The Clinical Utility of Viscoelastic Tests of Coagulation (TEG® & ROTEM®) in Liver Disease and Liver Surgery
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The Clinical Utility of Viscoelastic Tests of Coagulation (TEG® & ROTEM®) in Liver Disease and Liver Surgery Susan Veronica Mallett A thesis submitted for the degree of Doctor of Medicine (Research) University College London Division of Surgery & Interventional Science University College Medical School, Royal Free Campus University College London 1 I, Susan Veronica Mallett confirm that the work presented in this thesis is my own. Help and contribution of others to this work is specified in the acknowledgement section. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 This thesis is dedicated to my husband Tim, and also to my family for their unending support throughout my career. I also wish to express gratitude to my boss at UPMC, Yoogoo Kang, who introduced me many years ago to the concept of using viscoelastic tests to monitor coagulation in patients undergoing liver transplantation. 3 Acknowledgements I am very grateful to my supervisor Professor Barry Fuller for his guidance, help and patience throughout this research project. I also wish to acknowledge the late Professor Andy Burroughs, who was a great mentor to me, and a truly inspirational doctor. I would like to thank and acknowledge my clinical research fellows, Anita Sugavanam, Dominik Krzaniki and Nick Schofield, all of whom are now consultants. Their enthusiasm and hard work contributed to collecting much of this data. I would also like to thank my colleague, Dr Pratima Chowdary, for her advice, and for sharing her extensive knowledge of coagulation and liver disease. 4 Table of Contents Declaration 2 Dedication 3 Acknowledgements 4 Table of contents 5 List of figures 10 List of tables 12 List of abbreviations 13 General introduction and outline of chapters 15 Chapter 1: Models of coagulation and limitations of standard coagulation tests in liver disease 21 1.1: Introduction 22 1.2: Primary haemostasis 22 1.3: Secondary haemostasis 24 1.3.1: The coagulation cascade 24 1.3.2: The cell based model of coagulation 26 1.3.3: Initiation, amplification and propogation of coagulation 28 1.3.4: Controlling active coagulation 32 1.4: Fibrinolysis 34 1.5: Coagulation and liver disease 35 1.5.1: Primary haemostasis and liver disease 37 1.5.2: Secondary haemostasis and liver disease 39 1.5.3: Fibrinolysis and liver disease 39 5 1.6: Limitations of conventional coagulation tests in liver disease 40 1.7: Alternative global methods of monitoring coagulation 43 1.7.1: Thrombin generation assays 43 1.7.2: Viscoelastic tests of coagulation 44 Chapter 2: Principles of viscoelastic tests (VET) of coagulation 45 2.1: Introduction 46 2.2: Mechanical properties of the clot and relation to haemostasis 46 2.3: Principles of Thromboelastography 47 2.3.1: Basic principles 48 2.3.2: Limitations of VET 54 2.4: Correlation of conventional coagulation tests and VET 56 2.4.1: PT/INR 56 2.4.2: Platelet count 57 2.4.3: Clauss Fibrinogen 58 2.4.4: Fibrinolysis 60 2.5: Thrombin generation and VET 61 2.6: Conclusions 62 Chapter 3: The utility of viscoelastic tests of coagulation in patients with liver disease 63 3.1: Introduction 64 3.2: VET and chronic liver disease (CLD) 66 3.2.1: VET parameters and CLD 66 3.2.2.: Heparin like effect (HLE) and CLD 71 3.2.3: Hypercoagulability and CLD 73 6 3.3: VET and acute liver disease (ALD 75 3.3.1: VET parameters and ALD 75 3.3.2: Heparin like effect and ALD 78 3.4: Anticoagulation and Liver Disease 79 3.5: Conclusions 81 Chapter 4: The utility of viscoelastic tests in liver transplant surgery 83 4.1: Bleeding and coagulopathy during liver transplantation 84 4.2: VET and coagulation management 85 4.3: Conclusions 89 Chapter 5: Fibrinolysis during liver transplantation 91 5.1: Introduction 92 5.2: Aims of the study 94 5.3: Methods 94 5.4: Results 98 5.4.1: Prevalence of fibrinolysis 99 5.4.2: Blood results and blood product transfusion 100 5.5: Discussion 101 5.6: Conclusions 104 7 Chapter 6: Intraoperative hypercoagulability in patients undergoing liver transplantation 6.1: Introduction 106 6.2: Aims of the study 108 6.3: Methods 109 6.4: Results 111 6.4.1: Aetiology of liver disease in study population 112 6.4.2: Prevalence of hypercoagulability 113 6.4.3: Influence of stage of the procedure 114 6.4.4: Laboratory and transfusion data 117 6.4.5: Influence of aetiology of liver disease 118 6.4.6: Hypercoagulability and conventional coagulation tests 120 6.4.7: Perioperative thrombotic events 123 6.5: Discussion 124 6.6: Conclusions 129 Chapter 7: Alterations in coagulation profile following major liver resection 131 7.1: Introduction 132 7.2: Aims of the study 134 7.3: Methods 134 7.3.1: Patients 135 7.3.2: Laboratory assays 135 7.3.3: Statistical analysis 138 7.4: Results 138 7.4.1: Patient characteristics 139 8 7.4.2: Transfusion data 140 7.4.3: Changes in blood biochemistry and coagulation 140 7.4.4: Changes in pro and anti-coagulant levels 142 7.4.5: Changes in thrombin generation parameters 145 7.4.6: Changes in ROTEM parameters 145 7.5: Discussion 148 7.6: Conclusion 153 Chapter 8: Determining the efficacy of fresh frozen plasma to reverse coagulopathy following major hepatic resection 156 8.1: Introduction 157 8.2: Aims 158 8.3: Methods 158 8.3.1: Blood sampling and testing 159 8.3.2: FFP spiking 160 8.3.3: Statistical analysis 161 8.4: Results 161 8.4.1: Conventional and VET coagulation tests at baseline and POD 2 161 8.4.2: Changes in coagulation after FFP spiking in patients with INR > 1.5 162 8.5: Discussion 166 8.6: Conclusions 169 Chapter 9: Thesis discussion, conclusions, and future directions 171 Appendix 1: Summary of retrieved studies for systematic review 178 Appendix 2: Publications directly arising out of work described in this thesis 184 9 References 185 List of Figures Figure 1.1 Conventional coagulation cascade 25 Figure 1.2 Cell based model of coagulation 27 Figure 1.3 Initiation of coagulation 28 Figure 1.4 Propagation of coagulation 30 Figure 1.5 Fibrinolytic pathways 35 Figure 1.6 Schematic of “re-balanced” haemostasis in liver disease 36 Figure 2.1 Principles of thromboelastography (TEG®) 49 Figure 2.2 Principles of thromboelastometry (ROTEM®) 50 Figure 2.3 Schematic of TEG/ROTEM parameters 51 Figure 2.4 Different haemostatic profiles on TEG 52 Figure 2.5 ROTEM traces 53 Figure 2.6 Thrombin generation and TEG “V” curve 64 Figure 3.1 Thrombin generation curves in cirrhosis 68 Figure 3.2 Changes in ROTEM parameters in cirrhosis 69 Figure 3.3 Heparin like effect (HLE) demonstrated in cirrhotic patients with cirrhosis 73 Figure 3.4 Change in MA with increasing severity of SIRS 77 Figure 3.5 Pro and anticoagulant levels in acute liver failure 78 Figure 5.1 Grading of fibrinolysis on basis of TEG 97 Figure 6.1 Graphical representation of TEG 110 Figure 6.2 X-Y scatter plot of TEG G values against corresponding INR values 121 10 Figure 6.3 X-Y scatter plot of paired G and platelet count 122 Figure 6.4 X-Y scatter plot of INR and R time 123 Figure 7.1 Change in INR by post operative day (POD) 142 Figure 7.2 Change in pro-coagulant levels (II,V,VII and X) by POD 143 Figure 7.3 Change in Factor VIII and VWF by POD 143 Figure 7.4 Change in anti-coagulants levels by POD 144 Figure 7.5 Change in thrombin generation parameters by POD 147 Figure 7.6 Change in ROTEM parameters by POD 148 Figure 8.1 Change in TEG parameters from baseline to POD 2 165 11 List of tables Table 2.1 Description of TEG/ROTEM parameters 51 Table 3.1 TEG parameters and complication in patients with ALI/ALF 81 Table 5.1 Baseline characteristics of the two groups 98 Table 5.2 Primary and secondary diagnosis for both groups 98 Table 5.3 Comparison of blood component transfusion in the No Aprotinin group by degree of lysis 100 Table 5.4 Comparison of blood component transfusion between groups 100 Table 5.5 Comparison of conventional and viscoelastic coagulation tests in the two groups at start and end of case 101 Table 6.1 Aetiology of liver disease in study population 113 Table 6.2 Native and heparinase TEG parameters at baseline 115 Table 6.3 Distribution of normal and abnormal TEG parameters by stage of liver transplant 117 Table 6.4 Haematological parameters and transfusion requirements according to G values at baseline 118 Table 6.5 Prevalence of hypercoagulability according to disease aetiology 120 Table 7.1 Patient demographics, procedure, type and aetiology of hepatic lesions 139 Table 7.2 Intra and post-operative transfusion data 140 Table 7.3 Routine haematology, biochemistry and coagulation tests against time 141 Table 8.1 Changes in coagulation variables between baseline and POD 2 in patients with INR < and > 1.5 163 Table 8.2 Coagulation variables with FFP spiking in patients with INR >1.5 164 Table 8.3 Reduction in INR after FFP spiking 166 Table 8.4 Percentage of patients in which INR corrected below 1.5 166 12 List of Abbreviations used in the text ADP Adenosine diphosphate ALF Acute liver failure ALI Acute liver injury aPTT Activated partial thromboplastin time AT Antithrombin CAT Calibrated automated thrombogram COX Cyclo-oxygenase CCT Conventional coagulation tests CLD Chronic liver disease DVT Deep vein thrombosis EACA Epsilon aminocaproic acid EPCR Endothelial protein C receptor FF Functional fibrinogen FFP Fresh frozen plasma FDPs Fibrin degradation products GAG Glycosaminoglycan Gp-Ib Glycoprotein HLE Heparin like effect INR International normalized ratio LMWH Low molecular weight heparin LT Liver transplantation MELD Model of end stage liver disease NAFLD Non alcoholic fatty liver disease