Clinical Hematology Theory and Procedures F I F T H E D I T I O N Mary L. Turgeon, EdD, MT(ASCP) Clinical Laboratory Education Consultant Mary L. Turgeon & Associates Boston, Massachusetts & St. Petersburg, Florida Clinical Adjunct Assistant Professor Tufts University School of Medicine Boston, Massachusetts Professor College of Professional Studies Northeastern University Boston, Massachusetts Professor Physician Assistant Graduate Program South University Tampa, Florida TTuurrggeeoonn__FFMM..iinndddd ii 1100//2299//22001100 1122::5588::0077 PPMM Acquisitions Editor: Peter Sabatini Product Manager: Meredith L. Brittain Marketing Manager: Allison Powell Designer: Stephen Druding Production Services: SPi Technologies Fifth Edition Copyright © 2012, 2005 by Lippincott Williams & Wilkins, a Wolters Kluwer business. 351 West Camden Street Two Commerce Square Baltimore, MD 21201 2001 Market Street Philadelphia, PA 19103 All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their offi cial duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Lippincott Williams & Wilkins at 530 Walnut Street, Philadelphia, PA 19106, via email at [email protected], or via website at lww.com (products and services). Printed in China Library of Congress Cataloging-in-Publication Data Turgeon, Mary Louise. Clinical hematology : theory and procedures / Mary Louise Turgeon. — 5th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60831-076-0 1. Hematology. I. Title. [DNLM: 1. 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Lippincott Williams & Wilkins cus- tomer service representatives are available from 8:30 am to 6:00 pm, EST. 9 8 7 6 5 4 3 2 1 TTuurrggeeoonn__FFMM..iinndddd iiii 1100//2299//22001100 1122::5588::0077 PPMM Namaste To my husband, Dick Mordaunt May we continue to fulfi ll our dreams of adventure and learning TTuurrggeeoonn__FFMM..iinndddd iiiiii 1100//2299//22001100 1122::5588::0077 PPMM P R E F A C E It is a pleasure to author the 5th edition of Clinical classifi cations found in the recent World Health Organiza- Hematology. Since the 1st edition was published in 1988, tion Classifi cations appears in this edition. The treatment of each edition has included exciting changes in clinical hema- many hematology disorders, particularly effective therapy tology and posed challenges to learn more and teach more for chronic myelogenous leukemia and chronic lymphocytic in a fi xed time frame. The 5th edition retains the pedagogy leukemia, clearly focuses research on understanding the that set the standard for clinical laboratory science textbooks molecular aspects of diagnosis and treatment of many other since it was introduced in the 1st edition. Clinical Hematology blood disorders. now features integrated four-color images, tables, and boxes Numerous new discoveries associated with red blood cells throughout the book for ease of learning. New online ancil- have been reported since the 4th edition. New discoveries are laries include PowerPoint presentations, a quiz bank for stu- related to diagnosis and treatment of hemoglobin defects— dents, and more than 800 unique test questions for instructors that is, hemoglobinopathies. This information has a direct (see Additional Resources, below, for more information). application to the laboratory, where the importance of global Each chapter in this edition capitalizes on the strengths population migration creates new or an increased number of previous editions; up-to-date information presented at of patients with disorders that were not commonly seen in conferences and published in the professional literature; and clinical hematology before. In addition, this book describes comments received from students, faculty, faculty reviewers, exciting discoveries in iron metabolism and the relationship and working professionals from around the globe. Clinical of iron physiology to anemia of chronic disorders. Hematology has been classroom and laboratory “fi eld tested” Beginning with the 1st edition of Clinical Hematology, by medical laboratory technician (MLT) and medical labo- safety has been an important consideration. The 5th edi- ratory science (MLS) students, instructors, and the author. tion covers the latest safety information associated with the Hands-on presentation of the information and techniques importance of immune status—that is, screening and rec- discussed in Clinical Hematology underscores the impor- ommended vaccinations of employees, and proper removal tance of clarity, conciseness, and continuity of information of disposable gloves. ISO 15189, quality and preanalytical for the entry-level student. Sole authorship of this textbook error management issues, and a Spanish-English Phlebotomy ensures a smooth transition from chapter to chapter without guide (see Appendix D) are also included. The newest spec- unnecessary redundancy or changes in writing style. imen-related information in this edition includes additional types of evacuated tubes, environmental factors that infl u- ence evacuated tubes, order of draw of multiple evacuated THE AUDIENCE tubes collection, and order of draw of capillary specimens. Hematology instrumentation continues to expand the Clinical Hematology, 5th edition, is primarily intended to ful- menu of available assays. This edition presents the latest fi ll the needs of medical laboratory science (MLS) and medi- comparative instrument product information for cell count- cal laboratory technician (MLT) students and faculty as a ing and identifi cation, and blood coagulation testing. The time-tested book. MLT students may omit some portions of manual procedures chapter (Chapter 26) has been stream- the book depending on the length of the curriculum. Other lined, with older techniques moved to a web-based reposi- health professionals can use the book as an instructional or tory. The format of the procedures continues to comply with reference guide. Clinical Laboratory Standards Institute (CLSI) standards. The 1st edition of this book was the fi rst clinical laboratory science textbook to institute standardization of procedures WHAT IS NEW IN THIS EDITION using the CLSI protocol. The 5th edition continues with the innovative expansion of exciting molecular discoveries that assumed importance ORGANIZATIONAL PHILOSOPHY in the 4th edition—for example, p53 function in DNA repair and mechanisms of apoptosis. The book includes The six-part organization of Clinical Hematology follows knowledge recognized by the Nobel Prize in Physiology the original profi le for a logical combination of textbook, or Medicine in 2009 for discoveries of telomere structure cellular morphology atlas, and procedure manual. Part 1, and maintenance and covers other genetic irregularities The Principles of Hematology, discusses the newest funda- relevant to the pathophysiology and treatment of hemato- mental concepts including safety, quality assessment, and logic disease—for example, genetic abnormalities leading specimen collection. Chapter 3, Molecular Genetics and Cel- to ribosome dysfunction in Diamond-Blackfan anemia and lular Morphology, continues to be of extreme importance in genetic abnormalities in Fanconi anemia. The expansion of u nderstanding the pathophysiology and diagnosis of many iivv TTuurrggeeoonn__FFMM..iinndddd iivv 1100//2299//22001100 1122::5588::0077 PPMM Preface v blood disorders and related therapy. The last chapter in this Instructor Resources part, Chapter 4, presents the normal development of blood cells in humans. This is essential basic information. Approved adopting instructors will be given access to the fol- Parts 2 and 3 of Clinical Hematology focus on erythrocytes lowing additional resources: and leukocytes, respectively. The content of the chapters in ■ Two test banks—one contains more than 800 unique each of these parts progresses from normal structure and questions; the other contains all the review questions function to specifi c abnormalities in each grouping. from the book In Part 4, Additional Groups of Clonal Disorders, is in ■ PowerPoint slides for each chapter focus. Each of the two chapters investigates multiple disor- ■ An image bank of all the fi gures and tables in the book ders that share a common clonal origin. Part 5, Principles and Disorders of Hemostasis and Student Resources Thrombosis, presents a distinct specialty in hematology: blood coagulation. An abundance of new knowledge about Students who have purchased Clinical Hematology, 5th edition platelets and coagulation factors continues to emerge. have access to the following additional resources: The fi nal part, Part 6, focuses on hematological analysis. This section includes diversifi ed types of analysis including ■ A quiz bank of 270 questions body fl uid analysis, manual procedures, and instrumenta- ■ A lab manual of additional procedures tion. This part is conveniently located at the end of the book In addition, purchasers of the text can access the searchable for easy reference when reading other parts of the book. Full Text On-line by going to the Clinical Hematology Web Handy appendices include answers to review questions, site at http://thePoint.lww.com/Turgeon5e. medical terminology basics, SI units, a list of English-Span- ish medical phrases for the phlebotomist, the newest evacu- ated tube pictorial directory, and a sample Material Safety ACKNOWLEDGMENTS Data Sheet (MSDS). A glossary at the end of the book defi nes all the key words bolded throughout the text. My objective in writing Clinical Hematology, 5th edition, continues to be to share basic scientifi c concepts, procedural CHAPTER STRUCTURE AND FEATURES theory, and clinical applications with fellow teachers and stu- dents. Because the knowledge base and technology in hema- Each chapter of Clinical Hematology provides the following tology continues to expand, writing and revising a book that elements to enhance the usability of the text: addresses the need of teachers and students at multiple levels ■ Learning objectives provide a quick overview of the con- in the clinical sciences continue to be a challenge. In addi- tent to be covered. tion, this book continues to provide me with the opportunity ■ Case studies reinforce concepts with real-world applica- to learn and share my working and teaching experience, and tions. insight as an educator, with others. ■ Procedure boxes provide step-by-step information for Special thanks to John Goucher for initiating the project key processes. and to Meredith Brittain for her organizational efforts in the ■ Key terms that emphasize important concepts are itali- process of turning the manuscript into a four-color book. An cized and defi ned in the end-of-book glossary. additional thank you is extended to Christine Selvan and her ■ Review questions reinforce the student’s understanding team at SPi for their excellent performance in the prepara- of key concepts and aid in test preparation. tion of the manuscript for publication. ■ Chapter highlights enable a quick review of material Comments from instructors and students are welcome at learned in each chapter. [email protected]. Mary L. Turgeon ADDITIONAL RESOURCES Boston, Massachusetts St. Petersburg, Florida Clinical Hematology includes additional resources for both instructors and students that are available on the book’s companion Web site at http://thePoint.lww.com/Turgeon5e. TTuurrggeeoonn__FFMM..iinndddd vv 1100//2299//22001100 1122::5588::0077 PPMM C O N T E N T S Preface iv ■ REVIEW QUESTIONS 47 ■ REFERENCE 48 ■ BIBLIOGRAPHY 48 3 Molecular Genetics and Cellular Morphology . . . .50 PART ONE: Cellular Ultrastructure and Organization 50 The Principles of Hematology 1 Cellular Membranes 50 Cell Volume Homeostasis 52 1 Safety and Quality in the Hematology Reactive and Neoplastic Growth Processes 53 Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Cytoplasmic Organelles and Metabolites 53 Cellular Inclusions and Metabolites 54 An Overview of the Hematology Laboratory 1 Nuclear Characteristics 54 The Study of Hematology 1 Chromosomes 56 Functions of the Hematology Laboratory 1 Activities of the Nucleus 58 Safety in the Hematology Laboratory 2 The Foundations of Genetic Interactions 60 The Safety Offi cer 2 Genetic Alterations 61 Occupational Safety and Health Administration Acts and Molecular Techniques in Hematology 63 Standards 2 Minimal Residual Disease 63 Avoiding Transmission of Infectious Diseases 3 Hematopathology 67 Immune Status: Screening and Vaccination 5 Gene Rearrangement Studies 69 Safe Work Practices and Protective Techniques for ■ CHAPTER HIGHLIGHTS 69 Infection Control 6 ■ REVIEW QUESTIONS 70 Safety Manual, Policies, and Practices 6 Standard Precautions 6 ■ BIBLIOGRAPHY 72 Handwashing 6 4 Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Personal Protective Equipment 7 Hematopoiesis Defi ned 73 Decontamination of Work Surfaces, Equipment, and Spills 8 Origin of Blood Cells 73 General Infection Control Safety Practices 9 Types of Human Stem Cells 73 OSHA Medical Waste Standards 11 Early Development of Blood Cells 73 Quality Assessment in the Hematology Laboratory 12 Bone Marrow Sites and Function 75 Regulations and Organizations Impacting Quality 12 Cellular Elements of Bone Marrow 76 Components of Quality Assessment 12 Progenitor Blood Cells 76 Nonanalytical Factors in Quality Assessment 12 Erythropoiesis 79 Quality Control in the Hematology Laboratory 16 Granulopoiesis 79 Terms Used in Clinical Quality Control 16 Lymphopoiesis 79 Functions of a Quality Control Program 17 Megakaryopoiesis 79 Using Statistical Analysis of Results in Quality Assessment 18 Other Cells Found in Bone Marrow 79 Other Statistical Applications in the Hematology Laboratory 20 Interleukins 79 ■ CHAPTER HIGHLIGHTS 20 Hematopoietic Growth Factors 82 ■ REVIEW QUESTIONS 21 Examination of Maturing Blood Cells 83 ■ BIBLIOGRAPHY 23 General Cellular Characteristics 83 2 Principles of Blood Collection . . . . . . . . . . . . . . . . 25 Nuclear Characteristics 83 Cytoplasmic Characteristics 85 Quality in Phlebotomy 25 Mature Blood Cells in Peripheral Blood 86 Quality Assessment 25 ■ CHAPTER HIGHLIGHTS 86 Patient Care Partnership 25 ■ REVIEW QUESTIONS 87 The Phlebotomist as Laboratory Ambassador 26 ■ BIBLIOGRAPHY 87 Patients with Special Considerations 26 Pediatric Patients 26 Adolescent Patients 26 PART TWO: Geriatric Patients 26 Erythrocytes 89 Blood Collection Supplies and Equipment 26 Anticoagulants 26 5 Erythrocyte Maturation, Physiology, Adverse Effects of Additives 27 Safe Blood Collection 27 and Lifecycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Evacuated Blood Collection Tubes 29 Erythropoiesis 90 Anticoagulants and Additives in Evacuated Blood Tubes 31 Erythropoietin 90 Capillary Blood 31 General Characteristics of Maturation and Development 91 Specimen Handling Requirements 32 Developmental Stages 92 ■ CHAPTER HIGHLIGHTS 45 Reticulocytes 94 vi TTuurrggeeoonn__FFMM..iinndddd vvii 1100//2299//22001100 1122::5588::0077 PPMM Contents vii Disorders Related to Erythrocyte Maturation and Production 97 Physiology 150 Disorders of Erythropoietin 97 Laboratory Findings 150 Red Cell Increases 98 Chronic Blood Loss Anemia 150 Defective Nuclear Maturation 98 Etiology 150 Characteristics and Biosynthesis of Hemoglobin 98 ■ CHAPTER HIGHLIGHTS 151 Genetic Inheritance of Hemoglobin 98 ■ CASE STUDIES 151 Chemical Composition and Confi guration of Hemoglobin 98 ■ REVIEW QUESTIONS 153 The Role of 2,3-Diphosphoglycerate 99 ■ BIBLIOGRAPHY 153 Oxygen Dissociation and Alterations 99 Carbon Dioxide Transport 100 9 Aplastic and Related Anemias . . . . . . . . . . . . . . . 154 Biosynthesis of Hemoglobin 101 Aplastic Anemia 154 Disorders Related to Hemoglobin Biosynthesis 104 Etiology 154 Disorders of Heme (Porphyrin) Synthesis 104 Pathophysiology 155 Disorders of Iron Metabolism 105 Clinical Features 158 Disorders of Globulin Synthesis 108 Laboratory Findings 158 Ontogeny of Hemoglobin 108 Treatment 158 Variant Forms of Normal Hemoglobin 109 Congenital Red Blood Cell–Related Disorders 159 Abnormal Hemoglobin Molecules 110 Telomeres 159 Analysis of Hemoglobin 110 Laboratory Findings in Bone Marrow Failure Syndromes 160 Membrane Characteristics and Metabolic Activities of Pure Red Cell Aplasia 160 Erythrocytes 111 Diamond-Blackfan Anemia 160 Membrane Characteristics 112 Fanconi Anemia 161 Cytoplasmic Characteristics 113 Transient Erythroblastopenia of Childhood 162 Metabolic Activities 113 Congenital Dyserythropoietic Anemia 163 Catabolism of Erythrocytes 114 ■ CHAPTER HIGHLIGHTS 163 Measurement of Erythrocytes 116 ■ CASE STUDIES 163 Mean Corpuscular Volume 116 ■ REVIEW QUESTIONS 165 Mean Corpuscular Hemoglobin 117 ■ BIBLIOGRAPHY 165 Mean Corpuscular Hemoglobin Concentration 117 ■ CHAPTER HIGHLIGHTS 118 10 Iron Defi ciency Anemia and Anemia of Chronic ■ CASE STUDIES 119 Infl ammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 ■ REVIEW QUESTIONS 121 Scope of the Problem 166 ■ BIBLIOGRAPHY 124 Iron Defi ciency Anemia 166 6 Erythrocyte Morphology and Inclusions . . . . . . 126 Early Diagnosis 166 Etiology 166 Erythrocytes: Normal and Abnormal 126 Epidemiology 167 Types of Variations in Erythrocyte Size 126 Physiology 168 Kinds of Variations in Erythrocyte Shape 127 Pathophysiology 169 Alterations in Erythrocyte Color 134 Clinical Signs and Symptoms 170 Varieties of Erythrocyte Inclusions 135 Laboratory Characteristics 170 Alterations in Erythrocyte Distribution 137 Anemia of Infl ammation or Anemia of chronic Disorders 173 Parasitic Inclusions in Erythrocytes 137 Etiology 173 Malaria 137 Pathophysiology 173 Other Parasitic Inclusions 141 Laboratory Characteristics 174 ■ CHAPTER HIGHLIGHTS 142 Treatment 175 ■ CASE STUDY 142 ■ CHAPTER HIGHLIGHTS 175 ■ REVIEW QUESTIONS 143 ■ CASE STUDIES 176 ■ BIBLIOGRAPHY 144 ■ REVIEW QUESTIONS 179 ■ BIBLIOGRAPHY 180 7 Classifi cation and Laboratory Assessment of 11 Megaloblastic Anemias . . . . . . . . . . . . . . . . . . . . . 181 Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Megaloblastic Anemias 181 Causes of Anemia 145 Etiology 181 Clinical Signs and Symptoms of Anemia 145 Epidemiology 182 Classifi cation of Anemias 145 Physiology 182 Laboratory Assessment of Anemias 146 Vitamin B (Cobalamin) Transport 182 12 Quantitative Measurements of Anemia 147 Vitamin B (Cobalamin) and Folic Acid Defi ciencies 183 12 Semiquantitative Grading of Erythrocyte Morphology 147 Pathophysiology 184 Supplementary Assessment of Anemias 148 Gastric Pathological Findings 184 ■ CHAPTER HIGHLIGHTS 148 Clinical Signs and Symptoms 186 ■ REVIEW QUESTIONS 148 Laboratory Findings 186 ■ BIBLIOGRAPHY 149 Treatment and Monitoring Therapy 188 ■ CHAPTER HIGHLIGHTS 188 8 Acute and Chronic Blood Loss Anemias . . . . . . . 150 ■ CASE STUDY 190 Acute Blood Loss Anemia 150 ■ REVIEW QUESTIONS 191 Etiology 150 ■ BIBLIOGRAPHY 191 TTuurrggeeoonn__FFMM..iinndddd vviiii 1100//2299//22001100 1122::5588::0077 PPMM viii Contents 12 Hemolytic Anemias . . . . . . . . . . . . . . . . . . . . . . . . 192 Development and Proliferation of Neutrophils, Eosinophils, and Basophils 236 Hemolytic Anemias 192 Distribution of Neutrophils, Eosinophils, and Basophils 236 Inherited Hemolytic Anemia 192 Normal Maturational Characteristics of Neutrophils, Eosinophils, Acquired Hemolytic Anemia 197 and Basophils 237 Pathophysiology 200 Mature Forms 239 Diagnostic Tests 201 Granulation in Mature Forms 239 Paroxysmal Nocturnal Hemoglobinuria 201 The Monocytic-Macrophage Series 240 Etiology 201 Production and Development of Monocytes and Macrophages 240 Epidemiology 202 Morphological Characteristics 241 Pathophysiology 202 Reference Ranges of Granulocytes and Monocytes 241 Clinical Signs and Symptoms 202 Functional Properties of Granulocytes and Monocytes 242 Laboratory Findings 203 General Characteristics 243 Treatment 203 The Role of Macrophages 243 Paroxysmal Cold Hemoglobinuria 203 Acute Infl ammatory Response 243 ■ CHAPTER HIGHLIGHTS 203 Sepsis 245 ■ CASE STUDIES 204 Steps in Phagocytosis 245 ■ REVIEW QUESTIONS 207 Specialized Functions of Granulocytes 247 ■ BIBLIOGRAPHY 208 Assessment Methods 248 13 Hemoglobinopathies and Thalassemias . . . . . . . 210 Total Leukocyte Count 248 Differential Blood Smear Evaluation 248 Hemoglobin Defects 210 Absolute Cell Counts 248 Demographics 210 Erythrocyte Sedimentation Rate 248 Etiology 210 Assessment of Eosinophils and Basophils 249 Sickle Cell Disease 211 Leukocyte Alkaline Phosphatase Test 249 Etiology 212 Neutrophilic Function 249 Epidemiology 212 Neutrophilic Hypersegmentation Index 249 Pathophysiology 212 ■ CHAPTER HIGHLIGHTS 249 Clinical Signs and Symptoms 213 ■ CASE STUDY 250 General Signs and Symptoms 214 Laboratory Testing 214 ■ REVIEW QUESTIONS 251 Special Laboratory Testing 215 ■ BIBLIOGRAPHY 253 Management of Sickle Cell Disease 216 15 Nonmalignant Disorders of Granulocytes and Sickle Cell Syndromes: Pathogenesis and Monocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 New Approaches 218 Quantitative Disorders 254 Sickle b-Thalassemia 218 Leukocytosis 254 Sickle-C Disease 219 Leukocytopenia 255 Sickle Cell Trait 219 Morphological Abnormalities of Mature Granulocytes 256 Thalassemia 220 Toxic Granulation 256 Demographics 220 Döhle Bodies 256 Etiology 220 Hypersegmentation 256 Pathophysiology 220 Pelger-Huët Anomaly 256 b-Thalassemia 220 α-Thalassemia 223 May-Hegglin Anomaly 257 Chédiak-Higashi Syndrome 257 Other Hemoglobinopathies 224 Alder-Reilly Inclusions 258 Hemoglobin C Disease 224 Ehrlichia 258 Hemoglobin SC Disease 224 Abnormalities of Mature Granulocytes in Body Fluids 258 Hemoglobin D Disease 224 Qualitative Disorders 258 Hemoglobin E Disease 224 Defective Locomotion and Chemotaxis 258 Hemoglobin H Disease 225 Defects in Microbicidal Activity 259 Methemoglobinemia 225 Other Functional Anomalies of Neutrophils 259 Unstable Hemoglobins 225 Monocyte-Macrophage Disorders 259 Hereditary Persistance of Fetal Hemoglobin 225 Gaucher Disease 259 ■ CHAPTER HIGHLIGHTS 226 Niemann-Pick Disease 260 ■ CASE STUDIES 227 ■ CHAPTER HIGHLIGHTS 260 ■ REVIEW QUESTIONS 232 ■ CASE STUDIES 260 ■ BIBLIOGRAPHY 233 ■ REVIEW QUESTIONS 264 ■ BIBLIOGRAPHY 265 PART THREE: 16 Leukocytes: Lymphocytes and Plasma Cells . . . . 266 Leukocytes 235 Anatomical Origin and Development of Lymphocytes 266 Sites of Lymphocytic Development 266 14 Leukocytes: The Granulocytic and Monocytic Lymphocyte Physiology 267 Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Normal Reference Values 267 Introduction 235 Determining Absolute Lymphocyte Values 268 The Granulocytic Series 235 Morphological Characteristics of Normal Lymphocytes 268 Production of Neutrophils, Eosinophils, and Basophils 235 Maturational Stages 269 Sites of Development and Maturation 236 Specifi c Lymphocyte Morphological Variations 272 TTuurrggeeoonn__FFMM..iinndddd vviiiiii 1100//2299//22001100 1122::5588::0077 PPMM