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The Influence of Coagulation Factor XIII-A V34L Mutation on Clot Formation and Stability

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The Influence of Coagulation Factor XIII-A V34L Mutation on Clot Formation and Stability The influence of coagulation factor XIII-A V34L mutation on clot formation and stability Adomas Baranauskas Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Faculty of Medicine and Health October, 2019 The candidate confirms that the work submitted is his own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Adomas Baranauskas to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. Acknowlegements This research has been carried out by myself (Adomas Baranauskas) with the support of Dr Cédric Duval, Professor Robert Ariëns, Dr Richard Cubbon and Miss Helen McPherson. Dr Cédric Duval has contributed in training, advice and support in almost every matter throughout the PhD project, with significant contributions when using recombinant protein purification equipment as well as performing blood vessel isolation and FeCl3 injury during in vivo experiments. Professor Robert Ariëns has contributed to the work by advising and structuring the workflow of the project while providing feedback on data interpretations and thesis writing. Dr Richard Cubbon has contributed by familiarising me with light sheet microscope and image acquisition. Miss Helen McPherson has contributed by teaching me clot contraction experiments as well as overall good laboratory practice. In addition, I would love to take the opportunity to acknowledge people more personally and express my gratitude as follows: First and foremost, it would be an understatement saying that I had great supervision during my PhD here in LICAMM, University of Leeds. My supervisors Professor Robert Ariëns and Dr Cédric Duval were nothing but excellent, showing perfect balance between guiding me and trusting me with a freedom to act, which made feel like I was always able to use any given opportunity without worrying about failure. I was constantly surprised and humbled by the fact how frequently they made time for me to ask for advice or help, which I realise, has been an unbelievably fortunate situation for a PhD student and ensured that I have made the most out of my diverse research project. I am extremely grateful to both of my lovely supervisors for allowing me on-board and being remarkably inspiring, caring and thoughtful leaders. ii So many people have made my PhD experience enjoyable, that it would be difficult to name them all! Every single person from the Ariëns and Philippou group people made me feel like a part of a close, friendly and supportive community. I am grateful to all, who helped me along the way, cheered me up and facilitated my PhD work in the process. Huge thanks to all of the core team and, especially Mrs Julie Mawson, who made sure that I always had clean equipment to work with even if it meant bothering her at unusual hours. I’d like to thank Miss Helen McPherson for being so caring and thinking about the wellbeing of the whole group. Helen seemed to always know where things are put, how to run any experiment, and most importantly, proactively helped everyone at any moment. I am very grateful to Dr Richard Cubbon and Dr Ruth Hughes for familiarising me with light sheet imaging as well as Dr Nadira Yusupovna Yuldasheva and Dr Mike Drozd for expanding my knowledge about in vivo work. Big thanks to Dr Nathan Asquith for being a great friend, both encouraging and uplifting at moments of stress. I am also grateful to Dr Stephen Baker, who seemed to always have interesting matters to discuss, a joke to crack and made the office hours sociable. I would love to thank Dr Kingsley Simpson as well, for being a massive fun in the lab. And last, but not least, I am forever grateful to my supportive family and my love Ieva, who has always been by my side, keeping me motivated to work hard and inspiring me with her unbelievable work ethic. iii Abstract Background: Coagulation factor XIII (FXIII) is a key enzyme in stabilising blood clots by cross-linking fibrin molecules together, amongst other effects on fibrinolysis and matrix protein stabilisation. The human FXIII-A V34L sequence variant leads to increased activation rates, forming clots with thinner fibrin fibres and smaller pores, and has been reported to show protective effects against thrombotic diseases like venous thromboembolism. However, the complete mechanism(s) underpinning this effect has hitherto remained elusive. Aim: To establish a murine FXIII-A L34V model and study the role of this sequence variant, as well as that of FXIII itself, in thromboembolic disease. Methods: FXIII-A Knock-Out (FXIII-/-, already available in the laboratory), FXIII-A 34Val (generated by MRC Harwell for Leeds) and FXIII-A 34Leu (common variant, wild-type) mice were compared in their growth, plasma FXIII activation rates (biotin incorporation assay), turbidity for clot structure, fibrinogen concentrations (ELISA assay) and FXIII-A antigen levels (western- blotting). Whole blood clotting and lysis was measured by rotational thromboelastometry (ROTEM). Whole blood clot contraction, erythrocyte extrusion (haemoglobin) and two-hour clot weights were quantified. For pulmonary and cerebral embolism models, FeCl3 vascular injury was performed on inferior vena cava and carotid artery, respectively. Lungs or brains were optically cleared and imaged with a light sheet microscope. Pulmonary emboli volume and count were quantified using software, while cerebral emboli were quantified manually. iv Results: No significant differences between 34Leu and 34Val mice growth, whole blood contraction, serum haemoglobin, clot weight, ROTEM, plasma FXIII-A and fibrinogen levels were observed. FXIII-/- mice plasma contained no FXIII-A antigen, showed negligible fibrin cross-linking activity and had similar levels of fibrinogen as FXIII sufficient mice. FXIII-/- clots were less firm, easier to lyse, slower to form, retained fewer red blood cells, were lighter and formed thicker fibres than FXIII sufficient clots. 34Leu mice plasma showed increased FXIII-A activation rates over 34Val mice plasma. Increasing FXIII activation rates (34Leu > 34Val > FXIII-/-) increased both pulmonary emboli count and volume, while the trend in cerebral embolism differences was inconclusive. Conclusion: The murine FXIII-A 34Leu variant showed increased activation rates over the 34Val variant and altered thromboembolisation, particularly in the venous circulation. Potentially, increased FXIII activation may enhance venous thromboembolism by protecting emboli against fibrinolysis during their transit to the lungs. In the high shear stress arterial environment, effects of mechanical stabilisation by FXIII may counterbalance any effects on fibrinolysis. These studies show a potentially important role for FXIII- mediated clot stabilisation and protection against fibrinolysis that impact on thromboembolic diseases. Pulmonary embolism dependence on FXIII could be clinically relevant, where FXIII inhibition would act as prophylaxis for patients with a high risk of pulmonary embolism. v Table of contents Acknowlegements ....................................................................................... ii Abstract ....................................................................................................... iv Table of contents........................................................................................ vi List of tables ............................................................................................... xi List of figures ............................................................................................ xii List of equations....................................................................................... xiv List of abbreviations ................................................................................. xv Chapter 1 Introduction ................................................................................ 1 1.1 Cardiovascular diseases and thrombosis ........................................ 2 1.2 Venous thromboembolism ............................................................... 4 1.3 Atherothrombosis ............................................................................. 5 1.4 Immune system in coagulation ........................................................ 8 1.5 Coagulation cascade ....................................................................... 9 1.6 Fibrinogen ...................................................................................... 12 1.7 Fibrinolysis ..................................................................................... 14 1.8 Role of FXIII ................................................................................... 16 1.9 FXIII deficiency .............................................................................. 20 1.10 FXIII Structure ................................................................................ 21 1.11 FXIII A and B subunits ................................................................... 23 1.12 FXIII activation ............................................................................... 26 1.13 FXIII cross-linking effects ............................................................... 29 1.14 FXIII-A V34L .................................................................................
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