DTI) para medición de la concentración plasmática (cc) de dabigatran comparando dos coagulómetros de detección foto-óptica, comparar los resultados con el tiempo de Ecarin (ECT) y correlacionar las cc con las pruebas básicas de coagulación Tiempo de protrombina (TP), APTT y Tiempo de trombina (TT), y tiempo de veneno de víbora de Russell con fosfolípidos concentrados (DRVVTC). Se tomaron 43 muestras de plasma en el valle (10-14 h de la última toma) de 40 pacientes que recibían dabigatran. DTI y ECT presentaron (%) repetitividad <5,4% y <7,5%, CV interensayo <6% y <9%, respectivamente, en el protocolo EP15A2, aceptables para un Error Total permitido (TEa) <15%. Las cc medidas en pacientes fueron: mediana 83 (4-945) ng/mL. La comparación de equipos ACL TOP 300 y 500 dio resultados equivalentes por procedimiento alternativo de comparación de métodos. La comparación ECT vs. DTI fue satisfactoria por regresión de Deming (pendiente 1,143, ordenada al origen -19,33). Las correlaciones de cc vs. APTT, TP y DRVVTC fueron moderadas y no lineales tendiendo a plateau a cc>350 ng/mL, r2 0,59, 0,66 y 0,59, respectivamente. El TT fue extremadamente sensible: >120 s a cc 50 ng/mL. DTI presentó un buen desempeño analítico y permitió cuantificar dabigatran plasmático a cc bajas y altas en ambos equipos utilizados. ECT presentó resultados comparables a DTI. Se verifica una correlación moderada entre cc de dabigatran y las pruebas clásicas y DRVVTC, pudiendo ser estimadores de cc a partir de los 50 ng/mL.

The aims of the study were to verify the analytical performance of Dilute Thrombin Time (DTI) test to measure plasma dabigatran concentration (cc) in two photo-optical coagulometers, compare Ecarin clotting Time (ECT) and DTI results, and correlate cc with classical coagulation tests: prothrombin time (PT), APTT, thrombin time (TT) and diluted Russell Viper Venom Time tests with high phospholipid concentration (DRVVTC). Forty three plasma samples from 40 patients taking dabigatran were drown at through (10-14 hs.since last dose). DTI and ECT showed repetitivity (%) <5.4% and <7.5%, interassay CV <6% and <9%, respectively, following EP15A2 protocol, acceptable considering a Allowed Total Error (TEa)<15%. Patients` cc: median 83 (4-945) ng/mL. The comparison between ACL TOP 300 and 500 coagulometers showed equivalent results by using the alternative method comparison test. ECT vs. DTI: acceptable by Deming`s regression (slope 1.143, Y insert -19.33). cc vs. APTT, TP and DRVVTC: nonlinear and moderate correlations with plateau reached at cc >350 ng/mL, r2 0.59, 0.66 y 0.59, respectively. TT is extremely prolonged at cc >50 ng/mL. In conclusion: DTI showed a good analytical performance in both coagulometers. ECT showed comparable results to DTI. We verified that dabigatran cc presented moderate correlations with PT, APTT and DRVVTC, and that these tests could only qualitative estimate cc >50 ng/mL.

Os objetivos do trabalho foram verificar a qualidade analítica do ensaio tempo de trombina diluído (DTI) para medição da concentração plasmática (cc) de dabigatrana, comparando dois coagulômetros de detecção foto-óptica, comparar os resultados com o tempo de Ecarina (ECT) e correlacionar as cc com os testes básicos de coagulação Tempo de protrombina (TP), APTT e Tempo de trombina (TT), e tempo de veneno de víbora de Russell com fosfolipídios concentrados (DRVVTC). Foram tomadas 43 amostras de plasma no vale (10-14 h. da última toma) de 40 pacientes que recebiam dabigatrana. DTI e ECT apresentaram (%) repetitividade <5,4% e <7,5%, CV interensaio <6% e <9%, respectivamente, no protocolo EP15A2, aceitáveis para um Erro Total permitido (TEa) <15%. Cc medidas em pacientes: mediana 83 (4-945) ng/mL. Comparação de equipamentos ACL TOP 300 e 500: resultados equivalentes por procedimento alternativo de comparação de métodos. Comparação ECT vs. DTI: satisfatória por regressão de Deming (pendente 1,143, ordenada à origem -19,33). Correlações cc vs. APTT, TP e DRVVTC: moderadas e não lineares tendendo a plateau a cc>350 ng/mL, r2 0,59; 0,66 e 0,59, respectivamente. O TT é extremamente sensível: >120 s a cc 50 ng/mL. DTI apresentou um bom desempenho analítico e permitiu quantificar dabigatrana plasmática a cc baixas e altas em ambos os equipamentos utilizados. ECT apresentou resultados comparáveis com DTI. Verifica-se uma correlação moderada entre cc de dabigatrana e os testes clássicos e DRVVTC, podendo ser estimadores de cc a partir dos 50 ng/mL.

[Prognostic value of the expression of MDR-1 in acute myeloid leukemia]. / Importancia pronóstica de la expresion de MDR-1 en la leucemia mieloblástica aguda.

An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50% of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2% SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4% SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival.

Importancia pronostica de la expresion de MDR-1 en la leucemia mieloblastica aguda / Prognostic value of the expression of MDR-1 in acute myeloid leukemia

An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50 of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2 SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4 porcento SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival (AU)

Importancia pronóstica de la expresion de MDR-1 en la leucemia mieloblástica aguda. / [Prognostic value of the expression of MDR-1 in acute myeloid leukemia]

An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50

of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2

SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4

SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival.

Importancia pronostica de la expresion de MDR-1 en la leucemia mieloblastica aguda / Prognostic value of the expression of MDR-1 in acute myeloid leukemia

An important number of patients with Acute Myeloid Leukemia (AML) experience relapse or resistance to chemotherapy. One of the mechanisms involved in this resistance is the presence of glycoprotein P170 (gp-P 170), which results of the MDR-1 gene in leukemic cells. The objective of this article is to assess the prognostic impact of the expression of MDR-1 in a group of patients treated for AML. The expression of MDR-1 was retrospectively assessed in a cohort of 55 patients with AML, older than 16 years old, who received chemotherapy from 1990 to 2000. The presence of MDR-1/gp-P170 was evaluated on bone marrow biopsy by immunohisto-chemistry. A ROC curve established that an expression of > 50 of MDR-1 on blastic cells was significant for the achievement of complete remission. The expression of MDR-1+ correlated with the presence of leucocytosis (p:0.002), expression of CD34+ cells (p:0.006), less achievement of complete remission (p:0.001), more rate of relapse (p:0.02) and of non-favorable cytogenetics (p:0.02). The event-free survival was of 21.2 SE:9.3 with a follow up of 22 months for the group of MDR-1+ versus 56.4 porcento SE 12.5 with a follow-up of 78 months for the MDR-1-group (p:0.007). It can be concluded that the expression of MDR-1 is a prognostic factor of resistance to chemotherapy. These patients present a lower rate of complete remission, a higher rate of relapse with persistence of post treatment residual disease, which produces a shorter global survival