The Year in Hematology 1977 The Year in Hematology 1977

Edited by AlbertS. Gordon, Ph.D., F.R.S.M. Graduate School of Arts and Science New York University New York, New York Robert Silber, M.D. New York University School of Medicine New York, New York and Joseph LoBue, Ph.D. Graduate School of Arts and Science New York University New York, New York

SPRINGER SCIENCE+BUSINESS MEDIA, LLC Library of Congress Cataloging in Publication Data Main entry under title:

The Year in hematology, 1977.

Includes bibliographies and index. 1. Hematology. 2. Blood-Diseases. I. Gordon, Albert Saul, 1910- II. Silber, Robert, 1931- III. LoBue, Joseph. (DNLM: 1. Hematology-Period, W1 YE395) RC633.Y4 616.1'5 77-8412 ISBN 978-1-4899-6690-2 ISBN 978-1-4899-6688-9 (eBook) DOI 10.1007/978-1-4899-6688-9

© Springer Science+Business MediaNew York 1977 Originally published by Plenum Publishing Corporation in 1977 Softcover reprint of the hardcover 1st edition 1977

All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher Contributors

John W. Adamson, M.D., Associate Professor of Medicine, Division of Hematology, Department of Medicine, University of Washington School of Medicine; and Chief, Hematology Section, Veterans Administration Hospital, Seattle, Washington Israel F. Charo, M.S., M.D., Ph.D. Candidate, Department of Biochemis• try, State University of New York Downstate Medical Center, Brook• lyn, New York 11203 W. Cieplinski, M.D., Ph.D., Research Associate, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461 Martin J. Cline, M.D., Bowyer Professor of Medical Oncology, and Chief of Hematology-Oncology, Department of Medicine, University of California School of Medicine, Los Angeles, California 90024 Harvey J. Cohen, M.D., Ph.D., Associate, Division of Hematology• Oncology, Children's Hospital Medical Center; and Assistant Profes• sor of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Neville Colman, M.B., B.Ch., Ph.D., Research Associate, Veterans Administration Hospital, Bronx, New York 10468; and Assistant v vi CONTRIBUTORS

Professor of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 11209 Maryrose Conklyn, B.S., Graduate Student, Department of Biology, New York University Graduate School of Arts and Sciences, New York, New York 10003 Maria da Costa, M.D., Associate Professor of Medicine, Division of Hematology/Oncology, Department of Medicine, New York Medical College, New York 10029 Thomas C. Detwiler, Ph.D., Professor of Biochemistry, Department of Biochemistry, State University of New York Downstate Medical Cen• ter, Brooklyn, New York 11203 Alfred G. Ehlenberger, M.D., Ph.D., Resident, Department of Psychia• try, Stanford University Medical Center, Palo Alto, California 94304 Michael L. Freedman, A.B., M.D., Professor of Medicine, Department of Medicine, New York University Medical Center, New York, New York 10016 Robert C. Gallo, M.D., D.Sc. (hon.), Chief, Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, Maryland 20014; and Adjunct Professor of Genetics, George Washington University, Washington, D.C. 20007 David H. Gillespie, Ph.D., Head, Nucleic Acid Hybridization Section, Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, Maryland 20014 David W. Golde, M.D., Associate Professor of Medicine, University of California School of Medicine, Los Angeles, California 90024 Ronald B. Herberman, M.D., Chief, Laboratory of Immunodiagnosis, National Cancer Institute, Bethesda, Maryland 20014 Victor Herbert, M.D., J.D., Director, Hematology and Nutrition Labora• tory, Veterans Administration Hospital, Bronx, New York 10468; and Professor of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 11209 Elizabeth Jacob, M.D., Assistant Professor of Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 11209 Simon Karpatkin, M.D., Professor of Medicine, New York University Medical School, New York, New York 10016 Sanford B. Krantz, M.D., Professor of Medicine and Chief of Hematol• ogy, Departments of Medicine, Vanderbilt University School of \1ed• icine; and Veterans Administration Hospital, Nashville, Tennessee 37203 CONTRIBUTORS vii

Mahin D. Maines, Ph.D., Associate Professor, The Rockefeller Univer• sity, New York, New York 10021 Julia A. McMillan, M.D., Assistant Instructor, Department of Pediatrics, State University of New York, Upstate Medical Center, Syracuse, New York Victor Nussenzweig, M.D., Professor of Pathology, Department of Pathology, New York University School of Medicine, New York, New York 10016 Frank A. Oski, M.D., Professor and Chairman, Department of Pediatrics, State University of New York, Upstate Medical Center, Syracuse, New York Oscar D. Ratnoff, M.D., Professor of Medicine, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals of Cleveland, Cleveland, Ohio 441 06; Career Investigator of the American Heart Association Sheldon P. Rothenberg, M.D., Professor and Vice Chairman, Depart• ment of Medicine, and Chief, Division of Hematology/Oncology, New York Medical College, New York, New York 10029 M.D. Scharff, M.D., Professor and Chairman, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461 Robert Silber, M.D., Director of Hematology and Professor of Medicine, New York University School of Medicine, New York, New York 10016 Thomas P. Stossel, M.D., Chief, Medical Oncology Unit, Massachusetts General Hospital; and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts 02114 S. Donald Zaentz, M.D., Assistant Professor, Departments of Medicine, Division of Hematology, Vanderbilt University School of Medicine; and Veterans Administration Hospital, Nashville, Tennessee 37203 Preface

Scientists, physicians, or students cannot be considered educated unless acquainted with the important developments in their chosen discipline. Over the last decade there has been an enormous production of valuable experimental and clinical observations in hematology. The published information must be assessed as to how the new differs from the old, what can be discarded as of little use, and what should be avidly pursued in the hope of yielding significant answers to important questions. This review series will endeavor to provide a critical appraisal of some recent observa• tions of the normal and abnormal functions in the hematopoietic system, the overall objective being to provide current information in fields rich in new concepts which point the way to future work. The contributors to this first volume have attempted to present a summary of some high points of recent research against a background of historical perspective. Good reviews are not born from an instinctive ability for preparing compendia. Instead, they are the result of intelligent, patient, critical analysis which culminates in a scholarly labor of love. We thank our contributors for the generous gift of their time, and we trust

ix X PREFACE that their efforts will be rewarded by the expert guidance provided to students of hematology. The readers' reaction is invited to guide us in the preparation of future volumes.

Albert S. Gordon Robert Silber Joseph LoBue New York Contents

Chapter 1 Heme Metabolism: Factors Affecting the in Vivo Oxidation of Heme Mahin D. Maines 1.1. Introduction ...... 1 1.2. Heme and Bile Pigments ...... 1 1.3. Mechanism of Heme Oxidation ...... 6 1.3.1. Nonenzymatic Heme Oxidation ...... 6 1.3.2. Enzymatic Heme Oxidation ...... 9 1.3.3. Substrate Specificity...... 13 1.3.4. Heme Oxygenase: Postulated Mode of Action . 15 1.4. Factors Regulating Heme Degradation ...... 17 1.4.1. Heme (Hemoglobin, Hematin, Methemalbumin) ...... 17 1.4.2. Metals...... 19 1.4.3. Hormonal and Metabolic Factors...... 23 1.4.4. Effect of Endotoxins and Drugs on Heme Degradation ...... 27 1.5. Catabolism of Heme Compounds in Vivo ...... 29 1.5.1. Hemoglobin ...... 29 xi xii CONTENTS

1.5.2. Microsomal Cytochromes ...... 31 1.5.3. Myoglobin and Mitochondrial Cytochromes . . . 36 References ...... 38

Chapter 2 Hemoglobin Synthesis in Normal and Abnormal States Michael L. Freedman 2.1. Normal Hemoglobin Synthesis ...... 47 2.1.1. Ontogeny of Hemoglobin Synthesis ...... 47 2.1.2. Hemoglobin Synthesis during Erythropoiesis . . 48 2.1.3. Transcription, Processing, and Translation of Globin Messenger RNA ...... 53 2.1.4. Assembly of Hemoglobin...... 60 2.1.5. Molecular Control Mechanisms in Normal Hemoglobin Synthesis ...... 62 2.2. Abnormal Globin Synthesis ...... 71 2.2.1. Synthesis of Globin in Thalassemia and Related States ...... 71 2.2.2. Synthesis of Structurally Abnormal Hemoglobins ...... 7 8 2.2.3. Synthesis of Hemoglobin in Heme-Deficient States ...... 82 References ...... 85

Chapter 3 Clinical Significance of 2,3-Diphosphoglycerate in Hematology Frank A. Oski and Julia A. McMillan 3.1. Oxygen Transport and Delivery ...... 104 3.2. Factors Modifying Hemoglobin's Affinity for Oxygen . . . 107 3.3. Clinical Conditions Associated with Alterations in Red Cell 2,3-DPG ...... 110 3.3 .I. Cardiac Disease ...... 111 3.3.2. Hypoxemia of Altitude or Pulmonary Disease . 115 3.3.3. Anemia ...... 117 3.3.4. Abnormalities of Serum Inorganic Phosphate . 118 3.3.5. liver Disease ...... 119 3.3.6. Endocrine Disorders ...... 120 3.3.7. Blood Storage and Transfusion ...... 120 3.3.8. The Newborn Infant ...... 121 CONTENTS xiii

3.4. Physiologic Significance of Shifts in the Oxygen- Hemoglobin Dissociation Curve ...... 124 References...... 125

Chapter 4 The Interaction of Folate Ligands with Macromolecules Maria da Costa and Sheldon P. Rothenberg 4.1. Introduction ...... 131 4.2. Methods of Identification of Folate Binding Macromolecules ...... 132 4.3. Definition of Terminology ...... 133 4.4. Nonspecific Folate Binder Complexes in Serum ...... 135 4.5. Specific Folate Binder Complexes in Serum...... 136 4.6. Properties of the Specific Folate Binder in Serum ...... 138 4. 7. Significance of the Serum Folate Binder ...... 139 4.8. Serum Folate Binders and Radioassay for Folate ...... 140 4.9. Folate Binder in Erythrocytes ...... 141 4.10. Folate Binder in Granulocytes...... 141 4.11. Significance of Intracellular Folate Binder ...... 143 4.12. Folate Binders in Other Tissues ...... 144 4.13. Folate Binder in Milk ...... 145 4.14. Summary ...... 147 References ...... 14 7

Chapter 5 Pure Red Cell Aplasia Sanford B. Krantz and S. Donald Zaentz 5.1. Definition...... 153 5.2. Classification ...... 154 5.2.1. Congenital PRCA ...... 154 5.2.2. Acquired Primary PRCA ...... 155 5.2.3. Acquired Secondary PRCA ...... 155 5.3. Laboratory Manifestations ...... 159 5.3.1. Blood and Bone Marrow Morphology ...... 159 5.3.2. Other Laboratory Abnormalities ...... 160 5.4. Pathogenesis ...... 162 5.4.1. Congenital PRCA ...... 162 5.4.2. Acquired PRCA ...... 164 5.5. Treatment ...... 174 xiv CONTENTS

5.5.1. Congenital PRCA ...... 174 5.5.2. Acquired PRCA ...... 175 5.6. Conclusion ...... 182 References ...... 184

Chapter 6 Neutrophil Function: Normal and Abnormal Thomas P. Stossel and Harvey J. Cohen 6.1. Some General Comments Concerning Normal and Abnormal Neutrophil Function ...... 192 6.2. The Humoral Dimension of Neutrophil Function ...... 192 6.2.1. Factors with Chemotactic Activity for Neutrophils ...... 192 6.2.2. Inhibitors of Chemotactic Activity ...... 194 6.2.3. Opsonins ...... 195 6.2.4. Other Serum Factors ...... 195 6.3. The Cellular Dimension of Neutrophil Function ...... 197 6.3.1. Structure and Metabolism of Neutrophils . . . . . 197 6.3.2. Neutrophil Locomotion ...... 200 6.3.3. Ingestion ...... 201 6.3.4. Degranulation ...... 202 6.3.5. The Chediak-Higashi Syndrome...... 203 6.4. Oxygen Metabolism and Microbicidal Activity ...... 205 References ...... 210

Chapter 7 Phagocytosis: Role of C3 Receptors and Contact-Inducing Agents Alfred G. Ehlenberger and Victor Nussenzweig 7 .1. Introduction ...... 221 7.2. Role of Contact and Surface Forces in Phagocytosis . . . . 224 7.3. Role of C3 in Opsonization ..... :...... 225 7.4. The Effect of Binding and Contact-Inducing Agents on Ingestion ...... 230 References...... 236

Chapter 8 Leukocyte 5' -Nucleotidase Maryrose Conklyn and Robert Silber 8.1. Introduction ...... 241 CONTENTS xv

8.2. The Enzyme ...... 241 8.2.1. The 5'N Reaction ...... 241 8.2.2. Properties of the Enzyme ...... 242 8.2.3. Representative Methods Utilized in 5'N Assays 244 8.3. Studies on 5'N in Leukocytes ...... 245 8.3.1. Distribution of the Enzyme in Leukocytes . . . . . 245 8.3.2. Subcellular Localization of 5'N in Leukocytes . . 251 8.3.3. Studies of 5'N in Pathological Conditions . . . . . 252 8.3.4. Function of 5'N in Leukocytes ...... 255 8.4. Summary and Conclusions ...... 256 References ...... 2 58

Chapter 9 Metabolism and Functions of Monocytes and Macrophages Martin J. Cline and David W. Golde 9.1. Proliferation and Maturation ...... 263 9.1.1. Monoblast ...... 264 9.1.2. Promonocyte...... 264 9.1.3. Blood Monocyte...... 264 9.1.4. Tissue Macrophages ...... 265 9.2. Kinetics ...... 265 9.3. Metabolism ...... 266 9.4. Functions ...... 268 9.5. Defense against Microorganisms ...... 268 9.6. Removal of Damaged Cells and Inorganic Materials . . . . 270 9. 7. Cooperative Functions in Immune Responses ...... 271 9.8. Cell-Mediated Cytotoxicity and Antitumor Immunity . . . 272 9.9. Control of Granulopoiesis ...... 274 9.10. Mononuclear Phagocyte Dysfunction Syndromes ...... 275 9.11. Malignant Mononuclear Phagocytes ...... 27 6 9.12. Summary ...... 278 References...... 278

Chapter 10 The Production of Immunoglobulins by Mouse Myeloma Cells W. Cieplinski and M. D. Scharff 10.1. Introduction ...... 287 10.2. Plasma Cell Tumors and Cell Lines ...... 288 10.3. Types and Frequency of Spontaneous Variants ...... 290 10.4. Effect of Mutagenizing Agents on Mouse Myeloma Cells 292 10.5. Relationship to Human Heavy-Chain Disease ...... 293 xvi CONTENTS

10.6. Regulation of Immunoglobulin Synthesis, Assembly, and Secretion ...... 293 10.7. Posttranscriptional Events in the Production of Immunoglobulin ...... 297 10.8. Conclusions ...... 300 References ...... 301

Chapter 11 The Origin of RNA Tumor Viruses and Their Relation to Human Leukemia Robert C. Gallo and David H. Gillespie 11.1. Origin of RNA Tumor Viruses ...... 305 11.1.1. RNA-Containing Viruses Coded by Genes of Normal Cells...... 306 11.1.2. Type C RNA-Containing Viruses Not Coded by Genes of Normal Cells ...... 309 I 1.1.3. Class 2 Viruses Arise from Class 1 Viruses . . . . . 311 11.1.4. Type C RNA Viruses Are Transmitted among Hosts of Different Species in the Wild ...... 313 11.1.5. Primate Type C RNA Tumor Viruses ...... 314 11.2. Type C RNA Viruses in Human Cells ...... 318 11.2.1. Detection of Type C RNA Virus Components in Tissue of Leukemic Patients ...... 318 11.2.2. Natural Antibodies in Humans to Primate Type C Viruses ...... 327 11.3. Summary and Interpretations ...... 329 11.4. Deductions Concerning Viral Etiology of Human Leukemia ...... 330 References...... 336

Chapter 12 Immunological Aspects of Leukemia Ronald B. Herberman 12.1. Introduction ...... 345 12.2. Normal Cell Surface Markers and Leukemia-Associated Antigens ...... 346 12.2.1. Experimental Animal Systems ...... 34 7 12.2.2. Human Leukemia ...... 357 CONTENTS xvii

12.3. Immunosuppression in Leukemia ...... 362 12.3.1. Experimental Animal Systems ...... 362 12.3.2. Human Leukemia ...... 365 12.4. Immune Responses to Experimental Leukemias ...... 368 12.4.1. Humoral Immune Responses ...... 368 12.4.2. Cell-Mediated Immune Responses ...... 369 12.5. Clinical Studies on Immune Response to Leukemia- Associated Antigens ...... 370 12.5.1. Humoral Antibodies ...... 370 12.5.2. Cell-Mediated Immune Responses...... 373 12.6. Practical Clinical Applications of Immunology to Leukemia ...... 378 12.6.1. Diagnostic and Prognostic Tests...... 378 12.6.2. Immunotherapy...... 379 References ...... 380

Chapter 13 Antihemophilic Factor Oscar D. Ratnoff 13.1. Introduction ...... 399 13.2. Assays for Antihemophilic Factor ...... 400 13.3. The Site of Synthesis of AHF ...... 402 13.4. Purification of AHF...... 403 13.5. Chemical and Physical Properties of AHF ...... 403 13.5.1. Subcomponents of AHF ...... 405 13.6. The Antigenicity of AHF Preparations ...... 407 13. 7. Functions of AHF ...... 408 13.7.1. Procoagulant Activity ...... 408 13. 7.2. Ristocetin-Induced Platelet Aggregation ...... 409 13.7.3. Platelet Retention by Glass Bead Columns and Platelet Adhesion to Subendothelial Structures . 411 13.8. The AHF-like Properties of Platelets ...... 411 13.9. Variations in AHF in Physiologic and Nonhereditary Pathologic States ...... 412 13.10. Classic Hemophilia...... 413 13.10.1. The Nature of the Defect in Hemophilic Plasma 414 13.10.2. The Hereditary Nature of Classic Hemophilia and Detection of the Carrier State...... 415 13.10.3. Clinical Picture...... 417 13.10.4. Laboratory Diagnosis ...... 418 xviii CONTENTS

13.10.5. Therapy...... 419 13.1 0.6. Circulating Anticoagulants against A HF in Hemophilia and N onhemophilic States ...... 421 13.10.7. The Heterogeneous Nature of Classic Hemophilia ...... 423 13.11. Von Willebrand's Disease ...... 424 13.11.1. The Nature of von Wille brand's Disease ...... 424 13.11.2. Diagnosis ...... 427 13.11.3. Therapy...... 427 13.11.4. Variants of von Willebrand's Disease ...... 428 13.12. Acquired von Willebrand's Disease...... 429 13.13. Combined Deficiency of Antihemophilic Factor and Proaccelerin ...... 430 13.14. Combined Deficiency of Antihemophilic Factor and Plasma 1 hromboplastin Antecedent ...... 430 13.15. Animal Models of Hemophilia and von Willebrand's Disease ...... 431 References ...... 431

Chapter 14 Research on the Biochemical Basis of Platelet Function Thomas C. Detwiler and Israel F. Charo 14.1. Introduction ...... 455 14.2. Current Concepts of Platelet Function ...... 456 14.2 .1. The Physiological Role of Platelets ...... 456 14.2.2. Platelet Morphology ...... 456 14.2.3. In Vitro Responses of Platelets to Stimulation . . 458 14.2.4. Platelet Stimuli ...... 460 14.2.5. Inhibitors of Platelet Function ...... 460 14.3. Membranes ...... 460 14.3.1. Fluid Mosaic Model of Membranes ...... 460 14.3.2. Platelet Membranes...... 461 14.4. Physiological Stimuli ...... 463 14.4.1. Thrombin ...... 463 14.4.2. Collagen ...... 467 14.4.3. ADP ...... 471 14.4.4. Conclusion ...... 471 14.5. Intracellular Regulatory Mechanisms...... 472 14.5.1. Calcium ...... 472 14.5.2. Cyclic Nucleotides ...... 473 CONTENTS xix

14.5.3. Prostaglandins, Endoperoxides, and Thromboxanes ...... 475 14.5.4. Protein Kinases ...... 479 14.5.5. Conclusion ...... 480 14.6. Contractility ...... 480 14.6.1. Platelet Actomyosin ...... 481 14.6.2. Function of Platelet Contractile Proteins ...... 485 14.6.3. Microtubules ...... 486 14.6.4. Summary ...... 487 References ...... 487

Chapter 15 Significance of Platelet Volume Measurements Simon Karpatkin 15.1. Summary ...... 497 15.2. Introduction ...... 499 15.3. In Vivo Kinetic Studies during Basal Conditions ...... 501 15.4. Kinetic Studies during Thrombopoietic Stress ("Thrombopoietin" Injection) ...... 504 15.5. Kinetic Studies during Thrombopoietic Stress Induced by Blood Loss and/or Iron Deficiency ...... 505 15.6. Clinical Methodology for Platelet Volume Distribution Analysis of Human Platelets ...... 509 15.7. Clinical Significance of Megathrombocyte Measurements 511 15.8. Functional Capacity of Megathrombocytes ...... 514 15.9. Preferential Splenic Sequestration of Megathrombocytes 514 15.10. Platelet and Red Blood Cell Fragmentation in Severe Autoimmune Thrombocytopenia ...... 516 References ...... 520

Chapter 16 Mechanisms of Polycythemia John W. Adamson 16.1. Introduction ...... 523 16.2. Oxygen Transport and Erythropoietin Production in Normal Man ...... 523 16.3. Definition and Classification of Polycythemia...... 525 16.3.1. Normal Red Cell Mass ...... 526 XX CONTENTS

16.3.2. Increased Red Cell Mass ...... 527 16.4. Tissue Hypoxia...... 527 16.4.1. 0 2 Loading Defects ...... 527

16.4.2. 0 2 Transport Defects Due to Impaired Flow . . 530 16.4.3. 0 2 Unloading Defects...... 531 16.5. Autonomous Erythropoietin Production ...... 537 16.5.1. Neoplasms...... 537 16.5.2. Recessively Inherited Polycythemia ...... 538 16.6. Autonomous Marrow Function ...... 540 16.6.1. Pathogenesis ...... 540 16.6.2. Response to Humoral Regulators ...... 541 16.7. Overview ...... 543 References ...... 544

Chapter 17 Nutritional Anemias Overview; Megaloblastic Anemias Victor Herbert, Neville Colman, and Elizabeth Jacob 17.1. Nutritional Anemias Overview ...... 549 17.2. Folate (Folic Acid) Deficiency ...... 553 17.2.1. Frequency ...... 553 17.2.2. Diagnostic Aspects ...... 553 17.2.3. Metabolic Aspects ...... 555 17.2.4. Clinical Aspects ...... 557 17.3. Vitamin B12 Deficiency ...... 558 17.3.1. Inadequate Ingestion ...... 559 17.3.2. Stomach ...... 561 17.3.3. Small Bowel ...... 563 17.3.4. Pancreas ...... 567 17.3.5. Drugs ...... 567 17.3.6. Inadequate Utilization ...... 568 17.3.7. Increased Excretion ...... 568 17.3.8. Increased Requirement ...... 569 17.3.9. Increased Destruction ...... 569 References ...... 569

Index...... 583