Therapeutic Advances in Thrombosis (eBook)

Title page 5
Copyright page 6
Contents 7
Contributors 9
Foreword 12
Preface 13
CHAPTER 1: Arterial thrombosis: a brief overview 15
Introduction 15
Pathogenesis of arterial thrombosis 15
Platelets 17
Coagulation system 19
Effects of the severity of vessel wall damage and local geometry on the thrombotic response to atherosclerosis 21
Inflammation in arterial thrombosis 22
Platelets as circulating commodities in vascular disease 23
Summary 23
Acknowledgements 24
References 24
CHAPTER 2: Aspirin 26
Introduction 26
Mechanism of action of aspirin in inhibiting platelet function 26
Pharmacokinetics 27
Pharmacodynamics 27
Effects on TXA2 and PGI2 biosynthesis 27
Effects of aspirin not related to COX-1 inactivation 28
Drug interactions 29
Interindividual variability in response to low-dose aspirin 29
Efficacy and safety of low-dose aspirin 31
Prevention and treatment of atherothrombosis in high-risk patients 31
Patients at intermediate risk of vascular complications 32
Low-risk subjects 34
Summary 35
References 36
CHAPTER 3: Platelet ADP P2Y12 inhibitors: thienopyridines 40
Introduction 40
The ADP receptor 40
Thienopyridine ADP P2Y12 receptor antagonists 40
Ticlopidine 41
Clopidogrel 41
Mechanism of action 41
Pharmacodynamics 42
Clinical uses 42
Dosing and platelet responsiveness 45
Pharmacogenomics 48
Drug interactions 49
Stent thrombosis and clopidogrel duration 49
Perioperative bleeding and clopidogrel timing 50
Prasugrel 52
Mechanism of action 52
Platelet responsiveness and prasugrel dosing 52
Clinical studies 55
Summary 56
References 56
CHAPTER 4: Platelet ADP P2Y12 inhibitors: nonthienopyridines 61
Introduction 61
Ticagrelor 61
Mechanism of action 61
Pharmacokinetics 61
Clinical trials 63
Cangrelor 69
Pharmacodynamics 70
Clinical studies 70
Future agents 73
Elinogrel 73
BX 667 73
Summary 73
References 73
CHAPTER 5: Cilostazol and dipyridamole: more than weak inhibition of platelets 76
Introduction 76
Cilostazol 76
Dipyridamole 79
Summary 80
References 82
CHAPTER 6: Interrelationship of thrombin and platelets: the protease activated receptor-1 85
Introduction 85
Thrombin and its biology 85
Platelet physiology and receptors 86
Protease activated receptors 87
Structure and activation of PAR-1 88
Role of PAR-1 inhibitors in atherothrombosis 90
Aprotinin and PAR-1 95
Matrix metalloproteinases and PAR-1 96
PAR-1 in vasomotor tone, smooth muscle cells, and cardiomyocytes 97
Summary 97
References 98
CHAPTER 7: Glycoprotein IIb/IIIa inhibitors 101
Introduction 101
Role of glycoprotein IIb/IIIa in mediating aggregation and facilitating coagulation 101
Pharmacology of clinically available drugs 102
Clinical trials 104
Abciximab 105
Tirofiban 109
Eptifibatide 114
Comparability among agents 118
Role of glycoprotein IIb/IIIa inhibitors in the current-use of aspirin and P2Y12 oral receptor blockers and concluding remarks 120
References 121
CHAPTER 8: Unfractionated heparin and low molecular weight heparin in ischemic heart disease 125
Introduction 125
Pharmacology and mode of action 125
Unstable angina and non–ST-segment elevation myocardial infarction 126
Unfractionated heparin 126
Low molecular weight heparin 128
Low molecular weight heparin versus unfractionated heparin 128
Trials of low molecular weight heparin in the era of glycoprotein IIb/IIIa receptor antagonists 129
Low molecular weight heparin dosing issues 132
Low molecular weight heparin treatment of ST-segment elevation myocardial infarction 133
Low molecular weight heparin versus placebo 133
Low molecular weight heparin versus unfractionated heparin 133
Meta-analysis of role of heparins in acute coronary syndromes 135
Low molecular weight heparin in elective percutaneous coronary intervention 137
Low molecular weight heparin in patients ineligible for reperfusion 137
Summary 137
References 137
CHAPTER 9: Pentasaccharide derivatives 142
Introduction 142
Fondaparinux 142
Pharmacodynamics 142
Pharmacokinetics 144
Thrombocytopenia and heparin-induced thrombocytopenia 144
Neutralization 144
Clinical studies 145
Fondaparinux and acute coronary syndrome guidelines 156
Idraparinux and idrabiotaparinux 156
Summary 158
References 159
CHAPTER 10: Intravenous direct thrombin inhibitors 164
Introduction 164
Overview of direct thrombin inhibitors (Table ) 166
Specific direct thrombin inhibitors 166
Clinical use 168
Acute coronary syndromes 168
Venous thromboembolism 175
Heparin-induced thrombocytopenia 176
Atrial fibrillation 176
Summary 177
References 177
CHAPTER 11: Vitamin K antagonists 180
Introduction 180
Antithrombin therapy in acute myocardial infarction 181
Oral anticoagulation after myocardial infarction 182
Specific subgroups of patients 186
Future perspectives 191
Summary 191
References 191
CHAPTER 12: Oral direct thrombin inhibitors and oral factor Xa inhibitors 194
Oral direct thrombin inhibitors 194
Dabigatran etexilate 194
Oral factor Xa inhibitors 196
Rivaroxaban 196
Apixaban 198
Edoxaban 199
Other factor Xa inhibitors 200
Management of bleeding complications 200
References 200
CHAPTER 13: Thrombolytic therapy and concomitant antithrombotic therapies 203
Introduction 203
Fibrinolytic therapy: rationale and indication 203
Fibrinolytic agents 204
Streptokinase 204
Alteplase 204
Reteplase 205
Tenecteplase 205
Staphylokinase 205
Antithrombotic cotherapy in fibrinolysis 206
Aspirin 206
Thienopyridines 206
Unfractionated heparin 206
Low molecular weight heparin 208
Fondaparinux 209
Glycoprotein IIb/IIIa inhibitors 209
Intravenous direct thrombin inhibitors 210
Prehospital fibrinolysis 210
Fibrinolysis and the planning of percutaneous coronary intervention 211
Summary 213
References 213
CHAPTER 14: Antithrombotic therapy in ST-segment elevation myocardial infarction 219
Introduction 219
Anticoagulation 219
In primary percutaneous coronary intervention 219
As adjuvant in fibrinolytic therapy 220
Antiplatelet therapy 221
In primary percutaneous coronary intervention 221
In combination with fibrinolytic therapy 222
Duration of dual antiplatelet therapy and antithrombotic combination strategies after primary percutaneous coronary intervention 223
Antithrombotic strategies in patients without reperfusion therapy 223
References 223
CHAPTER 15: Antithrombotic therapy in non–ST-segment elevation acute coronary syndromes 227
Introduction 227
Pathophysiology of acute coronary syndromes 227
Platelet activation 228
The coagulation cascade 228
Antiplatelet agents (Table ) 228
Aspirin 231
ADP receptor antagonists 231
Glycoprotein IIb/IIIa inhibitors 234
Anticoagulants (Table ) 235
Heparins 235
Indirect factor Xa inhibitors: fondaparinux 238
Direct thrombin inhibitors 239
Future directions 240
Thrombin receptor inhibitors 240
Direct thrombin inhibitors 241
Direct factor Xa inhibitors 241
Novel P2Y12 ADP receptor antagonists 243
RNA aptamer factor IXa inhibitor: the REG-1 system 243
Summary 244
References 244
CHAPTER 16: Antithrombotic strategies in patients undergoing elective percutaneous coronary intervention 250
Introduction 250
Rationale for antithrombotic therapy in percutaneous coronary intervention 250
Available antithrombotic strategies 251
Antithrombin therapy plus oral antiplatelet therapy 251
Antithrombin plus oral antiplatelet therapy plus parenteral antiplatelet therapy 255
Antiplatelet therapy without antithrombin therapy 255
Summary and recommendations 257
References 258
CHAPTER 17: Antithrombotic management in patients with prosthetic valves 260
Introduction 260
Choice of prosthetic valve 260
Technical factors influencing thrombotic risk 261
Healing and incorporation of the prosthetic valve 262
Pathogenesis of valve thrombosis and embolism 263
Follow-up after valve replacement 265
Antithrombotic therapy according to valve type 265
Mechanical valves 265
Bioprostheses 265
Early postoperative anticoagulation 266
Optimum intensity of anticoagulation 267
General principles and choice of drug 267
Patient-specific and prosthesis-specific anticoagulation 268
Management of the high INR in prosthetic valve patients 270
Anticoagulation self-management 271
Antiplatelet therapy 272
Thromboembolic events despite anticoagulation 274
Sources of embolism 274
Hypercoagulability 275
Trigger factors 275
Valve thrombosis 275
Sewing ring thrombosis 276
Obstructive valve thrombosis 276
Interruption of anticoagulation for noncardiac surgery 278
References 279
CHAPTER 18: Stroke: thrombolysis and antithrombotic therapy 286
Introduction 286
Antithrombotic therapy in secondary stroke prophylaxis 286
Aspirin 286
Thienopyridines 287
Aspirin and dipyridamole 288
Anticoagulants 289
Thrombolysis in acute ischemic stroke 290
Alternative thrombolytic or antithrombotic agents in acute stroke 293
Acknowledgements 296
References 296
CHAPTER 19: Atrial fibrillation: current and forthcoming antithrombotic therapies 299
Atrial fibrillation 299
Definition 299
Classification 299
Epidemiology 300
Thromboembolic risk in atrial fibrillation 300
Prevention of thromboembolism 303
Anticoagulant therapy 303
Antiplatelet therapy 309
Risk of bleeding 311
How to practically choose antithrombotic therapy 311
Summary 313
References 314
CHAPTER 20: Venous thromboembolism: pathophysiology, diagnosis, and prophylaxis 320
Introduction 320
Pathophysiology 320
Individual risk factors for venous thromboembolism 321
Disease-related risk factors 323
Pregnancy and puerperium 324
Oral contraceptives and hormone replacement therapy 324
Diagnosis 324
Pretest probability 324
Diagnostic strategies 327
Suspected deep vein thrombosis 327
Suspected pulmonary embolism 327
Prophylaxis 328
References 329
CHAPTER 21: Antithrombotic therapy in venous thrombosis and pulmonary embolism 331
Introduction 331
Initial therapy 331
Thrombolytic agents 332
Inferior vena cava filters 333
Long-term therapy 333
New anticoagulants 333
Dabigatran 333
Rivaroxaban 333
Apixaban 335
Edoxaban 335
Idraparinux and idrabiotaparinux 335
Duration of anticoagulant therapy 335
Treatment in specific circumstances 336
Pregnancy 336
Antiphospholipid syndrome 336
Cancer 336
Obesity 336
Renal insufficiency 337
Superficial vein thrombosis 337
References 337
CHAPTER 22: Prevention and treatment of venous and arterial thrombosis in patients with specific conditions: diabetes, hypercoagulable states, pregnancy, and renal insufficiency 341
Introduction 341
Diabetes 341
Venous thromboembolism 341
Arterial thromboembolism 342
Blood changes in type 2 diabetes 343
The metabolic syndrome 343
Therapeutic considerations in diabetes and the metabolic syndrome 343
Hypercoagulable states 344
Definition 344
Hereditary thrombophilias 345
Acquired predisposition to thrombosis 347
Pregnancy 350
Antithrombotic drugs 350
Treatment of an acute episode of venous thromboembolism 351
Prophylaxis of venous thromboembolism 352
Renal diseases 355
Chronic kidney disease and thrombosis 355
Implications of thrombosis in the pathogenesis and progression of glomerulonephritis 359
Thrombotic microangiopathies and thrombosis 359
Renal transplantation 361
Nephrotic syndrome 361
Renal vein thrombosis 361
Vascular access thrombosis 362
Renal disease and coronary artery disease 362
References 362
CHAPTER 23: Genetics of the response to antithrombotic drugs and the need for monitoring 371
Introduction 371
Clopidogrel 371
Metabolism 371
Impact of the CYP2C19 variants 373
Other genetic variants 376
Impact of factors that modulate isoenzyme activity 377
What are the practical issues? 378
Summary 380
Warfarin 380
Genetics of warfarin response 380
Vitamin K cycle and global action of vitamin K antagonists 380
Metabolism of warfarin: role of CYP2C9 382
Target of warfarin: role of vitamin K epoxide reductase subunit 1 (VKORC1) genotype 383
Other candidates 385
Need for monitoring 385
Summary 387
References 387
Index 392