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The Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria.Pdf The Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria Richard John Kelly Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine January 2014 1 Jointly-Authored Publications The candidate confirms that the work submitted is his own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. The work in Chapter 3 of the thesis has appeared in publication as follows: Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117:6786-6792. I was responsible for designing the study, collecting and analysing the data and writing the paper. Dena Cohen and Walter Gregory performed the statistical analysis. All the other authors reviewed the paper. The work in Chapter 4 of the thesis has appeared in publication as follows: Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010;149:446-450. I was responsible for designing the study, collecting and analysing the data and writing the paper. All the other authors reviewed the paper. 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. 2 Abstract Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening condition caused by an expansion of a clone of haemopoietic stem cells (HSC) harboring a somatic mutation of the PIG-A gene. PNH blood cells are deficient in glycophosphatidylinositol- linked (GPI) proteins rendering PNH erythrocytes susceptible to complement attack which leads to intravascular haemolysis and an increased tendency to develop thromboses. The survival of 79 consecutive patients treated with eculizumab was compared to both age and sex matched normal controls and to 30 similar patients managed in the era immediately prior to anti-complement therapy. The survival of those treated with eculizumab was no different that of the control group and was significantly better than the group with PNH that did not receive eculizumab (p=0.3). Transfusion requirements and documented thromboses were reduced with eculizumab. Sixty-six percent of transfusion dependent patients became transfusion independent and thrombotic events reduced from 5.6 to 0.8 events per 100 years. Eleven women were monitored through 15 pregnancies whilst on eculizumab. There was 1 first trimester miscarriage and 15 healthy babies born. There were no maternal deaths observed and no thrombotic events occurred in the pregnancy or the postpartum period. Eculizumab did not appear to cross the placenta or be expressed in breast milk. Thirty-five patients were evaluated for PIG-M mutations to see if this mutation was prevalent in PNH. No PIG-M promoter mutations were identified. Two genes were evaluated to see if secondary mutations affecting them could account for clonal expansion in PNH. Thirty-six patients underwent JAK2 V617F mutation analysis with 1 patient shown to have a JAK2 mutation. Forty-two patients were evaluated for increased HMGA2 levels by 2 different PCR methods. There was an overall reduction in HMGA2 expression in PNH patients as compared to normal controls. An in vitro model of the bone marrow in PNH was developed and 18 PNH bone marrow samples were evaluated using this model. Colony forming assays (CFA) showed an increase in colony formation when T-cells were removed from the PNH bone marrow samples. This improvement was reversed when the T-cells were added back to the experiments. This work supports an immune mechanism for the expansion of the PNH clone. 3 Contents Jointly Authored Publications 2 Abstract 3 Contents 4 List of Figures 9 List of Tables 14 Publications Resulting from this Work 15 Acknowledgements 17 Abbreviations 18 1. Introduction 20 1.1. Identifying the Genetic Defect 22 1.1.1 Disruption of the Glycophosphatidylinositol Anchor 22 1.1.2 Haemolysis in PNH 25 1.2 Diagnosis 28 1.2.1 Historical Background 28 1.2.2 Current Techniques for Diagnosis 29 1.3 A Classification of PNH 31 1.4 The Relative Incidence of Molecular and Symptomatic PNH 31 1.5 Clinical Features of PNH 32 1.5.1 The Consequences of Haemolysis 33 1.5.2 Thrombosis 33 1.5.3 Renal Dysfunction 35 4 1.5.4 Pulmonary Hypertension 35 1.5.5 Quality of Life 36 1.5.6 Pregnancy 36 1.6 Mortality and Treatment Prior to Anti-complement Therapy 37 1.6.1 General Measures 37 1.6.2 Anticoagulation 37 1.6.3 Allogeneic Bone Marrow Transplantation 38 1.7 The Complement System 39 1.7.1 Targeting Complement 40 1.7.2 Anti-Complement Strategies in PNH 42 1.7.3 CD59 Replacement 42 1.7.4 Eculizumab 43 1.7.5 Eculizumab Clinical Studies in PNH 45 1.8 Pathogenesis 48 1.8.1 Bone Marrow Failure 48 1.8.2 Mutations in Normal Individuals, Other Conditions and in the Context of Antibody Therapy 49 1.9 Clonal Expansion 51 1.9.1 Multiple Clones and Clonal Dominance 51 1.9.2 Hypotheses of Clonal Expansion 51 1.9.3 Animal Models of PNH 52 1.9.4 Potential Mechanisms Mediating HSC Destruction 53 1.9.5 Humoral Antibody Dependent Cell Mediated Cytotoxicity (ADCC) and Complement 54 1.9.6 Cell Mediated Immunity and Natural Killer (NK) cells 54 1.9.7 The Wilms Tumour Gene 56 1.9.8 Secondary Genetic Mutations – HMGA2 57 1.9.9 Apoptosis 58 1.10 Haematopoietic Stem Cell Immunophenotype and Long Term Bone Marrow Culture (LTBMC) Studies 59 1.10.1 Early Progenitor Cells 59 1.10.2 Long Term Bone Marrow Cultures in PNH and AA 59 5 2 Materials and Methods 61 2.1 Patients 63 2.1.1 Patients Treated with Eculizumab 63 2.1.2 Patients Treated during Pregnancy 63 2.2 Evaluation of HMGA2 in PNH Patients and Normal Subjects 64 2.2.1 Patient and Control Groups 64 2.2.2 Red Cell Lysis 64 2.2.3 RNA Extraction 65 2.2.4 DNase Treatment 65 2.2.5 cDNA Synthesis 66 2.2.6 Quantitative PCR 66 2.2.7 Conventional PCR Reactions 69 2.2.8 Agarose Gel Electrophoresis 69 2.2.9 CD15 Positive Selection 69 2.3 Evaluation of Prevalence of PIG-M Promoter Site and JAK2 Mutations 70 2.3.1 Patient Cohort 70 2.3.2 Genomic DNA Extraction 70 2.3.3 Val617Phe JAK2 Point Mutation Analysis 71 2.3.4 PIG-M Promoter Mutation Analysis 72 2.4 Long Term Bone Marrow Cultures 73 2.4.1 Flow Cytometry Analysis of Bone Marrow 73 2.4.2 Isolation of Bone Marrow Mononuclear Cells 75 2.4.3 Isolation of Bone Marrow CD34+ Cells 75 2.4.4 T-cell Depletion of CD15+ Bone Marrow Mononuclear Cells 76 2.4.5 Isolation of T-cells from Bone Marrow Mononuclear Cells 76 2.4.6 Maintaining Long Term Cultures 77 2.4.7 Colony Forming Assays 78 2.4.8 Colony Analysis 78 3 Long-Term Follow Up of Patients with PNH 79 3.1 Introduction 81 3.2 Additional Patient Information 81 6 3.3 Eculizumab Therapy 82 3.4 Statistical Analysis 83 3.5 Individual Patient Data 84 3.6 Patient Data at Diagnosis and Prior to Starting Eculizumab 109 3.6.1 Sex 109 3.6.2 Age 110 3.6.3 Symptoms at Diagnosis 111 3.6.4 Cytopenias in PNH 111 3.6.5 Haemolysis as a Complication of PNH 112 3.6.6 Thrombosis as a Complication of PNH 112 3.7 Patient Data at the Start of Eculizumab Treatment 113 3.7.1 Laboratory Findings 113 3.7.2 Clone Evaluation 117 3.7.3 Other Laboratory Tests 117 3.8 Patient Data on Eculizumab Treatment 117 3.8.1 Complications of PNH 117 3.8.1.1 Intravascular Haemolysis 117 3.8.1.2 Thrombosis 122 3.8.1.3 Clone Evolution 123 3.8.2 Effects of Eculizumab 124 3.8.2.1 Platelets 124 3.8.2.2 Meningococcal Infection 124 3.8.2.3 Survival 124 3.9 Discussion 127 4 Management of Patients During Pregnancy 132 4.1 Introduction 133 4.2 Additional Patient Information 133 4.3 Individual Patient Data 133 4.4 Complications during Pregnancy 138 4.5 Delivery and the Postpartum Period 141 4.6 Discussion 142 7 5 PIG-M Mutations and Secondary Genetic Events 143 5.1 Rationale 144 5.2 PIG-M Promoter Mutations 145 5.2.1 PCR Amplification of the SP1 Binding Site 145 5.2.2 SAPEX Purification and Sequencing 146 5.3 JAK2 Mutation Analysis 150 5.4 HMGA2 Expression 152 5.5 Further Assessment of HMGA2 Expression using TaqMan Assay 156 5.6 Discussion 157 6 In Vitro Culture Experiments Involving PNH Stem Cells 160 6.1 Rationale 161 6.2 Normal Control Samples 161 6.3 Initial LTBMC Findings with PNH Samples 169 6.4 Difficulties with Stromal Layer 174 6.5 Minimisation Experiments 175 6.6 Extraction of T-cells from Bone Marrow MNCs 179 6.61 T-Cell Removal before MNCs Are Added to the Culture Model 179 6.62 T-Cell Removal Immediately Prior to the CFAs 187 6.7 Add-Back Experiments 188 6.8 Discussion 193 7 General Discussion 197 7.1 Clinical Overview of PNH 198 7.2 Complement and Future Therapies 199 7.3 Disease Pathogenesis - Secondary Genetic Events 201 7.4 Disease Pathogenesis – Escape of the Immune Attack 203 References 205 8 List of Figures Figure 1.1 GPI biosynthesis in the endoplasmic reticulum 25 Figure 1.2 Terminal complement activation causing cell lysis 27 Figure 1.3 FACS plot of erythrocytes in a PNH patient.
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