I . I Antithrombotics · Protein C/S-Thrombomodulin Complex 12 D. Platelet and Cellular...
Transcript of I . I Antithrombotics · Protein C/S-Thrombomodulin Complex 12 D. Platelet and Cellular...
, I . I
Antithrombotics
Contributors
W. Bell, P. Carmeliet, L. Chi, D. Collen, R.J.G. Cuthbert,C. Esmon, K.P. Gallagher, D. Ginsburg, T. Hara, L.A. Harker,T.A. Hennebry, M. Hollenberg, R.D. Hull, J.A. Jakubowski,R.E. Jordan, F. Kee, D. Keeling, S.D. Kimball, S. Kunitada,M.A. Lauer, L. Leblond, A.M. Lincoff, B.Lucchesi, T.E.Mertz,T. Nagahara, J. Pearson, G.F. Pineo, S. Rebello, J.R. Rubin,A.C.G. Uprichard, S. Watson, H.F. Weisman, P.D. Winocour
Editors
Andrew C.G. Uprichard and Kim P. Gallagher
Springer
Contents
CHAPTER 1The Coagulation Pathway and Antithrombotic StrategiesL. LEBLOND and P.D. WINOCOUR. With 7 Figures 1
A. Introduction 1B. The Coagulation Pathway 1
I. The Cascade/Waterfall Model 2II. The Revised Model 3
III. Structure-Activity Relationships of Coagulation Proteases.. 41. Thrombin 62. Factor Xa 73. Factor VII/Tissue Factor Complex 8
C. Physiological Regulators 9I. Antithrombin-III (ATIII) and Heparin Cofactor-II
(HCII) 10II. Tissue Factor Pathway Inhibitor 11
III. Protein C/S-Thrombomodulin Complex 12D. Platelet and Cellular Contributions 13
I. Cell Surface Dependence 14II. Platelet Participation 14
III. Vascular Contributions 15E. Fibrinolysis 16F. Antithrombotic Strategies 17
I. Coagulation Factor Inhibitors 181. Direct Thrombin Inhibitors 202. Thrombin Generation Inhibitors 23
a) Factor Xa Inhibitors 23b) Inhibitors of Other Coagulation Factors 23
II. Antiplatelet Agents 251. Platelet Adhesion and Activation Inhibitors 252. Fibrinogen Receptor Antagonists 28
III. Thrombolytic Agents 29IV. Other Strategies 30
G. Conclusion 30References 31
XII Contents
CHAPTER 2
New Developments in the Molecular Biology of Coagulationand FibrinolysisP. CARMELIET and D. COLLEN. With 7 Figures 41
A. Introduction 41I. The Coagulation System 41
II. The Plasminogen System 42III. Targeted Manipulation and Adenovirus-Mediated
Transfer of Genes in Mice 43B. Embryonic Development and Reproduction 43
I. Coagulation System 431. Tissue Factor and Factor VII 432. Thrombomodulin 523. Thrombin Receptor and Factor V 534. Fibrinogen 54
II. Fibrinolytic System 54III. Integrated View of a Role for the Coagulation and
Fibrinolytic System in Vascular Development 56C. Health and Survival 56
I. Coagulation System 56II. Fibrinolytic System 58
D. Hemostasis 58I. Coagulation System 58
II. Fibrinolytic System 60E. Thrombosis and Thrombolysis 61
I. Coagulation System 61II. Fibrinolytic System 61
III. Fibrin Deposits and Pulmonary Plasma Clot Lysis inTransgenic Mice 62
IV. Adenovirus-Mediated Transfer of t-PA or PAI-1 63F. Neointima Formation 64G. Atherosclerosis 66H. Tissue Remodeling Associated with Wound Healing 68
I. Conclusions 70References 70
CHAPTER 3
Epidemiology of Arterial and Venous ThrombosisF. KFE. With 4 Figures 77
A. Epidemiology: Its Potential and Its Limitations 77B. The Epidemiological Study of Arterial and
Venous Thrombosis 78I. Arterial Thrombosis 78
II. Venous Thrombosis 81
Contents XIII
C. Risk Factors for Arterial Thrombosis 83I. Fibrinogen 84
II. Fetal-Infant Origins Hypothesis ofIschemic Heart Disease 85
III. Insulin Resistance 87IV. Hyperhomocysteinemia 88
D. Risk Factors for Venous Thrombosis 89E. Future Directions in Epidemiological Research 93
I. Genetic Epidemiology 94II. Evidence Synthesis 95
References 96
CHAPTER 4
In Vivo Models of ThrombosisL. CHI, S. REBELLO, and B.R. LUCCHESI. With 5 Figures 101
A. Introduction 101B. Vessel Wall Injury-Induced Model of Thrombosis 102
I. Photochemical Reaction 102II. Laser 104
III. Mechanically Induced Injury 1051. Pinching or Crushing 1052. Perfusion with Saline or Air 1083. Endarterectomy and Balloon Angioplasty 109
IV. Electrical Current-Induced Injury 109C. Stasis/Hypercoagulability-Induced Models of Thrombosis 112
I. Wessler Test and Its Variants 112D. Foreign Surface-Induced Thrombosis 113
I. Eversion Graft 113II. Wire Coils 114
III. Preformed Thrombi 114IV. Hollenbach's Deep Venous Thrombosis Model 115V. A Novel Veno-Venous Shunt Model in Rabbit 116
E. Transgenic Animal Models 117F. Conclusions 120References 121
CHAPTER 5
Monitoring Antithrombotic TherapyR.J.G. ClTHUERT 129
A. Introduction 129I. Balancing Antithrombotic Efficacy Against the Risk
of Bleeding 129B. Warfarin ." 129
I. Mechanism of Action 1291. Effect on Vitamin K-Dependent Clotting Factors 129
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2. Kinetics of Vitamin K-Dependent Clotting FactorsDuring Warfarin Therapy 130
3. Variation in Pharmacological Response 130II. Laboratory Monitoring 131
1. Prothrombin Time for Monitoring WarfarinTherapy 131
2. Standardisation of Thromboplastin Reagents 1323. Choice of Thromboplastins for Clinical
Monitoring 132III. Determinants of Bleeding Risk 133IV. Practical Aspects of Warfarin Dosing 134V. Maintenance Treatment 134
1. Anticoagulant Clinics 1342. Computer-Assisted Monitoring and
Patient Self-Monitoring 135VI. Alternative Methods of Monitoring
Warfarin Therapy 1351. Functional Prothrombin Assay 1352. Prothrombin Fragment Fl .2 1353. Prothrombin-Proconvertin Ratio 136
C. Heparin 136I. Heparin Structure 136
II. Mechanism of Action 136III. Unfractionated Heparin 137
1. Pharmacokinetics 1372. Laboratory Monitoring by the Activated Partial
Thromboplastin Time (APTT) 1373. Heparin Resistance 1384. Dose-Adjustment Nomograms 1395. Subcutaneous Heparin Regimens 1396. Determinants of Bleeding Risk 1407. The Activated Clotting Time for Monitoring High
Dose Heparin Therapy 140IV. Low Molecular Weight Heparin 141
1. Pharmacokinetics 1412. Laboratory Monitoring by Chromogenic
Anti-Factor Xa Assays 1413. Clinical Efficacy and Bleeding Risks 142
D. Direct-Acting Antithrombin Agents 142I. Role of Thrombin in Thrombogenesis 142
II. Mechanism of Action and Clinical Studies 142III. Laboratory Monitoring 143
E. Thrombolytic Agents 143I. Clinical Use 143
II. Monitoring Thrombolytic Therapy 144
Contents XV
F. Antiplatelet Agents 144I. Aspirin 144
1. Clinical Effects 1442. Mechanism of Action 1453. Laboratory Monitoring 1454. Other Antiplatelet Agents 146
G. Summary/Conclusion 146References 148
CHAPTER 6
Use of Transgenic Mice in the Study of Thrombosis and HemostasisJ.M. PEARSON and D. GINSBURG. With 4 Figures 157
A. Introduction 157B. Overview of Coagulation and Fibrinolysis 157C. Transgenic Technology 159
I. Generation of Standard Transgenic Mice byZygote Injection 159
II. Generation of Knockout Mice 159D. Transgenic Mice Deficient in Coagulation Factors 161E. Transgenic Approaches to the Study of the
Fibrinolytic System 164I. Plasminogen 165
II. Plasminogen/Fibrinogen 166III. t-PA, u-PA and t-PA/u-PA 166IV. u-PAR and t-PA/u-PAR 167V. PAI-1 168
F. Summary 169References 170
CHAPTER 7
Current Antiplatelet TherapyJ.A. JAKIBOWSKI. R.E. JORDAN, and H.F. WIISM AN.
With 8 Figures 175
A. Introduction 175B. Platelets: Physiological and Pathological Activities 175
I. Physiological Activities 176II. Pathological Activities 177
C. Current Antiplatelet Therapy 177I. Aspirin 177
II. Dipyridamole 179III. Ticlopidine 180IV. Abciximab ISO
1. Preclinical Development ISO2. Clinical Pharmacolouv 183
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3. Additional Consequences 191a) Inhibition of Platelet Release 191b) Inhibition of Mac-1 Upregulation 191c) Inhibition of Platelet-Mediated Thrombin
Generation 192d) Characterization of Abciximab Binding to av/33 193
4. Clinical Experience 194a) Early Human Efficacy Studies 194b) The Phase III EPIC Trial 195c) The EPILOG Trial 198d) The CAPTURE Trial 200e) Clinical Summary of Abciximab 202
D. Investigational Agents 202I. GPIIb/IIIa Antagonists 202
II. Clopidogrel 203References 203
CHAPTER 8
Platelet Membrane Receptors and Signalling Pathways:New Therapeutic TargetsS.P. WATSON, D. KEELING, and M.D. HOLLENBERG. With 7 Figures . . . 209
A. Introduction 209I. Platelet Activation 209
II. Platelet Inhibition 210III. Regulation of Platelet Activation 211
B. Signalling by Cell Surface Receptors 211I. G Protein-Coupled Receptor Signalling 213
1. Guanine Nucleotide Binding Proteins andEffector Regulation 213
2. The G Protein GTP/GDP Cycle andEffector Modulation 215
3. G Protein-Regulated Effectors 216a) Adenylyl Cyclase 216b) Phospholipase C 217c) Other /Jy-Regulated Effectors: src Family Kinases
and PI 3-Kinase 217II. Tyrosine Kinase-Linked Receptors 218
III. Ion Channels and Their Receptors 219C. Signal Enzymes and Mediators 219
I. Phosphoinositide Metabolism 220II. Phospholipase A, 221
III. PI 3-Kinase 223
Contents XVII
IV. Cyclic Nucleotides 2231. cAMP 2232. cGMP 224
D. Platelet G Protein-Coupled Receptors 224I. Thrombin (PAR,) 224
1. Thrombin Binding Sites 2242. PAR,, A G Protein-Coupled Receptor for
Thrombin 2253. Other Protease-Activated Receptors (PARs) 2264. PAR, and Human Platelet Activation 227
II. Thromboxane A, (TP Receptor) 227III. ADP Receptors 228IV. 5-Hydroxytryptamine (5HT2A Receptor) 229V. Vasopressin (V, Receptor) 229
VI. Platelet Activating Factor (PAF) 230VII. Adrenaline (a,-Adrenoceptor) 230
VIII. Prostacyclin (IP Receptor) 231IX. Other Seven Transmembrane Receptors 231
E. Tyrosine Kinase-Linked Receptors 231I. Collagen 231
II. FcyRIIA 234III. Thrombopoietin 235
F. Adhesion Receptors 235I. Integrins 235
1. GPIIb-IIIa 2362. Other Platelet Integrins 238
II. GP-IX-V (vWf Receptor) 238III. PADGEM (P-Selectin) 239IV. PECAM-1 239V. GPIV 240
G. Clinical Settings for Antiplatelet Drugs 240I. The Platelet as a Target in Thrombotic Disease 240
II. Overview of Currently Used Agents 242III. Possible Settings for New Antiplatelet Agents 242
H. New Targets for Drug Development 242I. Receptors as Targets 243
1. ADP Receptors 2432. Adhesion Receptors 2443. Thrombin Receptor 245
II. Signalling Pathways as Targets 2471. Protein-Protein Interfaces 2482. Enzyme Targets 249
III. Development of New Drugs: Aspirin's Legacy 249References 250
XVIII Contents
CHAPTER 9
Heparin and Other Indirect Antithrombin AgentsW.R. BELL and T.A. HENNEBRY. With 1 Figure 259
A. Introduction 259I. Magnitude of the Problem of Intravascular Thrombosis
and Thromboembolic Disease 259B. Unfractionated Heparin:
The Prototypical Indirect Antithrombin 259I. History 259
II. Source 261III. Structure 261IV. Mechanism of Action 262V. Pharmacokinetics 265
1. Administration 265a) Intravenous Route 265b) Subcutaneous Route 266c) Novel Methods of Administration 267
2. Distribution 2673. Clearance 2674. Effect of Physiological State 2685. Drug Interactions 268
VI. Clinical Indications 2691. Venous Thrombosis and Thromboembolic Disease . . . . 2702. Use of Heparin in Acute Coronary Syndromes 2713. Heparin for Trousseau Syndrome:
A Unique Therapy 2724. Novel Uses of Heparin 273
VII. Therapeutic Monitoring 274VIII. Toxicity 276
IX. Antidotes: Reversal of Anticoagulant Effect 278C. Heparinoids and Related Anticoagulants 279
I. Pentosans (Sulfonated Xylans) 2791. Source 2792. Mechanism of Action 2803. Administration 2804. Clinical Uses 2805. Toxicity 2816. Clinical Relevance 281
II. Dermatan Sulfate 2821. Introduction 2822. Source 2823. Mechanism of Action 2824. Pharmacokinetics 2835. Clinical Use 283
Contents XIX
6. Clinical Relevance 284III. Sulodexide 284
1. Introduction 2842. Source 2843. Mechanism of Action 2854. Pharmacokinetics 2855. Clinical Indications 2866. Toxicity 2867. Future 286
IV. Danaparoid (Organan 10172) 2861. Introduction 2862. Source 2873. Mechanism of Action 2874. Pharmacokinetics 2875. Clinical Uses 2876. Toxicity 2887. Antidotes 2888. Future 288
V. Other Indirect Antithrombins 288D. Conclusion 289References 289
CHAPTER 10Low Molecular Weight HeparinG.F. PINEO and R.D. HULI 305
A. Introduction 305B. Discovery and Development of Low Molecular Weight
Heparins 305I. Properties of Unfractionated Heparin 305
II. Antithrombotic Properties of Low Molecular WeightHeparin 307
III. Advantages of Low Molecular Weight Heparin overUnfractionated Heparin 309
C. Use of Low Molecular Weight Heparins 310I. Prevention of Venous Thromboembolism 310
II. Orthopedic Surgery 311D. Trauma \ 312E. General Surgery 313
I. Medical Patients 314II. Low Molecular Weight Heparinoid 314
F. Treatment of Venous Thromboembolism 314G. Out-of-Hospital Treatment of Venous Thromboembolism
with Low Molecular Weight Heparin 316H. Role of Low Molecular Weight Heparin in the Prevention and
Treatment of Arterial Thrombosis 317
XX Contents
I. Unstable Angina 317II. Thrombotic Stroke 318
III. Peripheral Vascular Disease 318IV. Hemodialysis 319V. Other Vascular Problems 319
I. Current Recommendations for the Use of Low MolecularWeight Heparin 319
I. Prevention of Venous Thromboembolism 319II. Treatment of Venous Thromboembolism 320
J. Summary and Conclusions 320References 321
CHAPTER 11
Parenteral Direct AntithrombinsM.A. LAUER and A.M. LINCOFE. With 3 Figures 331
A. Introduction 331B. Thrombin: Structure and Function 331C. Limitations of Current Antithrombotic Therapy 333D. Direct Thrombin Inhibitors 334
I. Hirudin 334II. Other Direct Thrombin Inhibitors 335
E. Potential Roles for Direct Thrombin Inhibition 335I. Acute Myocardial Infarction, Adjunct to
Thrombolysis 3361. Preclinical Studies 3362. Phase II Clinical Trials 3363. Phase III Clinical Trials 3374. Further Acute Myocardial Infarction Studies 339
II. Unstable Angina and Myocardial Infarction WithoutST Elevation 3421. Phase II Clinical Trials 3422. Phase III Clinical Trials 343
III. Adjunct to Percutaneous Revascularization 3431. Preclinical Studies 3442. Phase II Clinical Trials 3443. Phase III Clinical Trials 344
IV. Deep Venous Thrombosis 345V. Heparin-Induced Thrombocytopenia 346
F. Rebound Phenomenon 346G. Summary and Future Directions 348References 348
Contents XXI
CHAPTER 12
Anticoagulant Therapy with Warfarin for Thrombotic DisordersL.A. HARKER. With 2 Figures 353
A. Introduction 353B. Pathogenesis 353C. Pharmacology 354
I. Mechanism of Action 354II. Assessment of Clinical Efficacy 354
III. Optimal Therapeutic Regimens 357IV. Benefits of Monitoring 359
D. Prevention and Management of VenousThromboembolism 359
I. Prevention of Venous Thrombosis FollowingOrthopedic Surgery 359
II. Prevention of Stroke and Venous Thromboembolism inAcute Myocardial Infarction 359
III. Treatment of Deep Venous Thrombosis 360E. Antithrombotic Therapy for Atrial Fibrillation 360F. Antithrombotic Therapy for Prosthetic Heart Valves 360G. Other Indications for Oral Anticoagulant Therapy 361H. Complications of Warfarin Therapy 361References 363
CHAPTER 13
Oral Thrombin Inhibitors: Challenges and ProgressS.D. KIMBALL. With 3 Figures 367
A. Introduction 367I. Role of Thrombin in Hemostasis and Thrombosis 367
II. Medical Need for Anticoagulant and AntithromboticDrugs 3701. Acute Anticoagulation 3712. Chronic Anticoagulation with Warfarin 372
B. Potential Advantages of Direct. Small Molecule Inhibitors 373C. Pharmacological and Pharmacokinetic Issues 374
I. Safety" 374II. Selectivity and Fibrinolytic Compromise 374
III. Pharmacodynamics: Efficacy and Kinetics ofInhibition 375
IV. The Rebound Phenomenon 377V. Oral Bioavailability and Pharmacokinetics 378
D. Thrombin Inhibitors in Development 379I. Bivalent Direct Thrombin Inhibitors 379
1. Hirudin 379
XXII Contents
2. Hirulog 381II. Reversible Inhibitors of Thrombin 381
1. Argatroban (Novastan) 3822. Napsagatran 3823. Inogatran 383
III. Covalent Inhibitors of Thrombin 3831. Efegatran 3842. Corvas: CVS 1123 3853. DuPont Merck: DuP 714 385
E. Summary and Conclusions 386References 386
CHAPTER 14
Inhibitors of Factor XaS. KUNI'I ADA, T. NAGAHARA, and T. HARA. With 6 Figures 397
A. Introduction 397B. Rationale of Factor Xa Inhibitors 397C. Pharmacological Profile of Factor Xa Inhibitors 399
I. ATIII-Dependent Inhibitors 400II. Direct Inhibitors 401
1. Naturally Occurring Inhibitors 4012. Synthetic Small Molecule Inhibitors 403
a) Peptidomimetics 403b) Benzamidine Derivatives 404c) Bisamidine Derivatives 405d) Argininal Derivatives 408e) Piperidinylpyridine Derivatives 410
D. ATIII-Independent Inhibition of Factor Xaon Prothrombinase 410
E. Comparative Antithrombotic Efficacy ofDirect Factor Xa Inhibitors 414
F. Summary and Conclusions 415References 415
CHAPTER 15
Inhibitors of Tissue Factor/Factor VilaK.P. GALLAGHER. T.E. MERTZ, L. CHI, J.R. RUBIN.
and A.C.G. UPRICHARD. With 4 Figures 421
A. Introduction 421B. Role in Hemostasis 422C. Structural Biology of Tissue Factor and Factor Vila 423D. Endogenous Regulators of Tissue Factor 429
I. Tissue Factor Pathway Inhibitor 429
Contents XX11I
II. Antithrombin 430E. Pathophysiology of TF/VIIa 430F. Experimental Inhibitors of TF/VIIa 432
I. Recombinant TFPI (rTFPI) and Truncated rTFPI 433II. Inactivated Factor Vila: FVIIai 435
III. Recombinant Nematode Anticoagulant Peptide(rNAPc2) 436
IV. TF Antibodies 437G. Summary and Conclusions 438References 439
CHAPTER 16
Natural Anticoagulants and Their PathwaysC.T. ESMON. With 5 Figures 447
A. Introduction 447I. The Protein C Activation Complex 450
II. The APC Anticoagulant Complex 453III. Inhibition of the Anticoagulant Complex 454
B. Modulation of the Protein C Pathway in Disease 455I. APC Resistance and Factor V Leiden 458
C. Thrombomodulin as an Antithrombotic Agent 458D. Protein C as an Antithrombotic Agent 459
I. Protein C and Arterial Thrombosis 461II. Reperfusion Injury 462
E. Protein S as an Antithrombotic Agent 463F. Mutations to Modulate Natural Anticoagulant Responses 463
I. Mutations in Protein C 463II. Mutations in Thrombin 464
G. Inactive Coagulation Factors as Antithrombotics 464H. Summary 466References 466
Subject Index 477