BOOK
Henry's Clinical Diagnosis and Management by Laboratory Methods E-Book
Richard A. McPherson | Matthew R. Pincus
(2017)
Additional Information
Book Details
Abstract
Recognized as the definitive reference in laboratory medicine since 1908, Henry's Clinical Diagnosis continues to offer state-of-the-art guidance on the scientific foundation and clinical application of today's complete range of laboratory tests. Employing a multidisciplinary approach, it presents the newest information available in the field, including new developments in technologies and the automation platforms on which measurements are performed.
- Provides guidance on error detection, correction, and prevention, as well as cost-effective test selection.
- Features a full-color layout, illustrations and visual aids, and an organization based on organ system.
- Features the latest knowledge on cutting-edge technologies of molecular diagnostics and proteomics.
- Includes a wealth of information on the exciting subject of omics; these extraordinarily complex measurements reflect important changes in the body and have the potential to predict the onset of diseases such as diabetes mellitus.
- Coverage of today's hottest topics includes advances in transfusion medicine and organ transplantation; molecular diagnostics in microbiology and infectious diseases; point-of-care testing; pharmacogenomics; and the microbiome.
- Toxicology and Therapeutic Drug Monitoring chapter discusses the necessity of testing for therapeutic drugs that are more frequently being abused by users.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | cover | ||
| Endsheet 2 | IFC1 | ||
| Half title page | i | ||
| Associate Editors | ii | ||
| Henry's Clinical Diagnosis and Management by Laboratory Methods | iii | ||
| Copyright Page | iv | ||
| Table Of Contents | v | ||
| Contributors | viii | ||
| Preface | xiv | ||
| Acknowledgments | xvii | ||
| 1 The Clinical Laboratory | 1 | ||
| 1 General Concepts and Administrative Issues | 2 | ||
| Key Points | 2 | ||
| Leadership and Management | 2 | ||
| Strategic Planning | 3 | ||
| Quality Systems Management | 3 | ||
| Human Resource Management | 5 | ||
| Laboratory Design and Service Models | 5 | ||
| Regulation, Accreditation, and Legislation | 6 | ||
| Safety | 7 | ||
| Biological Hazards | 8 | ||
| Chemical Hazards | 9 | ||
| Ergonomic Hazards | 10 | ||
| References | 10 | ||
| Selected References | 10 | ||
| References | 10.e1 | ||
| 2 Optimizing Laboratory Workflow and Performance | 11 | ||
| Key Points | 11 | ||
| Understanding Workflow | 11 | ||
| Data Collection Techniques | 11 | ||
| Sample and Test Mapping | 11 | ||
| Tube Analysis | 12 | ||
| Workstation Analysis | 12 | ||
| Instrument Audit | 13 | ||
| Test Menu | 14 | ||
| Processing Mode and Load Balancing. | 14 | ||
| Interviews | 14 | ||
| Task Mapping | 14 | ||
| Workflow Analysis | 14 | ||
| Workflow Modeling | 15 | ||
| Pneumatic Tube Transport of Specimens | 16 | ||
| Understanding Technology | 16 | ||
| The Role of Technology: Principles and Pitfalls | 16 | ||
| Optimizing Performance | 17 | ||
| References | 19 | ||
| Selected References | 19 | ||
| References | 19.e1 | ||
| 3 Preanalysis | 20 | ||
| Key Points | 20 | ||
| Precollection Variables | 20 | ||
| Physiologic Factors | 20 | ||
| Common Interferences | 21 | ||
| In Vivo | 21 | ||
| Tobacco Smoking | 21 | ||
| In Vitro | 22 | ||
| Collection-Associated Variables | 22 | ||
| Special Issues That May Impact Analysis | 22 | ||
| Immunoassays | 22 | ||
| Specimen Matrix Effects | 23 | ||
| Molecular Diagnostics | 23 | ||
| Effects of Drugs | 23 | ||
| Specimen Collection | 23 | ||
| The Test Order | 23 | ||
| Time of Collection | 23 | ||
| Specimen Acceptability and Identification Issues | 24 | ||
| Blood Collection Overview | 24 | ||
| Anticoagulants and Additives | 24 | ||
| Blood Collection Devices | 25 | ||
| Blood Storage and Preservation | 26 | ||
| Importance of Policies and Procedures | 26 | ||
| Blood Collection Techniques | 27 | ||
| Arterial Puncture | 27 | ||
| Arterial Puncture Technique | 27 | ||
| Finger or Heel Skin Puncture | 27 | ||
| Central Venous Access Devices | 28 | ||
| CVA Collection Technique | 28 | ||
| Urine and Other Body Fluids Collection | 28 | ||
| Urine | 28 | ||
| Special Urine Collection Techniques | 29 | ||
| Urine Storage and Preservation | 29 | ||
| Other Body Fluids | 29 | ||
| Cerebrospinal Fluid | 29 | ||
| Synovial Fluid | 30 | ||
| Pleural Fluid, Pericardial Fluid, and Peritoneal Fluid | 30 | ||
| Specimen Transport | 30 | ||
| Specimen Processing | 31 | ||
| Precentrifugation Phase | 31 | ||
| Centrifugation Phase | 31 | ||
| Equipment | 31 | ||
| References | 31 | ||
| Selected References | 31 | ||
| References | 32.e1 | ||
| 4 Analysis | 33 | ||
| Key Points | 33 | ||
| Principles of Instrumentation | 33 | ||
| Spectrophotometry | 33 | ||
| Velocity of Propagation | 34 | ||
| Energy of EMR | 34 | ||
| Scattering of Radiation | 34 | ||
| Rayleigh Scattering | 35 | ||
| Tyndall Effect | 35 | ||
| Raman Scattering | 35 | ||
| Beer-Lambert Law | 35 | ||
| Components of a Spectrophotometer | 36 | ||
| Radiant Energy Sources | 36 | ||
| Wavelength Selectors | 37 | ||
| Filters | 37 | ||
| Sample Containers (Cuvets) | 39 | ||
| Photodetectors | 39 | ||
| Photodiode Arrays. | 40 | ||
| Charge-Transfer Devices. | 40 | ||
| Signal Processors and Readout | 40 | ||
| Quality Assurance in Spectrophotometry | 40 | ||
| Types of Photometric Instruments | 40 | ||
| Reflectometry | 41 | ||
| Reflectometers | 42 | ||
| Molecular Luminescence Spectroscopy (Fluorometry) | 42 | ||
| Principle | 42 | ||
| Components of Fluorometers and Spectrophotofluorometers | 42 | ||
| Nephelometry and Turbidimetry | 43 | ||
| Principle | 43 | ||
| Nephelometer | 43 | ||
| Turbidimetry | 43 | ||
| Refractometry | 43 | ||
| Osmometry | 43 | ||
| Principle of Freezing-Point Osmometry | 44 | ||
| Freezing-Point Osmometer | 44 | ||
| Flow Cytometry | 44 | ||
| Instrument Components | 44 | ||
| Electrochemistry | 44 | ||
| Potentiometry | 44 | ||
| Reference Electrodes | 44 | ||
| Ion-Selective Electrode | 45 | ||
| pH Electrode | 45 | ||
| pCO2 Electrode | 46 | ||
| Coulometry | 46 | ||
| Amperometry | 46 | ||
| pO2 Gas-Sensing Electrode | 46 | ||
| Voltammetry | 46 | ||
| Conductance | 46 | ||
| Impedance | 46 | ||
| Electrophoresis and Densitometry | 46 | ||
| Isoelectric Focusing | 47 | ||
| Chromatography | 47 | ||
| Gas Chromatography | 48 | ||
| Liquid Chromatography | 49 | ||
| Mass Spectrometry | 49 | ||
| Atomic Weights (amu and Da) | 50 | ||
| Mass/Charge Ratio | 50 | ||
| Basic Components | 50 | ||
| Ion Source Unit | 50 | ||
| Mass Spectrometer Analyzer Unit | 50 | ||
| Ion Detector | 50 | ||
| Scintillation Counter | 51 | ||
| Capillary Electrophoresis | 52 | ||
| Nuclear Magnetic Resonance Spectroscopy | 53 | ||
| General Analytic Methods and Issues | 53 | ||
| Chemicals | 53 | ||
| Water | 54 | ||
| Types of Water Purity | 54 | ||
| Purification | 54 | ||
| Monitoring Water Purity | 54 | ||
| Once Your System Has Been Installed | 54 | ||
| Measurement of Mass | 54 | ||
| Types of Balances | 54 | ||
| Unequal-Arm Substitution Balances | 54 | ||
| Magnetic Force Restoration Balance | 54 | ||
| Top-Loading Balances | 55 | ||
| Electronic Balances | 55 | ||
| Calibration | 55 | ||
| Handling Weights Used for Testing Accuracy | 55 | ||
| Environmental Concerns for Best Weighing Accuracy | 55 | ||
| Balance Specifications | 55 | ||
| Laboratory Glassware and Plasticware | 55 | ||
| Types of Glassware | 55 | ||
| Types of Plasticware | 55 | ||
| Volumetric Laboratoryware | 56 | ||
| Pipets | 56 | ||
| Class A Designation | 56 | ||
| Types of Pipets | 56 | ||
| Micropipets | 56 | ||
| Pipet Calibration | 56 | ||
| Volumetric Flasks | 56 | ||
| Calibration of Volumetric Glassware | 56 | ||
| Thermometry | 56 | ||
| Types of Thermometers | 56 | ||
| Special Applications of Temperature-Sensing Devices | 57 | ||
| Mercury-Free Laboratories | 57 | ||
| Thermometer Calibration | 57 | ||
| Water Baths | 57 | ||
| Maintenance | 57 | ||
| Quality Control | 57 | ||
| Heating Blocks, Dry-Bath Incubators, and Ovens | 57 | ||
| Mixing | 57 | ||
| Single-Tube Mixers | 57 | ||
| Multiple-Tube Mixers | 57 | ||
| Aqueous Solution | 58 | ||
| Molarity | 58 | ||
| Millimoles | 58 | ||
| Normality | 58 | ||
| Molal | 58 | ||
| Dilutions | 58 | ||
| Acids, Alkalis, and pH | 59 | ||
| References | 59 | ||
| Selected References | 59 | ||
| References | 59.e1 | ||
| 5 Analysis | 60 | ||
| Key Points | 60 | ||
| Evolution of Automation | 60 | ||
| Preanalytic and Postanalytic Automation | 61 | ||
| Automated Delivery | 61 | ||
| Automated Specimen Processing | 61 | ||
| Postanalytic Processing | 61 | ||
| Emerging Technologies in Preanalytic and Postanalytic Processing | 62 | ||
| Automated Specimen Inspection | 62 | ||
| Radio-Frequency Identification | 62 | ||
| The Automated Chemistry Analyzer: Core Components | 62 | ||
| Sampling | 62 | ||
| Reagent Handling | 62 | ||
| Mixing and Incubation | 63 | ||
| Detection | 63 | ||
| Data Processing and Real-Time Monitoring | 63 | ||
| The Continuum of Chemistry Automation | 63 | ||
| Workstation | 63 | ||
| Workcell | 63 | ||
| Total Laboratory Automation | 63 | ||
| Laboratory Automation in Other Sections of the Lab | 64 | ||
| Hematology | 64 | ||
| Microbiology | 64 | ||
| Planning for Laboratory Automation | 64 | ||
| References | 65 | ||
| Selected References | 65 | ||
| References | 65.e1 | ||
| 6 Point-of-Care Testing and Physician Office Laboratories | 66 | ||
| Key Points | 66 | ||
| Introduction: Definition of Point-of-Care Testing | 66 | ||
| Regulatory Requirements | 66 | ||
| Laboratory Directorship | 67 | ||
| Compliance | 68 | ||
| Types of Point-of-Care Testing | 68 | ||
| Hematology | 68 | ||
| Chemistry | 68 | ||
| Microbiology | 69 | ||
| Advantages and Disadvantages of Point-of-Care Testing | 69 | ||
| Connectivity and Data Management | 69 | ||
| Implementation of a Point-of-Care Testing Program | 70 | ||
| Physician Offices | 70 | ||
| Hospitals and Medical Centers | 70 | ||
| Point-of-Care Committee and Management Team | 70 | ||
| Selection of Appropriate Tests | 71 | ||
| Selection of Appropriate Testing Devices and Methods | 71 | ||
| Policies and Procedures | 71 | ||
| Method Validations | 71 | ||
| Oversight of Training and Competency | 71 | ||
| Maintenance of a Point-of-Care Testing Program | 72 | ||
| Quality Assurance Program | 72 | ||
| Conclusions | 72 | ||
| References | 72 | ||
| Selected References | 72 | ||
| References | 72.e1 | ||
| 7 Postanalysis | 73 | ||
| Key Points | 73 | ||
| Assessment of Analytic Correctness of Results | 73 | ||
| Alarms and Flags | 73 | ||
| Flags for Problem Specimens | 74 | ||
| Flags for Specimens That Require Additional Analysis with Another Method | 74 | ||
| Flags for Problematic Results | 74 | ||
| Delta Checks | 74 | ||
| Assessment of Clinical Significance of Results | 74 | ||
| Critical Values | 74 | ||
| Reference Ranges | 74 | ||
| Definition of Reference Intervals | 74 | ||
| Factors That Influence Reference Ranges | 75 | ||
| Determination of Reference Ranges | 75 | ||
| Variability of Laboratory Results | 75 | ||
| General Principles for the Interpretation of Laboratory Results | 75 | ||
| Diagnostic Accuracy | 75 | ||
| Truth Table | 75 | ||
| Sensitivity and Specificity | 75 | ||
| Effect of Altering the Test Cutoff | 77 | ||
| The Need for High Sensitivity versus High Specificity | 77 | ||
| Predictive Value and Prevalence of Disease | 77 | ||
| Predictive Value and Accuracy | 78 | ||
| Bayes Theorem | 78 | ||
| Likelihood Ratio | 79 | ||
| Receiver Operator Characteristic Curves | 80 | ||
| Positivity Criterion | 80 | ||
| Evidence-Based Medicine | 81 | ||
| Systematic Reviews of Clinical Effectiveness Research and Clinical Practice Guidelines | 82 | ||
| Systematic Reviews | 82 | ||
| Clinical Practice Guidelines | 82 | ||
| References | 83 | ||
| Selected References | 83 | ||
| References | 83.e1 | ||
| 8 Interpreting Laboratory Results | 84 | ||
| Key Points | 84 | ||
| Interpreting and Correlating Abnormal Laboratory Values | 84 | ||
| General Considerations | 84 | ||
| Fundamental Principles in Interpretation of Values | 84 | ||
| Abnormalities in the Hematology Profile | 85 | ||
| Anemias | 85 | ||
| Microcytic Anemia | 85 | ||
| Serum Ferritin Levels | 86 | ||
| Use of Serum Iron and Iron-Binding Capacity | 86 | ||
| Use of Red Blood Cell Distribution Width | 86 | ||
| Normocytic Anemia | 86 | ||
| Hyperproliferative Normocytic Anemias | 86 | ||
| Hemolytic Anemia | 86 | ||
| Microangiopathic Hemolytic Anemia | 87 | ||
| Hypoproliferative Normocytic Anemias | 87 | ||
| Bone Marrow Hypoplasia/Aplastic Anemia | 87 | ||
| Myelodysplastic Syndrome | 87 | ||
| Anemia of Renal Failure | 88 | ||
| Macrocytic Anemia | 88 | ||
| Quantitative White Blood Cell Abnormalities | 88 | ||
| Infection | 88 | ||
| Elevated WBC Due to Leukemoid Reaction | 88 | ||
| Elevated WBC Due to Chronic Myelogenous Leukemia | 89 | ||
| Elevated WBC Due to Chronic Lymphocytic Leukemia | 89 | ||
| Leukocytosis Due to Acute Leukemias | 89 | ||
| Low White Cell Counts | 89 | ||
| Aplastic Anemia | 89 | ||
| Gram-Negative Sepsis as a Cause of Leukopenia | 89 | ||
| Coagulation Disorders | 89 | ||
| Abnormalities in Clinical Chemistry: Chemical Pathology | 90 | ||
| Electrolyte Abnormalities | 90 | ||
| Hyponatremia | 90 | ||
| Pseudohyponatremia | 91 | ||
| Hypernatremia | 91 | ||
| Hypokalemia | 91 | ||
| Hyperkalemia | 92 | ||
| Renal Disease | 92 | ||
| BUN and Creatinine | 92 | ||
| Calcium and Phosphate | 92 | ||
| Calcium and Albumin | 93 | ||
| Blood Gas Abnormalities | 93 | ||
| Anion Gap | 93 | ||
| Oxygenation | 94 | ||
| Glucose Abnormalities | 94 | ||
| Other Abnormal Laboratory Findings in Diabetes Mellitus | 95 | ||
| Liver Function Tests | 95 | ||
| Correlations of Liver Function Test Results with Other Laboratory Findings | 96 | ||
| Cardiac Function Tests | 96 | ||
| Diagnosis of Myocardial Infarction and Acute Coronary Syndrome | 96 | ||
| Diagnosis of Congestive Heart Failure | 97 | ||
| Skeletal Muscle Function | 97 | ||
| Pancreatic Function Tests | 97 | ||
| Markers for Inflammatory Conditions | 97 | ||
| Endocrine Function Testing | 97 | ||
| Principle | 97 | ||
| Thyroid Function | 97 | ||
| Adrenal Function | 98 | ||
| Parathyroid Hormone and Vitamin D | 98 | ||
| Vitamin D | 98 | ||
| Examples of Clinical Cases with Clinicopathological Correlations | 99 | ||
| Case A: Electrolyte Disorder | 99 | ||
| Evaluation | 99 | ||
| Case B: Complex Electrolyte Disorder | 99 | ||
| 2 Clinical Chemistry | 161 | ||
| 14 Evaluation of Renal Function, Water, Electrolytes, and Acid-Base Balance | 162 | ||
| Key Points | 162 | ||
| Introduction | 162 | ||
| Volume and Osmolality of Body Fluid | 163 | ||
| Measurement of Body Fluid Volumes | 163 | ||
| Body Fluid Volumes | 163 | ||
| Composition of the Body Fluid | 164 | ||
| Extracellular Composition | 164 | ||
| Intracellular Composition | 164 | ||
| Measurement of Plasma Osmolality | 165 | ||
| Effect of Hyperglycemia on Serum Na | 165 | ||
| Tonicity | 166 | ||
| Osmolality and Specific Gravity | 166 | ||
| Regulation of Extracellular Volume | 166 | ||
| Nonrenal Control of Water and Electrolyte Balance | 167 | ||
| Insensible Loss of Water from the Skin | 167 | ||
| Loss of Respiratory Water | 167 | ||
| Loss of Water in the Gastrointestinal Tract | 167 | ||
| Measurement of Renal Function | 167 | ||
| Concept of Clearance | 167 | ||
| Quick Formulas for the Calculation of Clearance | 168 | ||
| Conversion of Clearance in L/week to mL/min | 168 | ||
| Measurement of Glomerular Filtration Rate | 168 | ||
| Measurement of GFR with Exogenous Substances | 168 | ||
| Measurement of GFR with Endogenous Substances | 168 | ||
| Creatinine as a Measure of Renal Function | 168 | ||
| Creatinine Measurement | 169 | ||
| Cimetidine-Enhanced Creatinine Clearance | 169 | ||
| The Effect of Drugs on Serum Creatinine | 169 | ||
| Formulas to Estimate Creatinine Clearance as an Estimate of GFR | 169 | ||
| Urea as Measure of Renal Function | 170 | ||
| Measurement of Urea | 170 | ||
| Other Measures of GFR | 170 | ||
| Cystatin C | 170 | ||
| Beta-2 Microglobulin | 171 | ||
| Beta Trace Protein | 171 | ||
| Tryptophan Glycoconjugate | 171 | ||
| Urea Clearance and Urea/Creatinine Ratio in Serum | 171 | ||
| Glomerular Filtration Rate (GFR), Renal Plasma Flow (RPF), and Filtration Fraction (FF) | 171 | ||
| Fractional Excretion (FE) | 172 | ||
| Renal Failure Index (RFI) | 172 | ||
| Fractional Reabsorption (FR) | 172 | ||
| Free Water Clearance and Negative Free Water Clearance | 172 | ||
| Biomarkers of Acute Kidney Injury (AKI) | 172 | ||
| Kidney Injury Molecule-1 (KIM-1) | 173 | ||
| Neutrophil Gelatinase-Associated Lipocalin (NGAL) | 173 | ||
| Interleukin-18 (IL-18) | 173 | ||
| Fatty Acid–Binding Protein (FABP) | 173 | ||
| Disorders of Potassium | 174 | ||
| Control of Transcellular Flux of Potassium | 174 | ||
| Control of Renal Excretion of Potassium | 174 | ||
| Plasma Renin Activity (PRA), Plasma Aldosterone Concentration (PA), and Abnormalities in Potassium Metabolism | 175 | ||
| Causes and Pathogenesis of Hypokalemia | 175 | ||
| Differential Diagnosis of Hypokalemia | 176 | ||
| Causes and Pathogenesis of Hyperkalemia | 176 | ||
| Differential Diagnosis of Hyperkalemia | 177 | ||
| Disorders of Water, Sodium, and Antidiuretic Hormone (ADH) Metabolism | 178 | ||
| Regulation of Thirst and ADH Release | 178 | ||
| Urine Concentration and Dilution | 178 | ||
| Polyuria | 179 | ||
| Osmotic Diuresis | 179 | ||
| Water Diuresis | 179 | ||
| Causes and Pathogenesis of Hyponatremia | 180 | ||
| Causes and Pathogenesis of Hypernatremia | 181 | ||
| Acid-Base Disorders | 181 | ||
| Bicarbonate and CO2 Buffer System | 181 | ||
| Definitions of Acid and Base | 181 | ||
| Whole-Body Acid-Base Balance | 181 | ||
| Net Acid Production | 182 | ||
| Net Acid Excretion | 182 | ||
| Metabolic Acidosis | 182 | ||
| Classification | 182 | ||
| Renal Acidosis | 182 | ||
| Organic Acidosis | 183 | ||
| Lactic Acidosis | 183 | ||
| d-Lactic Acidosis | 183 | ||
| Ketoacidosis | 183 | ||
| Serum Anion Gap (AG) | 184 | ||
| Differential Diagnosis | 184 | ||
| 3 Urine and Other Bodily Fluids | 441 | ||
| 28 Basic Examination of Urine | 442 | ||
| Key Points | 442 | ||
| Urine Formation | 442 | ||
| Components of Basic (Routine) Urinalysis | 443 | ||
| Specimen Evaluation | 443 | ||
| Gross/Physical Examination | 443 | ||
| Appearance | 443 | ||
| Color | 443 | ||
| Red Urine. | 443 | ||
| Yellow-Brown or Green-Brown Urine. | 444 | ||
| Orange-Red or Orange-Brown Urine. | 444 | ||
| Dark Brown or Black Urine. | 444 | ||
| Blue, Green, or Blue-Green Urine. | 444 | ||
| Clarity (Character) | 444 | ||
| Chyluria. | 445 | ||
| Lipiduria. | 445 | ||
| Odor | 445 | ||
| Urine Volume | 445 | ||
| Increases in Urine Volume | 445 | ||
| Defective Hormonal Regulation of Volume Homeostasis. | 445 | ||
| Defective Renal Salt/Water Absorption. | 445 | ||
| Osmotic Diuresis. | 445 | ||
| Decreases in Urine Volume | 445 | ||
| Prerenal. | 445 | ||
| Postrenal. | 445 | ||
| Renal Parenchymal Disease. | 445 | ||
| Specific Gravity and Osmolality | 445 | ||
| Specific Gravity | 446 | ||
| 4 Hematology and Transfusion Medicine | 509 | ||
| 30 Basic Examination of Blood and Bone Marrow | 510 | ||
| Key Points | 510 | ||
| Hematology Principles and Procedures | 510 | ||
| Hemoglobin | 510 | ||
| Hemoglobin Derivatives | 510 | ||
| Hemiglobin (Methemoglobin) | 510 | ||
| Sulfhemoglobin | 511 | ||
| Carboxyhemoglobin | 511 | ||
| Measurement of Hb Concentration (Manual Technique of Hemoglobinometry) | 511 | ||
| Hemiglobincyanide Method | 511 | ||
| Principle. | 511 | ||
| Reagent. | 511 | ||
| Method. | 512 | ||
| Errors in Hemoglobinometry | 512 | ||
| Errors Inherent in the Sample. | 512 | ||
| Errors Inherent in the Method. | 512 | ||
| Errors Inherent in the Equipment. | 512 | ||
| Spectrophotometric Identification of Hemoglobins | 512 | ||
| Hematocrit (Packed Cell Volume) | 512 | ||
| Gross Examination | 513 | ||
| Hematocrit Measurement by Micromethod | 513 | ||
| Equipment | 513 | ||
| Procedure | 513 | ||
| Interpretation of Results | 513 | ||
| Sources of Error | 513 | ||
| Centrifugation. | 513 | ||
| Sample. | 513 | ||
| Other Errors. | 513 | ||
| Erythrocyte Indices | 513 | ||
| Mean Cell Volume | 513 | ||
| Mean Cell Hemoglobin | 513 | ||
| Mean Cell Hemoglobin Concentration | 513 | ||
| Manual Blood Cell Counts | 514 | ||
| Erythrocyte Counts: Manual | 514 | ||
| Semiautomated Methods | 514 | ||
| Reticulocyte Count: Manual | 514 | ||
| Principle | 514 | ||
| Reagent. | 514 | ||
| Controls. | 514 | ||
| Procedure | 514 | ||
| Reference Values | 514 | ||
| Interpretation | 514 | ||
| Sources of Variation | 514 | ||
| Physiologic Variation in Erythrocytes | 514 | ||
| Leukocyte Counts: Manual | 515 | ||
| Specimen Collection | 515 | ||
| Hemocytometer Method | 515 | ||
| Counting Chamber. | 516 | ||
| Diluting Fluid. | 516 | ||
| Procedure | 516 | ||
| Sources of Error. | 516 | ||
| Errors due to the nature of the sample. | 516 | ||
| Operator’s errors. | 516 | ||
| Errors due to equipment. | 516 | ||
| Inherent or field errors. | 516 | ||
| Nucleated red blood cells. | 516 | ||
| Reference Value. | 516 | ||
| Physiologic Variation in Leukocytes | 516 | ||
| Platelet Counts | 516 | ||
| Hemocytometer Method—Phase-Contrast Microscope | 517 | ||
| Specimen. | 517 | ||
| Diluent Solution. | 517 | ||
| Procedure | 517 | ||
| Calculation. | 518 | ||
| Sources of Error. | 518 | ||
| Falsely elevated counts. | 518 | ||
| Falsely low counts. | 518 | ||
| Reticulated Platelets | 518 | ||
| Physiologic Variation in Platelets | 519 | ||
| Instrument Technology | 519 | ||
| Hematology Analyzers | 519 | ||
| Electrical Impedance | 519 | ||
| Radiofrequency Conductivity | 519 | ||
| Light Scattering | 519 | ||
| Cytochemistry | 519 | ||
| Reporting/Flagging | 520 | ||
| Sources of Error | 520 | ||
| Automated Differential Leukocyte Counting | 520 | ||
| Digital Image Processing | 520 | ||
| Automated Reticulocyte Counting | 521 | ||
| Blood Film Examination | 521 | ||
| Examination of Wet Preparations | 521 | ||
| Making and Staining Blood Films | 521 | ||
| Wedge Method | 521 | ||
| Cover Glass Method | 521 | ||
| Spinner Method | 521 | ||
| Blood Stains | 521 | ||
| Wright’s Stain | 521 | ||
| Procedure | 522 | ||
| Staining Problems | 522 | ||
| Excessively blue stain. | 522 | ||
| Excessively pink stain. | 522 | ||
| Other staining problems. | 522 | ||
| Other Stains | 522 | ||
| Reference Method | 522 | ||
| Automated Slide Stainer | 522 | ||
| Review of Peripheral Smear | 522 | ||
| Erythrocytes | 522 | ||
| Color | 522 | ||
| Hemoglobin Content | 522 | ||
| Polychromatophilia | 523 | ||
| Size | 523 | ||
| Shape | 524 | ||
| Structure | 525 | ||
| Basophilic Stippling (Punctate Basophilia) | 525 | ||
| Howell-Jolly Bodies | 526 | ||
| Cabot Rings | 526 | ||
| Malarial Stippling | 526 | ||
| Rouleaux Formation | 526 | ||
| Nucleated Red Cells | 526 | ||
| Significance of Nucleated Red Cells | 527 | ||
| Leukoerythroblastic Reaction | 527 | ||
| Leukocytes on Peripheral Blood Smear Examination | 527 | ||
| Leukocytes Normally Present in Blood | 527 | ||
| Neutrophil (Polymorphonuclear Neutrophilic Leukocyte; Segmented Neutrophilic Granulocyte) | 527 | ||
| Eosinophil (Eosinophilic Granulocyte) | 528 | ||
| Basophil (Basophilic Granulocyte) | 528 | ||
| Monocyte | 529 | ||
| Lymphocyte | 529 | ||
| Artifacts | 529 | ||
| Broken Cells | 529 | ||
| Degenerative Changes | 530 | ||
| Contracted Cells | 530 | ||
| Endothelial Cells | 530 | ||
| Radial Segmentation of the Nuclei | 531 | ||
| Vacuolation | 531 | ||
| “Pseudophagocytosis” | 531 | ||
| Sources of Error in the Differential Leukocyte Count | 531 | ||
| Platelets on Peripheral Blood Smear Examination | 531 | ||
| Erythrocyte Sedimentation Rate | 531 | ||
| Plasma Factors | 532 | ||
| Red Cell Factors | 532 | ||
| Stages in the ESR | 532 | ||
| Methods | 532 | ||
| Westergren Method | 532 | ||
| Equipment. | 532 | ||
| Reagent. | 532 | ||
| Procedure | 532 | ||
| Modified Westergren Method | 532 | ||
| Sources of Error | 532 | ||
| Alternative Methods and Technologies to Measure ESR | 533 | ||
| Application | 533 | ||
| Bone Marrow Examination | 533 | ||
| Indications for Marrow Study | 533 | ||
| Preparation of the Aspirate and Biopsy Section | 534 | ||
| Marrow Films | 534 | ||
| Direct Films | 534 | ||
| Imprints | 534 | ||
| Crush Preparations | 534 | ||
| Special Studies | 534 | ||
| Histologic Sections | 534 | ||
| Staining Marrow Preparations | 534 | ||
| Romanowsky’s Stain | 534 | ||
| Perls’ Test for Iron | 534 | ||
| Procedure | 534 | ||
| Interpretation | 534 | ||
| Sections | 534 | ||
| Examination of Marrow | 536 | ||
| Peripheral Blood | 536 | ||
| Cellularity of the Marrow | 536 | ||
| Distribution of Cells | 536 | ||
| Maturation | 536 | ||
| Presence of Rare Cell Types or Abnormal Cells | 536 | ||
| Evaluation of the Biopsy Specimen | 538 | ||
| Interpretation | 538 | ||
| References | 538 | ||
| Selected References | 539 | ||
| References | 539.e1 | ||
| 31 Hematopoiesis | 540 | ||
| Key Points | 540 | ||
| Stem Cells | 540 | ||
| Hematopoietic Stem Cells and Progenitors | 540 | ||
| Hematopoietic Growth Factors | 541 | ||
| Hematopoietic Tissues | 542 | ||
| Embryonic and Fetal Hematopoiesis | 542 | ||
| Postnatal Hematopoiesis | 542 | ||
| Erythrocyte Production | 542 | ||
| Normoblastic Maturation | 542 | ||
| Megaloblastic Maturation | 544 | ||
| Regulation of Erythrocyte Production | 544 | ||
| Synthesis of Hemoglobin | 544 | ||
| Heme Synthesis | 544 | ||
| Globin Synthesis | 544 | ||
| Structure and Function of Hemoglobin | 546 | ||
| Erythrocyte Destruction | 546 | ||
| Degradation of Hemoglobin | 546 | ||
| Erythrokinetics | 546 | ||
| Measurements of Total Production of Erythrocytes or Hemoglobin | 547 | ||
| Measurements of Total Destruction of Erythrocytes or Hemoglobin | 547 | ||
| Measurements of Effective Production of Erythrocytes: Reticulocyte Count | 547 | ||
| Measurements of Effective Survival of Erythrocytes in Blood | 547 | ||
| Summary | 547 | ||
| Neutrophils | 547 | ||
| Morphology of Neutrophil Precursors | 547 | ||
| Distribution and Kinetics | 550 | ||
| Function | 550 | ||
| Eosinophils | 550 | ||
| Morphology of Eosinophil Precursors | 550 | ||
| Distribution and Kinetics | 551 | ||
| Function | 551 | ||
| Basophils and Mast Cells | 551 | ||
| Morphology | 551 | ||
| Distribution and Kinetics | 552 | ||
| Function | 552 | ||
| Monocytes and Macrophages | 552 | ||
| Morphology | 552 | ||
| Distribution and Kinetics | 553 | ||
| Function | 553 | ||
| Megakaryocytes | 553 | ||
| Morphology | 553 | ||
| Megakaryocytes in Blood | 553 | ||
| Distribution and Kinetics | 554 | ||
| Function | 554 | ||
| Lymphocytes | 554 | ||
| Primary Lymphoid Tissue | 554 | ||
| B Cell Development: Bone Marrow | 554 | ||
| T Cell Development: Thymus | 556 | ||
| Natural Killer Cells: Bone Marrow | 556 | ||
| Secondary Lymphoid Tissue | 556 | ||
| Lymphocyte Function and Physiology | 556 | ||
| References | 557 | ||
| Selected References | 558 | ||
| References | 558.e1 | ||
| 32 Erythrocytic Disorders | 559 | ||
| Key Points | 559 | ||
| Anemias | 559 | ||
| General Manifestations | 559 | ||
| Impaired Production—Iron Deficiency Anemia | 559 | ||
| Iron Metabolism (Beutler, 2010) | 559 | ||
| Iron Deficiency Anemia (IDA) | 560 | ||
| Clinical Features | 561 | ||
| Laboratory Features | 561 | ||
| Blood. | 561 | ||
| Marrow. | 561 | ||
| Serum Iron. | 562 | ||
| Serum (Total) Iron-Binding Capacity. | 562 | ||
| Percent Saturation of TIBC. | 562 | ||
| Serum Ferritin. | 562 | ||
| Erythrocyte Porphyrins. | 562 | ||
| Serum Transferrin Receptors. | 562 | ||
| Serum Transferrin Receptor–to–Serum Ferritin Ratio. | 562 | ||
| Reticulocyte Hemoglobin Content. | 562 | ||
| Hepcidin Level. | 562 | ||
| Differential Diagnosis | 562 | ||
| Management | 563 | ||
| Iron-Refractory Iron Deficiency Anemia (IRIDA) | 563 | ||
| Impaired Production— Megaloblastic Anemia | 563 | ||
| Macrocytosis with Normoblastic Marrow | 563 | ||
| Megaloblastic Anemia | 563 | ||
| Blood | 563 | ||
| Marrow. | 563 | ||
| Erythrokinetics. | 564 | ||
| Cobalamin (Vitamin B12) Metabolism | 564 | ||
| Cobalamin Deficiency | 564 | ||
| Inadequate Intake | 564 | ||
| Defective Production of Intrinsic Factor | 564 | ||
| Pernicious Anemia | 564 | ||
| Clinical Features | 564 | ||
| Gastric Findings | 564 | ||
| Immune Abnormalities | 565 | ||
| Pernicious Anemia in Children | 565 | ||
| Gastrectomy | 565 | ||
| Defective Absorption of Cobalamin | 565 | ||
| Malabsorption Syndromes. | 565 | ||
| Lack of Availability of Cobalamin. | 565 | ||
| Diagnosis of Cobalamin Deficiency | 565 | ||
| Therapeutic Trial. | 565 | ||
| Serum Cobalamin Assay. | 565 | ||
| Methylmalonic Acid and Homocysteine Assays. | 565 | ||
| Deoxyuridine Suppression Test. | 565 | ||
| Detecting the Cause of Cobalamin Deficiency | 566 | ||
| Folic Acid Metabolism | 566 | ||
| The Folate–Cobalamin Relationship | 566 | ||
| Folic Acid Deficiency (Green, 2010) | 566 | ||
| Inadequate Intake of Folate | 566 | ||
| Evolution of Laboratory Abnormalities. | 566 | ||
| Nutritional Folate Deficiency. | 566 | ||
| Liver Disease. | 566 | ||
| Defective Absorption of Folate | 566 | ||
| Increased Requirement for Folate | 567 | ||
| Inadequate Utilization of Folate | 567 | ||
| Diagnosis of Folate Deficiency | 567 | ||
| Serum and Red Cell Folate. | 567 | ||
| Urinary Formiminoglutamic Acid (FIGLU) | 567 | ||
| Deoxyuridine Suppression Test. | 567 | ||
| Plasma Homocysteine Assay. | 567 | ||
| Acute Megaloblastic Anemia | 567 | ||
| Therapy for Megaloblastic Anemia | 567 | ||
| Other Defects of Nucleoprotein Synthesis | 567 | ||
| Congenital Defects | 568 | ||
| Synthetic Inhibitors | 568 | ||
| Refractory Anemias | 568 | ||
| Impaired Production—Other | 568 | ||
| Anemia of Chronic Disease (Means, 2003; Nemeth & Ganz, 2014) | 568 | ||
| Anemia of Renal Insufficiency | 568 | ||
| Anemia in Liver Disease | 568 | ||
| Anemia in Endocrine Disease | 569 | ||
| Anemia Associated with Bone Marrow Infiltration (Myelophthisic Anemia) | 569 | ||
| Aplastic Anemia | 569 | ||
| Clinical Features | 569 | ||
| Etiology | 569 | ||
| Pathogenesis | 569 | ||
| Prognosis | 569 | ||
| Management | 570 | ||
| Idiopathic Acquired Aplastic Anemia | 570 | ||
| Blood | 570 | ||
| Bone Marrow. | 570 | ||
| Erythrokinetics. | 570 | ||
| Acquired Aplastic Anemia Associated with Chemical or Physical Agents | 570 | ||
| Toxic Aplastic Anemias. | 570 | ||
| Ionizing Radiation. | 570 | ||
| Hypersensitive Aplastic Anemias. | 570 | ||
| Acquired Aplastic Anemia Associated with Other Disease | 570 | ||
| Infection. | 570 | ||
| Paroxysmal Nocturnal Hemoglobinuria. | 571 | ||
| Pregnancy. | 571 | ||
| Thymoma. | 571 | ||
| Immunologic Diseases. | 571 | ||
| Inherited Aplastic Anemia | 571 | ||
| Fanconi’s Anemia. | 571 | ||
| Other Inherited Aplastic Anemias. | 571 | ||
| Pure Red Cell Aplasia | 571 | ||
| Transitory Arrest of Erythropoiesis (Transient Aplastic Crises) | 571 | ||
| Transient Erythroblastopenia of Childhood | 571 | ||
| Congenital Red Cell Aplasia (Diamond-Blackfan Anemia; Congenital Hypoplastic Anemia) | 571 | ||
| Acquired Pure Red Cell Aplasia | 572 | ||
| Sideroblastic Anemia | 572 | ||
| Hereditary Sideroblastic Anemias | 572 | ||
| Acquired Sideroblastic Anemias | 572 | ||
| Refractory Anemia with Ring Sideroblasts. | 572 | ||
| Secondary (Drug- or Toxin-Induced) Sideroblastic Anemia | 572 | ||
| Refractory Anemia | 572 | ||
| Congenital Dyserythropoietic Anemias | 572 | ||
| Blood Loss Anemia | 573 | ||
| Acute Posthemorrhagic Anemia | 573 | ||
| Chronic Posthemorrhagic Anemia | 573 | ||
| Hemolysis—General | 573 | ||
| Erythrocyte Survival Studies | 573 | ||
| Hemoglobin Destruction | 573 | ||
| Blood Film | 574 | ||
| Bone Marrow | 574 | ||
| Hemolysis—Membrane Disorders | 575 | ||
| Hereditary Spherocytosis | 575 | ||
| Osmotic Fragility Test | 575 | ||
| Autohemolysis Test | 575 | ||
| Additional Tests | 575 | ||
| Hereditary Elliptocytosis | 576 | ||
| Common HE | 576 | ||
| Hereditary Pyropoikilocytosis | 576 | ||
| Spherocytic HE | 576 | ||
| Southeast Asian Ovalocytosis | 576 | ||
| Hereditary Stomatocytosis | 576 | ||
| Paroxysmal Nocturnal Hemoglobinuria | 576 | ||
| Laboratory Diagnosis | 576 | ||
| Hemolysis—Hemoglobin Disorders | 577 | ||
| Normal Hemoglobins | 577 | ||
| Hb A (α2β2) | 577 | ||
| Hb F (α2γ2) | 577 | ||
| Hb A2 (α2δ2) | 577 | ||
| Embryonic Hemoglobins. | 577 | ||
| The Globin Gene Clusters. | 577 | ||
| Glycosylated Hemoglobins. | 577 | ||
| Laboratory Investigation of Hemoglobinopathies and Thalassemias | 578 | ||
| Cation-Exchange HPLC and Capillary Electrophoresis. | 578 | ||
| Hemoglobin Electrophoresis and Isoelectric Focusing. | 578 | ||
| Acid Elution Slide Test for F Cells. | 578 | ||
| Detection of F cells by Flow Cytometry. | 578 | ||
| Hb A2 Quantitation. | 578 | ||
| Sickling Test—Metabisulfite Slide Test. | 578 | ||
| Sickle Solubility Test. | 578 | ||
| DNA Analysis. | 578 | ||
| Structural Hemoglobin Variants | 578 | ||
| Abnormal Hemoglobin Syndromes | 579 | ||
| Sickling Disorders | 581 | ||
| Sickle Cell Trait (Hb AS) | 581 | ||
| Sickle Cell Disease (Hb SS) | 582 | ||
| Complications. | 582 | ||
| Diagnosis. | 584 | ||
| Hemoglobin SC Disease | 584 | ||
| Hb S/β-Thalassemia | 584 | ||
| Hb SS/α-Thalassemia | 584 | ||
| Hemoglobin SD Disease (Hb S/D–Los Angeles). | 584 | ||
| Hb S/O Arab. | 584 | ||
| Other Compound Heterozygosities with Hb S. | 584 | ||
| Other Common β-Chain Variants | 584 | ||
| Hb C Trait (β6 glu→lys). | 584 | ||
| Hb C Disease. | 585 | ||
| Hb C/β+-Thalassemia. | 585 | ||
| Hb C/β0-Thalassemia. | 585 | ||
| Hb E (β 26 glu→lys). | 585 | ||
| Hb E Trait (Hb AE). | 585 | ||
| Hemoglobin E Disease. | 585 | ||
| Hb E/β-Thalassemia. | 585 | ||
| Hb D Los Angeles (Punjab) (β121 glu→gln). | 585 | ||
| Common α-Chain Variants | 585 | ||
| Hb G Philadelphia (α 68asn→lys). | 585 | ||
| Disorders of Hemoglobin Function and Stability | 586 | ||
| Hemoglobins Associated with High Oxygen Affinity and Polycythemia | 586 | ||
| Hemoglobins Associated with Low Oxygen Affinity | 586 | ||
| M Hemoglobins: Pseudocyanosis | 586 | ||
| Unstable Hemoglobins | 586 | ||
| Heat Instability Test. | 586 | ||
| Isopropanol Precipitation Test. | 586 | ||
| Thalassemias | 586 | ||
| Molecular Defects | 587 | ||
| β-Thalassemias | 587 | ||
| Homozygous β-Thalassemia (Thalassemia Major; Cooley’s Anemia) | 587 | ||
| Heterozygous β-Thalassemia (β-Thalassemia Trait; Thalassemia Minor; Cooley’s Trait) | 588 | ||
| β-Thalassemia Trait with Normal Hb A2 | 589 | ||
| δβ0-Thalassemia | 589 | ||
| δβ+-Thalassemia: Lepore Hemoglobins | 589 | ||
| Hereditary Persistence of Fetal Hemoglobin | 589 | ||
| Deletional Pancellular HPFH | 589 | ||
| Hb Kenya | 589 | ||
| Nondeletional Pancellular HPFH | 589 | ||
| Heterocellular or Swiss-type HPFH | 589 | ||
| α-Thalassemias | 590 | ||
| α-Thalassemia Syndromes | 590 | ||
| Hemoglobin Bart’s Hydrops Fetalis (− −/− −). | 590 | ||
| Hemoglobin H Disease (−α/− −). | 590 | ||
| Hemoglobin H preparation. | 590 | ||
| α-Thalassemia Trait: Heterozygous α0-Thalassemia (− −/αα) or Homozygous α+-Thalassemia (−α/−α). | 590 | ||
| Silent Carrier α-Thalassemia (Heterozygous α+-Thalassemia) (αα/−α). | 591 | ||
| Hemoglobin Constant Spring (αCSα/). | 591 | ||
| Screening and Prenatal Diagnosis of Hemoglobin Disorders | 591 | ||
| Hemolysis—Metabolic Disorders | 591 | ||
| Erythrocyte Metabolism | 591 | ||
| Glucose-6-Phosphate Dehydrogenase Deficiency | 591 | ||
| Heinz Bodies | 593 | ||
| Ascorbate Cyanide Test | 593 | ||
| Fluorescent Spot Test | 593 | ||
| Quantitative Assay of G6PD. | 593 | ||
| Pyruvate Kinase (PK) Deficiency | 593 | ||
| Fluorescent Spot Test. | 594 | ||
| Quantitative Assay of PK. | 594 | ||
| Other Glycolytic Enzyme Deficiencies | 594 | ||
| Pyrimidine-5′-Nucleotidase Deficiency | 594 | ||
| Hemolysis—Acquired; Extrinsic | 594 | ||
| Chemical Agents | 594 | ||
| Agents Hemolytic to Normal Cells | 594 | ||
| Agents Hemolytic to Abnormal Cells | 594 | ||
| Physical Agents | 594 | ||
| Heat | 594 | ||
| Traumatic Hemolysis | 594 | ||
| Macroangiopathic Hemolytic Anemia (Cardiac Valvular Disease and Prostheses). | 594 | ||
| Thrombotic Microangiopathy (Microangiopathic Hemolytic Anemia). | 595 | ||
| Hemolytic-Uremic Syndrome | 595 | ||
| Thrombotic Thrombocytopenic Purpura (TTP) | 595 | ||
| Preeclampsia/Eclampsia | 595 | ||
| Infectious Agents | 595 | ||
| Immune Hemolytic Anemias | 596 | ||
| Autoimmune Hemolytic Anemia | 596 | ||
| Etiology and Pathophysiology. | 596 | ||
| AIHA Associated with Warm Antibody. | 596 | ||
| AIHA Associated with Cold Antibody. | 597 | ||
| Cold Agglutinin Disease | 597 | ||
| Paroxysmal Cold Hemoglobinuria | 597 | ||
| AIHA Associated with Warm and Cold Antibodies | 597 | ||
| Alloimmune Hemolytic Disease of the Newborn | 597 | ||
| Drug-Induced Immune Hemolytic Anemia | 598 | ||
| Formation of Ternary Complexes (Neoantigen Formation). | 598 | ||
| Adsorption of Drug to Red Cell Membrane. | 598 | ||
| Induction of Autoantibody by Drugs. | 598 | ||
| Nonimmunologic Adsorption of Immunoglobulins to Red Cell Membrane. | 598 | ||
| Laboratory Investigations of Anemia | 599 | ||
| Macrocytic Anemia (Increased MCV) | 599 | ||
| Megaloblastic Marrow | 599 | ||
| Nonmegaloblastic Marrow | 599 | ||
| Microcytic and Hypochromic Anemias (Decreased MCV and MCH) | 599 | ||
| Normocytic and Normochromic Anemias (Normal MCV) | 600 | ||
| Optimal Marrow Response: Reticulocyte Production Index Greater Than Two | 600 | ||
| Direct Antiglobulin (Coombs’) Test. | 600 | ||
| Inadequate Marrow Response: Reticulocyte Production Index Less Than Two | 600 | ||
| Polycythemia | 600 | ||
| Relative Polycythemia | 601 | ||
| Absolute Polycythemia | 601 | ||
| Appropriately Increased Erythropoietin Production Due to Hypoxia | 601 | ||
| Arterial Oxygen Unsaturation | 601 | ||
| High Oxygen Affinity Hemoglobinopathy | 601 | ||
| Inappropriate Erythropoietin Production | 601 | ||
| Neoplasms | 601 | ||
| Renal Disorders | 601 | ||
| Familial Polycythemia | 601 | ||
| Polycythemia Vera | 601 | ||
| Measurement of Erythrocyte and Plasma Volume | 601 | ||
| Erythrocyte Volume | 601 | ||
| Plasma Volume | 602 | ||
| Interpretation | 602 | ||
| The Porphyrias | 602 | ||
| Physiology | 602 | ||
| Approach to the Porphyrias | 602 | ||
| Clinical Porphyrias and Their Biochemical Basis | 602 | ||
| Neurovisceral Symptoms in Isolation | 602 | ||
| Acute Intermittent Porphyria (AIP) | 602 | ||
| Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP) | 604 | ||
| Neurovisceral Symptoms Plus Photosensitivity | 604 | ||
| Variegate Porphyria (VP) | 604 | ||
| Hereditary Coproporphyria (HCP) | 604 | ||
| Photosensitivity Plus Hemolytic Anemia | 604 | ||
| Porphyria Cutanea Tarda (PCT) | 604 | ||
| Congenital Erythropoietic Porphyria (CEP) | 604 | ||
| Photosensitivity in Isolation | 604 | ||
| Erythropoietic Protoporphyria (EPP) and X-linked Porphyria (XLP) | 604 | ||
| Analytic Techniques | 605 | ||
| References | 605 | ||
| Selected References | 605 | ||
| References | 605.e1 | ||
| 33 Leukocytic Disorders | 606 | ||
| Key Points | 606 | ||
| Leukocytes | 606 | ||
| Nonneoplastic Disorders | 606 | ||
| Granulocytic and Monocytic Disorders | 606 | ||
| Neutrophilia | 606 | ||
| Mechanisms | 606 | ||
| Determinants | 607 | ||
| Neutropenia | 607 | ||
| Morphologic Alterations in Neutrophils | 608 | ||
| Toxic Granulation | 608 | ||
| Döhle Inclusion Bodies | 608 | ||
| May-Hegglin Anomaly | 608 | ||
| Alder-Reilly Anomaly | 609 | ||
| Pelger-Huët Anomaly | 610 | ||
| Chédiak-Higashi Syndrome | 610 | ||
| Functional Disorders of Neutrophils | 610 | ||
| Leukocyte Adhesion Deficiency (LAD) Diseases | 610 | ||
| Eosinophilia | 611 | ||
| Basophilia | 611 | ||
| Monocytosis | 611 | ||
| Monocytopenia | 612 | ||
| Lymphocytic and Plasmacytic Disorders | 612 | ||
| Lymphocytes in Normal Individuals | 612 | ||
| Lymphocytosis | 612 | ||
| Lymphocytosis Associated with Viral Infection | 612 | ||
| Pertussis | 612 | ||
| Chronic Lymphocytosis/Persistent Polyclonal B Cell Lymphocytosis | 612 | ||
| Retrovirus-Associated Diseases and Conditions | 613 | ||
| Infectious Mononucleosis and Epstein-Barr Virus Infection | 613 | ||
| Etiology and Pathophysiology. | 613 | ||
| Clinical Features. | 614 | ||
| Complications. | 614 | ||
| Hematologic Features. | 614 | ||
| Serologic Findings in Immunocompetent Patients. | 614 | ||
| Differential Diagnosis. | 614 | ||
| Course. | 614 | ||
| Cytomegalovirus Infection | 614 | ||
| Toxoplasmosis | 614 | ||
| Autoimmune Lymphoproliferative Syndrome | 615 | ||
| Other Nonneoplastic Causes of Lymphadenopathy | 615 | ||
| Lymphocytopenia | 615 | ||
| Acquired Immunodeficiency Syndrome | 615 | ||
| Etiology. | 615 | ||
| Hematologic Features. | 615 | ||
| Plasmacytosis | 615 | ||
| Leukemoid Reactions | 616 | ||
| Congenital Neutrophilia. | 616 | ||
| Neutrophilic Leukemoid Reactions. | 616 | ||
| Eosinophilic Leukemoid Reactions. | 616 | ||
| Leukoerythroblastosis. | 616 | ||
| Lymphocytic Leukemoid Reactions. | 616 | ||
| Neoplastic Disorders Primarily Involving Leukocytes | 616 | ||
| Overview of Hematopoietic Neoplasms | 616 | ||
| Chronic Myeloproliferative Disorders | 617 | ||
| Chronic Myelogenous Leukemia | 617 | ||
| Clinical Features | 617 | ||
| Laboratory Features | 617 | ||
| Blood. | 617 | ||
| 5 Hemostasis and Thrombosis | 793 | ||
| 39 Coagulation and Fibrinolysis | 794 | ||
| Key Points | 794 | ||
| Overview of Coagulation and Fibrinolysis | 794 | ||
| Physiologic Hemostasis | 795 | ||
| Endothelium and Platelets | 795 | ||
| Coagulation Protein System | 796 | ||
| Characterization of Coagulation Proteins | 796 | ||
| Physiologic Protein Assemblies | 796 | ||
| The Formation of Fibrin and the Fibrinolytic System | 797 | ||
| The Anticoagulation Protein Systems | 798 | ||
| Protein C/Protein S System | 798 | ||
| Antithrombin | 799 | ||
| Tissue Factor Pathway Inhibitor | 799 | ||
| Prostacyclins and Nitric Oxide and Thrombospondin-5 | 799 | ||
| Current Hypothesis for Initiation of the Hemostatic System | 799 | ||
| Clinical Laboratory Hemostasis | 800 | ||
| Physiologic Hemostasis Versus Clinical Assays | 800 | ||
| Screening Tests for Coagulation Disorders | 800 | ||
| Activated Partial Thromboplastin Time | 800 | ||
| Prothrombin Time | 801 | ||
| Thrombin Time | 801 | ||
| Assays Used in Clinical Coagulation Testing | 801 | ||
| Practical Approach to Patients with Coagulation Disorders | 801 | ||
| Global Hemostasis Assays | 804 | ||
| Thrombin Generation | 804 | ||
| Overall Hemostasis Potential | 804 | ||
| Hereditary Coagulation Protein Defects | 804 | ||
| Deficiency of Factor VIII (Hemophilia a) or Factor IX (Hemophilia B) | 804 | ||
| Evaluation of Carriers | 805 | ||
| Treatment of Hemophilia | 805 | ||
| Complications of Treatment | 806 | ||
| Hereditary Deficiencies of Other Coagulation Factors | 806 | ||
| Disorders with Prolonged APTT and Normal PT | 807 | ||
| Factor XI | 807 | ||
| FXII, Prekallikrein, and High Molecular Weight Kininogen | 807 | ||
| Disorders with Prolonged APTT and PT | 807 | ||
| Disorders of Fibrinogen | 807 | ||
| FII Deficiency | 808 | ||
| FV Deficiency | 808 | ||
| FX Deficiency | 808 | ||
| Combined Deficiency of FV and FVIII | 808 | ||
| Combined Deficiency of Vitamin K–Dependent Clotting Factors | 808 | ||
| Disorders with Normal APTT and Prolonged PT | 809 | ||
| FVII Deficiency | 809 | ||
| Disorders with Normal APTT and PT | 809 | ||
| FXIII Deficiency | 809 | ||
| Hereditary Hemorrhagic Disorders of Fibrinolysis | 809 | ||
| Acquired Coagulation Disorders | 809 | ||
| Thrombotic Disorders and Disseminated Intravascular Coagulation | 809 | ||
| Liver Disease | 810 | ||
| Vitamin K Deficiency | 810 | ||
| Massive Transfusion | 810 | ||
| Acquired Coagulation Protein Inhibitors and Lupus Anticoagulant | 810 | ||
| References | 811 | ||
| Selected References | 811 | ||
| References | 811.e1 | ||
| 40 Platelet Disorders and von Willebrand Disease | 812 | ||
| Key Points | 812 | ||
| Normal Platelet Biology | 812 | ||
| Platelet Structure | 812 | ||
| Platelet Membrane Glycoproteins and Phospholipids | 813 | ||
| Role of Platelets in Hemostasis and Platelet-Activation Mechanisms | 813 | ||
| Platelet Activation and Signaling Events (see Fig. 40-2) | 813 | ||
| Platelet Coagulant Activity | 814 | ||
| Laboratory Evaluation of Platelet Function Disorders | 814 | ||
| Initial Laboratory Evaluation | 814 | ||
| Studies of Platelet Function | 814 | ||
| Bleeding Time | 814 | ||
| PFA-100/200 | 816 | ||
| Platelet Aggregation and Secretion Studies | 816 | ||
| Evaluation of Platelet Function Using Flow Cytometry | 816 | ||
| Quantitative Platelet Disorders | 816 | ||
| Thrombocytopenia | 816 | ||
| Congenital Thrombocytopenias | 817 | ||
| Autosomal Dominant Thrombocytopenias | 817 | ||
| Autosomal Recessive Thrombocytopenias | 819 | ||
| Sex-Linked Inherited Thrombocytopenias | 819 | ||
| Immune Thrombocytopenias | 819 | ||
| Drug-Induced Immune Thrombocytopenia (DITP) | 820 | ||
| Thrombocytosis | 821 | ||
| Inherited Disorders of Platelet Function | 821 | ||
| Overview | 821 | ||
| Disorders of Platelet Adhesion | 822 | ||
| Bernard-Soulier Syndrome | 822 | ||
| Disorders of Platelet Aggregation | 823 | ||
| Glanzmann Thrombasthenia | 823 | ||
| Disorders of Platelet Secretion and Granules | 823 | ||
| Deficiency of Granule Stores | 823 | ||
| δ-Storage Pool Deficiency | 823 | ||
| Gray Platelet Syndrome | 824 | ||
| Quebec Platelet Syndrome | 824 | ||
| Disorders of Platelet Secretion and Signaling Pathways | 824 | ||
| Defects in Receptors | 824 | ||
| Defects in G-Proteins and Their Activation | 824 | ||
| Defects in Phospholipase C Activation, Calcium Mobilization, and Protein Phosphorylation | 825 | ||
| Abnormalities in Arachidonic Acid Metabolism and Thromboxane Synthesis | 825 | ||
| Defects in Cytoskeletal Linking Proteins | 825 | ||
| Wiskott-Aldrich Syndrome | 825 | ||
| Kindlin-3 Deficiency–Leukocyte Adhesion Deficiency | 825 | ||
| Disorders of Platelet Procoagulant Activities: Scott Syndrome | 825 | ||
| Transcription Factor Mutations and Associated Platelet Dysfunction | 825 | ||
| RUNX1/CBFA2 Mutations (Familial Platelet Disorder with Predisposition to Acute Myelogenous Leukemia) | 825 | ||
| GATA-1 Mutations | 825 | ||
| FLI1 | 825 | ||
| GFI1B | 826 | ||
| Relative Frequencies of Various Inherited Platelet Disorders | 826 | ||
| Evaluation of Patients with Suspected Congenital Platelet Disorders | 826 | ||
| Therapy of Congenital Platelet Function Defects | 826 | ||
| Acquired Disorders of Platelet Function | 826 | ||
| Myeloproliferative Neoplasms | 826 | ||
| Acute Leukemias and Myelodysplastic Syndromes | 827 | ||
| Dysproteinemias | 827 | ||
| Uremia | 827 | ||
| Acquired Storage Pool Disease | 827 | ||
| Antiplatelet Antibodies and Platelet Function | 828 | ||
| Drugs That Inhibit Platelet Function | 828 | ||
| Von Willebrand Factor, von Willebrand Disease, and Thrombotic Thrombocytopenic Purpura | 829 | ||
| Von Willebrand Factor Biology | 829 | ||
| Laboratory Tests for von Willebrand Factor | 830 | ||
| Von Willebrand Disease | 830 | ||
| Type 1 vWD: Partial Quantitative Abnormality | 830 | ||
| Type 3 vWD: Severe Quantitative Abnormality | 831 | ||
| Qualitative Abnormalities: Type 2A, Type 2B, Type 2M, and Type 2N vWD | 831 | ||
| Type 2A | 831 | ||
| Type 2B | 831 | ||
| Type 2M | 831 | ||
| Type 2N (Normandy) | 831 | ||
| Platelet-Type vWD | 831 | ||
| Acquired von Willebrand Syndrome | 831 | ||
| Thrombotic Thrombocytopenic Purpura | 832 | ||
| References | 833 | ||
| Selected References | 833 | ||
| References | 833.e1 | ||
| 41 Laboratory Approach to Thrombotic Risk | 834 | ||
| Key Points | 834 | ||
| Endogenous Anticoagulant Pathways | 834 | ||
| Thrombophilic Proteins or Factors | 835 | ||
| Antithrombin | 835 | ||
| Protein C | 837 | ||
| Protein S | 837 | ||
| Activated Protein C Resistance and Factor VLeiden | 838 | ||
| Prothrombin g20210a | 838 | ||
| Elevation of Other Coagulation Factor Levels | 838 | ||
| Tissue Factor Pathway Inhibitor | 838 | ||
| Dysfibrinogenemia | 839 | ||
| Annexin A5 | 839 | ||
| Hypofibrinolytic Mechanisms | 839 | ||
| Acquired Hypercoagulable States | 839 | ||
| Antiphospholipid Syndrome and Lupus Anticoagulant | 839 | ||
| Other Coagulation Abnormalities | 840 | ||
| Hyperhomocysteinemia | 841 | ||
| General Aspects of the Laboratory Evaluation for Thrombotic Risk | 841 | ||
| References | 841 | ||
| Selected References | 841 | ||
| References | 841.e1 | ||
| 42 Antithrombotic Therapy | 842 | ||
| Key Points | 842 | ||
| Vitamin K Antagonists | 842 | ||
| Antithrombin-Dependent Parenteral Anticoagulants | 845 | ||
| Unfractionated Heparin | 845 | ||
| Heparin Resistance | 846 | ||
| Low Molecular Weight Heparin | 846 | ||
| Fondaparinux | 846 | ||
| Heparin-Induced Thrombocytopenia | 846 | ||
| Target-Specific Anticoagulants | 849 | ||
| Parenteral Agents | 849 | ||
| Oral Agents | 849 | ||
| Antiplatelet Therapy | 851 | ||
| Aspirin | 851 | ||
| P2Y12 Inhibitors | 852 | ||
| Glycoprotein IIb/IIIa Inhibitors | 853 | ||
| References | 853 | ||
| Selected References | 853 | ||
| References | 853.e1 | ||
| 6 Immunology and Immunopathology | 855 | ||
| 43 Overview of the Immune System and Immunologic Disorders | 856 | ||
| Key Points | 856 | ||
| Lymphoid Cells | 856 | ||
| T Lymphocytes | 856 | ||
| B Lymphocytes | 857 | ||
| Antigen-Presenting Cells | 857 | ||
| Natural Killer Cells | 857 | ||
| Nonlymphoid Cells | 857 | ||
| Neutrophils and Eosinophils | 857 | ||
| Basophils and Mast Cells | 857 | ||
| Humoral Factors | 857 | ||
| Immunoglobulins | 857 | ||
| Complement | 858 | ||
| Cytokines | 858 | ||
| Histocompatibility Antigens | 858 | ||
| Mechanisms of Immunologic Injury | 859 | ||
| Laboratory Applications of Immunologic Assessment | 859 | ||
| Therapeutics in Immunology | 860 | ||
| References | 861 | ||
| Selected References | 861 | ||
| References | 861.e1 | ||
| 44 Immunoassays and Immunochemistry | 862 | ||
| Immunoassays and Immunochemistry | 862 | ||
| General Characteristics of Antigen–Antibody Reaction | 862 | ||
| Characteristics of Antigens | 863 | ||
| Characteristics of Antibodies | 863 | ||
| Polyclonal Antibodies | 863 | ||
| Monoclonal Antibodies | 863 | ||
| Antibody Production by Recombinant Technology | 863 | ||
| Kinetics of Antigen–Antibody Reaction | 863 | ||
| Overview of General Principles of Immunoassays | 863 | ||
| Classes of Immunoassays | 863 | ||
| Conjugation Chemistry | 864 | ||
| Characteristics of the Solid Phase | 864 | ||
| Precipitin and Nephelometric Immunoassays | 865 | ||
| Background and Principles of Precipitin Reaction | 865 | ||
| Nephelometric Immunoassays | 866 | ||
| Particle Immunoassay | 866 | ||
| Principle of Particle Agglutination | 866 | ||
| Hemagglutination | 866 | ||
| Gelatin Particle Agglutination | 868 | ||
| Latex Agglutination | 868 | ||
| Latex Turbidimetric Assay | 868 | ||
| Particle-Counting Immunoassay | 868 | ||
| Other Particle Immunoassays | 868 | ||
| Summary | 868 | ||
| Radioimmunoassay | 870 | ||
| Background | 870 | ||
| Assay Principles and Methods | 870 | ||
| Summary | 872 | ||
| Enzyme Immunoassay | 872 | ||
| Background and Classification | 872 | ||
| Heterogeneous Enzyme Immunoassays | 872 | ||
| Colorimetric Enzyme Immunoassay | 873 | ||
| Fluorescent Enzyme Immunoassay | 873 | ||
| Chemiluminescent Enzyme Immunoassay | 873 | ||
| Homogeneous Enzyme Immunoassays | 874 | ||
| Background | 874 | ||
| Enzyme-Multiplied Immunoassay Technique | 874 | ||
| Substrate-Labeled Fluorescent Immunoassay | 875 | ||
| Apoenzyme Reactivation Immunoassay | 875 | ||
| Enzyme Inhibitory Homogeneous Immunoassay | 875 | ||
| Cloned Enzyme Donor Immunoassay | 877 | ||
| Summary | 878 | ||
| Fluorescent Immunoassay | 878 | ||
| Background and Classification | 878 | ||
| Heterogeneous Fluorescent Immunoassay | 878 | ||
| Fluoroimmunometric Method | 878 | ||
| Radial Partition Immunofluorometric Assay | 879 | ||
| Time-Resolved Fluoroimmunoassay | 879 | ||
| Homogeneous Fluorescent Immunoassay | 879 | ||
| Fluorescence Polarization Assay | 879 | ||
| Fluorescence Excitation Transfer Immunoassay | 880 | ||
| Fluorescent Protection Immunoassay | 880 | ||
| Chemiluminescent Immunoassay | 880 | ||
| Background | 880 | ||
| Chemiluminescent Immunoassay Using Acridinium Esters as Labels | 880 | ||
| Electrochemiluminescent Immunoassay | 880 | ||
| Noncompetitive Immunoassay for Small Molecules | 881 | ||
| Background | 881 | ||
| Anti-Idiotype Antibody-Based Immunoassay | 881 | ||
| Open-Sandwich Immunoassay | 882 | ||
| Antimetatype Antibody–Based Immunoassay | 882 | ||
| Sensitive Immunoassay Using Specimen-Pretreatment Methods | 882 | ||
| Background | 882 | ||
| Highly Sensitive Immunoassay for Viral Antigen Using Specimen-Pretreatment Method | 882 | ||
| Instrument Automation and Modulation of Assay Systems | 883 | ||
| Homogeneous Assay Systems | 883 | ||
| Heterogeneous Immunoassay Systems | 883 | ||
| Practical Flow of the Immunoassay in the Analytic System | 883 | ||
| Instrumentation and Key Points for Heterogeneous Immunoassay | 884 | ||
| Reaction Cuvette | 884 | ||
| Sampling and Fluid Delivery Type | 884 | ||
| Carryover | 884 | ||
| Bound/Fixed Separation and Washing Systems | 884 | ||
| High-Throughput Fully Automated Heterogeneous Immunoassay Systems | 884 | ||
| Remote Maintenance | 885 | ||
| Rapid and Simple Test Devices for Point-of-Care Testing | 885 | ||
| Background | 885 | ||
| Immunochromatographic Devices | 885 | ||
| Magnetic Biosensor Assay | 886 | ||
| Summary | 887 | ||
| Simultaneous Multiple Immunoassays | 887 | ||
| Background | 887 | ||
| Microspot Assay | 887 | ||
| Multianalyte Microarray Immunoassay | 887 | ||
| Flow Cytometric Immunoassay | 887 | ||
| Microchannel Assay Using Compact Discs | 888 | ||
| 7 Medical Microbiology | 1071 | ||
| 56 Viral Infections | 1072 | ||
| Key Points | 1072 | ||
| Introduction | 1072 | ||
| Cell Culture | 1074 | ||
| Antigen Detection | 1074 | ||
| Nucleic Acid Amplification Testing (NAAT) | 1074 | ||
| Viral Serology | 1076 | ||
| Clinical Viral Infectious Syndromes | 1076 | ||
| Herpetic Mucocutaneous Infections | 1077 | ||
| Specimen Collection and Handling Guidelines | 1078 | ||
| Cell Culture Isolation of Herpes Simplex Virus | 1078 | ||
| Direct Detection of Herpes Simplex Virus | 1079 | ||
| Nucleic Acid–Based Detection of Herpes Simplex | 1079 | ||
| Serologic Diagnosis | 1079 | ||
| Pediatric and Adult Viral Respiratory Syndromes | 1079 | ||
| Influenza | 1081 | ||
| Bronchiolitis | 1081 | ||
| Croup | 1081 | ||
| Metapneumovirus | 1082 | ||
| Adenovirus | 1082 | ||
| Coronavirus | 1083 | ||
| Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) | 1083 | ||
| Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) | 1083 | ||
| Bocaviruses | 1083 | ||
| Rhinoviruses (HRV) | 1083 | ||
| Specimen Collection | 1083 | ||
| Virus Antigen Assays | 1083 | ||
| Virus Isolation | 1084 | ||
| Molecular Detection Methods | 1084 | ||
| Infectious Mononucleosis and Related Infections | 1084 | ||
| Diagnosis of Infectious Mononucleosis | 1084 | ||
| Heterophile-Negative Infectious Mononucleosis | 1085 | ||
| Chronic Fatigue Syndrome | 1085 | ||
| Congenital and Perinatal Viral Infections | 1085 | ||
| Cytomegalovirus | 1086 | ||
| Rubella | 1087 | ||
| Herpes Simplex Virus | 1087 | ||
| Human Immunodeficiency Virus, Parvovirus, Enterovirus, and Hepatitis B Virus | 1087 | ||
| Viral Meningitis and Encephalitis | 1088 | ||
| Laboratory Diagnosis | 1089 | ||
| Viral Exanthems and Common Cutaneous Infections | 1090 | ||
| Viral Gastroenteritis | 1091 | ||
| Laboratory Diagnosis | 1092 | ||
| Viral Hepatitis | 1092 | ||
| Hepatitis A Virus (HAV) | 1092 | ||
| Hepatitis E Virus (HEV) | 1092 | ||
| Hepatitis B Virus (HBV) | 1092 | ||
| Hepatitis C Virus (HCV) | 1093 | ||
| Acquired Immunodeficiency Syndrome | 1093 | ||
| Virus-Associated Neoplasia | 1097 | ||
| Human Papilloma Viruses (HPV) | 1097 | ||
| Emerging Infections | 1097 | ||
| Ebola Viral Disease (EVD) | 1097 | ||
| References | 1097 | ||
| Selected References | 1098 | ||
| Websites and E-Mail Addresses | 1098 | ||
| References | 1098.e1 | ||
| 57 Chlamydial, Rickettsial, and Mycoplasmal Infections | 1099 | ||
| Key Points | 1099 | ||
| Chlamydial Infections | 1099 | ||
| Structure | 1099 | ||
| Replication | 1099 | ||
| Chlamydia trachomatis | 1100 | ||
| Epidemiology, Pathology, and Clinical Manifestations | 1100 | ||
| Chlamydophila (Formerly Chlamydia) psittaci | 1101 | ||
| 8 Molecular Pathology | 1299 | ||
| 65 Introduction to Molecular Pathology | 1300 | ||
| Key Points | 1300 | ||
| The Molecular Biology Revolution and Its Impact on the Practice of Pathology | 1300 | ||
| Discussion of Diagnostic Molecular Pathology | 1300 | ||
| Application of Molecular Pathology to Detection of Cancer | 1301 | ||
| Implications of Molecular Diagnostics on the Practice of Pathology and Medicine | 1301 | ||
| Redefining Disease | 1301 | ||
| Use of Molecular Biology in the Treatment of Disease | 1301 | ||
| Data Analysis | 1301 | ||
| Quality Assurance | 1302 | ||
| Some Caveats | 1302 | ||
| References | 1302 | ||
| Selected References | 1302 | ||
| References | 1302.e1 | ||
| 66 Molecular Diagnostics | 1303 | ||
| Key Points | 1303 | ||
| Nucleic Acid Biochemistry and Biology | 1303 | ||
| Molecular Composition and Structure | 1303 | ||
| Nucleic Acid–Associated Enzymes | 1305 | ||
| Replication of DNA | 1305 | ||
| Transcription of DNA to RNA | 1306 | ||
| Posttranscriptional Modification | 1306 | ||
| Translation of RNA to Protein | 1306 | ||
| Transcriptional Control | 1306 | ||
| Gene Regulation Mediated by Small RNA | 1307 | ||
| Epigenetics and Gene Regulation | 1307 | ||
| Mechanisms of DNA Repair | 1307 | ||
| DNA Mutations | 1308 | ||
| Nucleic Acid Analyses | 1308 | ||
| Electrophoretic Separation | 1309 | ||
| Nucleic Acid Hybridization | 1309 | ||
| Hybridization Assays: Basic Components | 1309 | ||
| Probe | 1310 | ||
| Sample | 1311 | ||
| Controlled Conditions Permissive for Complementary Base Pairing | 1311 | ||
| Detection of Hybrids | 1311 | ||
| Hybridization Assay Formats | 1311 | ||
| Liquid or Solution Phase Hybridization | 1311 | ||
| Solid-Support Hybridization | 1312 | ||
| Dot or Linear Array Hybridization | 1312 | ||
| Southern and Northern Hybridizations | 1312 | ||
| Microarray Hybridization (“DNA Chip Technology” or “Bead Arrays”) | 1312 | ||
| In Situ Hybridization | 1312 | ||
| Amplification Methods | 1313 | ||
| Polymorphism Detection Assays | 1313 | ||
| DNA Sequencing | 1313 | ||
| Relationship to Laboratory Evaluation of Disease | 1313 | ||
| Molecular Diagnosis | 1313 | ||
| Beyond Diagnosis | 1314 | ||
| References | 1314 | ||
| Selected References | 1315 | ||
| References | 1315.e1 | ||
| 67 Polymerase Chain Reaction and Other Nucleic Acid Amplification Technology | 1316 | ||
| Key Points | 1316 | ||
| Target Amplification Methods | 1316 | ||
| Polymerase Chain Reaction | 1316 | ||
| Reverse-Transcriptase Polymerase Chain Reaction | 1316 | ||
| Nested Polymerase Chain Reaction | 1317 | ||
| Multiplex Polymerase Chain Reaction | 1317 | ||
| End-Point Quantitative Polymerase Chain Reaction | 1318 | ||
| Real-Time (Homogeneous, Kinetic) Polymerase Chain Reaction | 1319 | ||
| Rapid-Cycle Polymerase Chain Reaction | 1321 | ||
| Digital Polymerase Chain Reaction | 1321 | ||
| Transcription-Based Amplification | 1321 | ||
| Strand-Displacement Amplification | 1322 | ||
| Loop-Mediated Amplification | 1323 | ||
| Helicase-Dependent Amplification | 1324 | ||
| Nicking Endonuclease Amplification | 1324 | ||
| Probe Amplification Methods | 1324 | ||
| Cleavase/Invader Technology | 1324 | ||
| Signal Amplification Methods | 1324 | ||
| Branched DNA | 1326 | ||
| Hybrid Capture Assays | 1326 | ||
| Summary | 1326 | ||
| References | 1326 | ||
| Selected References | 1326 | ||
| References | 1327.e1 | ||
| 68 Hybridization Array Technologies | 1328 | ||
| Key Points | 1328 | ||
| Array Technologies | 1328 | ||
| Macroarrays | 1329 | ||
| Microarrays | 1329 | ||
| Microarray Substrates | 1329 | ||
| Microarray Fabrication | 1329 | ||
| Delivery Technologies | 1329 | ||
| In Situ Synthesis | 1330 | ||
| Oligonucleotide Microarrays | 1330 | ||
| CDNA Microarrays | 1331 | ||
| Sequencing Arrays | 1331 | ||
| Hybrid Capture | 1331 | ||
| Reverse Line-Blot Hybridization | 1332 | ||
| Hybridization, Detection, and Image Analysis | 1332 | ||
| Bioinformatics | 1333 | ||
| Intellectual Property Issues | 1334 | ||
| Clinical Applications of Array Technology | 1335 | ||
| Array Technology in the Clinical Laboratory | 1335 | ||
| Array Technology in Clinical Disease | 1335 | ||
| Limitations | 1335 | ||
| References | 1336 | ||
| Selected References | 1336 | ||
| References | 1336.e1 | ||
| 69 Applications of Cytogenetics in Modern Pathology | 1337 | ||
| Key Points | 1337 | ||
| Definitions | 1337 | ||
| Cytogenetics | 1338 | ||
| Chromosomes | 1338 | ||
| Chromosome Structure | 1338 | ||
| Cell Culture | 1338 | ||
| Specimens | 1338 | ||
| Cell Culture Technique | 1339 | ||
| Staining | 1340 | ||
| Karyotype Analysis | 1340 | ||
| Computer-Assisted Imaging | 1340 | ||
| Fluorescence in Situ Hybridization | 1341 | ||
| Technique | 1341 | ||
| Multicolor Fluorescence in Situ Hybridization | 1343 | ||
| Microarray Technology | 1343 | ||
| Chromosome Abnormalities | 1344 | ||
| Numerical Abnormalities | 1345 | ||
| Euploidy | 1345 | ||
| Aneuploidy | 1345 | ||
| Structural Chromosome Abnormalities | 1345 | ||
| Conclusions | 1349 | ||
| Nomenclature | 1349 | ||
| Clinical Applications | 1350 | ||
| CONSTITUTIONAL CYTOGENICS | 1350 | ||
| Prenatal | 1350 | ||
| Postnatal | 1351 | ||
| Childhood and Adult | 1352 | ||
| Cancer Genetics | 1352 | ||
| Cytogenetic Disorders | 1353 | ||
| Chromosomal Aneuploidy Syndromes | 1353 | ||
| Autosomal Aneuploidies | 1353 | ||
| Sex Chromosome Aneuploidies | 1354 | ||
| Other Sex Chromosome Abnormalities | 1356 | ||
| Structural Chromosome Anomalies | 1356 | ||
| Microdeletion Syndromes and Contiguous Gene Syndromes | 1356 | ||
| Other Cytogenetic Phenomena | 1358 | ||
| Fragile X Syndrome | 1358 | ||
| Breakage Syndromes | 1358 | ||
| Summary | 1358 | ||
| References | 1358 | ||
| Selected References | 1359 | ||
| Further Reading | 1359 | ||
| References | 1359.e1 | ||
| 70 Establishing a Molecular Diagnostics Laboratory | 1360 | ||
| Key Points | 1360 | ||
| Special Considerations for Molecular Diagnostics Laboratories | 1361 | ||
| Infectious Disease | 1361 | ||
| Cancer | 1361 | ||
| Inherited Disorders | 1361 | ||
| Regulation and Regulatory Agencies | 1362 | ||
| Clinical Laboratory Improvement Acts of 1988 and 2003 | 1362 | ||
| Genetic Information Nondiscrimination Act | 1362 | ||
| Food and Drug Administration | 1362 | ||
| Analyte-Specific Reagents | 1363 | ||
| In Vitro Multivariate Index Assay or IVDMIA Draft Guidance | 1363 | ||
| Laboratory Design and Requirements | 1363 | ||
| Laboratory Design | 1364 | ||
| Practices to Aid in Contamination Control | 1364 | ||
| Equipment | 1365 | ||
| Personnel | 1365 | ||
| Laboratory Director | 1365 | ||
| Technical Supervisor | 1365 | ||
| Medical Technologists and Molecular Biology Technicians | 1365 | ||
| Certification of Personnel in Molecular Diagnostics | 1366 | ||
| Financial Management | 1366 | ||
| Reimbursement for Molecular Diagnostics Tests | 1366 | ||
| Patent Issues | 1367 | ||
| Laboratory Information System | 1367 | ||
| Test Management | 1368 | ||
| Menu/Selection | 1368 | ||
| Methods | 1368 | ||
| Clinical Test Formats | 1368 | ||
| Automated Platforms for Molecular Testing | 1369 | ||
| Quality Assurance and Quality Control of the Testing Process | 1369 | ||
| Quality Assurance | 1369 | ||
| Assay Design and Development | 1370 | ||
| New Test Verification/Validation | 1371 | ||
| Analytical Verification | 1371 | ||
| Clinical Verification | 1375 | ||
| Quality Control of the Testing Process | 1375 | ||
| Quality Control of Equipment | 1375 | ||
| Conclusion | 1376 | ||
| Selected References | 1376 | ||
| References | 1376.e1 | ||
| 71 Molecular Diagnosis of Genetic Diseases | 1377 | ||
| Key Points | 1377 | ||
| Choice of Techniques | 1378 | ||
| Choice of Applications | 1379 | ||
| Special Concepts Unique to Molecular Genetic Disorders | 1381 | ||
| Molecular Heterogeneity | 1381 | ||
| Variable Penetrance and Expressivity | 1381 | ||
| Uniparental Disomy | 1381 | ||
| Imprinting | 1381 | ||
| Anticipation | 1381 | ||
| Epigenetic Influences and Nonmendelian Inheritance | 1382 | ||
| Allele Frequencies and Mass Population Screening | 1382 | ||
| Predictive Genetic Testing | 1382 | ||
| Specific Disease Examples | 1382 | ||
| Cystic Fibrosis | 1382 | ||
| Duchenne Muscular Dystrophy | 1383 | ||
| Sickle Cell Anemia and Other Hemoglobinopathies | 1384 | ||
| Hereditary Thrombophilias | 1384 | ||
| Trinucleotide Repeat Expansion Disorders | 1385 | ||
| Fragile XA and Fragile XE Syndromes | 1385 | ||
| Neurodegenerative Disorders: Huntington Disease, X-linked Spinal and Bulbar Muscular Atrophy, Spinocerebellar Ataxias, and Dentatorubral-Pallidoluysian Atrophy | 1386 | ||
| Myotonic Dystrophy | 1386 | ||
| Friedreich Ataxia | 1386 | ||
| Laboratory Testing for Trinucleotide Repeat Disorders | 1388 | ||
| Prader-Willi and Angelman Syndromes | 1388 | ||
| Familial Cancers | 1388 | ||
| Tumor Suppressor Genes: Retinoblastoma as a Paradigm | 1389 | ||
| Oncogenes: Multiple Endocrine Neoplasia Type 2 as a Paradigm | 1390 | ||
| Hereditary Breast-Ovarian Cancer | 1390 | ||
| The Hereditary Colorectal Cancer Syndromes | 1390 | ||
| Hereditary Nonpolyposis Colorectal Cancer | 1390 | ||
| Familial Adenomatous Polyposis and Attenuated Familial Adenomatous Polyposis | 1391 | ||
| MYH-Associated Polyposis | 1391 | ||
| Laboratory Testing for Familial Cancer Mutations | 1391 | ||
| Hemochromatosis | 1391 | ||
| Spinal Muscular Atrophy | 1392 | ||
| Mitochondrial DNA Disorders | 1392 | ||
| Other Targets of Molecular Genetic Testing and Screening | 1392 | ||
| The New Frontier of Diagnostic Molecular Genetics: Genome-Level DNA Sequencing | 1393 | ||
| References | 1394 | ||
| Selected References | 1394 | ||
| References | 1395.e1 | ||
| 72 Identity Analysis | 1396 | ||
| Key Points | 1396 | ||
| Historical Background | 1396 | ||
| Advantages of DNA | 1397 | ||
| Genetic Markers | 1397 | ||
| Samples and Specimen Collection | 1397 | ||
| DNA Extraction and Quantification | 1398 | ||
| Test Methods and Marker Systems | 1398 | ||
| Short Tandem Repeats | 1398 | ||
| X and Y Chromosome Markers | 1400 | ||
| Mitochondrial DNA Sequencing | 1400 | ||
| Other Systems | 1400 | ||
| Analysis and Use of Test Data | 1401 | ||
| DNA in the Crime Laboratory | 1401 | ||
| DNA in the Pathology Laboratory | 1401 | ||
| Exclusion of Parentage | 1401 | ||
| Probability of Exclusion | 1402 | ||
| Combined Probability of Exclusion | 1403 | ||
| Inclusion of Parentage | 1403 | ||
| Paternity Index Calculation | 1403 | ||
| Likelihood of Parentage | 1404 | ||
| Estimating Parentage with an Absent Parent | 1404 | ||
| Reconstruction of Families | 1405 | ||
| Software Systems | 1405 | ||
| Quality Assurance Standards | 1405 | ||
| Conclusion | 1405 | ||
| References | 1406 | ||
| Selected References | 1406 | ||
| References | 1406.e1 | ||
| 73 Pharmacogenomics and Personalized Medicine | 1407 | ||
| Key Points | 1407 | ||
| Overview | 1407 | ||
| Basic Concepts | 1407 | ||
| Drug-Metabolizing Enzyme Pharmacogenomics | 1408 | ||
| Phase I Enzymes | 1408 | ||
| Phase II Enzymes | 1410 | ||
| Uridine Diphosphate Glucuronosyltransferases | 1410 | ||
| Sulfotransferases | 1412 | ||
| Glutathione S-Transferases | 1412 | ||
| N-Acetyltransferase | 1412 | ||
| Thiopurine S-Methyltransferase | 1412 | ||
| Drug-Transporter Pharmacogenomics | 1413 | ||
| ATP-Binding Cassette (ABC) Transporters | 1414 | ||
| ABCB1 | 1414 | ||
| ABCC1 and ABCC2 | 1414 | ||
| ABCG2 | 1416 | ||
| Solute Carrier Transporters | 1416 | ||
| Organic Anion Transporting Polypeptides | 1416 | ||
| Organic Cation Transporters (OCTs) | 1417 | ||
| Organic Anion Transporters (OATs) | 1418 | ||
| Drug Target Pharmacogenomics | 1418 | ||
| DNA Repair Genes | 1418 | ||
| Thymidylate Synthase | 1418 | ||
| Epidermal Growth Factor Receptor | 1419 | ||
| Human Leukocyte Antigen Pharmacogenomics | 1423 | ||
| Pharmacogenomics in Cancer Chemotherapy | 1424 | ||
| 5-Fluorouracil | 1424 | ||
| Irinotecan | 1425 | ||
| Tamoxifen | 1426 | ||
| Pharmacogenomics in Other Diseases | 1428 | ||
| Diabetes | 1428 | ||
| Human Immunodeficiency Virus | 1428 | ||
| Osteoporosis | 1429 | ||
| Psychiatric and Cognitive Disorders | 1429 | ||
| Epigenomics | 1429 | ||
| Conclusion | 1430 | ||
| References | 1430 | ||
| Selected References | 1430 | ||
| References | 1430.e1 | ||
| 9 Molecular Pathology | 1431 | ||
| 74 Diagnosis and Management of Cancer Using Serologic and Other Body Fluid Markers | 1432 | ||
| Key Points | 1432 | ||
| Serum Markers as an Effective Tool for Diagnosis and Monitoring of Cancer | 1433 | ||
| Functional Classification of Tumor Markers | 1433 | ||
| Oncoproteins are Markers for Cell Proliferation | 1434 | ||
| Tumor Suppressors/Cell Differentiation | 1434 | ||
| Adhesion Molecules and Metastasis | 1434 | ||
| Monoclonal Antibody–Defined Tumor Markers | 1434 | ||
| Other Markers | 1434 | ||
| Clinical Applications | 1435 | ||
| Screening | 1435 | ||
| Diagnosis | 1435 | ||
| Prognosis: Recurrence, Metastasis, and Survival | 1435 | ||
| Monitoring Treatment Response | 1436 | ||
| Recommendations for Ordering Tumor Marker Tests | 1436 | ||
| Individual Tumor Markers | 1438 | ||
| α-Fetoprotein | 1438 | ||
| Angiogenic Factors | 1438 | ||
| β2-Microglobulin | 1438 | ||
| Serum Free Light Chain Determinations | 1439 | ||
| Carcinoembryonic Antigen | 1440 | ||
| CA 15-3 and CA 27.29 | 1440 | ||
| CA 19-9, CA 50, and CA 19-5 | 1440 | ||
| CA 125 | 1441 | ||
| CA 72-4 | 1441 | ||
| Calcitonin | 1441 | ||
| Chromogranin A | 1441 | ||
| Cytokeratin 19 Fragment | 1441 | ||
| Human Chorionic Gonadotropin | 1441 | ||
| HER2/neu (c-erbB-2) ONCOPROTEIN | 1442 | ||
| p53 | 1442 | ||
| Parathyroid Hormone–Related Peptide | 1442 | ||
| Serum Markers for Prostate Cancer | 1442 | ||
| Serum Prostate-Specific Antigen | 1442 | ||
| Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer | 1443 | ||
| Free PSA, Complex PSA, and Percentage of Free PSA | 1443 | ||
| proPSA and Prostate Health Index | 1444 | ||
| PSA Doubling Time, Velocity, and Density | 1444 | ||
| Circulating Tumor Cells in Peripheral Blood | 1444 | ||
| Circulating Nucleic Acids in Peripheral Blood | 1445 | ||
| Cell-Free Nucleic Acid Testing in Cancer | 1445 | ||
| Gene Arrays Detecting Oncoprotein Abnormalities | 1446 | ||
| Circulating microRNA | 1446 | ||
| Gene Mutations | 1446 | ||
| Microsatellite Alterations | 1446 | ||
| Promoter Hypermethylation | 1446 | ||
| Cell DNA Testing for Cancer Using Fluorescence in Situ Hybridization | 1447 | ||
| Markers in Other Body Fluids | 1447 | ||
| Urine Markers for Prostate Cancer | 1447 | ||
| Urine Prostate Cancer Antigen 3 | 1447 | ||
| Urine TMPRSS2:ERG and Mi-Prostate Score | 1447 | ||
| Prostarix | 1447 | ||
| Urine Hypermethylated Glutathione S-Transferase pi 1 Gene | 1448 | ||
| Urine Metabolic Test for Adenomatous Polyps of Colon | 1448 | ||
| Fecal Occult Blood Testing and Mutant Protein Markers in Stool | 1448 | ||
| Conclusions | 1448 | ||
| References | 1448 | ||
| Selected References | 1449 | ||
| References | 1449.e1 | ||
| 75 Oncoproteins and Early Tumor Detection | 1450 | ||
| Key Points | 1450 | ||
| Overview | 1450 | ||
| Cell Biology and Mitogenesis | 1450 | ||
| Signal Transduction Pathways | 1451 | ||
| Oncoproteins in Tumor Detection | 1451 | ||
| Growth Factors | 1452 | ||
| Transforming Growth Factors α and β | 1452 | ||
| Platelet-Derived Growth Factor | 1453 | ||
| Basic Fibroblast Growth Factor | 1453 | ||
| Epidermal Growth Factor and Hepatocyte Growth Factor | 1453 | ||
| Growth Factor Receptors | 1454 | ||
| Epidermal Growth Factor Receptor | 1455 | ||
| HER2/neu Receptor | 1455 | ||
| HER2/neu Detects Pulmonary Neoplasms | 1455 | ||
| HER2/neu in the Detection of Hepatocellular Carcinomas | 1455 | ||
| p185erbB-2 ECD in Other Tumors | 1455 | ||
| E-Cadherin | 1456 | ||
| Metalloproteases in Pancreatic Cancer | 1456 | ||
| G-Proteins | 1456 | ||
| ras-p21 Protein | 1456 | ||
| ras-p21 in Lung and Colon Cancer | 1456 | ||
| ras-p21 in Angiosarcoma | 1457 | ||
| ras-p21 in Pancreatic Cancer | 1457 | ||
| Cytosolic Mitogenic Kinases | 1457 | ||
| Raf | 1457 | ||
| Nuclear Oncoproteins | 1457 | ||
| p53 and c-myc Proteins | 1457 | ||
| Detection of Malignancies by Assaying for p53 Protein | 1457 | ||
| Hepatocellular Carcinoma. | 1457 | ||
| Breast and Lung Cancers. | 1457 | ||
| Colon Cancer. | 1458 | ||
| Bladder Cancer. | 1458 | ||
| Leukemia. | 1458 | ||
| Circulating Anti-p53 Antibodies in Tumor Detection | 1458 | ||
| Negative Regulator of p53, S100, as a Tumor Marker for Malignant Melanoma. | 1458 | ||
| Antibodies to p53 Are Present in the Sera of Many Patients with Epithelial Cell Tumors and Lymphomas. | 1458 | ||
| Anti-p53 in Ovarian Cancer. | 1458 | ||
| Anti-p53 in Hepatocellular Carcinoma. | 1458 | ||
| Anti-p53 in Oral and Esophageal Cancers. | 1458 | ||
| Anti-p53 in Lung Cancers. | 1458 | ||
| Anti-p53 Predicts Cancer Occurrence in Patients with Asbestos Exposure. | 1458 | ||
| Anti-p53 in Colorectal Cancer. | 1459 | ||
| myc Oncogene–Encoded Protein in Tumor Detection | 1459 | ||
| Serum Anti–c-myc Protein Antibodies in Tumor Detection in Breast Cancer, Ovarian Cancer, Leukemias, and Lymphomas | 1459 | ||
| Combined Oncogene Marker Proteins for Detection of Colorectal Cancer | 1459 | ||
| Nuclear Matrix Proteins and Detection of Bladder Cancer | 1459 | ||
| NMP-22 Is an Excellent Biomarker for Bladder and Urothelial Cancers | 1459 | ||
| Bladder Tumor Antigen | 1459 | ||
| Minichromosome Maintenance Proteins | 1460 | ||
| Use of Multiple Oncoprotein Markers in the Diagnosis of Cancer | 1460 | ||
| Multiple Oncoprotein Assay in Patients at Risk for Tumor Development in Patients with Pneumoconiosis | 1460 | ||
| Oncoprotein Arrays Likewise Hold Promise in Detecting Antioncoprotein Antibodies in Sera | 1460 | ||
| Proteomic Approaches to Early Detection of Cancer in Serum | 1460 | ||
| Application of the Proteomic Approach to the Diagnosis of Cancers | 1461 | ||
| Ovarian Cancer | 1461 | ||
| Prostate Cancer | 1461 | ||
| Proteomics Show Promise in Early Tumor Detection | 1461 | ||
| Protein Arrays for Specific Types of Cancer | 1461 | ||
| Squamous Cell Carcinomas of the Head and Neck | 1461 | ||
| Breast Cancer | 1461 | ||
| Lung Cancer | 1461 | ||
| Diagnostic Efficacy of Serum Oncoproteins | 1461 | ||
| How Specific Is Oncoprotein Expression for Different Cancer Types? | 1461 | ||
| Sensitivities of Oncoprotein Expression | 1463 | ||
| Origins of Malignancies | 1463 | ||
| Tumor Size and Oncoprotein Levels | 1463 | ||
| Evaluation and Conclusions | 1463 | ||
| References | 1463 | ||
| Selected References | 1463 | ||
| References | 1464.e1 | ||
| 76 Molecular Diagnosis of Hematopoietic Neoplasms | 1465 | ||
| Key Points | 1465 | ||
| Role of Clinical Molecular Diagnostics in Hematologic Cancers | 1465 | ||
| Molecular Diagnosis of Leukemias | 1466 | ||
| Gene Fusion Concept in Leukemia and the Basis for Reverse-Transcription Polymerase Chain Reaction Analysis | 1466 | ||
| Acute Myeloid Leukemias | 1467 | ||
| Acute Promyelocytic Leukemia: t(15;17)(q22;q21)/PML-RARA Abnormality | 1468 | ||
| Core Binding Factor–Related Acute Myeloid Leukemias: t(8;21)(q22;q22)/RUNX1-RUNX1T1 and Inv(16)(p13q22) or t(16;16)(p13;q22)/ CBFB-MYH11 Abnormalities | 1470 | ||
| Acute Myeloid Leukemia with Other Translocations | 1470 | ||
| AML with 11q23/MLL | 1470 | ||
| AML with t(6;9)(p23;q34)/DEK-NUP214 | 1471 | ||
| AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1 | 1471 | ||
| AML (Megakaryoblastic) with t(1;22)(p13;q13)/RBM15-MKL1 | 1471 | ||
| Acute Myeloid Leukemias with FLT3, NPM1, and CEBPA Gene Mutations | 1471 | ||
| FLT3 Mutations in Acute Myeloid Leukemia | 1471 | ||
| NPM1 Mutations in Acute Myeloid Leukemia | 1472 | ||
| CEBPA Mutations in Acute Myeloid Leukemia | 1472 | ||
| Other Gene Mutations in Acute Myeloid Leukemias | 1472 | ||
| WT1 Mutations in Acute Myeloid Leukemias | 1472 | ||
| Acute Lymphoblastic Leukemia/Lymphoma—B and T Cell Lineage | 1473 | ||
| B Cell Lymphoblastic Leukemia/Lymphoma (Precursor B Cell Acute Lymphoblastic Leukemia, B-ALL) | 1473 | ||
| Major Translocation Fusion Gene Abnormalities in B Cell ALL | 1473 | ||
| Prenatal Origins of Childhood Leukemias | 1476 | ||
| BCR-ABL1–Like B-Acute Lymphoblastic Leukemia | 1476 | ||
| T Cell Lymphoblastic Leukemia/Lymphoma | 1476 | ||
| Molecular Diagnosis of Myeloproliferative Neoplasms | 1477 | ||
| Chronic Myelogenous Leukemia with t(9;22)(q34;q11)/BCR-ABL1 Positive | 1477 | ||
| Ph-Negative Myeloproliferative Neoplasms: Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis—JAK2, MPL Gene, and CALR Mutations | 1478 | ||
| Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia with CSF3R Gene Mutation | 1480 | ||
| Mastocytosis and the KIT D816V Gene Mutation | 1480 | ||
| Neoplastic Disorders Associated with Eosinophilia | 1480 | ||
| Molecular Diagnosis of Non-Hodgkin Lymphomas | 1481 | ||
| Rationale for Molecular Genetic Analysis in the Lymphoid Disorders | 1481 | ||
| Antigen Receptor Gene Rearrangements for Clonality Determination | 1481 | ||
| Mechanism of Antigen Receptor Gene Rearrangements | 1481 | ||
| Techniques to Detect Antigen Receptor Gene Rearrangements: Southern Blot Hybridization | 1481 | ||
| Advantages and Shortcomings of Southern Blot Hybridization and Polymerase Chain Reaction for Lymphoid Clonality Assessment | 1481 | ||
| Molecular Detection and Significance of Common Lymphoma-Associated Chromosomal Translocations | 1484 | ||
| t(14;18)/BCL2-IGH@ Abnormality in Follicular and Diffuse Large B Cell Lymphomas | 1484 | ||
| t(11;14)/CCND1-IGH@ Abnormality in Mantle Cell Lymphoma | 1485 | ||
| MALT1, BCL10, and FOXP1 Gene Abnormalities in Extranodal Marginal Zone B Cell Lymphomas | 1486 | ||
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Molecular and Cytogenetic Prognostic Markers | 1486 | ||
| Diffuse Large B Cell Lymphomas: Role of BCL6 and MYC Gene Abnormalities and Classification Based on Gene Expression Profiling | 1487 | ||
| MYC Gene Translocations in Burkitt Lymphomas and “High-Grade” B Cell Lymphomas, Unclassifiable | 1487 | ||
| MYD88 Mutation in Non-Hodgkin B Cell Lymphoma | 1488 | ||
| ALK Gene Abnormalities in Anaplastic Large Cell Lymphomas | 1488 | ||
| TCL1A Gene Abnormalities in T Cell Prolymphocytic Leukemia | 1489 | ||
| The Implication of Next Gene Sequencing (NGS) in Hematolymphoid Lesions | 1489 | ||
| Emerging Technologies Impacting Molecular Diagnosis and Prognosis Prediction in Hematolymphoid Neoplasia | 1489 | ||
| References | 1491 | ||
| Selected References | 1491 | ||
| References | 1491.e1 | ||
| 77 Molecular Genetic Pathology of Solid Tumors | 1492 | ||
| Key Points | 1492 | ||
| Molecular Genetic Pathology of Specific Solid Tumors by Major Organ | 1493 | ||
| Brain Tumor | 1493 | ||
| Glioblastoma Multiforme | 1493 | ||
| Oligodendroglioma | 1493 | ||
| Rhabdoid Tumor | 1496 | ||
| Breast Cancer | 1496 | ||
| Sporadic, Nonhereditary Breast Cancer | 1497 | ||
| Hereditary Breast Cancer | 1499 | ||
| Thyroid Cancer | 1499 | ||
| Papillary Thyroid Carcinoma | 1499 | ||
| Follicular Carcinoma | 1500 | ||
| Medullary Carcinoma | 1500 | ||
| Lung Cancer | 1500 | ||
| Hepatocellular Carcinoma | 1501 | ||
| Hepatic Adenomas | 1502 | ||
| Gastric Cancer | 1503 | ||
| Colorectal Cancer | 1504 | ||
| Hereditary Colonic Cancer Syndrome | 1505 | ||
| Familial Adenomatous Polyposis Syndrome | 1505 | ||
| Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) | 1505 | ||
| Familial Juvenile Polyposis Syndrome | 1506 | ||
| Peutz-Jeghers Syndrome | 1506 | ||
| Serrated Polyposis Syndrome (Formerly Known as Hyperplastic Polyposis Syndrome) | 1506 | ||
| MYH Polyposis and Inherited Colon Cancer Due to MYH Inactivation | 1506 | ||
| Pancreatic Cancer (Non-Neuroendocrine Tumor) | 1506 | ||
| Kidney Tumor | 1507 | ||
| Clear Cell Renal Cell Carcinoma (RCC) | 1507 | ||
| Papillary RCC | 1508 | ||
| Chromophobe Tumors | 1508 | ||
| Micropthalmia Transcription Factor (MiT) Family Translocation Renal Cell Carcinoma | 1508 | ||
| Xp11 Translocation or TFE 3-Associated RCC | 1508 | ||
| (6;11) Translocation TFEB-Associated RCC | 1508 | ||
| Succinate Dehydrogenase B (SDHB) Mutation–Associated RCC | 1508 | ||
| ALK Translocation RCC | 1509 | ||
| Hereditary Renal Cell Carcinoma Syndromes | 1509 | ||
| Gene Expression Profiling by Affymetrix in RCC | 1509 | ||
| Bladder Cancer | 1509 | ||
| Prostate Cancer | 1510 | ||
| Cervical Cancer | 1510 | ||
| Endometrial Cancer | 1511 | ||
| Ovarian Cancer | 1511 | ||
| Histologic Subtypes of Serous Carcinoma | 1512 | ||
| Molecular Classification of Ovarian Cancer | 1512 | ||
| Clear Cell Ovarian Carcinoma | 1512 | ||
| BRCA1 and BRCA2 in Ovarian Cancer | 1512 | ||
| Melanoma | 1512 | ||
| Molecular Genetic Pathology of Sarcoma | 1513 | ||
| Sarcomas with Fusion Genes | 1513 | ||
| Fusion Genes Involving TET Genes | 1513 | ||
| Ewing’s Sarcoma/Primitive Peripheral Neuroectodermal Tumor | 1513 | ||
| Clear Cell Sarcoma | 1513 | ||
| Extraskeletal Myxoid Chondrosarcoma | 1513 | ||
| Atypical Lipomatous Tumor, Well-Differentiated and Dedifferentiated Liposarcoma | 1513 | ||
| Myxoid/Round Cell Liposarcoma | 1514 | ||
| Low-Grade Fibromyxoid Sarcoma | 1514 | ||
| Hemangioma of Bone | 1514 | ||
| Fusion Genes Involving Receptor Tyrosine Kinase Genes | 1514 | ||
| Sarcoma with Fusion Genes Involving Chromatin Remodeling Genes | 1514 | ||
| Sarcoma with Fusion Genes Involving Growth Factors | 1514 | ||
| Sarcoma with Other Types of Fusion Genes | 1514 | ||
| Epithelioid Hemangioendothelioma | 1514 | ||
| Sarcomas with Oncogenic Mutations | 1515 | ||
| KIT and PDGFRA in Gastrointestinal Stromal Tumor | 1515 | ||
| Sarcomas with Variable Other Specific Pattern | 1515 | ||
| Nodular Fasciitis | 1515 | ||
| Inflammatory Myofibroblastic Tumor | 1515 | ||
| Aneurysmal Bone Cyst | 1515 | ||
| Sarcomas with Variable Complex Genetic Alterations with No Specific Pattern | 1515 | ||
| Molecular Genetic Pathology of Multiple Endocrine Neoplasia | 1515 | ||
| Cancers of Unknown Origin | 1517 | ||
| miRNA in Cancer | 1518 | ||
| Clinical Application of Next-Generation Sequencing | 1518 | ||
| References | 1519 | ||
| Selected References | 1519 | ||
| References | 1519.e1 | ||
| 78 High-Throughput Genomic and Proteomic Technologies in the Postgenomic Era | 1520 | ||
| Key Points | 1520 | ||
| Overview | 1520 | ||
| The Human Genome Project | 1521 | ||
| Public Sequencing Effort (Hierarchical Shotgun Sequencing) | 1521 | ||
| Private Sequencing Effort (Whole-Genome Shotgun Sequencing) | 1522 | ||
| Finishing the Sequence of the Human Genome | 1522 | ||
| High-Throughput Technologies | 1522 | ||
| Genomic | 1522 | ||
| Serial Analysis of Gene Expression | 1523 | ||
| Microarray | 1523 | ||
| Real Competitive Polymerase Chain Reaction | 1524 | ||
| Multiplex PCR | 1527 | ||
| xTAG Technology | 1527 | ||
| High-Resolution Melting Analysis | 1527 | ||
| Proteomic | 1528 | ||
| Mass Spectrometry | 1528 | ||
| Protein Arrays | 1528 | ||
| Secretome | 1528 | ||
| Molecular Markers for the Diagnosis of Human Neoplasia | 1528 | ||
| Genomic | 1528 | ||
| Proteomic | 1529 | ||
| Diagnostic Cancer Applications | 1529 | ||
| Small, Round Blue Cell Tumors | 1529 | ||
| Barrett’s Esophagus | 1530 | ||
| Thyroid Carcinoma | 1530 | ||
| Distinguishing Follicular Thyroid Carcinoma from Adenoma | 1530 | ||
| Adenocarcinoma | 1531 | ||
| Pancreatic Cancer | 1531 | ||
| Other Cancers | 1531 | ||
| Prognostic Molecular Markers of Disease | 1531 | ||
| Genomic | 1531 | ||
| Diffuse Large B-Cell Lymphoma (see also Chapter 76) | 1531 | ||
| Follicular Lymphoma | 1532 | ||
| Acute Myeloid Leukemia | 1532 | ||
| Breast Cancer | 1533 | ||
| Integrating Genomics and Proteomics | 1533 | ||
| Pitfalls of Molecular Markers for Both Prognostics and Diagnostics | 1533 | ||
| Microarray Data Sets | 1533 | ||
| “Overfitting” The Predictor | 1533 | ||
| The “Bystander” Effect | 1534 | ||
| Limitations of Proteomic Techniques | 1534 | ||
| Conclusion and Future Challenges | 1534 | ||
| References | 1534 | ||
| Selected References | 1534 | ||
| References | 1534.e1 | ||
| Appendix 1 Physiologic Solutions, Buffers, Acid-Base Indicators, Standard Reference Materials, and Temperature Conversions | e1 | ||
| Physiologic Solutions | e1 | ||
| Buffers* | e1 | ||
| Example 1 | e1 | ||
| Example 2 | e1 | ||
| Sorensen’s Phosphate Buffers | e1 | ||
| Tris(hydroxymethyl)aminomethane Buffer* | e1 | ||
| Acid-Base Indicators | e1 | ||
| Standard Reference Materials | e2 | ||
| Temperature Conversion | e2 | ||
| Selected References | e4 | ||
| Appendix 2 Desirable Weights, Body Surface Area, and Body Mass Index | e5 | ||
| Appendix 3 Approximations of Total Blood Volume | e9 | ||
| Adults | e9 | ||
| Children | e9 | ||
| Selected References | e9 | ||
| Appendix 4 Periodic Table of the Elements | e10 | ||
| References | e10 | ||
| Appendix 5 SI Units | e11 | ||
| References | e26 | ||
| Appendix 6 Common Chimeric Genes Identified in Human Malignancies | e27 | ||
| References | e29 | ||
| Appendix 7 Disease/Organ Panels | e31 | ||
| AMA Designated Disease/Organ Panels | e32 | ||
| References | e32 | ||
| Index | 1535 | ||
| A | 1535 | ||
| B | 1538 | ||
| C | 1539 | ||
| D | 1543 | ||
| E | 1544 | ||
| F | 1545 | ||
| G | 1546 | ||
| H | 1547 | ||
| I | 1549 | ||
| J | 1551 | ||
| K | 1551 | ||
| L | 1551 | ||
| M | 1553 | ||
| N | 1555 | ||
| O | 1556 | ||
| P | 1557 | ||
| Q | 1559 | ||
| R | 1559 | ||
| S | 1560 | ||
| T | 1562 | ||
| U | 1564 | ||
| V | 1564 | ||
| W | 1565 | ||
| X | 1565 | ||
| Y | 1565 | ||
| Z | 1565 | ||
| Guidelines for Ordering Blood for Elective Surgery | IBC2 | ||
| Also Referred to as Maximum Surgical Blood Order Schedule (MSBOS) | IBC2 | ||
| Cardiopulmonary/Cardiothoracic | IBC2 | ||
| General Surgery | IBC2 | ||
| Gynecology | IBC2 | ||
| Neurosurgery | IBC2 | ||
| Orthopedics | IBC2 | ||
| Otorhinolaryngology/Head and Neck Surgery | IBC3 | ||
| Plastic Surgery | IBC3 | ||
| Renal Transplantation | IBC3 | ||
| Urology | IBC3 | ||
| Vascular Surgery | IBC3 | ||
| References | IBC3 |