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Genètica Aplicada a La Clínica Neurovascular

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Genètica Aplicada a La Clínica Neurovascular ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials dʼinvestigació i docència en els termes establerts a lʼart. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix lʼautorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No sʼautoritza la seva reproducció o altres formes dʼexplotació efectuades amb finalitats de lucre ni la seva comunicació pública des dʼun lloc aliè al servei TDX. Tampoc sʼautoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices. WARNING. The access to the contents of this doctoral thesis and its use must respect the rights of the author. It can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes. Tesis doctoral Departament de Medicina GENÈTICA APLICADA A LA CLÍNICA NEUROVASCULAR Alberto Del Río Espínola Israel Fernández Cadenas Joan Montaner Villalonga José Álvarez Sabín Director Aquesta tesi doctoral s’ha realitzat al Laboratori de Recerca Neurovascular de l’Institut de Recerca de l’Hospital Universitari Vall d’Hebron, grup de recerca consolidat per l’Agència de Gestió d’Ajuts Universitaris i de Recerca de la Generalitat de Catalunya 2009-2013 (Nº expedient SGR 432; Grup de Recerca en Malalties Neurovasculars). El Laboratori de Recerca Neurovascular és membre de les xarxes RENEVAS (RD06/0026/0010), European Stroke Network (EUSTROKE 7FP Health F2-08-202213), International Genetics Stroke Consortium i del Consorci Espanyol de Genètica (Genestroke). El projecte Geno-tPA ha rebut el suport de les beques FIS (PJ060586) i Ramón Areces (2006). M‟'agradaria donar les gràcies, en primer lloc, als meus directors de tesi: Israel Fernández, Joan Montaner i José Álvarez Sabín per la seva confiança i consell durant aquests anys. No puc oblidar-me tampoc dels meus companys de laboratori, en particular tots els becaris que, com jo, s'han engrescat a l'aventura d'una tesi (la Tere, la Morancho, les Mires i la Jessy). ¡Ànims perquè, tard o d‟hora, tot arriba! El Manolo i la Dolors, amb el SPSS i els programilles del “R”, o la Cris Nafria que m‟ha demanat un munt d‟històries; la Maite i la Pilar, que sempre m‟aporten el punt de vista clínic tant necessari. La Miri pels seus consells a cultius i la Sophie per les seves correccions d‟anglès i francès ¡Merci beaucoup! I tots els neuròlegs de la unitat d‟ictus i els auxiliars (Sandra i Borja) i tècnics (Anita i Cris) per la seva ajuda a la recollida de mostres, la base d‟aquest treball. També vull agrair als postdocs (l'Anna Rosell, la Maria Borrell, la Mar i la Lidia) els seus valuosos consells als lab-meetings. Als membres del laboratori de patologia Mitocondrial (el Marc, el Javi, la MªCarmen, la Gise, el Ramiro, el Lluis, l'Emiliano, el Tomàs, la Yolanda i la MªJesús) i els seus caps (Ramón, Elena i Toni) perquè el laboratori 104 ha estat una segona llar per mi. A la Dorita del grup de Cardiologia, per introduir-me al món de la coagulació i als residents i adjunts de Bioquímica (Dra. Chacón, Roser, Marieta, Paula, Clara, Albert,...) per fer-me un cop de mà amb el nefelòmetre i el Triturus ¡I iniciar-me a la cuina japonesa! A les Roses, el Ricardo, la Marichu, la Marta Valeri, l'Àlex, la Irene i la Fàtima de la UCTS, perquè no podria comptar els picoxips o les seqüències que m'han “punxat” i sempre s'han implicat a la recerca que fem. I a les noies de Pneumologia (Maribel, Laura, Sara, Lola i Chus) perquè baixar a fer extraccions de DNA amb elles sempre és un plaer. 0 A tothom qui va colaborar al projecte CADASIL, perquè la seva ajuda des del primer dia no té preu: els Drs. García-Patos, Bassas, Ferrer, Fernández, Pozo i en especial l'Esther Solé, amb qui hem fet mà a mà la posada a punt del diagnòstic genètic. I també a tots els qui m'han donat consell sobre la via Notch: el Valentí, la Lide, el Pep, el Jordi, la Sònia, el Ramón Gimeno,... I a tota la Unité 740 de l‟INSERM (Charles, Marie, Valérie, Barbara, Céline, Minh, Snaigune, Mélanie, Françoise , Anne Blécon, Gwéndola, Pierre, Alexandra, Anne Joutel i Elisabeth) per la seva acollida durant els mesos que vaig passar a París. Van ensenyar-me que a la recerca, les idees són molt més importants que els diners. D‟altra banda, també vull donar les gràcies a tots aquells amb qui m'ho he passat molt bé dins i fora del lab: en Borja i el David, les noies d'Anatomia Patològica o les d‟Oncologia, per la mítica gresca amb el ron “Arehucas” o els viatges a Madrid i Menorca. I fent memòria, agrair a tota la colla dels ADHs (Xavi, Sergio, Gènia, Armando, Jone, Esther, Emma, Xavier i Jaume) i la UAB (Edu, Papitu i Ton) per engrescar-me a fer recerca durant aquelles pràctiques de l'AGAUR. No voldria acabar sense donar les gràcies també als meus amics i la família, perquè són qui t'ajuden a oblidar-te de la feina quan els resultats no t'acompanyen. I com no, a la Laura, la meva xicota, qui sempre m'ajuda a veure les coses d'una altra manera i no ser tan caparrut. I la seva familia, perquè em fan sentir un més de la colla i ens ho passem d'allò més bé viatjant amunt i avall. Segur que m‟he deixat algú, perquè heu estat molts els que m‟heu ajudat perquè hagi pogut escriure aquest treball, espero que em perdoneu. ¡GRÀCIES A TOTS! 1 I. ÍNDEX I. Índex .................................................................................................................. 2 I.I Índex d'abreviatures ............................................................................... 6 II. Executive summary ............................................................................................. 11 A. Introducció 1. L'ictus ........................................................................................................ 16 1.1 L'ictus hemorràgic ....................................................................... 17 1.2 L'ictus isquèmic ....................................................................... 20 1.2.1 Classificació etiològica .................................................. 20 1.2.2 Classificació clínica d'Oxford ....................................... 23 2. Historia natural de l'ictus isquèmic ........................................................... 24 2.1 Canvis hemodinàmics durant la isquèmia ................................... 25 2.2 La cascada isquèmica ............................................................... 25 2.3 Fenòmens inflamatoris durant la isquèmia cerebral ...................... 28 2.4 Mecanismes de mort cel·lular ...................................................... 32 3. Hemostasia, coagulació i fibrinòlisi ............................................................. 35 3.1 La coagulació .............................................................................. 36 3.1.1 Via extrínseca ............................................................... 38 3.1.2 Via intrínseca ............................................................... 39 3.1.3 Via comuna ............................................................... 41 2 3.2 L'anticoagulació .......................................................................... 42 3.2.1 Inhibidors dels factors de coagulació ............................. 42 3.2.2 Reguladors dels factors de coagulació ............................. 44 3.3 La fibrinòlisi .............................................................................. 44 3.4 L'antifibrinòlisi .............................................................................. 46 3.4.1 Inhibidors de la pro-fibrinòlisi ....................................... 46 3.4.2 Anti-fibrinòlisi directa ...................................................... 48
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