Antithrombotics

  • Andrew C.G. Uprichard, Kim P. Gallagher
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An up-to-date overview of blood coagulation, hemostatis, and thrombosis, this volume also provides a state-of-the-art report of current anti-thrombotic and anti-coagulant strategies as well as a summary of current research interest in the area and potential future targets. It attempts to balance traditional pharmacology with the newer sciences of molecular biology and in so doing, sets a framework for future advances in the field. The book is a concise, current and useful reference for the basic researcher as well as the practicing physician working in the fields of cardiology, internal medicine or surgery.
Inhoudsopgave
1: The Coagulation Pathway and Antithrombotic Strategies (With 7 Figures).- A. Introduction.- B. The Coagulation Pathway.- I. The Cascade/Waterfall Model.- II. The Revised Model.- III. Structure-Activity Relationships of Coagulation Proteases.- 1. Thrombin.- 2. Factor Xa.- 3. Factor VII/Tissue Factor Complex.- C. Physiological Regulators.- I. Antithrombin-III (ATIII) and Heparin Cofactor-II (HCII).- II. Tissue Factor Pathway Inhibitor.- III. Protein C/S-Thrombomodulin Complex.- D. Platelet and Cellular Contributions.- I. Cell Surface Dependence.- II. Platelet Participation.- III. Vascular Contributions.- E. Fibrinolysis.- F. Antithrombotic Strategies.- I. Coagulation Factor Inhibitors.- 1. Direct Thrombin Inhibitors.- 2. Thrombin Generation Inhibitors.- a) Factor Xa Inhibitors.- b) Inhibitors of Other Coagulation Factors.- II. Antiplatelet Agents.- 1. Platelet Adhesion and Activation Inhibitors.- 2. Fibrinogen Receptor Antagonists.- III. Thrombolytic Agents.- IV. Other Strategies.- G. Conclusion.- References.- 2: New Developments in the Molecular Biology of Coagulation and Fibrinolysis (With 7 Figures).- A. Introduction.- I. The Coagulation System.- II. The Plasminogen System.- III. Targeted Manipulation and Adenovirus-Mediated Transfer of Genes in Mice.- B. Embryonic Development and Reproduction.- I. Coagulation System.- 1. Tissue Factor and Factor VII.- 2. Thrombomodulin.- 3. Thrombin Receptor and Factor V.- 4. Fibrinogen.- II. Fibrinolytic System.- III. Integrated View of a Role for the Coagulation and Fibrinolytic System in Vascular Development.- C. Health and Survival.- I. Coagulation System.- II. Fibrinolytic System.- D. Hemostasis.- I. Coagulation System.- II. Fibrinolytic System.- E. Thrombosis and Thrombolysis.- I. Coagulation System.- II. Fibrinolytic System.- III. Fibrin Deposits and Pulmonary Plasma Clot Lysis in Transgenic Mice.- IV. Adenovirus-Mediated Transfer of t-PA or PAI-1.- F. Neointima Formation.- G. Atherosclerosis.- H. Tissue Remodeling Associated with Wound Healing.- I. Conclusions.- References.- 3: Epidemiology of Arterial and Venous Thrombosis (With 4 Figures).- A. Epidemiology: Its Potential and Its Limitations.- B. The Epidemiological Study of Arterial and Venous Thrombosis.- I. Arterial Thrombosis.- II. Venous Thrombosis.- C. Risk Factors for Arterial Thrombosis.- I. Fibrinogen.- II. Fetal-Infant Origins Hypothesis of Ischemic Heart Disease.- III. Insulin Resistance.- IV. Hyperhomocysteinemia.- D. Risk Factors for Venous Thrombosis.- E. Future Directions in Epidemiological Research.- I. Genetic Epidemiology.- II. Evidence Synthesis.- References.- 4: In Vivo Models of Thrombosis (With 5 Figures).- A. Introduction.- B. Vessel Wall Injury-Induced Model of Thrombosis.- I. Photochemical Reaction.- II. Laser.- III. Mechanically Induced Injury.- 1. Pinching or Crushing.- 2. Perfusion with Saline or Air.- 3. Endarterectomy and Balloon Angioplasty.- IV. Electrical Current-Induced Injury.- C. Stasis/Hypercoagulability-Induced Models of Thrombosis.- I. Wessler Test and Its Variants.- D. Foreign Surface-Induced Thrombosis.- I. Eversion Graft.- II. Wire Coils.- III. Preformed Thrombi.- IV. Hollenbach's Deep Venous Thrombosis Model.- V. A Novel Veno-Venous Shunt Model in Rabbit.- E. Transgenic Animal Models.- F. Conclusions.- References.- 5: Monitoring Antithrombotic Therapy.- A. Introduction.- I. Balancing Antithrombotic Efficacy Against the Risk of Bleeding.- B. Warfarin.- I. Mechanism of Action.- 1. Effect on Vitamin K-Dependent Clotting Factors.- 2. Kinetics of Vitamin K-Dependent Clotting Factors During Warfarin Therapy.- 3. Variation in Pharmacological Response.- II. Laboratory Monitoring.- 1. Prothrombin Time for Monitoring Warfarin Therapy.- 2. Standardisation of Thromboplastin Reagents.- 3. Choice of Thromboplastins for Clinical Monitoring.- III. Determinants of Bleeding Risk.- IV. Practical Aspects of Warfarin Dosing.- V. Maintenance Treatment.- 1. Anticoagulant Clinics.- 2. Computer-Assisted Monitoring and Patient Self-Monitoring.- VI. Alternative Methods of Monitoring Warfarin Therapy.- 1. Functional Prothrombin Assay.- 2. Prothrombin Fragment F1.2.- 3. Prothrombin-Proconvertin Ratio.- C. Heparin.- I. Heparin Structure.- II. Mechanism of Action.- III. Unfractionated Heparin.- 1. Pharmacokinetics.- 2. Laboratory Monitoring by the Activated Partial Thromboplastin Time (APTT).- 3. Heparin Resistance.- 4. Dose-Adjustment Nomograms.- 5. Subcutaneous Heparin Regimens.- 6. Determinants of Bleeding Risk.- 7. The Activated Clotting Time for Monitoring High Dose Heparin Therapy.- IV. Low Molecular Weight Heparin.- 1. Pharmacokinetics.- 2. Laboratory Monitoring by Chromogenic Anti-Factor Xa Assays.- 3. Clinical Efficacy and Bleeding Risks.- D. Direct-Acting Antithrombin Agents.- I. Role of Thrombin in Thrombogenesis.- II. Mechanism of Action and Clinical Studies.- III. Laboratory Monitoring.- E. Thrombolytic Agents.- I. Clinical Use.- II. Monitoring Thrombolytic Therapy.- F. Antiplatelet Agents.- I. Aspirin.- 1. Clinical Effects.- 2. Mechanism of Action.- 3. Laboratory Monitoring.- 4. Other Antiplatelet Agents.- G. Summary/Conclusion.- References.- 6: Use of Transgenic Mice in the Study of Thrombosis and Hemostasis (With 4 Figures).- A. Introduction.- B. Overview of Coagulation and Fibrinolysis.- C. Transgenic Technology.- I. Generation of Standard Transgenic Mice by Zygote Injection.- II. Generation of Knockout Mice.- D. Transgenic Mice Deficient in Coagulation Factors.- E. Transgenic Approaches to the Study of the Fibrinolytic System.- I. Plasminogen.- II. Plasminogen/Fibrinogen.- III. t-PA, u-PA and t-PA/u-PA.- IV. u-PAR and t-PA/u-PAR.- V. PAI-1.- F. Summary.- References.- 7: Current Antiplatelet Therapy (With 8 Figures).- A. Introduction.- B. Platelets: Physiological and Pathological Activities.- I. Physiological Activities.- II. Pathological Activities.- C. Current Antiplatelet Therapy.- I. Aspirin.- II. Dipyridamole.- III. Ticlopidine.- IV. Abciximab.- 1. Preclinical Development.- 2. Clinical Pharmacology.- 3. Additional Consequences.- a) Inhibition of Platelet Release.- b) Inhibition of Mac-1 Upregulation.- c) Inhibition of Platelet-Mediated Thrombin Generation.- d) Characterization of Abciximab Binding to ?v/?3.- 4. Clinical Experience.- a) Early Human Efficacy Studies.- b) The Phase III EPIC Trial.- c) The EPILOG Trial.- d) The CAPTURE Trial.- e) Clinical Summary of Abciximab.- D. Investigational Agents.- I. GPIIb/IIIa Antagonists.- II. Clopidogrel.- References.- 8: Platelet Membrane Receptors and Signalling Pathways: New Therapeutic Targets (With 7 Figures).- A. Introduction.- I. Platelet Activation.- II. Platelet Inhibition.- III. Regulation of Platelet Activation.- B. Signalling by Cell Surface Receptors.- I. G Protein-Coupled Receptor Signalling.- 1. Guanine Nucleotide Binding Proteins and Effector Regulation.- 2. The G Protein GTP/GDP Cycle and Effector Modulation.- 3. G Protein-Regulated Effectors.- a) Adenylyl Cyclase.- b) Phospholipase C.- c) Other ??-Regulated Effectors: src Family Kinases and PI 3-Kinase.- II. Tyrosine Kinase-Linked Receptors.- III. Ion Channels and Their Receptors.- C. Signal Enzymes and Mediators.- I. Phosphoinositide Metabolism.- II. Phospholipase A2.- III. PI 3-Kinase.- IV. Cyclic Nucleotides.- 1. cAMP.- 2. cGMP.- D. Platelet G Protein-Coupled Receptors.- I. Thrombin (PAR1).- 1. Thrombin Binding Sites.- 2. PAR1, A G Protein-Coupled Receptor for Thrombin.- 3. Other Protease-Activated Receptors (PARs).- 4. PAR1 and Human Platelet Activation.- II. Thromboxane A2 (TP Receptor).- III. ADP Receptors.- IV. 5-Hydroxytryptamine (5HT2A Receptor).- V. Vasopressin (V1 Receptor).- VI. Platelet Activating Factor (PAF).- VII. Adrenaline (?2-Adrenoceptor).- VIII. Prostacyclin (IP Receptor).- IX. Other Seven Transmembrane Receptors.- E. Tyrosine Kinase-Linked Receptors.- I. Collagen.- II. Fc?RUA.- III. Thrombopoietin.- F. Adhesion Receptors.- I. Integrins.- 1. GPIIb-IIIa.- 2. Other Platelet Integrins.- II. GP-IX-V (vWf Receptor).- III. PADGEM (P-Selectin).- IV. PECAM-1.- V. GPIV.- G. Clinical Settings for Antiplatelet Drugs.- I. The Platelet as a Target in Thrombotic Disease.- II. Overview of Currently Used Agents.- III. Possible Settings for New Antiplatelet Agents.- H. New Targets for Drug Development.- I. Receptors as Targets.- 1. ADP Receptors.- 2. Adhesion Receptors.- 3. Thrombin Receptor.- II. Signalling Pathways as Targets.- 1. Protein-Protein Interfaces.- 2. Enzyme Targets.- III. Development of New Drugs: Aspirin's Legacy.- References.- 9: Heparin and Other Indirect Antithrombin Agents (With 1 Figure).- A. Introduction.- I. Magnitude of the Problem of Intravascular Thrombosis and Thromboembolic Disease.- B. Unfractionated Heparin: The Prototypical Indirect Antithrombin.- I. History.- II. Source.- III. Structure.- IV. Mechanism of Action.- V. Pharmacokinetics.- 1. Administration.- a) Intravenous Route.- b) Subcutaneous Route.- c) Novel Methods of Administration.- 2. Distribution.- 3. Clearance.- 4. Effect of Physiological State.- 5. Drug Interactions.- VI. Clinical Indications.- 1. Venous Thrombosis and Thromboembolic Disease.- 2. Use of Heparin in Acute Coronary Syndromes.- 3. Heparin for Trousseau Syndrome: A Unique Therapy.- 4. Novel Uses of Heparin.- VII. Therapeutic Monitoring.- VIII. Toxicity.- IX. Antidotes: Reversal of Anticoagulant Effect.- C. Heparinoids and Related Anticoagulants.- I. Pentosans (Sulfonated Xylans).- 1. Source.- 2. Mechanism of Action.- 3. Administration.- 4. Clinical Uses.- 5. Toxicity.- 6. Clinical Relevance.- II. Dermatan Sulfate.- 1. Introduction.- 2. Source.- 3. Mechanism of Action.- 4. Pharmacokinetics.- 5. Clinical Use.- 6. Clinical Relevance.- III. Sulodexide.- 1. Introduction.- 2. Source.- 3. Mechanism of Action.- 4. Pharmacokinetics.- 5. Clinical Indications.- 6. Toxicity.- 7. Future.- IV. Danaparoid (Organan 10172).- 1. Introduction.- 2. Source.- 3. Mechanism of Action.- 4. Pharmacokinetics.- 5. Clinical Uses.- 6. Toxicity.- 7. Antidotes.- 8. Future.- V. Other Indirect Antithrombins.- D. Conclusion.- References.- 10: Low Molecular Weight Heparin.- A. Introduction.- B. Discovery and Development of Low Molecular Weight Heparins.- I. Properties of Unfractionated Heparin.- II. Antithrombotic Properties of Low Molecular Weight Heparin.- III. Advantages of Low Molecular Weight Heparin over Unfractionated Heparin.- C. Use of Low Molecular Weight Heparins.- I. Prevention of Venous Thromboembolism.- II. Orthopedic Surgery.- D. Trauma.- E. General Surgery.- I. Medical Patients.- II. Low Molecular Weight Heparinoid.- F. Treatment of Venous Thromboembolism.- G. Out-of-Hospital Treatment of Venous Thromboembolism with Low Molecular Weight Heparin.- H. Role of Low Molecular Weight Heparin in the Prevention and Treatment of Arterial Thrombosis.- I. Unstable Angina.- II. Thrombotic Stroke.- III. Peripheral Vascular Disease.- IV. Hemodialysis.- V. Other Vascular Problems.- I. Current Recommendations for the Use of Low Molecular Weight Heparin.- I. Prevention of Venous Thromboembolism.- II. Treatment of Venous Thromboembolism.- J. Summary and Conclusions.- References.- 11: Parenteral Direct Antithrombins (With 3 Figures).- A. Introduction.- B. Thrombin: Structure and Function.- C. Limitations of Current Antithrombotic Therapy.- D. Direct Thrombin Inhibitors.- I. Hirudin.- II. Other Direct Thrombin Inhibitors.- E. Potential Roles for Direct Thrombin Inhibition.- I. Acute Myocardial Infarction, Adjunct to.- Thrombolysis.- 1. Preclinical Studies.- 2. Phase II Clinical Trials.- 3. Phase III Clinical Trials.- 4. Further Acute Myocardial Infarction Studies.- II. Unstable Angina and Myocardial Infarction Without ST Elevation.- 1. Phase II Clinical Trials.- 2. Phase III Clinical Trials.- III. Adjunct to Percutaneous Revascularization.- 1. Preclinical Studies.- 2. Phase II Clinical Trials.- 3. Phase III Clinical Trials.- IV. Deep Venous Thrombosis.- V. Heparin-Induced Thrombocytopenia.- F. Rebound Phenomenon.- G. Summary and Future Directions.- References.- 12: Anticoagulant Therapy with Warfarin for Thrombotic Disorders (With 2 Figures).- A. Introduction.- B. Pathogenesis.- C. Pharmacology.- I. Mechanism of Action.- II. Assessment of Clinical Efficacy.- III. Optimal Therapeutic Regimens.- IV. Benefits of Monitoring.- D. Prevention and Management of Venous Thromboembolism.- I. Prevention of Venous Thrombosis Following Orthopedic Surgery.- II. Prevention of Stroke and Venous Thromboembolism in Acute Myocardial Infarction.- III. Treatment of Deep Venous Thrombosis.- E. Antithrombotic Therapy for Atrial Fibrillation.- F. Antithrombotic Therapy for Prosthetic Heart Valves.- G. Other Indications for Oral Anticoagulant Therapy.- H. Complications of Warfarin Therapy.- References.- 13: Oral Thrombin Inhibitors: Challenges and Progress (With 3 Figures).- A. Introduction.- I. Role of Thrombin in Hemostasis and Thrombosis.- II. Medical Need for Anticoagulant and Antithrombotic Drugs.- 1. Acute Anticoagulation.- 2. Chronic Anticoagulation with Warfarin.- B. Potential Advantages of Direct, Small Molecule Inhibitors.- C. Pharmacological and Pharmacokinetic Issues.- I. Safety.- II. Selectivity and Fibrinolytic Compromise.- III. Pharmacodynamics: Efficacy and Kinetics of Inhibition.- IV. The Rebound Phenomenon.- V. Oral Bioavailability and Pharmacokinetics.- D. Thrombin Inhibitors in Development.- I. Bivalent Direct Thrombin Inhibitors.- 1. Hirudin.- 2. Hirulog.- II. Reversible Inhibitors of Thrombin.- 1. Argatroban (Novastan).- 2. Napsagatran.- 3. Inogatran.- III. Covalent Inhibitors of Thrombin.- 1. Efegatran.- 2. Corvas: CVS 1123.- 3. DuPont Merck: DuP 714.- E. Summary and Conclusions.- References.- 14: Inhibitors of Factor Xa (With 6 Figures).- A. Introduction.- B. Rationale of Factor Xa Inhibitors.- C. Pharmacological Profile of Factor Xa Inhibitors.- I. ATIII-Dependent Inhibitors.- II. Direct Inhibitors.- 1. Naturally Occurring Inhibitors.- 2. Synthetic Small Molecule Inhibitors.- a) Peptidomimetics.- b) Benzamidine Derivatives.- c) Bisamidine Derivatives.- d) Argininal Derivatives.- e) Piperidinylpyridine Derivatives.- D. ATIII-Independent Inhibition of Factor Xa on Prothrombinase.- E. Comparative Antithrombotic Efficacy of Direct Factor Xa Inhibitors.- F. Summary and Conclusions.- References.- 15: Inhibitors of Tissue Factor/Factor Vila (With 4 Figures).- A. Introduction.- B. Role in Hemostasis.- C. Structural Biology of Tissue Factor and Factor Vila.- D. Endogenous Regulators of Tissue Factor.- I. Tissue Factor Pathway Inhibitor.- II. Antithrombin.- E. Pathophysiology of TF/VIIa.- F. Experimental Inhibitors of TF/VIIa.- I. Recombinant TFPI (rTFPI) and Truncated rTFPI.- II. Inactivated Factor Vila: FVIIai.- III. Recombinant Nematode Anticoagulant Peptide (rNAPc2).- IV. TF Antibodies.- G. Summary and Conclusions.- References.- 16: Natural Anticoagulants and Their Pathways (With 5 Figures).- A. Introduction.- I. The Protein C Activation Complex.- II. The APC Anticoagulant Complex.- III. Inhibition of the Anticoagulant Complex.- B. Modulation of the Protein C Pathway in Disease.- I. APC Resistance and Factor V Leiden.- C. Thrombomodulin as an Antithrombotic Agent.- D. Protein C as an Antithrombotic Agent.- I. Protein C and Arterial Thrombosis.- II. Reperfusion Injury.- E. Protein S as an Antithrombotic Agent.- F. Mutations to Modulate Natural Anticoagulant Responses.- I. Mutations in Protein C.- II. Mutations in Thrombin.- G. Inactive Coagulation Factors as Antithrombotics.- H. Summary.- References.
Productdetails
Uitgavejaar 2011
ISBN 9783642641909
Serie Handbook of Experimental Pharmacology
Verschijningsdatum 27 sep. 2011
Omvang 485
Redactie Andrew C.G. Uprichard, Kim P. Gallagher
Editie Softcover reprint of the original 1st ed. 1999
Auteur(s) Andrew C.G. Uprichard Kim P. Gallagher
Reeksnummer 132
Bindwijze Paperback
Taal Engels

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