Fibrinolytics and Antifibrinolytics

The Fibrinolytic Process.- Biochemistry of the Factors of the Fibrinolytic System.- A. Factors of the Fibrinolytic System.- I. Plasminogen — Plasmin.- 1. Plasminogen.- 2. Plasmin.- II. Plasminogen Activators.- 1. Activators in Body Fluids.- a) Blood Activator.- b) Urine Activator (Urokinase).- c) Activators from Other Body Fluids.- 2. Tissue Activators.- 3. Bacterial Activators.- a) Streptokinase.- b) Staphylokinase.- III. Inhibitors.- B. Mechanisms of the Fibrinolytic Process.- I. Plasmin Formation (Plasminogen Activation).- II. Formation of Activator (Mechanism of Action of Streptokinase).- III. Fibrin Dissolution.- Final Remarks.- References.- Fibrinogen and Fibrin Formation.- A. Physico-chemical Properties of Fibrinogen.- B. Biochemical Properties of Fibrinogen.- I. Subunits and Prosthetic Groups.- II. The Primary Structure.- 1. CNBr-Fragments.- 2. Disulphide Bridges.- 3. Plasmin Fragments.- III. The Antigenic Structure of Fibrinogen and the Location of Epitopes and Other Structural Elements.- C. Fibrin — The Ordered Structure of Fibrinogen.- I. Release of Fibrinopeptides.- II. Polymerization of Fibrin Monomers.- III. Stabilizing of the Fibrin Polymer.- D. Fibrinogen in Health and Disease.- References.- Fibrinogen and Fibrin Degradation Products.- A. Degradation of the Fibrinogen Molecule.- I. Degradation by Thrombin.- II. Degradation by Plasmin.- III. Degradation by Both Plasmin and Thrombin.- IV. Degradation by Other Enzymes.- 1. Thrombin-like Enzymes.- 2. Pancreatic Proteases.- 3. Proteases from Other Sources.- B. Biological Activities.- I. Products of Thrombin Action.- 1. Fibrin Monomer.- 2. Fibrinopeptide A and B (FpA, FpB).- II. Products of Plasmin Action.- 1. Clottability.- 2. Anticlotting Activity.- a) Inhibition of Thrombin.- b) Inhibition of Fibrin Polymerization.- c) Inhibition of Thromboplastin Generation.- 3. Interference of FDP with Platelet Function.- 4. Effects on Smooth Muscle, Heart and Permeability of Biological Membranes.- 5. Stimulation of Fibrinogen Biosynthesis.- 6. Other Effects.- C. Immunologic Properties of FDP.- D. Detection and Quantitation of FDP.- I. Immunologic Assays.- II. Radioimmunoassay.- III. Staphylococcal Clumping Test (SC).- IV. Thrombin and Reptilase Time.- V. Detection of Soluble Fibrin Complexes.- VI. Practical Value.- E. The Role of FDP in Clinical Practice.- References.- The Measurement of Fibrinolytic Activities.- A. Methods for Measuring the Spontaneous Fibrinolytic Activity of Blood.- I. Whole Blood Lysis Test.- II. Euglobulin Clot Lysis Test.- III. Dilute Clot Lysis Time Methods.- 1. Dilute Whole Blood Clot Lysis Time.- 2. Schneider’s Test.- IV. Fibrin Plate Method.- V. Determination of Fibrin/Fibrinogen Degradation Products (FDP).- 1. Tanned Red Cell Hemagglutination Inhibition Immunoassay (TRCHII).- 2. Latex Agglutination Tests.- 3. Immunochemical Method According to Niléhn.- a) Malignant Diseases.- b) Renal Diseases.- c) Conditions Associated with Abnormal Proteolysis.- 4. Radioimmunoassay for Determination of FDP.- B. Fibrinolytic Response to Stimuli, with Special References to Venous Occlusion Test.- C. The Fibrin Slide Method (Todd’s Method).- D. Release of Fibrinolytic Agents from Tissue Cultures (“Culture with Clot” Method).- References.- Activators of Fibrinolysis.- Biochemistry of Streptokinase.- A. Assays of Streptokinase Activity.- I. Clot Lysis Assay.- II. Lysine Methyl Ester Assay.- III. Casein Assay.- IV. NPGB Burst Assay.- B. Preparation of Streptokinase.- I. Preparation of High Purity Streptokinase.- II. Affinity Column Preparation of Streptokinase*.- C. Physical Properties of Streptokinase.- D. Mechanism of Streptokinase Activity.- References.- Pharmacology of Streptokinase.- A. Characteristics and Requirements for Pharmacological Examination.- I. Selection of Experimental Animals.- II. Formation of Plasminogen Activator.- III. Formation of AntiStreptokinase.- IV. Formation of Pyrogenic Substances.- B. Toxicity.- C. Pharmacodynamics.- I. Fibrinolytic Effect.- II. Effects on Smooth Muscle, Heart and Circulation.- D. Pharmacokinetics.- I. Native Streptokinase.- II. Radiolabeled Streptokinase.- E. Thrombolytic Effect.- F. Clinical Pharmacology.- References.- Clinical Use of Streptokinase.- A. Fundamentals of Clinical Use.- I. Thrombolytic Effect.- II. Effect on Hemostasis.- III. Immunologic Reactions.- IV. Influence on Kinin Formation.- B. Therapeutic Use.- I. Indications.- II. Contraindications.- III. Administration.- IV. Dosage.- 1. Initial Dose.- 2. Maintenance Dose.- 3. Special Dosage Schemes.- V. Control of Therapy.- VI. Side-Effects.- C. Results of Therapy.- I. Venous Thrombosis.- 1. Thrombosis of Deep Veins.- 2. Thrombosis of Veins of Organs.- 3. Priapism.- 4. Special Forms of Venous Thrombosis.- II. Pulmonary Embolism.- III. Arterial Thrombosis and Embolism.- 1. Acute Occlusion.- 2. Chronic Occlusion.- IV. Ischemic Heart Disease.- V. Thrombosis and Embolism of Retinal Vessels.- VI. Thrombosis of the Microvasculature.- VII. Other Fields of Application.- References.- Urokinase.- A. Origin of Urokinase.- I. Urokinase as Excreted Blood Activator.- II. Urokinase Produced in the Ureters and Bladder.- III. Urokinase Produced in the Kidneys.- IV. Comparison of Urokinase with Other Activators.- V. Urokinase from Tissue Cultures.- B. Physiology and Pathophysiology.- C. Purification and Isolation of Urokinase.- D. Biochemical Properties of Urokinase.- I. Characterization.- II. Urokinase and Plasminogen Activation.- III. Esterolytic and Amidolytic Activity of Urokinase.- IV. Inhibition of Urokinase.- V. Determination of Urokinase Activity and Units.- E. Experimental Pharmacology.- I. Urokinase Preparation for Thrombolysis.- II. Experimental Thrombolysis.- F. Clinical Use of Urokinase.- I. General Aspects.- II. Thrombolysis with Urokinase.- 1. Preliminary Investigations.- 2. Urokinase in Pulmonary Embolism.- 3. Urokinase in Myocardial Infarction.- 4. Urokinase in Cerebral Vascular Disease.- 5. Urokinase in Peripheral Thrombosis.- 6. Urokinase in Ophthalmology.- 7. Local Use of Urokinase.- III. Urokinase as Diagnostic Tool.- G. Conclusion.- References.- Synthetic Fibrinolytic Agents. Induction of Fibrinolytic Activity In Vitro.- Historical Remarks.- A. Methods for the In Vitro Assessment of Fibrinolysis-Inducing Capacity of Synthetic Organic Compounds.- I. Rotating Standard Clot.- II. Hanging Clot.- III. Plasma Clot.- B. Mechanism of Action.- I. Diffusion into Clots.- II. Adsorption onto Fibrin.- III. Suppression of Antiplasmin and Antiactivator Activity.- C. Synergism of Action Between Synthetic Fibrinolytic Compounds, the Natural Plasminogen Activators and Proteolytic Enzymes.- I. Synergism with Urokinase.- II. Synergism with Streptokinase.- III. Synergism with the Endogenous Plasminogen Activator.- IV. Synergism with Proteolytic Enzymes.- V. Synergism Among Synthetic Fibrinolytic Compounds.- D. Structure-Activity Relationship of Synthetic Fibrinolytic Compounds.- E. Binding of Synthetic Fibrinolytic Compounds to Albumin.- F. Enhancement by Hydrazine and Cobra Venom Factor of the Fibrinolytic Activity Induced by Synthetic Compounds In Vitro.- G. Induction of Fibrinolytic Activity In Vitro and In Vivo.- H. Effect of Synthetic Fibrinolytic Agents on Thrombocytes, Erythrocytes and some Clotting Factors.- References.- Indirect Fibrinolytic Agents.- A. Neurotransmitters and Autacoids.- I. Sympathomimetic Amines.- 1. Adrenaline.- a) Pharmacological Aspects.- b) Clinical Aspects.- 2. Noradrenaline.- 3. Phenylephrine.- 4. Dopamine.- 5. ? and ? Adrenoceptor Stimulating and Blocking Agents.- a) Clinical Aspects.- b) Pharmacological Aspects.- II. Cholinomimetics and Cholinolytics.- 1. Acetylcholine.- 2. Atropine.- 3. Nicotine.- III. Biogenic Amines.- 1. Serotonin.- a) Pharmacological Aspects.- b) Clinical Aspects.- 2. Histamine.- a) Biochemical Aspects.- b) Pharmacological Aspects.- c) Clinical Aspects.- IV. Biogenic Peptides.- 1. Hypotensive Polypeptides.- 2. Hypertensive Polypeptides.- B. Hormones.- I. Pituitary Hormones.- 1. Anterior Pituitary Hormones.- 2. Posterior Pituitary Hormones.- II. Steroid Hormones.- 1. Nonanabolic Steroids.- 2. Anabolic Steroids.- a) Male Sexual Hormones.- ?) Pharmacological Aspects.- ?) Clinical Aspects.- b) Female Sexual Hormones.- III. Thyroid Hormones.- IV. Insulin.- 1. Clinical Aspects.- 2. Pharmacological Aspects.- V. Antidiabetic Drugs.- 1. Sulfonylureas.- 2. Biguanides.- a) Phenformin.- b) Metformin.- c) Buformin.- VI. Combination of Biguanides and Anabolic Steroids.- 1. Combination Phenformin-Ethylestrenol.- 2. Combination Phenformin-Stanozolol.- 3. Combination Metformin-Ethylestrenol.- C. Anticoagulants and Related Compounds.- I. Heparin.- II. Heparinoids.- III. Oral Anticoagulants.- IV. Clofibrate.- D. Vasodilators.- E. Diuretic Drugs.- F. Anti-Inflammatory Drugs.- G. Pyrogens.- H. Miscellaneous Drugs.- I. Antibiotics.- II. Monoamine Oxidase Inhibitors.- III. Amino Acids and Derivatives.- IV. Chemical Emulsifying and Dispersing Substances.- V. Vegetable Extracts.- VI. Animal Extracts.- Conclusion.- References.- Fibrinolytically Active Enzymes.- Plasmin.- A. Plasminogen, the Zymogen Precursor of Plasmin.- I. Preparation.- II. Physical and Chemical Properties.- III. Primary Structure of Human Plasminogen.- 1. NH2-Terminus (Glu1-Lys77).- 2. Heavy (A) Chain (Lys78-Arg561).- 3. Light (B) Chain (Val561-Asn790, or Val1-Asn230).- IV. Activation of Human Plasminogen.- 1. Mechanism.- 2. Kinetics.- B. Plasmin.- I. Preparation.- II. Physical and Chemical Properties.- III. Nomenclature.- IV. Assay Methods.- V. Kinetic Parameters.- C. Human Plasmin-Derived Heavy (A) and Light (B) Chains.- D. Equimolar Plasminogen-Streptokinase, Plasmin-Streptokinase, and Plasmin-Derived Light (B) Chain-Streptokinase Complexes.- I. Preparation.- II. Plasminogen Activator Activity.- E. Limited Proteolysis of Protein Substrates.- References.- Fungal Proteases.- A. Proteases from Aspergillus oryzae.- I. Isolation, Purification and Chemical Characteristics.- 1. Aspergillin O.- 2. Protease I, Brinase, Brinastrase.- a) Preparation of Crude Enzyme.- b) Determination of Proteolytic Activity.- c) Differential Analysis of Proteases.- d) Separation of Proteases.- e) Properties of Proteases.- 3. CA-7, Brinase, Brinolase.- a) Preparation of Crude Enzyme.- b) Purification of Enzyme.- c) Determination of Fibrinolytic Activity.- d) Characterization of Purified Enzyme.- 4. Comparison of Swedish and Canadian Enzymes.- II. Biological and Pharmacologic Properties.- 1. Inhibition by Plasma and Serum.- 2. Pharmacokinetics.- 3. Proteolysis.- a) Fibrin.- b) Fibrinogen.- c) Other Natural Proteins and Synthetic Substrates.- 4. Hemostasis.- a) Coagulation.- b) Platelet Function.- 5. Physicochemical Effects.- 6. Kininogenesis.- 7. Antigenicity.- 8. Toxicity.- III. Experimental Thrombolysis.- 1. In Vitro Experiments.- 2. In Vivo Experiments.- a) Systemic Administration.- b) Local Administration.- IV. Other Experimental Proteolytic Uses.- 1. Tissue Culture.- 2. Enzymatic Zonulysis in Ophthalmology.- V. Clinical Thrombolysis.- 1. Systemic Infusion.- 2. Local Perfusion.- a) Cannula Declotting.- b) Intra-arterial Instillation.- c) Intra-articular Instillation.- VI. Other Clinical Uses.- 1. Inhibition of Platelet Aggregation.- 2. Chemotherapy of Malignant Disease.- VII. Clinical Control of Therapy.- 1. Brinase-Inhibitor Assay.- 2. Protease Resistance Test.- 3. Photometric Determination of Inhibitors on Chromogenic Substrate.- 4. Photometric Determination of Inhibitors on Azocollagen Substrate.- 5. Critique of Tests.- B. Protease from Aspergillus ochraceus.- I. Isolation, Purification and Chemical Characteristics.- 1. Preparation of Crude Enzyme.- 2. Purification of Enzyme.- 3. Characterization of Purified Enzyme.- II. Biological and Pharmacologic Properties.- 1. Inhibition.- 2. Proteolysis.- a) Fibrin and Fibrinogen.- b) Other Natural Proteins.- 3. Hemostasis.- a) Coagulation.- b) Platelet Function.- 4. Toxicity.- III. Experimental Thrombolysis.- 1. In Vitro Experiments.- 2. In Vivo Experiments.- a) Systemic Administration.- b) Local Administration.- IV. Other Experimental Uses.- V. Clinical Thrombolysis.- 1. Coagulation.- 2. Determination of Dosage.- 3. Therapeutic Use.- C. Protease from Trichothecium roseum.- I. Isolation and Purification.- II. Biological Properties.- 1. Fibrinolysis.- 2. Thrombolysis.- D. Protease from Armillaria mellea.- I. Isolation, Purification and Chemical Characteristics.- II. Biological Properties.- References.- Defibrinogenation with Thrombin-like Snake Venom Enzymes.- A. Introduction.- I. Specific Defibrinogenation.- II. Occurrence of Thrombin-like Enzymes in Snake Venoms.- III. Nomenclature.- B. Characterization of Ancrod and Batroxobin.- I. Physicochemical Properties.- 1. Ancrod.- 2. Batroxobin.- II. Enzymatic Properties.- 1. Specificity.- 2. Activators and Inactivators.- 3. Stability.- III. Immunochemical Properties.- IV. Assay Methods.- 1. Assay on Human Plasma.- 2. Assay on Fibrinogen.- 3. In Vivo Activity Test on Mice.- C. Pharmacologic Properties of Ancrod and Batroxobin.- I. Toxicity.- 1. Mice.- 2. Rat.- 3. Rabbit.- 4. Cat.- 5. Dog.- 6. Monkey (Yellow-Faced Baboon).- 7. Pigeon.- II. Teratology.- III. Absorption and Metabolic Transformation of Ancrod and Batroxobin.- IV. Effect of Ancrod and Batroxobin on Fibrinogen Metabolism.- 1. Fibrinogen Depletion.- 2. Fibrinogen Removal.- V. Effect of Ancrod and Batroxobin on the Plasminogen Metabolism.- VI. Effect of Ancrod and Batroxobin on Hemostatic and Coagulation Parameters.- 1. The Hemostatic Function in the Defibrinogenated State.- 2. Effects of Ancrod and Batroxobin on Platelets.- 3. Effect of Ancrod and Batroxobin on Plasma Coagulation Factors.- VII. Effect of Ancrod and Batroxobin on Wound Healing.- VIII. Effect of Ancrod and Batroxobin on Hemorheology.- D. Preclinical Trials.- I. Antithrombotic Effect of Ancrod and Batroxobin.- II. Defibrinogenation and Transplant Rejection.- III. Defibrinogenation and Tumor Growth.- E. Clinical Experience.- I. Dose-Response Studies.- II. Laboratory Monitoring.- III. Exploratory Clinical Trials.- IV. Comparative Clinical Trials.- V. Immunologic Resistance to Ancrod and Batroxobin.- VI. Side-Effects.- References.- Antifibrinolytics.- Naturally Occurring Inhibitors of Fibrinolysis.- A. Endogenous Inhibitors.- I. Inhibitors from Plasma.- II. Inhibitors from Blood Platelets.- III. Inhibitors from Other Body Fluids and Tissues.- B. Animal Inhibitors.- I. Aprotinin.- 1. Chemistry.- 2. Mechanism of Action.- 3. Determination of Activity, Standardization.- 4. Experimental Pharmacology.- a) Toxicity.- b) Pharmacokinetics.- c) Antifibrinolytic Action.- 5. Clinical Pharmacology.- a) Pharmacokinetics.- b) Therapeutic Use.- ?) Indications.- ?) Side-Effects.- ?) Doses.- II. Miscellaneous Inhibitors.- C. Plant Inhibitors.- References.- Synthetic Inhibitors of Fibrinolysis.- A. Chemistry.- I. ?-Aminocaproic Acid.- II. Cyclic Aminocarboxylic Acids.- III. Derivatives of Benzamidine.- IV. Other Synthetic Inhibitors of Fibrinolysis.- B. Mode of Action.- I. Influence on the Activation of Plasminogen.- II. Influence on Plasmin.- 1. Inhibition of Proteolytic and Esterolytic Activity.- 2. Inhibition of Fibrinolytic Activity.- III. Influence on Other Enzymes.- IV. Physico-Chemical Effects.- C. Assay Methods.- I. Chemical Methods.- II. Biological Methods.- D. Experimental Pharmacology.- I. Toxicity.- II. Side-Effects.- III. Pharmacokinetics.- 1. EACA.- 2. PAMBA.- 3. AMCA.- 4. EACA and PAMBA Derivatives.- IV. Antifibrinolytic Action.- 1. Prevention of Experimental Fibrinolysis.- 2. Hemostatic Effect.- 3. Other Effects Connected with the Inhibition of Fibrinolysis.- 4. Combination with Naturally Occurring Inhibitors.- E. Clinical Pharmacology.- I. Pharmacokinetics.- 1. EACA.- 2. PAMBA.- 3. PAMBA Derivatives.- 4. AMCA.- II. Therapeutic Uses.- 1. Mode of Action.- 2. Side-Effects.- 3. Contraindications.- 4. Indications.- a) Bleeding after Operations on Activator-Rich Organs.- b) Bleeding in the Region of the Oral, Nasal and Pharyngeal Mucosa.- c) Bleeding in the Gastrointestinal Tract.- d) Bleeding in the Urinary Tract.- e) Uterine Bleeding.- f) Bleeding in Obstetrical Complications.- g) Subarachnoidal Bleeding.- h) Bleeding in Carcinoma and Leukemia.- i) Extracorporeal Circulation.- k) Control of Therapeutic Fibrinolysis.- l) Bleeding of Unknown Etiology.- m) Thrombocytopenia and Hemophilia.- n) Wound Healing.- o) Allergic Reactions.- 5. Administration and Dosage.- References.- Author Index.