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.
Inhalt
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 (…