Cardiovascular Thrombus: From Pathology and Clinical Presentations to Imaging, Pharmacotherapy and Interventions

Cardiovascular Thrombus: From Pathology and Clinical Presentations to Imaging, Pharmacotherapy and Interventions provides a comprehensive, up-to-date presentation of the research and clinical practices as related to the contemporary aspects of the diagnosis and management of cardiovascular thrombosis. The formation, identification and management of cardiovascular thrombus is of paramount importance for researchers and practicing physicians, yet it remains one of the most challenging diagnostic and clinical scenarios. This important reference connects between research, up-to-date clinical knowledge, and the technological tools  available for diagnosis and management of thrombus in cardiovascular medicine. The book includes comprehensive descriptions and review of pathology, clinical presentations, diagnosis, pharmacotherapy, interventions and future trends. It is the perfect reference for basic science students and researchers in general and interventional cardiology, general and  interventional radiology, vascular medicine specialists, and vascular, general and cardiac surgeons.

• Provides comprehensive presentation of the pathophysiology, clinical presentations and diagnosis of cardiovascular thrombosis
• Includes the most up-to-date information on the practical management of patients with thrombus related conditions
• Written by the leading experts in the field
• Describes the current and upcoming pharmacotherapy and technology available for thrombus research and treatment

• Language: English
• Publisher: Academic Press
• Release date: Aug 18, 2018
• ISBN: 9780128126165

Book preview

Cardiovascular Thrombus

From Pathology and Clinical Presentations to Imaging, Pharmacotherapy and Interventions

On Topaz, MD, FACC, FACP, FSCAI

Professor of Medicine, Duke University School of Medicine, Chief, Division of Cariology, Director, Interventional Cardiology, Charles George Veterans Affairs Medical Center, Asheville, North Carolina, USA

Table of Contents

Cover image

Title page

Copyright

Dedication

List of Contributors

Foreword

Preface

Chapter 1. Histopathology of Cardiovascular Thrombus

Prevalence of Heart Disease

Coronary Thrombosis: Incidence and Etiology

Necrotic Core Expansion (Plaque Fissure and Intraplaque Hemorrhage)

Conclusion

Chapter 2. Pathology of Arterial Thrombosis: Characteristics and Thrombus Types

Introduction

Atherosclerosis

Types of Thrombi During Acute Myocardial Infarction

Methods to Detect Thrombi

Risk Factors for Arterial and Venous Thrombosis

Atherosclerosis, Inflammation, and Thrombosis

Treatment of Athero-crystalloids

Treatment of Arterial Thrombosis

Fibrinolysis

Clot Retraction and Fibrinolysis

Chapter 3. Fibrin Clot Structure and Function: A Novel Risk Factor for Arterial and Venous Thrombosis and Thromboembolism

Introduction

Fibrin and Clot Formation

Factor XIII

Fibrinolysis

Clot Mechanics

Alternative mRNA Fibrinogen Splicing

Fibrin Clot Structure and Coronary Artery Disease

Fibrin Clot Structure and Venous Thrombosis

Role of Smoking, Diabetes, and Glycation

Stroke, Peripheral Disease, and Aneurysm

Medication and Clot Structure

Conclusions

Chapter 4. The Role of Platelets in the Pathophysiology of Atherosclerosis and Its Complications

Platelets

Platelet Activation and Function

Platelets as Modulators of Inflammation: Relevance to Atherosclerosis

The Role of Inflammation in Atherosclerosis

Monocytes

Polymorph–Platelet Interactions

Netrin-1

Antiplatelet Therapy as a Possible Novel Approach to Inhibiting Atherosclerosis

Conclusions

Chapter 5. Mathematical Models of Thrombus Formation and Fibrinolysis

Introduction

Overview of Differential Equations

Brief Biological Background

Models of Thrombin Generation and Thrombus Formation

Models of Fibrin Polymerization

Models of Fibrinolysis

Summary

Chapter 6. Animal Models of Thrombosis

Brief Overview of the Pathogenesis of the Thrombotic Process

Development of Animal Models of Thrombosis

Small Animal Models of Thrombosis: The Murine Models

Large Animal Models of Thrombosis

Arteriovenous Shunt and Perfusion Chambers: In Vivo/Ex Vivo Models of Thrombosis in Large Animal Models

Animal Models of Venous Thrombosis

Other Models of Thrombosis

Conclusions and Future Challenges

Chapter 7. Imaging Modalities for Detection and Treatment of Cardiovascular Thrombus

Introduction

Thrombus-Containing Lesion in the Coronary Circulation

Noncoronary Thrombus

Chapter 8. Utilization of Magnetic Resonance Imaging and Magnetic Resonance Angiography for Cardiac Thrombus

Introduction

Technique and Image Acquisition

Cardiomyopathy and Left-Ventricular Thrombus

Cardiac Magnetic Resonance Characteristics of Thrombus

Atrial Fibrillation

Conclusion

Chapter 9. Acute Myocardial Infarction: STEMI and NSTEMI

Introduction

Antiplatelet Therapy in Acute Coronary Syndrome

Anticoagulation

Factor Xa and Thrombin Inhibitors in Acute Coronary Syndromes

Conclusions

Chapter 10. Acute Coronary Syndrome: Thrombotic Lesions in Patients With Unstable Angina

Unstable Angina

Pathology and Pathophysiology of the Thrombotic Lesion

Vulnerable Plaque

Clinical Presentation

Noninvasive Diagnosis

Invasive Diagnosis

Treatment

Long-Term Therapy and Outcomes

Summary

Chapter 11. Practical Perspectives on the Guidelines for Management of Coronary Thrombus

Introduction

Prognostic Significance of Thrombus

Management of High Thrombus Burden

Pharmacological Strategies for Intracoronary Thrombus

Mechanical Strategies

Approaches in Exception to the Current Guidelines

Expert Opinion

Summary

Chapter 12. Thrombus Classifications: Critical Tools for Diagnostic and Interventional Cardiovascular Procedures

Introduction

Rationale for Utilization of Thrombus Classifications

Thrombus: From Formation to Accumulation

Scoring Systems for Coronary Thrombus

The Angry Thrombus Phenomenon

Thrombus Scoring in Noncoronary Vasculature

Thrombus Grading in Peripheral Arterial Disease

Summary

Chapter 13. Impact of Thrombus Burden on Myocardial Damage in the Setting of Primary Percutaneous Coronary Intervention

The Role of Thrombus in the Pathophysiology of ST-Segment Elevation Myocardial Infarction

Thrombus Recognition and Classifications

Relationship Between Thrombus Burden and Distal Embolization

Impact of Distal Embolization on Myocardial Damage and Clinical Outcomes

Role of Mechanical Adjunctive Devices in Thrombus Removal and Myocardial Damage

Chapter 14. The Impact of Thrombus as a Cause and as a Result of Complicated Percutaneous Coronary Intervention

Introduction

Thrombus as the Cause of Complications

Thrombus as the Result of Complicated Percutaneous Coronary Intervention

Conclusions

Chapter 15. Stent Thrombosis: Early, Late, and Very Late

Definition of Stent Thrombosis

Incidence of Stent Thrombosis

Clinical Presentation, Diagnosis, and Mortality

Pathophysiologic Mechanisms of Stent Thrombosis

Pharmacotherapy

Intravascular Imaging: Identification of Potential Mechanisms/Stent Optimization

Conclusion

Chapter 16. Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration

Introduction

Bare Metal Stents Versus Drug-Eluting Stents

Drug-Eluting Stents Versus Drug-Eluting Stents

Bio-resorbable Vascular Scaffold Thrombosis

Dual Antiplatelet Therapy

Bare Metal Stents

Factors Influencing Optimal Dual Antiplatelet Therapy Duration

Risk-Predictive Models

Dual Antiplatelet Therapy Interruption/Discontinuation

Stopping Dual Antiplatelet Therapy for Noncardiac Surgery

Chapter 17. Aspiration Catheters and Protection Filters

Introduction

Aspiration Thrombectomy

Embolic Protection Devices

Summary

Chapter 18. Power-Sourced Mechanical Thrombectomy in the Management of Thrombus-Containing Atherosclerotic Lesions

Introduction

Thrombus as a Dynamic Vascular Structure

Power-Sourced Thrombectomy Tools: Rationale for Utilization

Lasers

Rheolytic Thrombectomy

X-Sizer Thrombectomy System

Ultrasound

Summary

Chapter 19. Dedicated Thrombus-Containing Stent Platforms

Introduction

Mesh-Covered Stents: Rationale and Technical Characteristics

Studies Evaluating the MGuard Stent

Self-Expanding and Self-Apposing Stents: Rationale

STENTYS Stent: Design and Technical Characteristics

Conclusions and Recommendations

Chapter 20. Dissolution of Thrombus With Ultrasound: A Journey Through Physics, Basic Research, and Clinical Utilization

Introduction

Inherent Selectivity

First-Generation Device

Second-Generation Device

Future Directions: Noninvasive Ultrasound Thrombolysis

Reflections

Chapter 21. The Role and Impact of Thrombus in Formation and Revascularization of Chronic Total Occlusions

Formation of Chronic Total Occlusion

Structural Features of Chronic Total Occlusion

Clinical Aspects

Percutaneous Revascularization

Dedicated Thrombus Pharmacotherapy in Chronic Total Occlusion

Revascularization Tools for Chronic Total Occlusion

Chronic Total Occlusion in Peripheral Arterial Disease

Summary

Chapter 22. Encounters With Thrombus and Thrombosis in a Major Academic Center: Cases as Pictures at an Exhibition

Summary

Introduction

Intracoronary Thrombus: Distinction Between Acute, Subacute, and Organized Thrombus

Intracardiac Thrombus: Clinical Situations and Detection

Thrombosis Following Catheter-Based Structural Heart Interventions (Figs. 22.23–22.25)

Chapter 23. Thrombosis in Atrial Fibrillation

Atrial Fibrillation: Prevalence, Types, and Clinical Implications

Determinants of Thromboembolism Formation in Atrial Fibrillation

Clinical Factors in Thrombosis Formation in Atrial Fibrillation

Imaging of Thrombosis in Atrial Fibrillation

Pharmacological Treatment of Thrombus Formation in Atrial Fibrillation

Mechanical Treatments for the Prevention of Atrial Thrombosis Formation

Summary

Chapter 24. Acute and Chronic Pulmonary Embolism: Perspectives on Diagnosis and Management

Introduction

Pathogenesis and Risk Factors for Venous Thromboembolism

Diagnosis of Acute Pulmonary Embolism

Management of Acute Pulmonary Embolism

Chronic Thromboembolic Pulmonary Hypertension

Chapter 25. Surgical Management of Cardiovascular Thrombotic Conditions

Introduction

Surgical Management of Acute Pulmonary Embolism

Management of Prosthetic Heart Valve Thrombosis

Left-Ventricular Assist Device Thrombosis: Natural History, Diagnosis, and Surgical Treatment

Chapter 26. The Spectrum of Clinical Presentations and Management Options for the Treatment of Degenerative Atherothrombotic Disease of Saphenous Vein Grafts

Introduction

Pathophysiology of Venous Graft Failure

Perioperative Measures to Decrease Graft Failure

Diagnosis and Treatment Options

Considerations of Saphenous Vein Grafts and Percutaneous Coronary Intervention

Embolic Protection Devices

Thrombectomy Devices

Stents in Saphenous Vein Graft Interventions

Novel Stents for Saphenous Vein Graft Percutaneous Coronary Intervention

Adjunctive Pharmacotherapy for Management of Saphenous Vein Graft Disease

Summary

Chapter 27. Prosthetic Heart Valve Thrombosis

Introduction

Prevalence and Incidence

Mechanisms of Thrombosis

Clinical Presentation and Diagnosis

Treatment and Prevention

Conclusion

Chapter 28. Experimental Designs for In Vitro Assessment of Valve Thrombosis

Introduction

Blood Compatibility Assessment of Materials

Hemodynamic Factors

Antithrombotic Treatment

Conclusions

Chapter 29. Ventricular Assist Device Thrombosis: Past, Present, and Future

Introduction and History

Incidence and Event Rate

Cellular and Molecular Mechanisms of Pump Thrombus Formation

Risk Factors for Pump Thrombosis

Management and Mitigation of Risk Factors and Prevention of Pump Thrombosis

Pump Thrombosis Presentation

Diagnosis of Pump Thrombosis

Treatment of Pump Thrombosis

Current and Future Directions

Summary

Chapter 30. Vascular Closure Devices and Thrombosis

Introduction

Thrombosis in Percutaneous Atrial Septal Occlusion Devices

Key Gaps in the Evidence and Avenues for Further Research

Conclusions

Chapter 31. Management Strategies for Thrombosis of Major Abdominal Aortic Branches: The Superior Mesenteric and Renal Arteries

Introduction

Anatomy

Pathophysiology of Acute Mesenteric Ischemia

Case Studies

Acute Renal Artery Thrombosis

Summary

Chapter 32. Thrombotic Lesions in the Lower Extremity Peripheral Arteries: Diagnosis and Management

Introduction: Thrombus in Peripheral Arterial Disease

Thromboembolic Occlusions in Lower Extremity Peripheral Arteries

In Situ Thrombotic Occlusions in Lower Extremity Arteries

Treatment of Thrombus in Lower Extremity Peripheral Arteries

Use of Anticoagulants and Antiplatelets With Thrombectomy

Conclusion

Chapter 33. Thrombosis of the Venous Vasculature: Diagnosis and Management

Introduction

Deep Venous Thrombosis of the Lower Extremity

Upper Extremity Thrombosis

Superior Vena Cava Thrombosis

Portal Vein Thrombosis

Hepatic Vein Thrombosis

Renal Vein Thrombosis

Septic Thrombophlebitis

Cerebral Venous Thrombosis

Chapter 34. Revascularization for Acute Ischemic Stroke: Contemporary Perspectives on the Role and Yield of Thrombolytic Therapy and Endovascular Intervention

Introduction

Evolution of Thrombolysis in Stroke Management

Endovascular Management of Acute Ischemic Stroke (Table 34.2)

Reperfusion Scales

Mechanical Thrombectomy Efficacy Trials

Time-Based Versus Tissue-Based Approaches for Patient Selection

Guidelines for Thrombolysis and Endovascular Therapy

Future Perspectives

Chapter 35. Treatment Options for Recurrent Thromboembolism in Patients With Cryptogenic Cerebrovascular Events: Medical Therapy Versus Device Closure or Surgical Repair of Patent Foramen Ovale

Introduction

Medical Therapy

Device Closure

Chapter 36. Left-Atrial Appendage Occluders: Recent Advances and Unresolved Issues

Introduction

Background

Currently Available Devices

Planning Atrial Fibrillation Ablation

Results with Left-Atrial Appendage Occluders

Amplatzer Cardiac Plug

Indications

LAAO as an Alternative to Oral Anticoagulation When Oral Anticoagulation Is Possible

LAAO as Replacement for Anticoagulation When Anticoagulation Is Unwarranted

Patients With an Increased Bleeding Risk Under Systemic Anticoagulation: A Relative Contraindication

LAAO as a Complement to Anticoagulation

LAAO in the Presence of Left-Atrial Thrombus

LAAO as Adjunct to Atrial Fibrillation Ablation and Following Left-Atrial Appendage Isolation

Anticoagulation

Long-Term Antithrombotic Therapy

Antithrombotic Treatment in Cases of Lariat

The Use of Novel Oral Anticoagulants With LAAO

Thrombus on the Device

Incomplete Occlusion of the Left-Atrial Appendage

Summary

Chapter 37. Thrombophilia: Contemporary Perspectives

Introduction

Inherited Thrombophilia

Acquired Thrombophilia

Antiphospholipid Antibody Syndrome

Heparin-Induced Thrombocytopenia

Myeloproliferative Neoplasms

Chapter 38. Infectious Diseases and Cardiovascular Thrombosis

Introduction

Infective Endocarditis

Epidemiology

Microbiology

Pathogenesis and Pathophysiology

Immunopathological Factors

Clinical Features

Laboratory Studies and Diagnosis

Management

Organism-Specific Antibiotic Considerations

Surgery

Septic Venous Thrombophlebitis

Jugular Venous Thrombosis

Cavernous Sinus Thrombosis

Septic Pelvic Phlebitis

Catheter-Related Septic Thrombosis

Chapter 39. Thrombosis in Pregnancy

Pathophysiology

Thrombophilia and Pregnancy

Diagnosis

Venous Thromboembolism Prevention

Venous Thromboembolism Treatment

Pathophysiology of Gestational Vascular Diseases

Conclusions

Chapter 40. The Role of Interventional Cardiology in the Management of Thrombotic Conditions in the Pediatric Population

Introduction

Etiology of Thrombosis

Consequences of Thrombosis

Transcatheter Therapy

Suction or Aspiration Thrombectomy [11,12]

Balloon Angioplasty and Stent Placement

Thrombosis in Congenital Heart Disease

Cardiac Surgery

Systemic-to-Pulmonary Artery Shunt Thrombosis

Vessel Rehabilitation

Thromboembolism

Venous Filter Placement

Complications Following Catheter-Based Interventions

Conclusion

Chapter 41. Kawasaki Disease: The Phenomenon of Thrombotic Coronary and Vascular Aneurysms in the Young and Adults—A Japanese Perspective

Introduction

Pathogenesis

Treatment

Treatment of Adult Patients With Cardiovascular Sequelae in Kawasaki Disease

Chapter 42. Thrombus Pharmacotherapy

Introduction

Oral Anticoagulants

Antiplatelet Agents

Parenteral Anticoagulants

Glycoprotein IIb/IIIa Inhibitors

Chapter 43. Antithrombotic Treatment in Patients Undergoing Transcatheter Aortic Valve Replacement

Introduction

Recommended Pharmacological Therapy for Surgical Aortic Valve Replacement

Recommended Pharmacological Therapy for Transcatheter Aortic Valve Replacement

Platelet Dysfunction in Aortic Stenosis and Dual Antiplatelet Therapy Hypothesis

Data Regarding Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Replacement

Patients Requiring Anticoagulation Therapy and Transcatheter Aortic Valve Replacement

Summary

Chapter 44. Antifibrinolytics: Pharmacologic Profile and Clinical Utilization

Introduction

Historical Perspective of Antifibrinolytic Agents

Special Concerns in Cardiac Surgery

Perioperative Guidelines/Blood Conservation

Antifibrinolytic Agents: Pharmacology, Pharmacokinetics, Dosing, Clinical Outcomes, and Adverse Effects

Conclusions

Chapter 45. The Realm of Drug, Biological Product and Supplement-Induced Thrombosis and Thromboembolic Risk

Introduction

Drug-Induced Thrombosis

Prescription Medications/Biological Products

Herbals/Supplements

Recreational Drugs

Summary

Index

Copyright

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Dedication

To my Patricia;

I consent with these excerpts from the experts:

Who ever loved that loved not at first sight?

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List of Contributors

George S. Abela, MD, FACC,     Chief, Division of Cardiology Professor, Medicine Michigan State University East Lansing, MI, United States

Nayef A. Abouzaki, BS, MD

Assistant Professor of Medicine Virginia Commonwealth University Richmond, VA, United States;

Interventional Cardiologist Hunter Holmes McGuire Veterans Affairs Medical Center Richmond, VA, United States

Abdulmohsin Ahmadjee, MD,     Michigan State University East Lansing, MI, United States

Ayman Al-Salaimeh, MD,     Assistant Professor Department of Neurology Kentucky Neuroscience Institute University of Kentucky Lexington, KY, United States

Mohammed Aladdin, MD,     The Brooklyn Hospital Department of Radiology Division of Interventional Radiology Brooklyn, NY, United States

Felipe N. Albuquerque, MD,     Division of Cardiology – University of Miami Miller School of Medicine Miami, Florida, United States

Robert A.S. Ariëns, BSc, PhD

Professor of Vascular Biology Univeristy of Leeds Leeds, United Kingdom

Head of Discovery and Translational Science Department; Leeds Institute of Cardiovascular and Metabolic Medicine United Kingdom

Elad Asher, MD, MHA,     Interventional Cardiologist, Director Intensive Cardiac Care Unit Deputy Director Cardiology Devision Assuta Ashdod University Hospital Ashdod Israel

Ali N. Azadani, PhD,     Department of Mechanical and Materials Engineering University of Denver Denver, CO, United States

Lina Badimon, PhD, FESC, FAHA

Professor Director - Cardiovascular Program ICCC Institut de Recerca Hospital de la Santa Creu i Sant Pau IIB-Sant Pau, Barcelona;

CIBERCV-ISCIII, Madrid, Spain;

Cardiovascular Research Chair UAB, Barcelona, Spain

Stephen R. Baker, BSc, PhD,     Postdoctoral Research Fellow Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds Leeds, United Kingdom

Subhash Banerjee, MD,     Chief of Cardiology VA North Texas Health Care System Professor of Medicine, University of Texas Southwestern Medical Center Dallas, TX United States

Brittany E. Bannish, PhD,     Associate Professor of Mathematics and Statistics University of Central Oklahoma Edmond, OK, United States

Anthony A. Bavry, MD, MPH

Associate Professor of Medicine Cardiovascular Medicine University of Florida Gainesville, FL, United States;

Interventional Cardiologist Medical Service Cardiology, Malcom Randall VAMC North Florida/South Georgia Veterans Health System Gainesville, FL, United States

Roy Beinart, MD,     Davidai Arrhythmia Center Leviev Heart Institute Sheba Medical Center and Sackler School of Medicine Tel Aviv University Ramat Gan, Israel

Soumaya Ben-Aicha, MSc,     Cardiovascular Program ICCC Institut de Recerca Hospital de la Santa Creu i Sant Pau IIB-Sant Pau, Barcelona, Spain

Emmanouil S. Brilakis, MD, PhD

Director Center for Complex Coronary Interventions Minneapolis Heart Institute Minneapolis, MN, United States;

Adjunct Professor Internal Medicine University of Texas Southwestern Medical Center Dallas, TX, United States

Rhoda B. Brosnan, MD, FACC,     Asheville Cardiology Associates Director Cardiology Course University of North Carolina Asheville School of Medicine Asheville, NC, United States

Arka Chatterjee, MD,     Assistant Professor of Medicine Division of Cardiovascular Disease University of Alabama at Birmingham AL, United States

Gabriele Cioni, MD, PhD,     High Complexity Internal Medicine Internal and Emergency Medicine University of Florence, Florence, Italy

Brian Clapp, MA, MBBS, PhD,     Consultant Cardiologist Department of Cardiology Guy's and St Thomas' NHS Trust Honorary Senior Lecturer, King’s College London St Thomas’ Hospital London, United Kingdom

Haim D. Danenberg, MD, FACC,     Professor of Medicine Department of Cardiology Hadassah Hebrew University Medical Center Jerusalem, Israel

P.P.T. de Jaegere, MD, PhD, FESC,     Professor of Cardiology Erasmus Medical Center Department of Interventional Cardiology Erasmus Medical Center Rotterdam, The Netherlands

Eduardo de Marchena, MD,     Professor of Medicine and Surgery Division of Cardiology University of Miami Miami, FL, United States

Kalpa De Silva, MBBS, PhD, MRCP,     Consultant Cardiologist, Bristol Heart Institute Honorary Lecturer, University of Bristol United Kingdom

Danny Dvir, MD,     University of Washington Seattle, WA, United States

Islam Y. Elgendy, MD,     Department of Medicine – Division of Cardiovascular Medicine University of Florida Gainesville, FL, United States

Ran Eliaz, MD,     Department of Cardiology Hadassah Hebrew University Medical Center Jerusalem, Israel

Albert Ferro, PhD, FRCP, FBPhS, FBIHS,     Professor of Cardiovascular Clinical Pharmacology School of Cardiovascular Medicine & Sciences, King's College London Honorary Consultant Physician Guy's and St Thomas’ Hospitals London, United Kingdom

Aloke V. Finn, MD,     CVPath Institute Gaithersburg, MD, United States

Joel E. Fishman, MD, PhD,     Professor Department of Radiology University of Miami Miller School of Medicine Miami, FL, United States

Moshe S. Fuksbrumer, MD,     Department of Radiology Division of Interventional Radiology The Brooklyn Hospital Brooklyn, NY, United States

Ali Ghodsizad, MD, PhD,     Division of Cardiothoracic Surgery and The Miami Transplant Institute University of Miami Miller School of Medicine and Jackson Memorial Hospital Miami, Florida, United States

Michael Glikson, MD,     Director of Jesselson Integrated Heart Center Immediate past president of the Israel Heart Society Shaare Zedek Medical Center Jerusalem Israel

Larry B. Goldstein, MD, FAAN, FANA, FAHA

Ruth L Works Professor and Chairman Department of Neurology University of Kentucky Lexington, KY, United States

Co-Director, Kentucky Neuroscience Institute Lexington, KY, United States

Sudheer Gorla, MD,     Jackson Memorial Hospital Miami, Florida, United States

Avishai Grupper, MD,     Davidai Arrhythmia Center Leviev Heart Institute Sheba Medical Center and Sackler School of Medicine Tel Aviv University Ramat Gan, Israel

Oliver P. Guttmann, MD, MRCP

Department of Cardiology Barts Health NHS Trust London, United Kingdom;

NIHR Cardiovascular Biomedical Research Centre Barts Heart Centre London, United Kingdom

Lindsay Harris, PharmD, BCCCP,     Mission Health System and the University of North Carolina Eshelman School of Pharmacy Clinical Pharmacist, Critical Care Assistant Professor of Clinical Education Asheville, North Carolina, United States

Daniel Havlichek Jr. MD, FACP,     Professor of Medicine Division of Infectious Diseases Michigan State University Division of Infectious Diseases East Lansing, MI, United States

Christopher Hawk, MD,     Division of Cardiology University of Miami Miller School of Medicine Miami, Florida, United States

Timothy Henry, MD

Lee and Harold Kapelovitz Chair in Research Cardiology Cedars Sinai Heart Institute Los Angeles, CA, United States

Minneapolis Heart Institute Minneapolis, MN, United States

David A. Hirschl, MD,     Assistant Professor Radiology Montefiore Medical Center Bronx, NY, United States

Ron Hoffman, MD

Assistant Professor of Medicine The Ruth and Bruce Rappaport Faculty of Medicine Technion-Israel Institute of Technology Haifa, Israel

Deputy Director, Department of Hematology and Bone Marrow Transplantation Rambam Health Care Campus Haifa, Israel

Holly Humphrey, MD, FACC

Clinical Assistant Professor Department of Internal Medicine Section on Cardiovascular Medicine Wake Forest University School of Medicine Winston-Salem, NC, United States

Department of Medicine, Cardiology W.G. Bill Hefner VA Medical Health Care System Salisbury, NC, United States

Hiroyuki Jinnouchi, MD,     CVPath Institute Gaithersburg, MD, United States

Gregory K. Jones, MD,     FACC Chief Electrophysiology Services Division of Cardiology Charles George Veterans Affairs Medical Center Asheville, NC, United States

Daniel A. Jones, PhD, MRCP

Department of Cardiology Barts Health NHS Trust London, United Kingdom;

NIHR Cardiovascular Biomedical Research Centre Barts Heart Centre London, United Kingdom

Ion S. Jovin, MD

Director, Cardiac Catheterization Laboratory Medicine/Cardiology MvGuireVAMC Richmond, VA, United States

Associate Professor Medicine/Cardiology Virginia Commonwealth University Richmond, VA, United States

Judit Karacsonyi, MD

VA North Texas Health Care System and UT Southwestern Medical Center Dallas, TX Division of Invasive Cardiology United States;

Second Department of Internal Medicine and Cardiology Center, University of Szeged Szeged, Hungary

Michael A. Kelley,     Department of Applied Mathematics and Statistics Colorado School of Mines Golden, Colorado, United States

Dean J. Kereiakes, MD, FACC, FSCAI

Medical Director, The Carl and Edyth Lindner Center for Research and Education The Christ Hospital Heart and Vascular Center Cincinnati, Ohio, United States

Professor of Clinical Medicine, The Ohio State University Columbus, Ohio, United States

J. Kevin Harrison, MD,     Duke University Medical Center Durham, NC, United States

Ran Kornowski, MD, FESC, FACC

Chairman, Department of Cardiology Rabin Medical Center, Beilinson Hospital Petach Tikva, Israel;

Professor of Cardiovascular Medicine Sackler Faculty of Medicine Tel Aviv University, Israel

Mordechai R. Kramer, MD, FCCP

Head, Pulmonary Division Rabin Medical Center, Beilinson Campus Petah Tikva, Israel;

Professor of Medicine Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Madhab Lamichhane, MD,     Michigan State University East Lansing, MI, United States

Antonio Landi, MD,     Division of Cardiology Department of Cardiac, Thoracic and Vascular Sciences University of Padova Medical School, Padova, Italy

Kerry Layne,     Cardiovascular Division King’s College London London, United Kingdom

Massoud A. Leesar, MD,     Professor of Medine, Section Chief Interventional Cardiology Medicine UAB, Birmingham, AL, United States

Karin Leiderman, PhD,     Assistant Professor Department of Applied Mathematics and Statistics Colorado School of Mines Golden, CO, United States

Neil P. Lewis, MD, PhD, FACC

Medical Director Heart Failure MCS, Transplantation Department Cardiology McGuire VAMC Richmond, VA, United States;

Professor of Medicine Department Cardiology VCU, Richmond, VA, United States

Jurgen Ligthart,     Erasmus University Rotterdam Rotterdam, The Netherlands

Michael Lishner, MD,     Professor of Medicine Sackler Faculty of Medicine Tel Aviv University Head, Research Institute Head, Department of Medicine A Meir Medical Center Kfar Saba, Israel

Alejandro E. Macias, MS,     Division of Cardiothoracic Surgery and the Miami Transplant Institute University of Miami Miller School of Medicine and Jackson Memorial Hospital

Michael Magarakis, MD,     Division of Cardiothoracic Surgery and the Miami Transplant Institute University of Miami Miller School of Medicine and Jackson Memorial Hospital Miami, Florida, United States

Ahmed N. Mahmoud, MD,     Department of Medicine Division of Cardiovascular Medicine University of Florida Gainesville, FL, United States

Dhruv Mahtta, MD, MBA,     Department of Medicine University of Florida Gainesville, FL, United States

Anit Mankad, MD

Assistant Professor of Medicine, Virginia Commonwealth University Health System Richmond, VA, United States;

Transplant Cardiologist, Hunter Holmes McGuire VA Medical Center Richmond, VA, United States

Claudia A. Martinez, MD,     Associate Professor Clinical Medicine University of Miami Miller School of Medicine Miami, FL, United States

Rodrigo Mendirichaga, MD,     Section of Cardiovascular Medicine Boston Medical Center, Boston University School of Medicine Boston, MA, United States

Elizabeth Michalets, PharmD, BCPS, FCCP,     Mission Health System and the University of North Carolina Eshelman School of Pharmacy Manager, Pharmacy Education and Research Professor of Clinical Education Asheville, NC, United States

Benjamin Michalove, PharmD, CPP,     PGY1 Pharmacy Residency Program Director Clinical Pharmacy Specialist Charles George Veterans Affairs Medical Center Asheville, NC, United States

Subhashis Mitra, MD,     Assistant Professor Department of Medicine Michigan State University East Lansing, MI, United States

Srikanth Nagalla, MBBS, MS,     Associate Professor of Medicine Program Director, Hematology/Oncology Fellowship Division of Hematology/Oncology UT Southwestern Medical Center Dallas, TX, United States

Massimo Napodano, MD, PhD,     Interventional Cardiology Department of Cardiac Thoracic and Vascular Sciences University of Padova Padova, Italy

Peter O’Kane, BSc, MBBS, MD, FRCP,     Consultant Interventional Cardiologist Dorset Heart Centre Royal Bournemouth Hospital Bournemouth, Dorset, United Kingdom

Takayuki Onishi, MD,     Chief, Department of Cardiology Hiratsuka Kyosai Hospital Hiratsuka, Kanagawa, Japan

Yuko Onishi, MD,     Director, Department of Cardiology Hiratsuka Kyosai Hospital Hiratsuka, Kanagawa, Japan

Amir Orlev, MD,     Barts Health NHS Trust London, United Kingdom

Ada M. Palmisano,     Department of Applied Mathematics and Statistics Colorado School of Mines Golden, Colorado, United States

Gabriella Passacquale, MD, PhD,     Clinical Lecturer Clinical Pharmacology Cardiovascular Division King's College London London, United Kingdom

Brian T. Peek, PharmD

Chief of Pharmacy Coordinator Research and Development Charles George Veterans Affairs Medical Center Asheville, NC, United States;

Clinical Associate Professor of Pharmacy Practice Wingate University School of Pharmacy Wingate, NC, United States

Divaka Perera,     Department of Cardiology Guy’s & St. Thomas’ Hospital London, United Kingdom

Andres M. Pineda, MD,     Cardiac Catheterization Laboratory University of Florida College of Medicine – Jacksonville Division of Cardiology Jacksonville, FL, United States

Sunil V. Rao, MD,     Professor of Medicine Duke University Medical Center Section Chief, Cardiology Durham VA Medical Center NC, United States

Krishnaraj S. Rathod, MRCP

Department of Cardiology Barts Health NHS Trust London, United Kingdom;

NIHR Cardiovascular Biomedical Research Centre Barts Heart Centre London, United Kingdom

Evelyn Regar,     University Hospital Zurich Zürich, Switzerland

Claire Ren

Erasmus University Rotterdam Rotterdam, The Netherlands

British Heart Foundation Clinical Research Fellow King’s College London London, UK

Uri Rosenschein, MD, MBA, FACC, FESC, FSCAI,     Chief, Department of Cardiology Bnai Zion Medical Center Professor of Medicine Technion Medical School Haifa, Israel

Matthew J. Ryan, BSc (Hons), MBChB, MRCP,     British Heart Foundation Clinical Research Fellow, King's College London London, United Kingdom

Negar Salehi, MD,     Michigan State University East Lansing, MI, United States

Tomas A. Salerno, MD,     Division of Cardiothoracic Surgery and The Miami Transplant Institute University of Miami Miller School of Medicine and Jackson Memorial Hospital Miami, FL, United States

Satinder K. Sandhu, MD,     Clinical Professor Pediatrics Director, Pediatric Cardiac Cath Lab Director, Adult Congenital Heart Disease University of Miami, Miller School of Medicine & Jackson Memorial Hospital Miami, FL, United States

Ian J. Sarembock, MB, ChB, MD, FACC, FSCAI,     Medical Director, Valve & Structural Heart Disease Division Harold C. Schott Foundation Endowed Chair in Structural Heart The Christ Hospital Health Network & Lindner Center for Research and Education Cincinnati, OH, United States

Edward J. Sawey, MD

Fellow in Cardiology Virginia Commonwealth University Health System Richmond, VA, United States;

Hunter Holmes McGuire VA Medical Center Richmond, VA, United States

Amit Segev, MD,     Leviev Heart Center Sheba Medical Center Tel Hashomer, Israel

Nicolas W. Shammas, MD, MS, EJD, FACC, FSCAI

Adjunct Clinical Associate Professor Internal Medicine University of Iowa Hospitals and Clinics Davenport, IA, United States

Research Director and Founder Midwest Cardiovascular Research Foundation Davenport, IA, United States

Yu-Min Shen, MD,     Associate Professor of Medicine Division of Hematology/Oncology UT Southwestern Medical Center Dallas, TX, United States

Arthur Shiyovich, MD

Department of Cardiology Institute of Interventional Cardiology Rabin Medical Center Petach Tikva, Israel;

Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Satya S. Shreenivas, MD,     Division of Interventional Cardiology Division of Valve and Structural Heart The Christ Hospital Heart and Vascular Center and The Lindner Center for Research and Education Cincinnati, OH, United States

James Smith, MD,     Wake Forest Baptist Health Winston-Salem, NC, United States

Elliot J. Smith, MD, FRCP

Department of Cardiology Barts Health NHS Trust London, United Kingdom

NIHR Cardiovascular Biomedical Research Centre Barts Heart Centre London, United Kingdom

Emily Stumpf, DO,     Jackson Memorial Hospital Miami, Florida, United States

Allyne Topaz, MD,     Senior Resident, PG-4, Department of Surgery Brooklyn Medical Center Brooklyn, NY, United States

Imre Ungi, MD,     Division of Invasive Cardiology Second Department of Internal Medicine and Cardiology Center University of Szeged Szeged, Hungary

Avraham Unterman, MD, MBA

Pulmonologist, Pulmonary Division Rabin Medical Center Beilinson Campus, Petah Tikva, Israel;

Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel

Gemma Vilahur, PhD, FESC,     Senior Researcher Cardiovascular Program ICCC Institut de Recerca Hospital de la Santa Creu i Sant Pau IIB-Sant Pau, Barcelona; CIBERCV-ISCIII, Madrid, Spain

Renu Virmani, MD,     Medical Director/President CVPath Institute, Inc. Gaithersburg, United States

Thomas E. Watts, MD,     Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham, AL, United States

Emily E. Wood, PharmD

Clinical Pharmacy Specialist Charles George Veterans Affairs Medical Center Asheville, NC, United States;

Adjunct Faculty Member Mercer University College of Pharmacy Atlanta, GA, United States

Arwa Younis, MD,     The Leviev Heart Center Sheba Medical Center and Sackler School of Medicine Tel Aviv University Ramat Gan, Israel

Richard L. Zampolin, MD,     Montefiore Medical Center Albert Einstein School of Medicine Bronx, NY, United States

Foreword

It gives me great pleasure to contribute the foreword for the first edition of this splendid book by Dr. On Topaz, Professor of Medicine, Duke University School of Medicine, and Chief, Division of Cardiology, Charles George Veterans Affairs Medical Center, Asheville, North Carolina, entitled Cardiovascular Thrombus: From Pathology and Clinical Presentation to Imaging, Pharmacotherapy, and Interventions, by the publisher Elsevier.

There is no doubt about the importance of thrombosis in medicine today. It serves in clinical medicine as an important growth area of research and clinical activities, as well as a major topic involving a multidisciplinary group approach that includes internal medicine, hematology, radiology, general cardiology, interventional cardiology, and cardiac surgery. Although the role of thrombosis leading to both chronic cardiovascular disease and acute life-threatening complications has been recognized for many years, clinical developments in recent years have helped to illuminate the pathophysiological changes affecting both thrombosis and thrombolysis, as well as our ability to diagnose and modify these processes.

This book provides a comprehensive, contemporary source of research and clinical practice related to the current aspects of the diagnosis and management of cardiovascular thrombosis. It is well known that the hemostatic system serves to maintain a delicate balance between the processes of coagulation and anticoagulation, platelet activation and inhibition, and activation and inhibition of fibrinolysis to ensure vascular patency. Abnormalities in these processes can precipitate hemorrhage or arterial and venous thrombosis. Acute thrombotic events characterize common clinical manifestations of cardiovascular disease, including acute coronary syndrome, myocardial infarction, and ischemic stroke. Antithrombotic interventions, such as aspirin, platelet receptor inhibitors, P2Y12 inhibitors, and thrombolytic agents, underpin the management of cardiovascular disease, highlighting the critical role of thrombosis in cardiovascular morbidity and mortality.

This book has been published at a most opportune time. It is among the first books yet written on this important subject, and I believe it is among the more ambitious and best productions on this topic. It is designed to help physicians in all specialties as they apply recent information about thrombosis, the coagulation system, and cardiovascular diseases. The editor and the contributing authors are highly respected world leaders in this field and their background, personal contributions, and deep knowledge of the subject complement one another remarkably. At the same time, the book is intensely practical, thus bringing the unique knowledge and insights of the contributing authors and the editor to bear on the interpretation of the experimental and clinical observations in this rapidly expanding field.

Cardiovascular thrombus is of paramount importance for researchers and practicing physicians, yet it remains among the most challenging diagnostic and clinical scenarios. This important reference book bridges the gap between research, up-to-date clinical information, and the technological facets of thrombus formation, diagnosis, and management in cardiovascular medicine. The book includes complete coverage of pathology, clinical presentations, diagnosis, pharmacotherapy, interventions, and future trends set in a comprehensive, up-to-date format. Furthermore, this book also considers the potential future applications of various technologies in furthering our understanding of the mechanisms contributing to formation of cardiovascular thrombus and to thrombus resolution, which may ultimately lead to the identification of additional therapeutic pathways that could be targeted for development of new antithrombotic therapies.

I would like to congratulate Dr. On Topaz and his excellent group of distinguished contributing authors who accomplished in each chapter of this book the indispensable concepts required to approach critical diagnostic and therapeutic needs in clinical cardiovascular medicine. The introduction of newer techniques for the diagnosis and treatment of thrombotic cardiovascular disease has changed considerably the diagnostic and therapeutic scenarios. The recent advances in the study of thrombosis have altered permanently the management of patients with cardiovascular disease as well as healthy persons who are at risk for development of cardiovascular thrombotic diseases.

Finally, I wish that all readers of this book enjoy and use it as a beneficial tool as much as I myself did. I believe that this textbook will prove invaluable to all researchers and investigators of thromboembolic disorders, as well as to noninvasive cardiologists, interventional cardiologists and radiologists, vascular and cardiovascular surgeons, internists, hematologists, vascular medicine specialists, pharmacists, and medical students, all of whom wish to consider choices and make informed clinical decisions when dealing with cardiovascular thrombus and thromboembolic problems in their daily practice.

Igor F. Palacios, MD, FACC, FACP, FSCAI,     Director of Interventional Cardiology, Massachusetts General Hospital, Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Preface

The extraordinary work of art on the book's cover illustrates dramatically the ominous threat thrombus imposes on the heart and great vessels and, by implication, the entire cardiovascular system and life. This painting on canvas by the artists Scott Meskill and Shannon Donnelly reflects their visual interpretation of thrombus and thrombosis while they were in attendance at an Emergency Medicine conference. We chose to exhibit this painting as the gate opener to an all-inclusive book, covering the full spectrum of cardiovascular thrombus.

My personal odyssey toward all things thrombus was launched during fellowships training in cardiovascular pathology, cardiology, and interventional cardiology. This education brought to light the prevalence and catastrophic effects of cardiovascular thrombus as observed from the unique perspective of these intertwining disciplines. In the pathology suite, we studied hearts, vessels, organs, and accompanying thrombi in patients who had died from complications attributed to cardiovascular thrombi, gaining a final view on the inflicted damage. Thus, clinically, I serve as a long-standing observer to the ubiquitous and rich clinical presentations of cardiovascular thrombi, while participating in the development of dedicated management strategies and related technologies.

As clinicians, we constantly witness and deal with the tremendous injury thrombi cause patients. Intriguingly, thrombus is an essential component of hemostasis, yet its formation frequently serves as a harbinger of vascular complication or as a blatant testimonial to an already existing cardiovascular damage. Thrombus is omnipresent in the arterial and venous circulation, inside cardiac chambers, adhering to valves, lodging in the great vessels, and embolizing through the vasculature to many organs. The extraordinary pathology and complex morphologic features of different types of thrombi and related physical and rheolytic properties are of significant interest to many. Indeed, thrombi are a study in biologic contradictions: some firmly attach to structures and vessels while others float freely. Thrombi vary in age and often exhibit fresh layers interspersed with or superimposed over old layers. A thrombus size can be anywhere from microscopic to large—at times even reaching a monstrous length and shape. Thrombi are built of unique constituents and carry select signature receptors that excrete procoagulants and vasoactive reactants, making them strongly susceptible to accumulation. The brittle and unstable nature of thrombi means unpredictable clinical outcomes, thrombi are commonly resistant to extraction yet prone to embolization even if treated.

While writing the chapter The Thrombus-Containing Lesion for consecutive editions of the Textbook of Interventional Cardiology, edited by Topol and Teirstein, Elsevier, I developed a growing interest in the potential of a new book aimed at comprehensive coverage of contemporary research, clinical, diagnostic, management, and therapeutic aspects of cardiovascular thrombus. The publisher Elsevier readily agreed to embrace this quest, and I am grateful for the privilege of editing this book. Accordingly, special thanks to Ms. Stacy Masucci, Senior Acquisitions Editor, Biomedical Research and Reference, at Elsevier. Personal appreciation is expressed to Mr. Samuel Young, the book's project manager. Ms. Arya Dowis, 4th year medical student from the Edward Via College of Osteopathic Medicine, provided thoughtful academic contributions to the book project which are highly appreciated. All along this project, here at the Charles George Veterans Affairs Medical Center, the gifted Matt Holtz, BS, RCIS, provided outstanding technical support, excellent electronic media preparation, and insightful advice.

Upon the publication of this book, I wish to express a deep gratitude to the distinguished contributing authors, comprising scientists, researchers, and clinicians who responded affirmatively to my invitation, generously contributing their time and talent. Consequently, the scientific data as published in this book represent an array of contemporary views on multiple topics. The contributing authors and I trust that the readership, including students, scientists, and clinicians alike, from the vast fields of medicine, will benefit from the teaching points and profound expertise and stands to find this book a comprehensive and interesting resource.

Finally, our sincere wish is that this book will cultivate further research and lead to the development of new therapies. May many patients around the world benefit from the knowledge gained by the readers.

On Topaz, MD,     Asheville, NC, USA

Chapter 1

Histopathology of Cardiovascular Thrombus

Hiroyuki Jinnouchi, Aloke V. Finn, and Renu Virmani     CVPath Institute, Gaithersburg, MD, United States

Abstract

The causes of coronary thrombus have been reported to occur from plaque rupture, plaque erosion, and calcified nodule. Of the three plaque types, plaque rupture is the most common cause of thrombosis, occurring in 65%–75% of individuals dying from sudden coronary death or acute myocardial infarction, whereas erosion occurs in 25%–30% and calcified nodule in 2%–7%. The site of rupture is characterized by a ruptured thin fibrous cap, heavily infiltrated by macrophages, with an underlying large necrotic core and a calcified plaque. The main risk factors are high cholesterol and a high total cholesterol/high-density lipoprotein cholesterol ratio and smoking. At the site of rupture or erosion the thrombus is predominantly made up of aggregated platelets, while the propagated thrombus is a red thrombus consisting of fibrin and red cells. Distal emboli are more common in erosions, and composed mainly of platelets. Erosions occur principally in younger individuals, especially women with a smoking history. The underlying plaque consists of pathological intimal thickening or fibroatheroma; however, distinct morphological features of erosion-prone plaques have not been identified. Calcified nodule is another substrate for thrombosis, especially in elderly males with heavily calcified arteries, high plaque burden, and tortuous arteries, usually with diabetes or metabolic syndrome.

Keywords

Calcified nodule; Erosion; Fissure; Healed plaque; Intraplaque hemorrhage; Plaque rupture

Prevalence of Heart Disease

A hundred  years ago the percentage of deaths from cardiovascular disease was less than 10%. This number has increased dramatically with industrialization. In 2013, cardiovascular disease accounted for 31% of all deaths worldwide and more than 17.3 million deaths per year. In high-income countries, it accounts for approximately 40%, whereas in low- and middle-income countries it accounts for nearly 28%. It is estimated that the number of deaths from cardiovascular disease will be more than 23.6 million by 2030. In the United States, heart disease (including coronary heart disease, hypertension, and stroke) is the No. 1 killer. Coronary heart disease accounts for one in seven deaths in the United States, resulting in 360,000 fatalities per year. From 2004 to 2014, the annual death rate from coronary heart disease declined to 35.5%. Despite this improvement the incidence of sudden cardiac death, which occurs predominantly in the home or residence (70% of all sudden cardiac deaths), has not changed in the past 40–50  years, accounting for >300,000 to 350,000 deaths annually [1,2].

Coronary Thrombosis: Incidence and Etiology

Until 2000 it was generally believed that coronary thrombosis occurs mainly from plaque rupture, and the American Heart Association classification of atherosclerosis in 1995 by Stary et al. divided atherosclerosis into six types based on the fact that plaque rupture was the only cause of coronary thrombosis [3]. In 2000 we classified coronary thrombosis as occurring from three main causes: plaque rupture, plaque erosion, and calcified nodule. In 1994, Wal et al. reported their findings in about 20 sudden coronary death cases. According to this report, the incidences of plaque rupture and erosion were 60% and 40%, respectively [4]. In addition, in 1996, we reported our findings from 50 sudden coronary death victims who died from coronary thrombosis and showed that 44% of the individuals had plaque erosions and 56% had plaque rupture. More recently, in a review of 1847 autopsy cases of hospital-based acute myocardial infarction and sudden coronary death, plaque ruptures or fissures accounted for 73% of deaths, and the remaining 27% were from erosions [5]. In 2015 our institute reported findings from 442 cases of sudden coronary death. Coronary thrombosis accounted for 70% of the deaths, with the most frequent cause being plaque rupture (65%), followed by plaque erosion (30%) and calcified nodules (5%) [6] (Table 1.1). In a 2013 paper, the frequency of coronary thrombosis, as assessed by optical coherence tomography (OCT) in 126 patients presenting with acute coronary syndrome, was plaque ruptures in 44%, followed by plaque erosions in 31.0% and calcified nodules in 8% [7]. However, there are some drawbacks to OCT for evaluating causes of thrombosis and these include limited resolution and inability to penetrate deep into the plaque, with a majority of assessments requiring aspiration of the thrombus prior to imaging, which itself can disrupt plaque architecture. In the current definition by OCT, thrombus attached to the underlying intact plaque is recognized as plaque erosion, whereas probable plaque erosions are defined as luminal irregularities in the absence of underlying necrotic core or calcium. However, the diagnosis of erosion by OCT remains controversial and requires further proof and refinement to improve its diagnostic ability compared with the gold standard of histology.

Table 1.1

Histological definition of CTO was defined as lumen area occupied by proteoglycan and /or collagen with or without neovascularization and chronic inflammation.

Organized thrombi with healed myocardial infarction  =  62/74 (84%). No thrombi (stable plaque) with healed myocardial infarction  =  71/132 (54%). CAD, coronary artery disease; CTO, chronic total occlusion.

Reprinted from Yahagi K, et al. Sex differences in coronary artery disease: pathological observations. Atherosclerosis 2015;239(1):260–7 © with permission from Elsevier.

Plaque Rupture

Plaque rupture is defined by the presence of a disrupted thin fibrous cap with overlying thrombus and an underlying necrotic core. The underlying necrotic core in plaque rupture usually occupies >30% of the total plaque area [8–10] (Fig. 1.1A). The thin fibrous cap is made up of type I collagen with very few smooth muscle cells interspersed, but is infiltrated by varying numbers of macrophages and T lymphocytes. The mean fibrous cap thickness at the rupture site is 23  ±  19  μm, and 95% of the fibrous caps are <64  μm [5]. The disrupted fibrous cap allows contact of flowing blood with the highly thrombogenic necrotic core. This blood allows large numbers of platelets to be activated and aggregate at the rupture site forming a white thrombus (Figs. 1.2 and 1.3). The thrombus may or may not lead to a complete obstruction of the coronary lumen. If there is obstruction and a side branch is present proximal to the obstruction site, the thrombus propagates to the side branch and consists of layers of fibrin (lines of Zahn) separated by red blood cells, classified as a red thrombus. Eventually, if the thrombus is not removed or crushed by angioplasty or thrombolysis, it will organize by infiltration of inflammatory cells, especially macrophages, releasing growth factors that attract endothelial cells and smooth muscle cells, which proliferate and deposit extracellular matrix consisting of proteoglycans and collagen, leading to organization of the thrombus and chronic total occlusion of the coronary artery.

Ruptured plaques (PRs) are believed to be preceded by thin-cap fibroatheromas (TCFAs), also called vulnerable plaques, which are likely precursor lesions of PRs, except that the cap is intact and less than 65 μm, the necrotic core is smaller, and the lesions are less calcified. We have reported on the radiographic appearance of calcium in ruptures, erosions, and TCFAs. Calcification is greatest in ruptures, followed by TCFAs, and least in erosions [11]. With regard to location of disruption of the fibrous cap in PRs, human autopsy studies have shown that rupture occurs not only at shoulder regions but also at the midportion of the fibrous cap [12]. In addition, rupture at the thinnest, midportion of the fibrous cap was associated with exercise [12]. Also, emotional stress has been reported to precipitate cardiac events [13]. Select proteases secreted by macrophages possibly weaken the fibrous cap, and high shear and tensile stress all may be involved in triggering rupture [14,15]. In addition, microcalcification (>5  μm) originating from dying macrophages or smooth muscle cells has also been hypothesized to possibly trigger rupture, possibly due to increased stress that leads to interfacial debonding [16,17].

In 1997, Burke et al. reported an association between serum lipid profile (total cholesterol, high-density lipoprotein (HDL) cholesterol, ratio of total cholesterol to HDL), smoking (serum thiocyanate, a surrogate marker for smoking), and plaque rupture in 113 men who died suddenly. Among them, 96.5% had one or more risk factors regardless of etiology of coronary thrombus, with smoking being a predictor of acute thrombosis [18]. Plaque rupture was associated with high total cholesterol, low HDL cholesterol, and elevated ratio of total to HDL cholesterol. In addition, patients who had high levels of total cholesterol had a greater number of TCFAs. Diabetes was a predictor of stable plaque, as well as total and distal plaque burden. Lesions from type 2 diabetic subjects have larger mean necrotic cores (P  <  .01), and macrophages, T cells, and HLA-DR are significantly greater in diabetic subjects (P  =  .03, P  =  .003, and P  <  .0001, respectively) compared with nondiabetics [19].

Figure 1.1  Human coronary lesion morphologies categorized as lesions with acute thrombi. Histological and schematic images are shown for (A) plaque rupture, (B) plaque erosion with underlying pathological intimal thickening ( PIT ), (C) plaque erosion with underlying fibroatheroma ( FA ), and (D) calcified nodule. Arrowheads indicate fibrous cap. NC , necrotic core; Th , thrombus. 

Histological images in (A), (B), and (D) reprinted from Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J 2013;34(10):719–28 by permission of Oxford University Press and the European Society of Cardiology. (C) Reprinted from Otsuka F, et al. Clinical classification of plaque morphology in coronary disease. Nat Rev Cardiol 2014;11:379–89 with permission from Elsevier.

Figure 1.2  Thrombus propagation in plaque rupture. (A) Composition of a longitudinal section of the LAD coronary artery with plaque rupture; the rupture site is marked by the arrowhead (Movat pentachrome, original magnification ×20). (B) The same longitudinal section as in (A) stained with Carstairs' method for the detection of fibrin (dark red) and platelets (blue-gray). The proximal thrombus consists predominantly of fibrin with red cells interspersed, while the distal portion of the rupture site is platelet rich. (C) Platelets were further confirmed using antibody directed against glycoprotein IIIa. (D) Proximal propagated portion of the thrombus showing mostly fibrin and red cells; mild layered reactivity is seen for platelets. LD , left diagonal branch; LAD , left anterior descending. 

Reproduced with permission from Virmani R, Narula J, Leon MB, Willerson JT, editors. The vulnerable atherosclerotic plaque. Plaque Rupture. MA, USA: Blackwell Futura; 2007 [Chapter 3]. p. 53. Figure 3.15.

Figure 1.3  Ruptured plaque associated with nonocclusive luminal thrombus. A 45-year-old man with a history of hypertension, diabetes mellitus, and hyperlipidemia died suddenly after jogging during his lunch break. (A) A postmortem angiography showed mild luminal narrowing with haziness at proximal RI. (B–D) Serial OCT images revealed the presence of plaque rupture (in C, D) with nonocclusive luminal thrombus (white arrowhead in D) and an adjacent distinct superficial signal-rich region (thin white arrows in B) with rapid attenuation (white arrowheads in B), indicating thin-cap fibroatheroma. Disrupted fibrous cap also shows distinct superficial signal-rich region (thin white arrows in C and D). (E) Histology confirmed the presence of plaque rupture with an acute fibrin-rich thrombus (shown as Thr) overlying the NC (section stained with Movat pentachrome). (F) Immunostaining for CD68-positive macrophages demonstrated substantial infiltration of foamy macrophages within the disrupted fibrous cap (thin black arrows). LAD, left anterior descending artery; LCX, left circumflex artery; LM, left main coronary artery; NC, necrotic core; OCT, optical coherence tomography; RI, ramus intermedius. 

Reprinted from Otsuka F, et al. Clinical classification of plaque morphology in coronary disease. Nat Rev Cardiol 2014;11:379–89 with permission from Elsevier.

Several OCT studies have demonstrated that plaque rupture is the most frequent cause of acute coronary syndromes [20,21]. These studies reported the mean thickness of the fibrous cap as 54  μm (interquartile range 50–60  μm); in 67% the thickness was <70  μm, and 95% had a cap thickness <80  μm. These clinical data are consistent with our histological autopsy data, considering tissue shrinkage is a well-known phenomenon of fixation and dehydration during preparation of paraffin sectioning and staining. Moreover, there are important differences between OCT and histology in terms of definition of plaque rupture, specifically the presence of intraplaque cavity. The OCT definition of plaque rupture includes presence of a disrupted thin fibrous cap but also intraplaque cavity; the latter is likely an artifact of aspiration thrombectomy along with contrast flushing. Histopathology studies have never reported intraplaque cavity in autopsy studies in patients who had never undergone any intervention. In addition, it is possible that intraplaque cavities may also be associated with distal embolization into intramyocardial coronary arteries.

Necrotic Core Expansion (Plaque Fissure and Intraplaque Hemorrhage)

Two factors contribute to the sudden increase in lesion enlargement prior to plaque rupture. These include plaque hemorrhage with or without plaque fissure and silent, asymptomatic plaque ruptures. In the 1960s, Constantinides and colleagues put forth the concept of cracks or fissures communicating with the luminal as one of the pathways by which blood could enter lesions (Fig. 1.4A) [22]. In the 1980s, Michael Davies expanded this concept and described this lesion as plaque fissures, which were observed in 63% of patients dying of coronary thrombosis. The fissure occurred at the junction of the plaque cap with the more normal intima, communicating with the underlying necrotic core that occupied <15% of the vessel circumference [23,24]. Davis highlighted that fissures should be distinguished from plaque ruptures. Plaque ruptures are usually surrounded by an obvious luminal thrombus. On the other hand, fissures are most likely to involve an intraintimal thrombus composed of fibrin and platelets with interspersed erythrocytes. In addition, even if thrombi exist, luminal thrombi related to fissures are most commonly very small. In fact, plaque fissure is characterized as a tear in an eccentric plaque with underlying small necrotic core, and the fibrous cap is not thin. The path of the fissure is generally derived from the necrotic core reaching the lumen, lined by a few macrophages, and red blood cells and fibrin are observed in the tract and within the necrotic core. In our hands the incidence is <10%.

Furthermore, intraplaque vasa vasorum in our experience is the dominant cause of intraplaque hemorrhage (Fig. 1.4). In 1938 Wartman suggested that intraplaque hemorrhage is a major contributor to the progression of coronary lesions. These studies involved injection of silicon polymer into atherosclerotic human coronary arteries, which demonstrated an elaborate microvascular network (the vasa vasorum) extending from the adventitia through the media into the thickened intima, whereas nonatherosclerotic vessels rarely had vasa vasorum. We believe intraplaque hemorrhage arises from disruption of thin-walled microvessels that are lined by a discontinuous endothelium without supporting pericytes [25]. Moreover, we and others have suggested that intraplaque hemorrhage and rupture of the fibrous cap are associated with an increased density of microvessels [12,26,27]. Intraplaque vasa vasorum reaches the intima most frequently from the adventitia. Kumamoto et al. have shown that intraplaque hemorrhage is 28 times more likely to originate from the adventitia compared with the lumen [28]. In addition, highly calcified and fibrotic arteries (stable plaque) generally had low vascular density, and luminal stenosis and inflammation. We reported that hemorrhage into a preexisting necrotic core plays an important role in its expansion [29]. The free cholesterol in the necrotic core may arise from the red cell membranes, which are the richer in free cholesterol than any other cell membrane in the body. Furthermore, in our previous study we showed that intraplaque hemorrhage is probably derived from the leaky vasa vasorum [29,30]. The intraplaque vasa vasorum lacks competent endothelial junctions and is usually not supported by pericytes, which is not true of the adventitial vasa vasorum. The endothelium of neoangiogenic vessels also showed intracytoplasmic vacuoles, membrane blebs, and basement membrane detachments [25,31]. Inadequate endothelial junctions promote red cell leakage and are associated with indicators of inflammation, such as macrophages and T lymphocytes [31,32].

Figure 1.4  Plaque morphologies that can lead to necrotic core expansion. Histological and schematic images are shown for (A) plaque fissure and (B) intraplaque hemorrhage. Arrowheads indicate neoangiogenesis. 

Reprinted from Yahagi K, et al. Nat Rev Cardiol 2015;13:79–98 with permission from Elsevier.

Erosion

Erosions are the second most prevalent cause of coronary thrombosis (Fig. 1.1B and C). Erosion lesions have a luminal thrombus and the underlying plaque, which shows a lack of endothelium but is rich in smooth muscle cells and proteoglycans with very few macrophages and T cells [5]. The lesions underlying plaque erosion are mostly characterized as early lesions with rare calcification compared with the advanced lesions of plaque ruptures. The type of plaque located underneath erosions consists of pathological intimal thickening (16%) without necrotic core and hemorrhage, early fibroatheroma (34%), and a late fibroatheroma (50%) [33]. In addition, the underlying media is intact, with well-defined internal and external elastic lamina (IEL and EEL) observed in 32% of cases; focally disrupted IEL (from inflammation and angiogenesis) is seen in 52%, and cases in which both IEL and EEL are disrupted are uncommon (16%). The medial smooth muscle cells behave more like a normal vessel (mildly stenotic), with highest expression of smooth muscle α-actin, followed by smooth muscle myosin heavy chain and smoothelin, thus supporting the concept that erosions may be a result of vasospasm. The types of proteoglycan underneath the erosions are mostly composed of versican and hyaluronan, whereas PRs show a minimum of proteoglycan and hyaluronan, but are rich in type I collagen. At the interphase of thrombus and underlying plaque in erosions there is a high expression of CD44, which promotes thrombosis [34]. Calcification is not observed in more than half of erosions (56%), microcalcification is detected in 40% of erosions, and fragmented calcification and sheets of calcification are in less than 2% [33]. Erosion is generally associated with negative remodeling, whereas plaque rupture is associated with positive remodeling [35]. Usually erosions are observed at a single site (96%), and only rarely are observed at multiple sites (4%). Most erosions are eccentric (82%), whereas ruptures are equally eccentric and concentric (54% and 46%, respectively) [36]. At the time of presentation, the thrombus has been shown more frequently to be older, showing signs of early healing, i.e., nuclear breakdown of leukocytes, and/or proliferation of smooth muscle and endothelial cells especially in 88% of plaque erosions, compared with 54% of PRs (P  <  .0001). Plaque erosions frequently show more distal emboli than plaque ruptures (71% vs. 42%, respectively) [15]. The lesions of erosions are less stenotic (70  ±  11%, in cross section) compared with those of ruptures (78  ±  12%, in cross section P  <  .03).

The tissue at the interface of thrombus involves activated smooth muscle cells, which are present in a proteoglycan-rich matrix composed mainly of hyaluronan, versican, and collagen type III. By contrast, the fibrous cap of plaque ruptures consists of primarily collagen type I, biglycan, and decorin [36,37]. Usually, erosions show minimal inflammation with a few or absent macrophages and T lymphocytes and the plaque is not disrupted [37]. A previous study reported that 68% of erosions showed absent or minimal inflammation within the transition zone between thrombus and underlying plaque and the remaining 32% had mild inflammation. In addition, 34% of erosions show no or minimal inflammation in the adventitial/medial border, whereas inflammation is mild in 50% and rarely moderate or severe, in 18% of cases (14% and 4%, respectively) [38]. Morphological features of the underlying lesions of erosions are poorly understood. In addition, plaque erosions were more commonly seen in women, with over 80% of coronary thrombi seen at autopsy in women <50  years of age being plaque erosions, whereas the frequency of erosion in older women (>50  years) is rare. Patients with acute coronary syndromes undergoing OCT who have evidence of erosion are also younger than those identified as having plaque rupture or calcified nodule (53.8  ±  13.1  years vs. 60.6  ±  11.5 and 65.1  ±  5.0  years, respectively; P  <  .01). Furthermore, only 40% of plaque erosions showed severe narrowing (>75% cross-sectional area narrowing), whereas 48% had 51%–75% narrowing, while the remaining 12% had <50% narrowing [36,38].

It was not possible to diagnose plaque erosion in patients presenting with acute coronary syndrome in the catheterization lab until the introduction of OCT in clinical practice. As the use of OCT has been expanded, it has become possible to observe the underlying plaques with ruptured fibrous caps or intact fibrous caps leading to coronary thrombotic events [39]. Definite OCT plaque erosion was defined as the presence of no disruption of underlying plaque with an acute luminal thrombus [7]. Also, the diagnosis of probable OCT erosion requires a luminal irregular surface or attenuation of underlying plaque by thrombus with no superficial lipid or calcification at the proximal or distal sections of culprit lesions. Previous OCT studies showed a 31% prevalence of plaque erosions in patients presenting with acute coronary syndromes. However, an OCT-defined distinction between erosion, plaque rupture, and calcified nodule can be difficult to make. Although OCT has good axial resolution, it cannot clearly identify differentiated cell types. In addition, the presence of luminal thrombus attenuates the depth of light penetration of OCT in the presence of blood in the lumen (Fig. 1.5).

Figure 1.5  Multiple plaque erosions in three major coronary arteries. (A) Postmortem radiography showed mild focal calcification in all major coronary arteries. (B) Histologic examination showed the left circumflex artery ( LCX ) with a nonocclusive platelet-rich organizing thrombus ( Th ) with underlying late fibroatheroma. (C) The right coronary artery ( RCA ) showed a luminal fibrin-rich organizing thrombus with an underlying late fibroatheroma. (D) The diagonal branch artery also showed a luminal fibrin-rich organizing thrombus with an underlying pathological intimal thickening. High-power images from boxes in (C) and (D) are shown. Fibrin-rich thrombi with a few inflammatory cells are seen on the luminal surface. Corresponding macrophage ( MΦ ) stain and optical frequency domain imaging ( OFDI ) images (Terumo, Tokyo, Japan) are depicted. Moderate macrophage infiltration is seen around the circumference of the vessel ( red arrowheads ); however, the culprit site ( white arrows ) is devoid of macrophages in the RCA. Note the absence of macrophages in the diagonal branch (macrophage-stained section of D). OFDI showed luminal surface irregularity with minimal attenuation because the thrombus had focal areas of platelets interspersed with large areas of fibrin in the RCA and the diagonal branch ( white arrows ), and a bright layer with attenuation ( red arrowheads ) indicates presence of macrophages in the RCA (C). (Bottom) Serial sections at high power stained by hematoxylin and eosin ( H&E ), platelet ( PLT ; CD61), fibrin (fibrin II), and macrophage (CD68) from the box in (D) are shown. Platelet stains (brown) show few superficial and interspersed platelets with a predominance of fibrin (brown, adjacent section) and rare macrophage infiltration (brown). ∗Placement of the guidewire. L , lumen; LAD , left anterior descending; NC , necrotic core. 

Reprinted from Yahagi K, et al. JACC Cardiovasc Imag 2014;7:1172–4 with permission from Elsevier.

Calcified Nodule

Calcified nodule is the least frequent cause of coronary thrombosis [9]. Calcified nodule is characterized as a luminal surface disrupted by nodules of dense calcium with overlying thrombus and little or no underlying necrotic core in arteries that are highly calcified and tortuous and often have large sheets of calcification (Fig. 1.1D). In 236 autopsy cases, the prevalence of calcified nodule was only 5% [6]. Although the mechanism of calcified nodules remains unknown, it is believed that fragmentation of calcified plates is the underlying mechanism. Fragments of calcified plates lead to small nodules of calcification, which disrupt the overlying fibrous cap and endothelial lining, attracting platelets and fibrin that lead to a luminal thrombus. Intraplaque fibrin is often observed in nodular calcification, possibly resulting from discontinuity of surrounding capillaries. Most eruptive calcified nodules are eccentric lesions where calcified nodules protrude into the overlying lumen with endothelial disruption that initiates platelet adherence. The location of calcified nodules is most frequently in the mid-right coronary artery or left anterior descending artery at sites of maximal torsion [9]. In addition, calcified nodules are most frequent in older individuals with renal failure, diabetes, and coronary tortuosity. It is important to recognize the difference between eruptive calcified nodule and nodular calcification; the latter occurs within the plaque and does involve the fibrous cap or the lumen but is often associated with medial wall disruption with or without extension into the adventitia.

In OCT studies, calcified nodular tissue has been defined as an accumulation of nodular calcification (small calcium deposits) with disruption of the fibrous cap on the calcified plate and an overlying white thrombus. Calcium was defined as a signal-poor or heterogeneous region with