Capítulo 11

Rol del laboratorio en el tratamiento del tromboembolismo venoso

Susana Ouviña

CONTROL DEL TRATAMIENTO CON DICUMARINICOS

Los dicumarínicos son antagonistas de la vitamina K y actúan interfiriendo en la interconversión de la vitamina K y su epóxido, generando deficiencia funcional de los factores II,VII, X y IX y de los inhibidores Proteína C, S y Z.

El control y seguimiento de los pacientes bajo tratamiento con dicumarínicos se realiza mediante el tiempo de protrombina (TP) a partir del cual se calcula el RIN (Razón Internacional Normatizada) (1). El TP es sensible a la deficiencia de factores II, VII y X (vitamina K dependientes); al factor V y a deficiencias menores de 80 mg/dl de fibrinógeno.

RIN= [TP paciente (seg) / MNTP (seg)] ISI

MNTP es la media geométrica del TP calculada en cada laboratorio con al menos 20 plasmas obtenidos en el día de sujetos sanos adultos. El ISI (Índice Internacional de Sensibilidad) es un valor que relaciona la tromboplastina, reactivo que se utiliza para realizar el TP, con un patrón internacional; este valor es informado por el fabricante en el inserto del reactivo y es lote, aparato y método de detección dependiente (2). El valor de ISI del sistema tromboplastina/equipo debería ser menor de 1,2- 1,4. A mayor ISI, mayor será el error en la determinación del RIN, con el consiguiente impacto en la conducta terapéutica. El TP/RIN no se ve afectado por heparina, ya que las tromboplastinas comerciales contienen un inhibidor de la heparina. En el caso de heparina no fraccionada, concentraciones en el plasma del paciente mayores de 1 UI/ml afectarían el TP/RIN y en el caso de las heparinas de bajo peso molecular concentraciones mayores de 2 U anti-FXa/ml afectarían el TP/RIN.

CONTROL DEL TRATAMIENTO CON HEPARINA NO FRACCIONADA

APTT

Es la prueba de elección para el control de la terapia con heparina no fraccionada (HNF) (3). Se considera que el tratamiento es adecuado cuando el APTT del paciente prolonga entre 1,5 y 2,5 los valores del APTT basal, que corresponde a una heparinemia de 0,2-0,4 UI/ml (rango terapéutico recomendado, probado en animales) o de 0,3 a 0,7 U anti-FXa/ml si se utilizaron calibradores que expresan su actividad en unidades de anti-FXa. Los diferentes reactivos comerciales de APTT varían en su respuesta a la heparina. Debido a esto debe establecerse el rango terapéutico en cada laboratorio para el sistema reactivo APTT/equipo: es el rango de APTT que corresponde a 0,2-0,4 UI/ml ó 0,3-0,7 U anti-FXa (4). Toma de muestra para el control: HNF en infusión continua: deben haber transcurrido al menos cuatro horas de haber aplicado el bolo inicial; HNF endovenoso intermitente: realizar el control una hora antes de la siguiente aplicación; Inyección subcutánea (heparina cálcica): si se aplica cada doce horas, la toma de muestra debe hacerse en la mitad del intervalo de doce horas, es decir, a las seis horas de la aplicación. Si la dosis debió ser modificada, el nuevo control puede realizarse a las dos horas del cambio. Una complicación importante de la terapia con heparina es la trombocitopenia inducida por heparina por lo cual debe monitorearse cada 2 o 3 días el recuento de plaquetas (5). Generalmente la realización del APTT y del recuento de plaquetas sería suficiente para el control.

Determinar heparinemia es útil en ciertos casos, por ejemplo: cuando no se logra una adecuada prolongación a pesar de altas dosis de heparina, cuando la variabilidad de los resultados de APTT dificulta el control del tratamiento o en casos en que el APTT basal del paciente está muy prolongado (por ejemplo por presencia de inhibidor lúpico).

HEPARINA DE BAJO PESO MOLECULAR

Las heparinas de bajo peso molecular (HBPM) son obtenidas a partir de la HNF mediante despolimerización de sus cadenas por métodos químicos o enzimáticos. Se obtienen productos que son diferentes estructuralmente y que poseen distinta capacidad antitrombótica/anticoagulante (anti-FXa/anti-FIIa). La HBPM se une a la antitrombina potenciando la inhibición del FXa. Las heparinas de bajo peso molecular en general no requieren de control de laboratorio, pero existen ciertas situaciones clínicas en las que sería conveniente hacerlo: pacientes añosos, pacientes pediátricos, embarazo, obesos, o ante fallo renal o hepático (6).

Determinación de la actividad anti-FXa

El método cromogénico es el recomendado. La curva de calibración debe realizarse con la heparina que esté recibiendo el paciente o un calibrador comercial calibrado contra estándar internacional, el cual tiene una relación anti-FXa/anti-FIIa de 2,5. Estos calibradores no pueden utilizarse en el caso de bemiparín, cuya relación anti-FXa/anti-FIIa es 1:9. El nivel plasmático máximo de la HBPM luego de la inyección subcutánea se alcanzaría entre las 3 y las 5 horas; la toma de muestra debería hacerse a las 4 horas de la aplicación.

FONDAPARINUX

El fondaparinux, un pentasacárido sintético, es un inhibidor indirecto del FXa, que se enlaza a la antitrombina con alta afinidad potenciando la unión de ésta al FXa. El fondaparinux produce, a dosis fijas subcutáneas, una respuesta predecible sin necesidad de monitorización (7).

Determinación de la actividad anti-FXa

El método cromogénico es el recomendado. La curva de calibración debe realizarse con calibradores comerciales específicos para fondaparinux o bien preparando un pool de plasmas normales con diluciones crecientes de fondaparinux.

CONTROL DE LOS NUEVOS ANTICOAGULANTES ORALES

Los denominados nuevos anticoagulantes orales (NOACs) son inhibidores directos y selectivos del FIIa o del FXa que fueron desarrollados para ser utilizados en dosis fijas y no necesitar ser controlados en el laboratorio. El efecto inhibitorio de los NOACs sobre el FIIa o el FXa es directo, o sea que no requiere la acción de la antitrombina. Al presente no poseen antídoto. Si bien los NOACs no necesitan control de laboratorio, existen ciertas situaciones clínicas en las que sería necesario hacerlo: pacientes añosos, obesos, falla renal o hepática; en caso de sangrado del paciente, previo a una cirugía o cualquier procedimiento invasivo, o en caso de evaluar el efecto de otra medicación que esté recibiendo el paciente.

Dabigatrán

Es un inhibidor directo y selectivo del FIIa y el pico de acción se alcanza a las 2 horas de su administración. La concentración en plasma de dabigatrán puede evaluarse a través de cromatografía líquida de alta resolución seguida de espectrometría de masa (HPLC-MS). El APTT se prolonga a mayor concentración de dabigatrán en plasma pero a concentraciones elevadas de la droga el APTT no varía en forma lineal con la concentración, tendiendo a un plateau; y a concentraciones bajas podría dar normal. El Tiempo de Trombina es muy sensible a la presencia de dabigatrán, su utilidad sería como indicador de ausencia de la droga en plasma si da normal. No sirve para monitorear el tratamiento (8).

Tiempo de Coagulación con Ecarina (TCE)

El reactivo utilizado es un veneno de víbora Echis Carinatus que activa el FII a meizotrombina, que a su vez actúa sobre el Fibrinógeno generando fibrina. La prolongación del TCE es proporcional a la concentración de dabigatrán en plasma, pero si la concentración es mayor de 500 ng/ml la respuesta del TCE tiende a un plateau. La curva de calibración debe realizarse con calibradores específicos. La meizotrombina formada también puede determinarse por método cromogénico que presenta una buena linealidad entre la absorbancia determinada y la concentración de la droga.

Diluted Thrombin Inhibitor Time (DTI)

Este test es un Tiempo de Trombina realizado con trombina humana en alta concentración y la muestra del paciente diluida en plasma normal en relación 1:8. DTI correlaciona bien hasta 500 ng/ml de dabigatrán. Existe un reactivo comercial que contiene pool de plasmas normales liofilizados y trombina humana liofilizada.

Rivaroxabán

Es un inhibidor directo y selectivo del FXa y el pico plasmático se registra a las 3 horas (9). La concentración de la droga en plasma se puede determinar por HPLC-MS como en el caso del dabigatrán.

Determinación de la actividad anti-FXa por método cromogénico

El efecto del rivaroxabán en plasma puede ser evaluado a través de su actividad anti-FXa por método cromogénico. Si bien se basa en el método para dosar heparina de bajo peso molecular, debe estar adaptado para rivaroxabán: diluciones, calibradores apropiados de la droga.

TP/RIN: El TP es sensible a la acción de rivaroxabán, pero no a bajas concentraciones (menos de 50 ng/ml), la respuesta varía según la tromboplastina utilizada y el ISI para rivaroxabán es diferente del ISI para los dicumarínicos. Un TP realizado con una tromboplastina sensible no descartaría la presencia de la droga a baja concentración, pero excluiría nivel terapéutico de anticoagulación.

Tiempo de Coagulación inducido por Protrombinasa (PICT)

Este test utiliza FXa, veneno de víbora de Russell y calcio como reactivos, tiene una relación lineal (tiempo vs concentración) hasta 200 ng/ml de la droga, a concentraciones mayores pierde sensibilidad presentando un plateau.

Apixabán

Inhibe de manera directa, específica, competitiva y reversible al FXa. Tiene una vida media entre 7-11 horas (10). Como en el caso del dabigatrán y el rivaroxabán, la concentración de apixabán en plasma puede determinarse por HPLC-MS.

Determinación de la actividad anti-FXa por método cromogénico

El nivel de apixabán en plasma puede evaluarse a través de su actividad anti-FXa por método cromogénico. Como en el caso del rivaroxabán, se recomienda no usar test con el agregado de antitrombina, adaptar el método para apixabán con diluciones adecuadas y utilizar calibradores específicos.

TP/RIN

El TP es poco sensible a la presencia de apixabán, la respuesta varía mucho según la tromboplastina utilizada y la concentración de la droga. A concentraciones terapéuticas la razón TP paciente/TP normal es menor de 1,2 con la mayoría de las tromboplastinas, por lo que no puede utilizarse para el monitoreo de apixabán.

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