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Antiphospholipid Antibodies and the Protein C Pathway Antiphospholipid antibodies and the protein C pathway Christopher Gardiner MSc FIBMS Thesis submitted to the University College London for the degree of Doctor of Philosophy 2008 l UMI Number: U591573 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U591573 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Declaration I, Christopher Gardiner, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract The antiphospholipid syndrome (APS) is characterised by the presence of antiphospholipid antibodies (aPA) associated with thrombosis (arterial and venous) and pregnancy morbidity. This thesis has aimed to investigate the frequency of protein C pathway defects in patients with aPA and to study clinical correlates; examine the mechanisms of antiphospholipid interference in the protein C pathway; and to assess activated protein C (APC) resistance in patients with aPA in terms of thrombin generation. Although have I have discovered a high degree of heterogeneity in the phenotype of patients with APS, I have demonstrated APC resistance and increased thrombin generation in the majority of patients with APS. While in some cases, APC resistance is clearly immunoglobulin mediated, it is a multifactorial phenomenon with many confounding variables. My data suggest that immunoglobulin dependent APC resistance may occur through P2 glycoprotein-I dependent and independent mechanisms. In a detailed study of women with a history of pregnancy morbidity, I have found evidence for an underlying prothrombotic condition, which is due in part to a deficiency of tissue factor pathway inhibitor. This is associated with resistance to APC and increased thrombin generation, both of which may be attenuated through the restoration of normal TFPI levels by low molecular weight heparin. 3 Acknowledgments I would like to express my gratitude to my supervisors Ian Mackie and Sam Machin, for their support, guidance, criticism and encouragement. A word of thanks is also due to my colleagues Hannah Cohen, Paul Harrison, Andrew Lawrie, Mike Nash, Carol Briggs, Ian Longair and Steve Austin for their help and encouragement over the last five years. There are several people in industry whose generosity has allowed me to complete this work: Helen Watts, Andy Smith and Alan Grant from Instrumentation Laboratory for arranging the loan of the ACL9000 analyser and helping me to program it; John Brandt at Eli Lilley for donating the recombinant human APC; the Chiron Corporation provided the recombinant TFPI; and Steffen Rosen, at Rossix, who provided the stabilised phospholipid emulsion and useful advice. Last but not least, I would like to thank my wife Alex for her belief, patience, support, understanding and sense of humour when I needed it most. 4 Table of contents Declaration 2 Abstract 3 Acknowledgments 4 Table of contents 5 List of t a b l e s .....................................................................................................................................................8 List of figures ...................................................................................................................................................9 L ist of abbreviations ...............................................................................................................................11 Chapter 1 Introduction 12 1.1 H istory of antiphospholipid a n t ib o d ie s ............................................................................. 12 1.2 D etection of antiphospholipid a n t ib o d ie s ........................................................................13 1.3 T he antiphospholipid sy n d r o m e ................................................................................................17 1.3.1 Thrombosis......................................................................................................................17 1.3.2 Pregnancy morbidity.................................................................................................... 18 1.3.3 Other conditions associated with antiphospholipid antibodies.........................19 1.4 N ormal haemostasis .........................................................................................................................20 1.4.1 Primary haemostasis ....................................................................................................21 1.4.2 The role o f the endothelium........................................................................................ 22 1.4.4 Inhibitors o f coagulation.............................................................................................27 1.4.5 The protein C system.................................................................................................... 28 1.4.6 The role of phospholipids in haemostasis...............................................................35 1.5 P roposed m echanism s for pathogenesis of antiphospholipid a n tibo d ies .. 37 1.5.1 Endothelial activation..................................................................................................37 1.5.2 Monocyte activation......................................................................................................38 1.5.3 Platelet activation......................................................................................................... 38 1.5.4 The role o f anti P2 Glycoprotein-I antibodies........................................................38 1.5.5 anti-prothrombin........................................................................................................... 39 1.5.6 inhibition o f activated protein............................................................................... C 40 1.6 A ntiphospholipid antibo dy interference in laboratory screening te st s41 1.7 A ims of this t h e sis .............................................................................................................................. 42 Chapter 2 Methods 43 2.1 B lood collection ................................................................................................................................43 2.2 P rotein C pathw ay screening t e s t s ......................................................................................43 2.3 P rotein C a s s a y ................................................................................................................................... 45 2.4 Protein S a s s a y .....................................................................................................................................45 2.5 Factor V L eiden mutation a n a l y s is ....................................................................................45 2.6 A ctivated protein C resistance test (Commercial clotting test) ................46 2.7 A ntiphospholipid a ntibo dy d e t e c t io n ................................................................................ 46 2.8 En do g en o u s APC ratio (E A P C R )............................................................................................ 47 2.8 P hospholipid vesicle preparation ...........................................................................................49 2.9 S u b -sampling throm bin generation m ethod ................................................................... 50 2.10 A utom ated throm bin generation m e t h o d .....................................................................52 2.11 P rothrombin a s s a y .........................................................................................................................54 2.12 Factor V L eiden a n d prothrombin gene mutation a n a l y sis ............................ 54 2.13 TFPI ANTIGEN ELISA ......................................................................................................................... 54 2.14 A utom ated TFPI sensitivity in d e x ......................................................................................54 2.15 A nti -TFPI antibo dy detection by E L IS A .........................................................................55 2.16 Factor VIII a s s a y ............................................................................................................................. 56 2.17 A ffinity purification of immunoglobulin Ig G ...........................................................56 2.18 A ffinity purification of immunoglobulin IgM ...........................................................57 Chapter 3. Factors influencing commercial protein C pathway screening tests 59 5 3.1 Introduction ...........................................................................................................................................59 3.2 M aterials a n d m e t h o d s ................................................................................................................. 60 3.2.1 Patients and samples.....................................................................................................60
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