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Thrombin Generation, Tissue Factor Microvesicles and the Endothelium in Multiple Myeloma and Pancreatic Cancer During Treatment

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Thrombin Generation, Tissue Factor Microvesicles and the Endothelium in Multiple Myeloma and Pancreatic Cancer During Treatment Thrombin generation, Tissue Factor Microvesicles and the Endothelium in Multiple Myeloma and Pancreatic Cancer during treatment. Dr Mufuliat Adeola Adesanya, M.B.Ch.B, M.Sc. Doctor of Philosophy University of Hull and University of York Hull York Medical School January 2018 Abstract Cancer and its anti-neoplastic treatment are frequently complicated by venous thromboembolism (VTE) occurrence. Multiple myeloma (MM), a haematological malignancy and Pancreatic cancer (PC), a solid tumour are two common malignancies with similarly high VTE incidence, which worsens during treatment. Thrombin production is a key step in the pathologic evolution of VTE and may play an important role in determining VTE risk in cancer patients. The calibrated automated thrombography (CAT) assay is emerging as a reliable tool for real time estimation of thrombin generation (TG) potential, and there is a clinical need for such knowledge on the dynamic pathways underlying the thrombotic phenotype of various malignancies. Hypothetically, TG measurement may also provide a view of the haemostatic variances that exist in MM and PC as cancers with high VTE incidences. Therefore, this thesis aimed to explore the TG changes that exist in both malignancies in patients before, during and after treatment. It also explores the interaction of Tissue Factor (TF) associated with Microvesicles (MVs) or TFMVs with tumour stroma especially the endothelium, or any procoagulant changes such as thrombin production due to this interaction; and thus, aimed to study TFMVs involvement through the disruption of endothelial haemostasis. The results presented in this thesis demonstrate that solid and haematological malignant cells have significantly differing TG kinetics that may correlate with TF expression levels, and that TG parameters identified changes in MM during treatment, specifically the Lag times and Times- to-Peak parameters were progressively elevated until the third chemotherapy cycle. In summary, procoagulant activity on the endothelium can be stimulated by TFMVs produced by cancer cells in vitro, and this study of thrombin as a procoagulant factor in MM and PC and its relationship to TFMVs may lead to future understanding of their important role in cancer VTE development, and thus merits further study. 2 List of contents Abstract .................................................................................................................... 2 List of contents ......................................................................................................... 3 List of tables ........................................................................................................... 10 List of figures .......................................................................................................... 12 List of abbreviations ............................................................................................... 15 Acknowledgements ................................................................................................ 19 Author’s declaration ............................................................................................... 21 Publications ............................................................................................................ 22 Chapter:1 General Introduction ......................................................................... 25 1.1 Cancer ...................................................................................................... 25 1.1.1 Cancer biology and haemostasis ........................................................ 26 1.1.2 Cancer VTE: occurrence, risk and clinical implications ....................... 26 1.1.2.1 VTE risk in Cancer ................................................................................... 29 1.1.2.2 Chemotherapy and the risk of VTE .......................................................... 32 1.1.2.3 VTE prognosis and anti-thrombotic interventions ................................... 35 1.2 Coagulation cascade ................................................................................. 37 1.2.1 Phases of coagulation ........................................................................ 38 1.3 Role of haemostatic factors in cancer thrombosis .................................... 43 1.4 Thrombin.................................................................................................. 45 1.4.1 Thrombin structure ........................................................................... 45 1.4.2 Thrombin importance in VTE ............................................................. 50 1.4.3 Thrombin measurement .................................................................... 51 1.5 Tissue Factor (TF) ..................................................................................... 54 1.5.1 TF structure ....................................................................................... 54 3 1.5.2 TF-FVII complex ................................................................................. 56 1.5.3 TF-FVII: signalling and upregulation ................................................... 58 1.5.4 TF involvement in Cancer VTE ........................................................... 59 1.6 Microvesicles (MVs) ................................................................................. 61 1.6.1 MV Origins ........................................................................................ 61 1.6.2 MV structure and function ................................................................ 62 1.6.3 MV intracellular formation, release, acquisition and signalling mechanisms .................................................................................................... 64 1.7 Endothelium and TFMVs in Cancer VTE .................................................... 73 1.8 Multiple Myeloma (MM) .......................................................................... 76 1.8.1 Description and Pathology................................................................. 76 1.8.2 Epidemiology..................................................................................... 77 1.8.3 Risk factors ........................................................................................ 77 1.8.4 Staging .............................................................................................. 78 1.8.5 Clinical presentation and Treatment.................................................. 79 1.9 Thrombosis in MM ................................................................................... 80 1.10 Pancreatic Cancer (PC) .......................................................................... 82 1.10.1 Description and Pathology ............................................................. 82 1.10.2 Epidemiology ................................................................................. 85 1.10.3 Risk factors .................................................................................... 86 1.10.4 Staging ........................................................................................... 88 1.10.5 Clinical presentation and Treatment .............................................. 89 1.11 Thrombosis in PC .................................................................................. 90 1.12 Aims...................................................................................................... 92 1.12.1 Objectives ...................................................................................... 93 Chapter:2 Materials and Methods ..................................................................... 95 2.1 Cell culture ............................................................................................... 95 2.2 Cell lines ................................................................................................... 95 2.2.1 HUVECs ............................................................................................. 95 4 2.2.2 Cancer cell lines ................................................................................. 96 2.2.2.1 MM and other haematological cancer cells ............................................. 97 2.2.2.2 PC cells and other solid cancer cells ........................................................ 97 2.2.1 Passaging .......................................................................................... 98 2.2.2 Ethics statement ............................................................................... 98 2.2.3 Cryopreservation ............................................................................... 98 2.3 Cell count and viability assay .................................................................... 99 2.4 MV preparation ...................................................................................... 101 2.4.1 MV-rich media preparation: ............................................................ 101 2.4.2 HUVECs culture in tumour-MV-rich media and platelet free plasma (PFP) ........................................................................................................ 102 2.4.2.1 HUVECs culture in platelet free plasma (PFP) of cancer patients ........... 103 2.5 Clotting time (CT) assessment ................................................................ 103 2.5.1 Cells and cell-free supernatant CT assessment ................................ 103 2.5.2 Patient Platelet-free plasma CT assessment .................................... 104 2.6 Flow cytometry .....................................................................................
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