Fibrinolytics andAntifibrinolytics

Contributors

F. Bachmann, D.C. Berridge, C. Bode, H. Bounameaux,F.J. Castellino, J.H. Chesebro, A.C. Chiu, D. Collen,G.J. del Zoppo, W. Dietrich, P. Donner, J.J. Emeis, L. Flohe,V. Fuster, R. Gallo, W.A. Gunzler, V. Gurewich, E. Haber,S.B. Hawley, R. Hayes, T. Herren, XL. Hoover-Plow, J. Horrow,T. Kooistra, E.K.O. Kruithof, H.R. Lijnen, VJ. Marder,L.A. Miles, K. Peter, E.F. Plow, V.A. Ploplis, A. Redlitz,M.S. Runge, CM. Samama, M.M. Samama, A.A. Sasahara,W.-D. Schleunig, G.V.R.K. Sharma, O. Taby, E.J. Topol,M. Verstraete, S. Xue

Editor:

F. Bachmann

Springer

Contents

Section I: Molecular Biology, Biochemistry, Physiology, and Pharmacologyof the Plasminogen-Plasmin Enzyme System

CHAPTER 1

The Fibrinolytic System and Thrombolytic AgentsF. BACHMANN. With 1 Figure 3

A. The Fibrinolytic System 3B. Mechanisms which Lead to the Lysis of a Thrombus 5C. Pathophysiology of the Fibrinolytic System 7

I. Decreased Fibrinolytic Activity andDeep Venous Thrombosis 7

1. Familial Thrombophilia with High PAI-1 Levels 72. Acquired Association of Hypofibrinolysis and

Deep Venous Thrombosis 7II. Impaired Fibrinolysis and Coronary Heart Disease 9

D. Thrombolytic Therapy 10I. Basic Considerations 10

1. The Proteolytic State and Bleeding Complications 102. Thrombin Generation and Reocclusion 103. Delay to Treatment 104. Platelet Activation 115. Contraindications for Thrombolytic Therapy 116. Fibrin Specificity 117. Antigenicity 128. Treatment of Elderly Patients 12

E. Milestones in Thrombolytic Therapy ofAcute Myocardial Infarction 13

I. First Generation Agents 13II. Second Generation Agents 13

III. Third Generation Agents 13IV. The Future of Thrombolytic Therapy 15

XII Contents

List of Abbreviations and Acronyms 15References 15

CHAPTER 2

Plasminogen and StreptokinaseF.J. CASTELLINO and V.A. PLOPLIS. With 3 Figures 25

A. Primary Structure of Human Plasminogen 25B. Gene Organization of Human Plasminogen 28C. The Activation of Human Plasminogen 29

I. General Considerations 29II. Activation of Human Plasminogen by Two-chain Urokinase

and Tissue-type Plasminogen Activator 331. Mechanism of Activation of Human Plasminogen 332. Positive and Negative Activation Effectors 34

III. Activation of Human Plasminogen bySingle-chain Urokinase 35

IV. Activation of Human Plasminogen by Streptokinase 361. Structural and Activation Features of Streptokinases . . . 362. Mechanism of Activation of Human Plasminogen

by Human Host-derived Streptokinase 393. Functional Regions of Human Plasminogen and

Human-derived Streptokinase thatMediate Activation 41

V. Activation of Human Plasminogen by Staphylokinase 42D. Spontaneous and Induced Phenotypes of

Plasminogen Deficiency 43List of Abbreviations 44References 45

CHAPTER 3

Tissue-type Plasminogen Activator (tPA)F. BACHMANN. With 2 Figures 57

A. Milestones in Tissue-type Plasminogen Activator(tPA) Research 57

B. Sources of tPA 58C. Metabolism of tPA 59D. Structure and Biochemistry of tPA 60

I. Gene Structure of tPA 601. Translated Regions 602. 5' and 3' Flanking Regions 603. Polymorphisms 62

II. Protein Structure of tPA 621. Primary Amino Acid Sequence 62

Contents XIII

a) The Finger Domain 63b) The Epidermal Growth Factor Domain 63c) The Kringle Domains 64d) The Protease (Catalytic) Domain 65

2. Crystal Structure of the Protease Domain 653. Glycosylation of tPA 65

III. Enzymatic Properties of tPA 661. Enzyme Kinetics in the Absence and Presence

of Fibrin 662. Differences Between sc-tPA and tc-tPA 673. Localization of the Epitopes in Fibrin that Enhance

the Rate of Plasminogen Activation by tPA 68IV. Interactions of tPA with Serpins 68

E. The tPA Receptors 70I. Activation Receptors 70

II. Clearance Receptors 711. The Mannose Receptor 712. The LDL Receptor-Related Protein

(LRP, a2-Macroglobulin Receptor) 72F. Pathophysiology of tPA 72

I. Intravascular Function of tPA 72II. Other Functions of tPA 74

List of Symbols and Abbreviations 75References 76

CHAPTER 4

Urinary-type Plasminogen Activator (uPA)W.A. GUNZLER and L. FLOHE. With 2 Figures 91

A. Milestones in uPA Research 91B. Nomenclature of uPA Forms 92C. Sources of uPA 93D. Assay of uPA 93E. Biochemistry of uPA 94

I. The uPA Gene 94II. The uPA Structure 95

III. Non-protein Components of uPA 97IV. Proteolytic Conversions of uPA 9SV. uPA Activity 99

F. Physiology of uPA 100I. Intravascular and Intratubular Functions of uPA 102

II. Role of uPA in Tissue Remodeling and Cell Migration . . . . 102List of Abbreviations 103References 103

XIV Contents

CHAPTER 5

The Inhibitors of the Fibrinolytic SystemE.K.O. KRUITHOF. With 1 Figure I l l

A. Introduction . . .B. Oh-Antiplasmin

I. Gene and Protein StructureII. Target Enzyme Specificity .

III. a2-Antiplasmin Deficiencies

11111314

C. Plasminogen Activator Inhibitor Type 1 114I. Gene Structure 114

II. Protein Structure 115III. Target Enzyme Specificity of PAI-1 116IV. Deficiencies, Knockout, and Overexpression in MiceV. Role of PAI-1 in Cell Migration

VI. Distribution of PAI-1 In VivoVII. Gene Regulation of PAI-1

VIII. PAI-1 as a Marker for Vascular and Arterial Disease

16161718181819

IX. PAI-1 and the Acute Phase ResponseX. PAI-1 and Septicemia

D. Plasminogen Activator Inhibitor Type 2 119I. Gene and Protein Structure 119

II. Target Enzyme Specificity 120III. Distribution of PAI-2 In Vivo 120IV. Gene Regulation of PAI-2 121V. The Physiological Role of PAI-2 121

E. Plasminogen Activator Inhibitors in Pregnancy 121F. Therapeutic Applications of PAI-1 and PAI-2 122

I. PAI-1 123II. PAI-2 123

G. Other Protease Inhibitors of the Fibrinolytic System 123H. Inhibitors of Plasminogen Binding to Fibrin or Cell Surfaces 124

I. Histidine-rich Glycoprotein 124II. Lipoprotein(a) 125

III. Carboxypeptidases 126I. Conclusions 126List of Abbreviations 127References 127

CHAPTER 6

Assembly of the Plasminogen System on Cell SurfacesE.F. PLOW, A. REDLITZ, S.B. HAWLEY, S. XUE, T. HERREN,

J.L. HOOVER-PLOW, and L.A. MILES. With 3 Figures 141

A. Introduction 141B. Plasminogen Receptors 142

Contents XV

I. General Characteristics 142II. Nature of Plasminogen Receptors 143

III. Regulation of Plasminogen Receptors 145C. tPA Receptors 148

I. General Characteristics 148II. Recognition of tPA 148

III. Cellular Distribution of tPA Receptors 1481. Endothelial Cells 1482. Circulating Blood Cells 1493. Cells of Neuronal Origin 1494. Vascular Smooth Muscle Cells 1495. Tumor Cells 149

D. Urokinase Receptors 150I. General Characteristics 150

II. The Urokinase Receptor, uPAR 1501. Cellular Distribution of uPAR 1502. Recognition Specificity of uPAR 1503. The uPAR Gene 1514. The uPAR Protein 1515. Regulation of uPAR Expression 1536. Non-proteolytic Functions of uPAR 153

III. Other uPA Receptors 154E. Functional Consequences of Receptor Occupancy 155

I. Kinetic Consequences 1551. Plasminogen Receptors 155

a) Enhanced Plasminogen Activation 156b) Amplification Loops 156c) Protection of Plasmin Activity 156d) Enhancement of Plasmin Activity 156

2. uPA Receptors 1563. tPA Receptors 157

II. Functional Consequences 157List of Abbreviations 158References 158

Section II: Clinical Use of Thrombolytic AgentsIn Acute Myocardial Infarction

CHAPTER 7

Streptokinase and Anisoylated Lys-Plasminogen StreptokinaseActivator ComplexV.J. MARDER and F. BACHMANN. With 2 Figures 173

A. Introduction 173I. Pharmacology 173

1. Streptokinase (SK) 173

XVI Contents

2. Anisoylated Lys-Plasmin(ogen) Streptokinase ActivatorComplex (APSAC, anistreplase) 174

II. The Proteolytic State 174III. Factors Influencing the Lysis of Thrombi and Emboli 176

B. Therapeutic Results in Acute Myocardial Infarction 177I. Streptokinase 177

1. Early Studies with Intravenous Streptokinase 1772. Intracoronary Administration 1783. High-Dose Intravenous Administration

of Streptokinase 179a) Dose-Ranging Studies and Anti-SK Antibodies . . . . 179b) Patency vs Recanalization Rate 180c) Mortality Reduction 182d) Delay to Treatment 183e) Bleeding Complication 185f) Patient Selection, Contraindications 187g) Other Side Effects 188h) Laboratory Monitoring 188i) Rethrombosis 188

II. Anisoylated Lys-Plasmin(ogen) Streptokinase ActivatorComplex (APSAC, Anistreplase) 189

1. Randomized Clinical trials 1892. Pre-hospital Treatment 189

List of Abbreviations 193References 193

CHAPTER 8

Tissue-Type Plasminogen Activator (tPA)D. COLLEN. With 2 Figures 209

A. Introduction 209B. Development of tPA as a Thrombolytic Agent 212

I. Isolation and Purification of tPA 212II. Cloning and Expression of the tPA cDNA 214

III. Experimental Coronary Thrombosis Models for AMI 215IV. First Administration of tPA to Patients with AMI 215

C. Clinical Trials with tPA in AMI 216I. Early Clinical Studies in AMI 216

II. tPA Trials, 1986-1989 218III. tPA Trials, 1990-1995 220IV. Further Attempts to Improve the Efficacy of Thrombolysis

and to Reduce the Incidence of Reocclusion 221List of Abbreviations 222References 223

Contents XVII

CHAPTER 9

Urokinase and Single-Chain Urokinase-Type Plasminogen Activator(Pro-urokinase)V. GUREWICH 231

A. History 231B. Nomenclature 232C. Biochemistry of Pro-UK/UK (sc-uPA/tc-uPA) 232

I. The Intrinsic Activity of Pro-UK (sc-uPA) 233II. Fibrinolysis by Pro-UK/UK (sc-uPA/tc-uPA) 234

III. Contrasting Properties of Pro-UK and tPA 235IV. Pro-UK/UK and Platelets 237

D. Pharmacokinetics 238E. Clinical Studies in Acute Myocardial Infarction 239

I. Urokinase 2391. Controlled Trials of UK vs Controls 2392. Prehospital vs In-hospital Thrombolysis with UK 2403. Comparative Trials of UK vs SK or tPA 240

II. Pro-urokinase 2411. Early Dose-finding Studies 2412. Randomized Trials of Pro-UK vs SK 2433. Randomized Trial of Pro-UK vs tPA 245

HI. Non-specific Plasminogen Activation 245IV. Combinations of Pro-UK and UK or tPA 246

1. Early Dose-finding Studies of Pro-UK and UK 2462. Early Dose-finding Studies of Pro-UK and tPA 2473. Larger Clinical Trial with Pro-UK and tPA 247

V. Bolus administration of Pro-UK 248VI. Heparin and Pro-UK 248

F. Second Generation Pro-UK 24SG. Conclusions 249List of Abbreviations 251References 251

CHAPTER 10

Comparative Evaluations of tPA vs SK with Particular Referenceto the GUSTO-I TrialA.C. CHIL and E.J. Toi>ot . With 1 Figure 261

A. Introduction 261B. Evolution of Thrombolytic Therapies 261

I. Rationale for Thrombolysis 2MII. Early Angiographic Patency Trials. tPA vs SK 2M

III. Adjunctive Therapies: Heparin and Aspirin 263IV Major Comparative Thrombolytic Trials 264

XVIII Contents

C. The GUSTO-I Trial 268I. Design of the Trial 268

II. Primary Results of GUSTO-I 271III. The GUSTO-I Angiographic Substudy 274IV. Further Analysis of GUSTO-I Results 278V. Other GUSTO-I Substudies 278

VI. Epilogue 281List of Abbreviations and Acronyms 281References 282

CHAPTER 11

Conjunctive Therapy to Reduce the Occurrence of CoronaryReocclusion After Thrombolytic Treatment of AMIR. HAYES, R. GALLO, V. FUSTER, and J. CHESEBRO. With 8 Figures 287

A. Introduction 287B. The Role of Thrombin and Platelets in Thrombus Formation . . . . 287C. Evidence for the Efficacy of Thrombolytic Therapy 289

I. Importance of Achieving Patency of the InfarctRelated Artery 290

II. Limitations of Thrombolytic Therapy 292III. The Role of Platelets and Thrombin in Resistance 292

to Therapy 2921. Thrombin 2922. Platelets 295

D. Antithrombotic Therapy 296I. Thrombin Inhibition 296

1. Heparin 2962. Low-Molecular-Weight Heparin 3003. Hirudin 3014. Hirulog 3045. Argatroban 3046. Efegatran 305

II. Antiplatelet Agents 3051. Aspirin 3052. Glycoprotein Ilb/IIIa Antagonists 3063. Other Drugs Inhibiting Platelet Function 3084. Physical Coujunctive Therapy 309

E. Outlook 309List of Abbreviations 309References 311

Contents XIX

Thrombolytic Treatment of Other Clinical Thromboembolic Conditions

CHAPTER 12

New Concepts in Thrombolysis of Pulmonary EmbolismA.A. SASAHARA and G.V.R.K. SHARMA. With 5 Figures 325

A. Introduction 325B. Treatment with Thrombolytic Therapy 327C. Established Clinical Effect of Thrombolytic Therapy 328

I. Thrombolytic Agents Hasten ThromboembolicResolution 328

II. Results of Pulmonary Angiography 328III. Results of Perfusion Lung Scan 328IV. Hemodynamic Observations 329V. Thrombolytic Therapy Removes Pulmonary

Thromboemboli More Completely thanHeparin Therapy 330

VI. Thrombolytic Agents Hasten Dissolution of Thrombiin the Venous System of the Legs 332

VII. Thrombolytic Therapy Can Be Administered Safely 332D. Possible Unestablished Clinical Effects 334

I. Thrombolytic Agents May Decrease Mortality fromPulmonary Embolism 334

II. Thrombolytic Therapy Improves Long-termHemodynamic Status 335

E. New Thrombolytic Regimens 336F. Surgical Therapy 341G. Adjunctive Therapy 343List of Abbreviations 343References 344

CHAPTER 13

Deep Venous ThrombosisH. BOUNAMEAUX 349

A. Introduction 349B. Treatment Regimens 349C. Immediate Effects of Thrombolytic Therapy of DVT:

The Definite Risk 350D. Late Effects of Thrombolytic Therapy of DVT:

The Potential Benefit 352E. The Benefit-to-Risk Balance 353F. How to Reduce the Risk and Improve the Benefit? 354

I. Reducing Hcmorrhagic Risk 354II. Improving Thrombolytic Efficacy 355

G. Miscellaneous Venous Indications 356

XX Contents

I. Phlegmasia Caerulea Dolens 356II. Superior or Inferior Vena Cava Syndrome 356

III. Deep Venous Thrombosis of the Upper Limbs 356IV. Venous Thrombosis of Unusual Localization 356V. Thrombosis of Central Venous Catheters 357

H. Laboratory Monitoring 357I. Treatment of Bleeding 358J. Conclusions and Perspectives 358List of Abbreviations and Acronyms 359References 359

CHAPTER 14

Peripheral Arterial OcclusionsD.C. BERRIDGE 363

A. Introduction 363B. Current Indications 364C. Contra-Indications 366D. Drugs Available 367

I. Streptokinase 367II. APSAC, Anistreplase (Acylated-Plasminogen-

Streptokinase-Activator Complex) 367III. Urokinase and Pro-Urokinase 368IV. Recombinant Tissue Plasminogen Activator (tPA) 368V. Staphylokinase 368

E. Techniques Used 368I. Systemic Administration 368

II. Local Low-dose Intra-thrombotic Administration 369III. High-dose Bolus 369IV. Pulse-Spray Administration 370V. Enclosed Thrombolysis 371

VI. Intra-operative Lysis 372F. Comparative Results 373

I. Streptokinase vs Recombinant TissuePlasminogen Activator 373

II. UK vs Recombinant Tissue Plasminogen Activator 374III. Pro-UK vs. UK 374IV. Surgery vs Thrombolysis 374

G. Long-Term Results 378H. Adjuvant Treatment 378I. Complications 379

I. Major Hemorrhage 379II. Minor Hemorrhage 379

III. Cerebrovascular Accident 379IV. Distal Embolization 380V. Pericatheter Thrombosis 380

Contents XXI

VI. Allergic Reactions 380VII. Other Complications 380

J. Summary 381List of Abbreviations and Acronyms 381References 381

CHAPTER 15

Thrombotic Cerebrovascular DiseaseG.J. DEL ZOPPO 387

A. Introduction 387B. Focal Cerebral Ischemia 388

I. Considerations for Tissue Salvage 388II. Hemorrhagic Transformation 389

III. Neurological Outcome 390C. Plasminogen Activators in Focal Cerebrovascular Ischemia 392

I. Completed Stroke 393II. Acute Stroke 394

1. Carotid Territory Ischemia 394a) Angiography-Controlled Trials 394

a) Intra-Arterial Local Infusion 394p) Intravenous (Systemic) Infusion 397y) Single Photon-Emission Computed

Tomography (SPECT) 400b) Sympton-Based (Clinical Outcome) Trials 400

2. Vertebrobasilar Territory Ischemia 408a) Angiography-Controlled Trials 408

a) Intra-Arterial (Local) Infusion 408P) Intravenous (Systemic) Infusion 409

III. Other Conditions 4091. Retinal Vascular Occlusion 4092. Dural Sinus Thrombosis 410

D. Ongoing Stroke Trials with Thrombolytic Agents 410E. Conclusion 411List of Abbreviations and Acronyms 411References 412

Thrombolytic Agents in Development, Biochemistry, Pharmacology -Efficacy in Animal Experiments and First Clinical Trials

CHAPTER 16

StaphylokinaseH.R. LIINEN and D. Con IN. With 3 Figures 425

A. Introduction 425B. Gene and Protein Structure of Staphylokinase 426

XXII Contents

I. Production of Staphylokinase 426II. Gene Structure of Staphylokinase 427

III. Protein Structure of Staphylokinase 428C. Plasminogen Activation by Staphylokinase 429

I. Interaction with Plasmin(ogen) 429II. Kinetics of Plasminogen Activation 431

III. Mechanism of Plasminogen Activation 431D. Fibrin-Specificity of Staphylokinase 432

I. Inhibition of Plasmin-Staphylokinase Complex bya2-Antiplasmin 432

II. Effect of Fibrin on Plasminogen Activationby Staphylokinase 433

III. Molecular Mechanism of Fibrin-specificity in Plasma 433E. Fibrinolytic Properties of Staphylokinase in Plasma In Vitro 435

I. Fibrinolytic Potency and Fibrin-specificity 435II. Species-specificity 437

F. Thrombolytic Properties of Staphylokinase in Animal Models . . . . 437I. Hamsters with Pulmonary Embolism 437

II. Rabbits with Jugular Vein Thrombosis 438III. Rabbits with Arterial Thrombosis 438IV. Rabbit Embolic Stroke Model 438V. Baboons with Venous and Arterial Thrombosis 438

G. Thrombolytic Properties of Staphylokinase in Patients 439I. Acute Myocardial Infarction 439

II. Peripheral Arterial Occlusion 440H. Pharmacokinetic Properties of Staphylokinase 441

I. In Animal Models 441II. In Patients 441

I. Immunogenicity of Staphylokinase 442I. In Animal Models 442

II. In Patients 442III. Attempts to Reduce Immunogenicity 443

J. Conclusions 443List of Abbreviations and Acronyms 444References 444

CHAPTER 17

Desmodus rotundus (Common Vampire Bat)Salivary Plasminogen ActivatorW.-D. SCHLEUNING and P. DONNER. With 5 Figures 451

A. Introduction 451B. Natural History of Vampire Bats 453C. Biochemistry 453

I. Purification 453

Contents XXIII

II. Cloning and Expression 454III. DSPA Gene Expression in Hetereologous Host Cells 455IV. Three-dimensional Structure of the Protease Domain 456V. Enzymology 456

D. Pharmacology 459I. In Vitro Clot Lysis 459

II. Carotid and Femoral Artery Thrombosis in Rabbits 461III. Myocardial Infarction in Dogs 461IV. Experimental Pulmonary Embolisms in Rats 462V. Bleeding Models 463

E. Pharmacokinetics 464F. Toxicology 466G. Phase I Clinical Studies 466H. Phase Ib Clinical Studies 467I. Conclusions and Perspectives 467List of Abbreviations and Acronyms 468References 468

CHAPTER 18

Thrombus-Targeting of Plasminogen ActivatorsC. BODE, K. PETER, M.S. RUNGE, and E. HABER 473

A. Introduction 473B. The Principle of Antibody Targeting 474

I. Antifibrin Antibodies 474II. Antiplatelet Antibodies 474

III. Chemical Conjugates or Recombinant Fusion Proteins . . . . 475C. Synthesis, Purification, and Characterization of Chemical

Antibody-Plasminogen Activator Conjugates 475I. Synthesis 475

II. Purification 476III. Characterization 476

1. Antifibrin-UK Conjugates 4772. Antifibrin-tPA Conjugates 4773. Antifibrin-scuPA Conjugates 4784. Antiplatelet-UK Conjugates 4785. Antiplatelet-scuPA Conjugates 478

D. Targeting with Bifunctional Antibodies 479I. Principal Considerations 479

II. Bispecific IgG (Intact Antibodies) 479III. Bispecific (Fab')2 480IV. Bispecific Antibodies by Hybrid-Hybridoma Technique . . . . 480V. Double Targeting 481

E. Expression and Characterization of Recombinant Antitibrin-Plasminogen Activator Fusion Proteins 481

XXIV Contents

I. Antifibrin-SK Constructs 481II. Antifibrin-tPA Constructs 481

III. Antifibrin-scuPA Constructs 482F. Other Approaches of Targeting Plasminogen Activators

to Thrombi 484G. Targeting the Thrombin Inhibitor Hirudin to Fibrin 486

I. General Considerations 486II. Chemical Conjugates 486

III. Recombinant Fusion Protein 486H. Conclusion and Outlook 487List of Abbreviations and Acronyms 488References 488

CHAPTER 19

The Hunt for the Ideal Thrombolytic Agent:Mutants of tPA and uPA, Chimera of Both Molecules, FibrolaseM. VERSTRAETE. With 3 Figures 493

A. Mutants and Variants of Single-Chain Urokinase-TypePlasminogen Activator 493

I. Plasmin-Resistant Mutants of sc-uPA 493II. Low-Molecular-Weight sc-uPA 493

III. Mutant of sc-uPA Resistant to PAI-1 494B. Mutants of Tissue-Type Plasminogen Activator (tPA) 494

I. Mutants with Modified Epidermal GrowthFactor Domain 494

II. Mutants with Modified or Deleted Finger Domain 495III. Deletion of the Finger and Epidermal Growth

Factor Domains 495IV. Deletion of the Epidermal Growth Factor and Finger

Domains and of Glycosylation Sites 496V. Mutants Consisting of Kringle 2 and the

Protease Domain 496VI. Mutant Consisting of Kringle 2 with Point Mutation

in Linkage to Protease Light Chain 501VII. Mutant with Modifications in Kringle 1 503VII. Recombinant TNK-tPA 503IX. Unglycosylated Protease Domains of tPA 510

C. Chimeric Plasminogen Activators 510D. Fibrolase 512E. Other Fibrinolytic Agents 512List of Abbreviations and Acronyms 512References 513

Contents XXV

CHAPTER 20

Agents which Increase Synthesis and Release of Tissue-TypePlasminogen ActivatorT. KOOISTRA and J.J. EMEIS. With 3 Figures 521

A. Introduction 521I. The Plasminogen/Plasmin System 521

II. Intravascular Fibrinolysis 521III. Tissue-Type Plasminogen Activator (tPA) in

the Circulation 522IV. Involvement of the Endothelium in Plasma Fibrinolysis . . . . 523

B. Regulation of Constitutive tPA Synthesis 524I. General 524

II. Intracellular Signaling and Activation of ProteinKinase C 525

III. Retinoids 526IV. Steroid Hormones 528V. Sodium Butyrate and Other Inhibitors of Histone

Deacetylase 529VI. Triazolobenzodiazepines 530

C. Regulated Secretion of tPA 531I. General 531

II. The Endothelial tPA Storage Compartment and theCirculatory Regulation of tPA 532

III. Cellular Mechanisms Involved in RegulatedtPA Secretion 535

IV. Compounds Affecting Regulated tPA Secretion in Man . . . . 5361. The Occurrence of Regulated tPA Secretion in Man. . . . 5362. Adrenergic Agents 5383. Vasopressin 5394. DDAVP 5395. Acetylcholine and Methacholine 5416. Bradykinin and Substance P 5417. Coagulation Activation Products 5428. cAMP 5429. Miscellaneous Compounds 542

10. Abnormal Release of tPA 543D. Increase of tPA Activity by Inhibition of PAI-1 543List of Abbreviations and Symbols 544References 544

XXVI Contents

Autifibrinolytic Agents

CHAPTER 21

Structure, Pharmacology, and Clinical Use of Antifibrinolytic AgentsCM. SAMAMA, W. DIETRICH, J. HORROW, O. TABY, and M.M. SAMAMA.With 3 Figures 559

A. Introduction 559B. Pharmacology and Clinical Use of EACA and TA 559

I. e-Aminocaproic Acid (EACA) 5611. Pharmacology 5612. Non-Cardiac Surgery 561

a) Urologic Surgery 561b) Oral Surgery 561c) Liver Transplantation 562

3. Use in Cardiac Surgery 5624. Adverse Effects 562

II. Tranexamic Acid 5641. Pharmacology 5642. Nonsurgical Applications 5643. Noncardiac Surgery 5654. Cardiac Surgery 5655. Adverse Effects 565

C. Pharmacology of Aprotinin 567I. Structure 567

II. Pharmacology 567III. Pharmacokinetics 568IV. Clinical Use 568

1. History 5682. Mode of Action of Aprotinin

(Clinical Point of View) 5693. Efficacy of Aprotinin Treatment 5714. Miscellaneous Uses 572

a) Orthotopic Liver Transplantation (OLT) andElective Liver Resection 572

b) Orthopedic Surgery 5745. Side Effects of Aprotinin Therapy 574

D. Conclusion 575List of Abbreviations and Acronyms 576References 576

Subject Index 587