Coagulation in Cancer (eBook)

Coagulation in Cancer 2
Preface 6
References 8
Contents 10
Contributors 12
Part 1: Alterations in Hemostasis Due to Cancer 15
Dysregulation of Hemostasis by Cancer 16
1.1 Model of Coagulation 16
1.1.1 Initiation 17
1.1.2 Amplification 17
1.1.3 Propagation 19
1.1.4 Localization 19
1.2 Dysregulation of Coagulation in Cancer 20
1.2.1 Altered Tissue Factor in Cancer 21
1.2.2 Tissue Factor Expression on Tumor Cells 21
1.2.3 Tissue Factor on Endothelium 21
1.2.4 Tissue Factor Microparticles 21
1.2.5 Inflammatory Cells and Endothelium 24
1.3 Other Dysregulations of Coagulation 24
1.3.1 Platelet Activation on Endothelium 24
1.3.2 Downregulation of Thrombomodulin on Endothelium 24
1.4 Summary 24
References 25
Effect of Cancer on Platelets 29
2.1 Introduction 29
2.2 Thrombosis and Cancer 30
2.3 Laboratory Findings in Cancer Hypercoagulation 30
2.4 Role of Platelets in Metastasis 31
2.5 Tumor Cell Adhesion 32
2.6 Role of Thrombin 34
2.7 Genetic Models 35
2.8 Platelets as Regulators of Angiogenesis 35
2.9 Clinical Trials 36
2.10 Does Thrombin Influence Tumor Dormancy? 37
References 38
Activation of Clotting Factors in Cancer 43
3.1 Introduction 43
3.2 Epidemiology 44
3.3 Mechanisms of Cancer-Induced Thrombosis 45
3.4 Molecular Pathogenesis of Thrombosis in Cancer - Direct Link to Oncogenesis 45
3.5 Targeting Tissue Factor and Other Coagulation Intermediates in Cancer Therapy 47
3.6 Summary 50
References 50
The Role of Plasminogen-Plasmin System in Cancer 54
4.1 Introduction 54
4.2 Historical Background 55
4.3 Plasminogen-Plasmin System 55
4.3.1 Plasminogen Activators 56
4.3.2 Inhibitors of the Plasminogen-Plasmin System 58
4.4 Plasminogen Activator Inhibitors (PAIs) 58
4.4.1 Plasminogen Activator Inhibitor Type 1 (PAI-1) 58
4.4.2 Regulation of PAI-1 60
4.4.3 Plasminogen Activator Inhibitor Type 2 (PAI-2) 60
4.4.4 Thrombin-Activatable Fibrinolytic Inhibitor (TAFI) 61
4.5 Role of the Plasminogen - Plasmin System in Tumor Growth and Metastasis 62
4.5.1 Tumor Cell Proliferation and Apoptosis 63
4.5.2 Tumor Cell Migration and Invasion 64
4.5.3 Tumor Angiogenesis 64
4.6 Role of the Plasminogen-Plasmin System in Thrombotic Complications in Cancer 64
4.7 The Plasminogen-Plasmin System in Acute Leukemia 65
4.8 Clinical Observations of the Plasminogen-Plasmin System in Cancer 66
4.9 Conclusion 70
References 70
The Coagulation System and Angiogenesis 78
5.1 Introduction 78
5.2 Platelets and Angiogenesis 78
5.3 Tissue Factor and Angiogenesis 80
5.4 Thrombin 81
5.5 Fibrin 82
5.6 Plasmin/Angiostatin 83
5.7 Anticoagulation and Angiogenesis 83
5.8 Antiangiogenic Therapy and Coagulation 85
5.9 Conclusions 86
References 86
Part 2: Thrombotic Disorders Associated with Cancer 92
Overview of Cancer and Thrombosis 93
6.1 Introduction 93
6.2 Epidemiology 94
6.3 Pathophysiology 94
6.4 Symptoms and Diagnosis 96
6.5 Thrombophilia Screening in Cancer 97
6.6 Prophylaxis of Venous Thromboembolism in Cancer Patients 98
6.7 Central Venous Catheters and Thromboembolism 98
6.8 Therapy 99
6.9 Cancer-Specific Thromboembolic Syndromes 100
6.9.1 Non-Bacterial Thrombotic Endocarditis 100
6.9.2 Hepatic Veno-Occlusive Disease (VOD) 100
6.9.3 Thromboembolism with Myeloproliferative Syndromes 101
6.10 Summary 101
References 101
Risk Factors for Thrombosis in Cancer Patients 105
7.1 Introduction 105
7.2 General Risk Factors for Venous Thromboembolism 106
7.3 Genetic Risk Factors for Venous Thromboembolism 109
7.4 Cancer-Specific Risk Factors for Venous Thromboembolism 110
7.5 Summary 116
References 117
Thrombotic Microangiopathy Syndromes 125
8.1 Introduction 125
8.2 Cancer-Associated Thrombotic Microangiopathy 126
8.2.1 Epidemiology 126
8.2.2 Clinical Presentation 127
8.2.3 Pathophysiology 127
8.2.4 Therapy 130
8.3 Drug-Associated Thrombotic Microangiopathies 132
8.3.1 Mitomycin-C 132
8.3.2 Gemcitabine 133
8.3.3 VEGF Inhibitors 134
8.3.4 Other Medications Associated with TMA 136
8.4 Thrombotic Microangiopathy Associated with Hematopoietic Stem Cell Transplantation 137
8.4.1 Cyclosporine-associated TMA 138
8.4.2 Tacrolimus-associated TMA 139
8.5 Conclusion 140
References 140
Disseminated Intravascular Coagulation (DIC) in Cancer 147
9.1 Introduction 147
9.2 Concept of DIC 148
9.3 Pathophysiology of Cancer Associated DIC 148
9.4 Procoagulant Mediators 148
9.4.1 Tissue Factor (TF) 149
9.4.2 Cancer Procoagulant (CP) 149
9.4.3 Alteration of Fibrinolytic Activities in the Mediation of Thrombosis and DIC in Cancer 149
9.4.4 Cytokines in Cancer as Mediators of Thrombogenesis 150
9.4.5 Interaction of Tumor and Host Cells and Their Influence on Thrombogenesis 150
9.5 Diagnosis of DIC in Cancer 151
9.6 Management of DIC in Cancer 155
9.6.1 Treatment of the Underlying Malignancy 155
9.6.2 Use of Heparin in Treatment of Cancer-Related DIC 156
9.6.3 Use of Warfarin in Treatment of Cancer-Related DIC 157
9.6.4 Replacement Therapy in Cancer-Related DIC 157
9.6.5 Other Therapeutic Modalities in Cancer-Related DIC 157
9.7 Summary 160
References 160
Myeloproliferative Neoplasms: Thrombophilic Clonal Stem Cell Diseases 167
10.1 Introduction 167
10.2 Pathogenesis 167
10.3 Diagnosis 169
10.4 Clinical Features 169
10.5 Prognosis 173
10.6 Treatment 178
10.6.1 Polycythemia Vera and Essential Thrombocythemia 178
10.6.2 Myelofibrosis 179
10.6.3 Anti-JAK2 Investigational Therapy 180
References 181
Chemotherapy-Associated Thrombosis 190
11.1 Introduction 190
11.2 Pathogenesis/Pathophysiology of Chemotherapy-Associated Thrombosis 191
11.3 Therapy-Associated Thrombosis in Breast Cancer 191
11.3.1 Tamoxifen 191
11.3.2 Aromatase Inhibitors 193
11.4 Therapy-Associated Thrombosis in Multiple Myeloma 193
11.4.1 Thalidomide 193
11.4.2 Lenalidomide 197
11.5 Other Anti-Neoplastic Agents Associated with VTE 197
11.5.1 Cisplatin-Based Regimens 197
11.5.2 l-Asparaginase 198
11.5.3 5-Fluorouracil 199
11.5.4 Bevacizumab 199
11.6 Supportive Therapy with Hematopoietic Growth Factors and Risk for VTE 200
11.6.1 Recombinant Human Erythropoietins 200
11.6.2 Leucocyte Growth Factors (G-CSF and GM-CSF) 201
11.7 Other Agents 201
11.7.1 Corticosteroids 201
11.8 Prevention of VTE in Patients Receiving Chemotherapy 202
11.8.1 Prophylaxis in Solid Tumors 202
11.8.2 Prophylaxis in Multiple Myeloma 202
11.8.3 Prophylaxis in Myeloproliferative Disease 205
11.9 Predictive Model for Chemotherapy Associated Thrombosis 205
11.10 Summary 206
References 206
Catheter-Related Thrombosis 216
12.1 Thrombotic Complications of Central Venous Catheters 216
12.2 Diagnosis of Central Venous Catheter-Related Deep Vein Thrombosis 218
12.3 Risk Factors for the Development of Central Venous Catheter-Related Deep Vein Thrombosis 219
12.4 Prophylaxis for Catheter-Related Deep Vein Thrombosis 221
12.5 Management of the Thrombotic Complications of Central Venous Catheter in Cancer Patients 223
References 226
Thrombosis in Childhood Cancer 231
13.1 Introduction 231
13.2 Epidemiology 231
13.2.1 Incidence in the General Pediatric Population 231
13.2.2 Incidence in the Pediatric Cancer Patients 232
13.3 Unique Attributes of the Pediatric Hemostatic System 234
13.3.1 Primary Hemostasis 234
13.3.2 Secondary Hemostasis 235
13.3.3 Inhibitory Proteins 235
13.3.4 Fibrinolysis 235
13.4 Prothrombotic State in Children with Cancer 236
13.4.1 Procoagulant Properties of Cancer in Children 237
13.5 Role of Thrombophilia 238
13.6 Role of Central Venous Catheters 238
13.7 Role of Chemotherapy 241
13.8 Prophylaxis and Treatment 243
References 245
Treatment of Venous Thrombosis 251
14.1 Introduction 251
14.2 Initial Therapy of VTE 251
14.2.1 Choice of Anticoagulants 252
14.2.2 Once or Twice Daily Dosing of Low-Molecular-Weight Heparin 253
14.3 Long-Term Therapy 253
14.3.1 Vitamin K Antagonists (VKA) 254
14.3.2 Low-Molecular-Weight Heparin 254
14.3.3 Pentasaccharides 258
14.4 Duration of Therapy 259
14.5 Challenges in the Treatment of Cancer-Associated Thrombosis 259
14.5.1 Treatment of VTE in Patients with Bleeding 259
14.5.2 Treatment of Recurrent VTE 260
14.6 Quality of Life 262
14.7 Antineoplastic Potential of LMWHs 262
References 263
Effects of Anticoagulants on Cancer: Heparins 266
15.1 Introduction 266
15.2 Anticoagulants as Chemotherapeutic Agents 267
15.3 Beneficial Effects of the Heparins on Survival in Cancer Patients 268
15.4 Experimental Models of Tumor Growth and Metastasis 272
15.5 The Role of Heparins on Cancer Progression and Metastasis in Experimental Studies 272
15.6 Potential Mechanisms to Explain the Suppression of Cancer Cell Growth and Proliferation by the Heparins 273
15.6.1 Inhibition of Thrombin Generation 273
15.6.2 Tissue Factor 274
15.6.3 Heparanase 274
15.7 Adhesion Molecules - P-Selectin and L-Selectin 275
15.7.1 Angiogenesis 275
15.8 Conclusion 277
References 278
Part 3: Bleeding Disorders Associated with Cancer 283
Thrombocytopenia and Cancer 284
16.1 Introduction 284
16.2 Thrombocytopenia Due to Peripheral Destruction 284
16.2.1 Disseminated Intravascular Coagulation 284
16.2.2 Thrombotic Thrombocytopenic Purpura (TTP) 286
16.2.3 Immune Mediated Thrombocytopenia (ITP) 287
16.2.4 Heparin Induced Thrombocytopenia (HIT) 288
16.3 Thrombocytopenia Due to Decreased Production 290
16.3.1 Bone Marrow Suppression Due to Tumor Involvement 290
16.3.2 Treatment-Related Bone Marrow Suppression 291
16.3.3 Treatment of Thrombocytopenia Related to Decreased Production 292
16.4 Summary: Diagnostic Evaluation 293
16.4.1 Thrombocytopenia with Abnormal Peripheral Smear 293
16.4.2 Thrombocytopenia with Normal Peripheral Smear 294
References 295
Bleeding Disorders Associated with Cancer Dysproteinemias 299
17.1 Introduction 299
17.2 Bleeding Diathesis in Amyloidosis and Waldenström Macroglobulinemia 300
17.3 Abnormalities of Primary Hemostasis 302
17.4 Abnormalities of Secondary Hemostasis and Fibrinolysis 303
17.5 Treatment-Associated Coagulation Abnormalities 304
17.6 Bleeding Management (see Chap. 18) 305
References 306
Control of Bleeding in Cancer 309
18.1 Causes of Bleeding in Patients with Cancer 309
18.1.1 Cancer Invasion 309
18.1.2 Thrombocytopenia 310
18.1.3 Coagulation Abnormalities 311
18.1.4 Use of Drugs 311
18.1.5 Treatment-Associated Bleeding 311
18.1.6 Dysproteinemias 312
18.2 Management of Bleeding Diathesis 312
18.2.1 General Measures 312
18.2.2 Local Measures 313
18.2.3 Packing 313
18.2.4 Topical Hemostatics 314
18.2.5 Radiation Therapy 314
18.2.6 Endoscopy 314
18.2.7 Palliative Embolization 315
18.2.8 Systemic Interventions (Table 18.3) 315
18.2.9 Platelet Transfusions 315
18.2.9.1 Platelet Products 316
18.2.9.2 Indications for Transfusion 316
18.2.9.3 Platelet Dose 317
18.2.9.4 Expected Response to Platelet Transfusion 317
18.2.9.5 Refractoriness to Platelet Transfusions 318
18.2.10 Plasma Products 318
18.2.11 Vitamin K and Reversal of Warfarin Effect 320
18.2.12 Desmopressin 320
18.2.13 Antifibrinolytic Agents 322
18.2.14 Recombinant Factor VIIa 323
18.2.15 Activated Prothrombin Complex Concentrate 324
References 325
Index 331