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TESIS Def-080610 TESIS DOCTORAL UTILIDAD DE LOS BIOMARCADORES PLASMÁTICOS EN EL DIAGNÓSTICO, TRATAMIENTO Y PRONÓSTICO DE LA ENFERMEDAD CEREBROVASCULAR AGUDA Maite Mendioroz Iriarte Directores: Dr. Joan Montaner Vilallonga Dr. Israel Fernández-Cadenas Dr. José Álvarez-Sabín DEPARTAMENT DE MEDICINA. FACULTAT DE MEDICINA UNIVERSITAT AUTÒNOMA DE BARCELONA Barcelona, 2010 Esta tesis ha sido realizada en parte gracias a la financiación del Instituto Carlos III (beca para la formación en investigación) y al Fondo de Investigación Sanitaria (FIS) FI05/00081. Los experimentos se han llevado a cabo en el Laboratorio de Investigación Neurovascular (LIN) (Institut de Recerca) del Hospital Vall d’Hebron. El LIN forma parte de la red de investigación para el ictus RENEVAS (RD06/0026/0010) y de la European Stroke Network (EUSTROKE 7FP Health F2-08-202213). Algunos de los estudios han sido financiados parcialmente por becas procedentes de Biosite Inc y del FIS (FIS 05/322, FIS 06/0586, FIS PI08/361). 3 “Ves cosas y dices, ¿por qué? pero yo sueño cosas que nunca fueron y digo, ¿por qué no? George Bernand Shaw (1856-1950) 5 AGRADECIMIENTOS El esfuerzo de escribir una tesis puede parecer enorme pero se hace más llevadero si estás rodeada de personas que te quieren y que saben demostrártelo. Gracias a todos los que habéis estado a mi lado durante este tiempo y, con paciencia y cariño, me habéis llevado en volandas hasta el día de hoy. En primer lugar quiero dar las gracias a Joan Montaner, por haberme ofrecido la oportunidad de trabajar en el Laboratorio de Investigación Neurovascular durante estos años, él me ha confiado importantes retos y me ha contagiado su pasión por los biomarcadores. A Israel, por introducirme en el mundo de los SNPs y acompañarme en las excursiones GRECOS, entre otras muchas cosas, algún día te cambiarás a g-mail. A Pilar, compañera de batallas en las consultas hospitalarias y gran maestra de la exactitud científica. A mis compañeros del grupo de genética; a Alberto, que siempre me hace ver las cosas un punto más allá y persiste en su lucha contra los GOMs; y a Sophie, que es una crack. Al resto de mis compañeros de la Unidad Neurovascular y del Lab de arriba, con los que he compartido tantas y tantas reuniones; gracias también a Laura y Anita, que me asistieron en mis primeras alícuotas allá por mis, ya lejanos, comienzos. Especialmente quiero dar las gracias a mis compañeras del “zulo”, Dolors, Cristina, Jessy y Laura, las que día a día me hacen reír y, al mismo tiempo, me ayudan a concentrarme en mi burbuja. Es una suerte enorme que nos hayamos encontrado y tendremos que celebrarlo con un tiramisú. Decía William Osler que la medicina es la ciencia de la incertidumbre y el arte de la probabilidad, pero no podemos olvidar que los pacientes son de carne y hueso y que no hay nada más concreto que su sufrimiento. Aliviar ese sufrimiento debería ser el objetivo último de nuestra tarea como médicos e investigadores. A ellos, a los pacientes y a sus familiares, especialmente a los que padecen enfermedades minoritarias, quiero agradecer la confianza que me han mostrado. Gracias también a todos aquellos pacientes que de forma 7 altruista han colaborado en los trabajos de investigación que constituyen esta tesis. Gracias a mis amigos, por compartir tan buenos momentos y poblar la tierra con su descendencia; en especial a Susana, por contagiarme su indomable energía. El agradecimiento más profundo se lo debo a mis padres, Javier y Feli, ellos me han querido de una forma absolutamente incondicional y han puesto ilusión y sacrificio, a partes iguales, para que yo pudiera elegir libremente y desarrollar mi profesión. Sois mis héroes. Gracias a mi hermana, Miriam, amiga y confidente. Ella ha estado pendiente de mí en muchos momentos difíciles y ha sido un gran apoyo para redactar esta tesis. Espero que traigas ese oro líquido de las tierras belgas para que lo celebremos. Gracias a Iván, mi compañero e intérprete de mis sueños. Él conoce perfectamente el esfuerzo que me ha supuesto redactar esta tesis y me ha apoyado día a día. Gracias por compartir mi vida, mis ilusiones y sujetar la hamaca en la que descanso cada día. Por último, quiero agradecer a todas aquellas personas que he encontrado a lo largo del tiempo, y que me han enseñado, con su rigor y dedicación científica, de qué material está hecha la ciencia. 8 ÍNDICE 9 ÍNDICE ÍNDICE DE ACRÓNIMOS ………………………………………………………….……. 15 1. INTRODUCCIÓN 1.1 El Ictus Isquémico ......................................................................................... 19 1.1.1 Epidemiología y Factores de Riesgo ...................................................... 25 1.1.2 Diagnóstico del Ictus Isquémico ............................................................. 25 1.1.2.1 Pruebas de Evaluación Diagnóstica ................................................. 29 1.1.2.2 Etiología del Ictus Isquémico. La Clasificación TOAST .................... 33 1.1.3 Tratamiento del Ictus Isquémico en Fase Aguda .................................... 33 1.1.3.1 El Tratamiento Fibrinolítico ............................................................... 33 1.1.3.2 Otros Tratamientos ........................................................................... 38 1.1.3.3 Eficacia del Tratamiento Fibrinolítico: la Recanalización del vaso ............................................................................................. 40 1.1.3.4 Seguridad del Tratamiento Fibrinolítico: la Transformación Hemorràgica ......................................................... 44 1.1.4 Pronóstico del Ictus Isquémico ............................................................... 48 1.1.4.1 Pronóstico Vital ................................................................................. 48 1.1.4.2 Pronóstico Funcional ........................................................................ 49 1.1.4.3 Factores Pronósticos ........................................................................ 50 1.2 Los Biomarcadores en el Ictus ...................................................................... 51 1.2.1 Utilidad de los Biomarcadores en el Ictus ............................................... 51 1.2.2 Biomarcadores y Diagnóstico del Ictus ................................................... 54 1.2.2.1 Biomarcadores relacionados con el Diagnóstico del Ictus …………………………………………………………………... 57 1.2.2.2 Caspasa 3 ......................................................................................... 61 1.2.2.3 Dímero D ........................................................................................... 64 1.2.2.4 S100B ............................................................................................... 68 1.2.2.5 Srage ................................................................................................ 72 1.2.3 Biomarcadores y Tratamiento del Ictus Isquémico ................................ 76 11 1.2.3.1 Biomarcadores relacionados con la Eficacia del Tratamiento Fibrinolítico ………………………………………………………………. 77 1.2.3.2 Trombina ........................................................................................... 78 1.2.3.3 Biomarcadores relacionados con la Seguridad del Tratamiento Fibrinolítico .................................................................................... 84 1.2.3.4 Poteína C Activada (APC) ............................................................. 88 1.2.4 Biomarcadores y Pronóstico del Ictus ................................................. 1.2.4.1 Biomarcadores relacionados con el Pronóstico del Ictus .............. 92 1.2.4.2 Osteopontina (OPN) ...................................................................... 95 1.2.4.3 Péptido Natriurético Cerebral (BNP) ............................................. 97 2. OBJETIVOS …………………………………………………………………………. 105 3. COPIA DE LAS PUBLICACIONES ……………………………………………….. 107 3.1 Biomarcadores plasmáticos en la enfermedad vascular cerebral isquémica …….. 109 3.2 A panel of biomarkers including caspase-3 may differentiate 111 acute stroke from stroke mimicking conditions at the emergency department ……… 3.3 Differentiating ischemic from hemorrhagic stroke using plasma biomarkers: the S100b/rage pathway ….. ………………………………………………. 129 3.4 Lower concentrations of thrombin-antithrombin complex (tat) correlate to higher recanalisation rates among ischaemic stroke patients treated with t-PA … 147 3.5 Endogenous activated protein c predicts hemorrhagic transformation and mortality after tissue plasminogen activator treatment in stroke patients ………. 149 3.6 Osteopontin predicts long-term functional outcome among ischemic stroke patients …………………………………………………………….. 151 3.7 Brain natriuretic peptide predicts worsening and mortality in acute stroke patients …………………………………………………………………….. 169 4. RESUMEN Y DISCUSIÓN DE LOS RESULTADOS ……………………………. 179 5. CONCLUSIONES …………………………………………………………………… 201 6. REFERENCIAS BIBLIOGRÁFICAS ………………………………………………. 205 7. ANEXOS ……………………………………………………………………………… 239 12 ÍNDICE DE ACRÓNIMOS 13 ACRONIMOS ACM: arteria cerebral media Fn: fibronectina AGEs : advanced glycation FpA: fibrinopéptido A endproducts GFAP: glial fibrillary acidic protein AGTRL1: gen del receptor de la GWAS: genome wide association angiotensina II study AIT: accidente isquémico transitorio HDL: high-density lipoprotein ALOX5AP: arachidonate 5- HIF-1α: hypoxia-inducible factor 1 lipoxygenase-activating protein alfa. ANP: péptido natriurético atrial HTA: hipertensión arterial APC: activated protein C ICAM-1: intercellular adhesion AST: Australian Streptokinase Trial molecule-1
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