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PDF Hosted at the Radboud Repository of the Radboud University Nijmegen PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/72445 Please be advised that this information was generated on 2021-10-09 and may be subject to change. Thrombin Generation Molecules and Tools Een wetenschappelijke proeve op het gebied van de Natuurwetenschappen, Wiskunde en Informatica Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann, volgens besluit van het College van Decanen in het openbaar te verdedigen op maandag 3 november 2008 om 15:30 uur precies door Sander Sebastiaan van Berkel geboren op 19 juni 1979 te de Bilt Promotores: Prof. dr. F.P.J.T. Rutjes Prof. dr. H.C. Hemker (Universiteit Maastricht) Co-promotor: Dr. F.L. van Delft Manuscriptcommissie: Prof. dr. ir. J.C.M. van Hest Dr. ir. P.J.L.M. Quaedflieg (DSM Pharmaceutical Products, Geleen) Dr. ir. D.T.S. Rijkers (Universiteit Utrecht) Paranimfen: Stan Groothuys Ton Dirks The research described in this thesis was financially supported by the Council of the Technical Sciences (STW) of the Netherlands Organization for Scientific Research. van Berkel, S.S. (Sander) Thrombin Generation; Tools and Molecules Printing: PrintPartners Ipskamp ISBN: 90-9023540-0 Cover design: Remko van Vught No part of this book may be reproduced by any mechanical, photographic or electronic process, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use without the written permission of the author. Gelukkig is de mens die wijsheid vindt en inzicht verkrijgt (Spreuken 3:13) Fortunate is the man who finds wisdom and that gathers understanding Voorwoord Het schrijven van een proefschrift dat is één, het schrijven van een dankwoord dat is een tweede. Aangezien heel veel mensen hebben bijgedragen, hetzij door middel van goede ideeën, praktisch werk of in de vorm van mentale steun, wil ik zonder één uitzondering te maken al die mensen bedanken die daartoe behoren. Toch wil ik de volgende pagina’s gebruiken om een aantal mensen in het speciaal te bedanken. Ten eerste wil ik Prof. Floris Rutjes hartelijk danken voor het in mij gestelde vertrouwen. Floris, de afgelopen vier jaar heb ik intensief van jouw kennis gebruik mogen maken. Ik heb dan ook veel geleerd in die periode en ik wil je daar heel graag voor bedanken. Als tweede wil ik graag mijn andere promotor Prof. Coen Hemker bedanken voor zijn inspanning om mijn promotieonderzoek tot een succes te maken. Coen, “domme vragen bestaan niet, domme antwoorden wel.” Dank je dat je altijd mijn ‘domme vragen’ van een juist antwoord wist te voorzien. Floris van Delft, jou wil ik graag bedanken voor je begeleiding, je praktische weetjes, je creatieve, nieuwe ideeën, en bij afwezigheid van andere Floris je supervisie. Graag wil ik de leden van de manuscriptcommissie (Jan van Hest, Dirk Rijkers en Peter Quaedflieg) bedanken voor hun inspanningen en suggesties met betrekking tot mijn proefschrift en hun betrokkenheid bij de voortgang van mijn project. Veel mensen hebben bijgedragen aan mijn promotie, maar slecht twee mensen hebben mij gestimuleerd om te gaan promoveren. En die mensen (Nanouk Verbeek en Nicole van Straten) ben ik daar dan ook zeer dankbaar voor, want het was geweldig, en ja ik zou het zo nog een keer doen! Er is maar één daadwerkelijke reden dat dit boekje zo absurd dik is geworden en dat komt door de inspanning van vele studenten en dat is wel een bedankje waard. Jordi, wat heb jij geleden! Niet alleen omdat je mijn eerste “uitprobeer-student” was maar ook vanwege het project waar je aan werkte. Desalniettemin hebben we ontzettend veel lol gehad, getuige de rode en blauwe vlekken op de grond! Bas, alias bouwvakker. Elke dag schouders eronder, een glimlach op je gezicht en aan het werk! Geweldig die instelling, vooral omdat het altijd gepaard ging met een flinke dosis inzet en uiteindelijk mooie resultaten heeft opgeleverd! Marjoke, 223 experiment en een verslag van 83 pagina’s (exclusief ministage)... Ik ben dan ook zeer benieuwd naar de dikte van jouw proefschrift. Promotieonderzoek, met jou mentaliteit, zal absoluut slagen! Dan hebben we Silvie, klein blond meisje dat haar hoofdvak stage vrijwel geheel zelfstandigheid heeft uitgevoerd (aangezien ik er niet altijd was...). Vervolgens ook nog op de proppen komen met mooie resultaten, ik heb dan ook alle vertrouwen in jouw als AiO. Helene, ik heb een geweldige hoeveelheid respect voor jou. Als student van mij (en Ton) heb jij je geweldig ingezet om fantastische resultaten te behalen. Zelf na je stage heb je nog de nodige experimenten uitgevoerd om maar te kunnen publiceren, en het is gelukt, super! Naast bovengenoemde studenten heb ik ook het genoegen gehad om “tweede supervisor” te zijn van Dennis Pingen en Marloes v.d. Wal. Ook jullie wil ik bedanken voor jullie inzet en enthousiasme waarmee jullie hebben bijdragen aan mijn promotieonderzoek. Verder wil ik graag mijn ministage studenten (Sanne, Remko, Maciej, Marjoke en Silvie) bedanken voor een ieder zijn bijdrage. Veel van het onderzoek dat ik heb gedaan was in samenwerking met andere en dat betekent nog meer mensen om te bedanken. Om te beginnen Kaspar, samen hebben wij een heel mooi project op poten gezet waarvan ik hoop dat het een mooie plaats in jou proefschrift krijgt. Het was niet alleen leuk om jou samen te werken maar ook zeer leerzaam en jouw enthousiasme maakt het helemaal een feest! Verder wil ik een aantal mensen van nucleaire geneeskunde (Prof. Otto Boerman en dr. Peter Laverman) bedanken voor een goede en succesvolle samenwerking. Natuurlijk zijn er een groot aantal mensen die hebben bijgedragen aan een fantastische werksfeer en/of behulpzaam zijn geweest tijdens mijn promotieperiode. Hierbij denk ik aan mensen van lab 03.230 (Stan, Sjef, Dennis, Koen, Brian, Valeria, Jasper en alle student), UL379 (Piotr en Roy), en het lab in Maastricht (Rob, Raed en Erik), Chiralix (in het bijzonder Richard Blaauw), en natuutrlijk alle mensen van de v Rutjes, van Hest, Nolte en Rowan groep (dus zo’n beetje iedereen!). Daarnaast wil ik de mensen verantwoordelijk voor massa-spectrometrie, NMR-spectrometrie, kristallografie en logistiek bedanken voor hun inzet en ondersteuning. Er zijn nog twee mensen in het speciaal zonder wie er misschien geen promotieonderzoek, proefschrift en promotie waren geweest. Deze mensen, Peter van Dijk en Jacky Versteeg, zijn goud waard. Jullie steun en oneindige bereidwilligheid om mij te helpen is ongehoord en mijn dank daarvoor is groot. I also wish do thank my foreign colleagues and friends (Marta, Dani, Pili, Heather, Daniel, Andres, Marco, Paco, Valeria, Nuria, Anna and many others) for the great times in the lab but especially out-side of the lab. You made me realized that there is still a lot to learn from other cultures and habits. Een andere niet onbelangrijk buiten-het-lab activiteit waren de bowling avonden waarvoor ik de mensen van het bowlingteam, Roelieboelie, Johan (alias V), Ton, Kassie en Bas G. zeker niet onbetuigd wil laten. Het waren geweldige avonden en ik hoop dat we deze in de toekomst zeker zullen blijven herhalen! Dan nog een speciaal dankwoord voor mijn paranimfen. Ton, veel van het werk beschreven in dit proefschrift is voortgevloeid uit samenwerkingen die ik met jou heb gehad. In alle gevallen heeft dit geleid tot geweldig goed werk. Ik dank je voor al energie die je in onze projecten hebt gestoken, een betere paranimf had ik mij niet kunnen wensen! Stan, mijn labmaatje, mijn drinkgabber, en nu ook mijn paranimf. Dank je voor alle dingen die je mij hebt geleerd en alle geweldige momenten op- en buiten het lab. Maar bovenal bedankt voor een fantastische vriendschap! Maria, life can sweep you off your feet and take you in all kinds of directions. One of these directions resulted in me meeting you. Ever since I am with you I feel like I can do everything! You make me see what is important in life, and that’s not always work. You have brought out the best in me, especially in the last months. And for all of this and even more I thank you. Te quiero cariño. Mijn laatste woorden zijn voor mijn familie (Syb, Sas, Mam, Pap, Robert en natuurlijk Yannick). Jullie zijn een geweldig stelletje mensen! Zonder jullie permanente, onvoorwaardelijk steun, aandacht, zorg en liefde zou ik dit nooit hebben bereikt. Maar mooier is nog dat ik dankzij jullie het gevoel van onmetelijk dankbaarheid heb leren kennen. Bedankt voor alles! Perfectum est. Sander vi Table of contents Voorwoord v List of abbreviations x Chapter 1 Introduction: Account on Thrombin Generation 1.1 Thrombosis 14 1.2 Haemostatic system 15 1.2.1 Coagulation mechanism 15 1.2.2 Feedback activation and inhibition 19 1.2.3 Role of platelets and surface bound enzymes 20 1.2.4 Fibrinolysis 20 1.3 Measuring thrombin 21 1.3.1 Classical thrombin generation test 22 1.3.2 Optical density based thrombin generation test 23 1.3.3 Fluorescence based thrombin generation test 25 1.4 Application of the thrombin generation test 27 1.4.1 Diagnosis 27 1.4.2 Treatment 28 1.5 Substrate development 29 1.5.1 Fluorogenic peptide substrates 30 1.5.2 Biohybrid fluorogenic peptide substrates 33 1.6 Outline of thesis 34 1.7 References 36 Chapter 2 Design and Synthesis of Novel Peptide-based Fluorogenic Thrombin Substrates 2.1 Introduction 42 2.2 Design and synthesis of peptide-based fluorogenic substrates 43 2.3 Synthesis of fibrinogen-like fluorogenic
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