Division of HaematologyJohns Hopkins University Medical SchoolBaltimore Maryland 3393_C000.fm Page vi Monday, November 19, 2007 1:58 PM... ADCC antigen-dependent cellular cytotoxicity AM
Trang 3CRC Press Taylor & Francis Group
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© 2008 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S Government works Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1 International Standard Book Number-13: 978-0-8493-3393-4 (Hardcover) This book contains information obtained from authentic and highly regarded sources Reprinted material is quoted with permission, and sources are indicated A wide variety of references are listed Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use
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Library of Congress Cataloging-in-Publication Data
Desk reference for hematology / edited by N.K Shinton 2nd ed.
p ; cm.
Rev ed of: CRC desk reference for hematology c1998.
Includes bibliographical references and index.
ISBN 0-8493-3393-8 (alk paper)
1 Hematology Handbooks, manuals, etc 2 Blood Diseases Handbooks, manuals, etc 3
Blood Handbooks, manuals, etc I Shinton, N K (N Keith) II CRC desk reference for hematology
[DNLM: 1 Hematologic Diseases Handbooks 2 Hematology Handbooks WH 39 D459 2006]
RB145.C69 2006
Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com
3393_C000.fm Page ii Monday, November 19, 2007 1:58 PM
Trang 4CRC Press is an imprint of the
Taylor & Francis Group, an informa business
Boca Raton London New York
Trang 5The intention of the publishers, editor, and authors of this book is to provide a majorsource of easily obtained, reliable information on hematology in one book, with specifictopics arranged in alphabetical order As this is mainly based on well-established knowl-edge, it has not been closely referenced The references provided here have been confined
to guidelines, reviews, and recently published articles on topics that are either sial or for which opinion has yet to be consolidated In addition, there is a bibliography
controver-of recommended further reading
The information has been made concise by the use of extensive cross-referencing withinthe book, as indicated by words printed in boldface Words thus highlighted within anarticle indicate that further information on the subject is available in a separate articleidentified by the emboldened words
Common abbreviations are listed in a separate table at the front of the book and arewidely identified throughout the text Acronyms for combination therapies are listedunder cytotoxic agents Manuscript references are superscript numbers; in-text referencesare numbers in brackets [1]
The nomenclature regarding hematopoietic and lymphoid tissue is that used in theWorld Health Organization (WHO) Classification of Tumors of Hematopoietic and Lym-phoid Tissues, a summary of which is included as an Appendix Color photographs ofcells or tissues have not been included, as these are well presented in many easily obtain-able publications Likewise, details of laboratory technical procedures are not included
It is my great pleasure to acknowledge the help that I have received from the authorsand from colleagues, in particular Dr R A Shinton, senior lecturer in medicine, University
of Birmingham, Birmingham, U.K., for reading the manuscript and Mrs Anne Caine,administrator, Division of Clinical Sciences, Warwick Medical School, University of War-wick, Coventry, U.K., for help in data processing
N K Shinton
Editor3393_C000.fm Page iv Monday, November 19, 2007 1:58 PM
Trang 6The indications and dosage of all drugs in this book are those recommended in the medicalliterature and in conformance with general medical practice The drugs do not necessarilyhave specific approval by the U.S Food and Drug Administration or of the EuropeanPharmaceutical Commission, either for use in the disorders or in the dosages recom-mended The package insert for each drug should be consulted for indications, contrain-dications, dosage, and adverse drug reactions, particularly in respect to weight and age
in children It is advisable for those using a specific drug to be aware of any revisedrecommendations, especially when prescribing drugs that have recently become available.3393_C000.fm Page v Monday, November 19, 2007 1:58 PM
Trang 7Rajesh Chopra, Ph.D., F.R.C.P., F.R.C Path.
University College Hospital Medical School
London, U.K
Christopher D Fegan, M.D., F.R.C.P., F.R.C.Path.
Llandaff HospitalCardiff, Wales, U.K
Edward C Gordon-Smith, M.A., M.Sc., M.B., F.R.C.P., F.R.C.Path.
Robert A Kyle, M.D.
Department of Hematology and Internal Medicine
Mayo ClinicRochester, Minnesota
Edwin Massey, M.B., F.R.C.P., F.R.C.Path.
National Blood ServiceBristol, U.K
Alan Morris, B.A., D.Phil.
Department of Biological SciencesUniversity of Warwick
Coventry, U.K
Miguel Ortin, M.D., Ph.D., M.R.C Path.
St George’s HospitalLondon, U.K
K John Pasi, M.B., Ph.D., F.R.C.P., F.R.C.Path., F.R.C.P.C.H.
Department of HaematologyThe Royal London HospitalLondon, U.K
Geoffrey D Poole, M.Sc., F.I.B.M.S
National Blood ServiceBristol, U.K
R Martin Rowan (deceased), F.R.C.P.(G), F.R.C.P.(E), F.R.C.Path.
TOA Medical Electronics (Europe)and
University of GlasgowGlasgow, Scotland, U.K
N Keith Shinton, M.D., F.R.C.P., F.R.C.Path.
Clinical Sciences, Research InstituteWarwick Medical School
University of WarwickCoventry, U.K
Jerry Spivak, M.D.
Division of HaematologyJohns Hopkins University Medical SchoolBaltimore Maryland
3393_C000.fm Page vi Monday, November 19, 2007 1:58 PM
Trang 8List of Comprehensive Entries
ABO(H) blood groups 1
Acquired aplastic anemia 6
Acquired immunodeficiency syndrome 9
Acute myeloid leukemia 25
Adverse reaction to drugs 42
Allogeneic stem cell transplantation 51
Anemia 63
Arterial thrombosis 86
Autologous blood transfusion 99
Autologous stem cell transplantation 101
Blood components for transfusion 116
Blood donation 126
Bone marrow 133
Cell-adhesion molecules 151
Cell cycle 154
Cell signal transduction 160
Cell surface receptors 171
Chronic myelogenous leukemia 187
Coagulation-factor concentrates 193
Cobalamins 200
Cold agglutinin disease 206
Colloids for infusion 208
Colony forming units 211
Complement 215
Cytokines 230
Cytotoxic agents 237
Deoxyribonucleic acid 246
Disseminated intravascular coagulation 255
Drugs used for hematological disorders 263
Erythrocytosis 280
Essential thrombocythemia 286
Factor VIII 294
Fanconi anemia 302
Fetal/neonatal transfusion 307
Fibrinogen 310
Fibrinolysis 314
Flow cytometry 321
Folic acid 326
Gene therapy 343
Genomics 347
Graft-versus-host disease 357
Granulocytes 360
Hemapheresis 373
Hematology 377 3393_C000.fm Page vii Monday, November 19, 2007 1:58 PM
Trang 9Hematopoiesis 381
Hemoglobin 399
Hemoglobinopathies 409
Hemolytic anemias 416
Hemolytic disease of the newborn 420
Hemophilia A 427
Hemorrhagic disorders 432
Hemostasis 435
Heparin 438
Hereditary hemochromatosis 443
Histiocytes 451
Hodgkin disease 457
Human immunodeficiency viruses 463
Human leukocyte antigen 468
Immune thrombocytopenic purpura 486
Immunodeficiency 490
Immunoglobulins 496
Infectious mononucleosis 508
Inflammation 510
Interleukins 514
Ionizing radiation 526
Iron 527
Iron deficiency 531
Leukemogenesis 549
Lymphocytes 570
Lymphoproliferative disorders 580
Malaria 593
Megaloblastosis 607
Molecular genetic analysis 618
Monoclonal antibodies 622
Monoclonal gammopathies 624
Myelodysplasia 633
Myeloma 640
Myeloproliferative disorders 644
Neonatal hematology 651
Neutropenia 657
Neutrophil 663
Neutrophilia 669
Non-Hodgin lymphoma 673
Paroxysmal nocturnal hemoglobinuria 692
Plasmacytoma 706
Platelet 707
Platelet function disorders 711
Point-of-care-testing 721
Polycythemia rubra vera 723
Porphyrias 727
Pregnancy 734
Pretransfusion testing 738
Prion disease 742
Protein C 745
Pure red cell aplasia 755 3393_C000.fm Page viii Monday, November 19, 2007 1:58 PM
Trang 10Red blood cell 766
Red blood cell transfusion 777
Reticulocytes 790
Rhesus (Rh) blood groups 793
Sickle cell disorder 806
Spleen 819
Thalassemia 836
Thrombocytopenia 843
Thrombosis 849
Thrombotic thrombocytopenic purpura 851
Transfusion-transmitted infection 862
Vascular endothelium 877
Venous thromboembolic disease 883
Viral infection disorders 888
Von Willebrand disease 895
Warfarin 899
Warm autoimmune hemolytic anemia 904 3393_C000.fm Page ix Monday, November 19, 2007 1:58 PM
Trang 11List of Illustrations
1 Diagrammatic representation of ABH blood group biochemistry 2
2 Schematic diagram of proximal events in immune-mediated marrow failure 7
3 Changes in CD4 cell counts (●) and plasma viremia () during HIV infection 10
4 Morphological changes in apoptosis 84
5 Separation of whole blood into components 118
6 Simplified scheme of plasma fractionation 121
7 Diagrammatic representation of the structure of bone marrow at a diaphysis 134
8 The integrin receptor family 152
9 Phases of the cell cycle: restriction point 155
10 Phases of the cell cycle: early G1-S transition 156
11 Phases of the cell cycle: late G1-S transition 156
12 Phases of the cell cycle: G2-M transition 157
13 The stages of mitosis 158
14 Intracellular signal transduction pathways 161
15 Ras-mediated signal transduction pathways 164
16 Role of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) in cytokine signaling 167
17 The canonical Wnt signaling pathway 169
18 Cross talk between tumor cells, endothelial cells, and stromal cells is modulated by the Notch pathway and stimulates tumor angiogenesis 170
19 Proposed mechanisms of the Hh pathway activation 171
20 G-protein-coupled receptors Classical examples of seven-transmembrane (7TM)-receptor signaling 172
21 Cytokine receptor superfamily type 2 174
22 Role of checkpoint kinases in DNA damage 177
23 Structure of methylcobalamin 200
24 Bone marrow colony forming units (in vitro) 211
25 A schema of contact activation 221
26 Hypothetical genealogy of hematopoietic tissue-supporting cells 243
27 Structure of DNA 247
28 Replication of DNA 248
29 Domain structure of factor V and factor VIII 292
30 Model of factor VIII and thrombin cleavage sites 294
31 Central role of factor X in the final common pathway of coagulation 297
32 Activation of factor XI 299
33 Conversion of fibrinogen to cross-linked fibrin 311
34 Plasmin digestion of fibrinogen and non-cross-linked fibrin by plasmin 312
35 Plasmin digestion of cross-linked fibrin 313
36 Normal fibrinolysis 315
37 Conversion of plasminogen to plasmin 316
38 Diagrammatic representation of cell-counting and cell-volume measurement by aperture impedance and the effect of nonaxial flow 323
39 Schematic illustration of a hydrodynamic-focused (sheathed flow) counter using the light-scattering principle 323 3393_C000.fm Page x Monday, November 19, 2007 1:58 PM
Trang 1240 Diagrammatic representation of cytometry by light scattering 324
41 Structure of folic acid 327
42 Reduced forms of folic acid 327
43 Compounds of folic acid 328
44 Folates in metabolic pathways 328
45 Gene-expression analysis using oligonucleotide microarray 348
46 Gene-expression analysis in two tissue samples using spotted DNA microarray 349
47 Granulocyte compartments 360
48 Changes in nuclear shape during neutrophil maturation 361
49 The Latham bowl 374
50 Temporal appearance of different types of assayable hematopoietic cells 382
51 Migration of progenitors that leads to definitive hematopoiesis 383
52 Schematic view of transcription factors and hematopoiesis 383
53 Stages of hematopoiesis in the embryo and fetus 385
54 Proportions of the various human hemoglobin polypeptide chains through early life 385
55 Proposed hierarchy of hematopoietic colony-forming potential 389
56 Molecular regulation of hematopoietic stem-cell niche 392
57 Surface phenotype of mouse and human hematopoietic stem cells 395
58 Structure of heme 397
59 Chemical steps in the biosynthesis of hemoglobin 398
60 Diagrammatic representation of the tertiary configuration of the myoglobin of sperm whale 400
61 Diagrammatic representation of the relationship between α- and β-globin chains in the hemoglobin tetramer 400
62 Steps in the development of hemoglobin shown diagrammatically 402
63 Oxygenated and deoxygenated hemoglobin molecule 402
64 Oxygen-dissociation curve 403
65 Degradation of hemoglobin 404
66 Diagrammatic representation of the overall hemostatic response following vessel wall injury 435
67 Classical “waterfall” hypothesis of coagulation 436
68 A revised coagulation cascade 437
69 Human immune deficiency virus (HIV) life cycle 464
70 The evolution of plasma laboratory markers of the naturalization of HIV infection 466
71 Induction of an immune response 467
72 Purine metabolism to uric acid 478
73 Schematic diagram of an immunoglobulin 497
74 Schematic diagram of light- and heavy-chain genes in mature B-cells 500
75 The structure of the V-Cµ-Cδ region of the heavy-chain genes of the mature B-cell 500
76 An IgG antibody positioned between two RBCs at the minimum distance of approach 506
77 Degradation of sphingolipids 561
78 Diagrammatic representation of the structure of a liver lobule 564
79 Diagrammatic representation of the lymph-node structure 568
80 Development of T-cells 573
81 Development of B-cells 573
82 Development of NK-cells 574 3393_C000.fm Page xi Monday, November 19, 2007 1:58 PM
Trang 1383 Flow diagram of investigation of macrocytic anemias 592
84 Life cycle of malaria plasmodium 593
85 Flow diagram of the investigation of microcytic anemia 614
86 Cycle of mitotic nuclear division 616
88 Polymerase chain reaction 620
89 Types of serum monoclonal protein 625
90 Diagnoses in patients with monoclonal protein 625
91 Relationship of the origin of myeloproliferative disorders 645
92 Simplified schematic diagram of the pathophysiology of neutropenia 657
93 Mechanisms of neutrophilia 669
94 Flow diagram of the investigation of normocytic anemia 680
95 Diagrammatic representation of nuclear shapes in Pelger-Huët anomaly 697
96 Diagrammatic representation of platelet ultrastructure 708
97 Cell signal transduction in the platelet-release reaction 710
98 Examples of platelet aggregation tracings 716
99 Structural formula of the porphyrin nucleus and diagrammatic representation of some naturally occurring porphyrins 730
100 Schematic diagram of the prion hypothesis 742
101 Diagrammatic representation of protein C and protein S activity 746
102 The proteomic process 749
103 Comparison of MALDI and SELDI mass spectroscopy 750
104 Diagrammatic representation of prothrombin activation 751
105 Red blood cell membrane cytoskeleton proteins 767
106 Metabolism of glucose by red blood cells 770
107 Diagrammatic representation of the histological structure of the spleen 820
108 Hypothetical stem cell development 827
109 Chart of thromboelastogram tracing 847
110 Diagrammatic representation of the structure of the thymus 853
111 Transcriptional regulation 860
112 Translation initiation in eukaryotes 866 3393_C000.fm Page xii Monday, November 19, 2007 1:58 PM
Trang 14List of Tables
1 Frequencies of the Major ABO Blood Groups 3
2 Laboratory Determination of ABO Blood Groups 4
3 Drugs Associated with Acquired Aplastic Anemia 6
4 Definition of Disease Severity of Aplastic Anemia (AA) 8
5 Morphological Features of Acute Lymphoblastic Leukemia 18
6 Classification and Incidence of Acute Lymphoblastic Leukemias by Immunophenotyping 19
7 Chromosomal Translocations and Genetic Alterations in Acute Lymphoblastic Leukemia 19
8 Prognostic Factors in Acute Lymphoblastic Leukemia 23
9 Association of FAB Subtype with Phenotypic Expression in Acute Myeloid Leukemia 26
10 Association of FAB Type with Chromosomal Abnormalities in Acute Myeloid Leukemia 28
11 Laboratory Features in Patients with Disseminated Intravascular Coagulation (DIC) in Acute Promyelocytic Leukemia 30
12 Hematological Adverse Reactions to Drugs 42
13 Drugs Commonly Causing Agranulocytosis 47
14 Hematological Effects of Alcohol 49
15 Indications for Allogeneic Stem Cell Transplantation, by Disease 52
16 Morphologic Classification of Anemia 65
17 Common Causes of Anemia by Morphology 65
18 Causes of Aplastic Anemia 82
19 Risk Factors for Arterial Thrombosis 88
20 Classification of Autoimmune Hemolytic Anemias 98
21 Indications for Autologous Blood Transfusion Procedures 99
22 Comparison of Intraoperative Blood Salvage (IBS) Systems 101
23 Advantages and Disadvantages of Autologous and Allogeneic Stem Cell Transplantation 102
24 Conditioning Protocols for Autologous Stem Cell Transplantation Used in Acute Myeloid Leukemia 102
25 Granules of Basophils and Mast Cells 110
26 Causes of Basophilia 111
27 Composition of Platelet Concentrates 120
28 Patients at Risk for TA-GVHD 124
29 Properties of Some Less Commonly Encountered Antigens and Antibodies of Blood Group Systems 130
30 Cytochemical and Histochemical Stains and Their Identifications 138
31 Causes of Bone Marrow Hypoplasia 140
32 The β1 (CD29, very late antigen [VLA]) Integrin Family 152
33 The β2 (CD18, leukocyte integrins) Integrin Family 153
34 The β3 (CD61, cytoadhesin) Integrin Family 153
35 The Selectin Family 154
36 Cytokine Signaling Abnormalities 171 3393_C000.fm Page xiii Monday, November 19, 2007 1:58 PM
Trang 1537 Staging of Chronic Lymphocytic Leukemia 187
38 Diagnostic Criteria for Chronic Neutrophilic Leukemia 191
39 Coagulation Factors and Their Synonyms 198
40 Ligands of Cobalamin 200
41 Typical Compositions of Human Albumin Solutions 209
42 Cytokine Nomenclature: Early Interleukins 232
43 Cytokine Nomenclature: Hematopoietic Factors 232
44 Cytokine Nomenclature: Nonhematopoietic Growth Factors and Other Growth Regulatory Cytokines 232
45 Cytokine Nomenclature: Antiviral Cytokines — Interferons (IFNs) 233
46 Cytokine Nomenclature: Tumor Necrosis Factors 233
47 Cytokine Nomenclature: Cytokines Involved in Pregnancy and Proliferation of Embryonic Cells 233
48 Summary of Major Cytokine Functions 234
49 Cytotoxic Combination Therapy 238
50 Reference Ranges in Health of Differential Leukocyte Counts (× 109/l) 252
51 Hemostatic Abnormalities in DIC 257
52 Clinical Manifestations of DIC 258
53 Drugs Associated with Vascular Purpura 263
54 Commonly Used Drugs in Hematological Disorders 263
55 Phenotypes and Genotypes of the Duffy (Fy) Blood Group System 266
56 Causes of Dyserythropoiesis 267
57 Platelet Abnormalities in Dysmegakaryopoiesis 269
58 Content of Eosinophil Granules 274
59 Inflammatory Mediators 276
60 Erythrocyte Sedimentation Rate Ranges in Health 280
61 Causes of Erythrocytosis 281
62 Clinical Features of Fanconi Anemia 302
63 Properties of Fc Receptors 304
64 Clinical Disorders Related to Abnormal Fibrinolysis 319
65 Common Fluorochromes 324
66 Folates and Their Activities 327
67 A Grading System for Chronic Graft-versus-Host Disease 358
68 Causes of Granulomata Formation 363
69 Disorders Causing Heinz Body Formation 371
70 Adverse Effects of Apheresis Donation 374
71 Temporal Expression of Globin Chains 386
72 Hematopoietic Growth Factors 390
73 Hematopoietic Regulators 391
74 Structure of Physiological Hemoglobin Chains 401
75 Reference Ranges in Health of Hemoglobin in Peripheral Blood 404
76 Classification of Hemolytic Anemias 418
77 Hereditary Hematological Disorders 443
78 Specialized Organ Role of Histiocytes 454
79 Estimated Regional Incidence of HIV Infection by 2005 468
80 Action of Drugs on Immune Functions 494
81 Relationship of Immunodeficiency with Common Infections 495
82 Antibiotics Appropriate to Opportunistic Infections 496
83 IgG Subtype Properties 498
84 Causes of Ineffective Erythropoiesis 507 3393_C000.fm Page xiv Monday, November 19, 2007 1:58 PM
Trang 1685 Roles of the Tissue Macrophages (Histiocytes) in Inflammation 511
86 Commonly Used Therapeutic Interferons and Their Brand Names 514
87 Summary of Sources, Stimuli, and Biological Activity of Interleukins 515
88 Dose-Related Effects of Penetrating Ionizing Radiation 526
89 Common Phenotypes and Genotypes of the Kell Blood Group System 538
90 Phenotypes and Genotypes of the Kidd (Jk) Blood Group System 540
91 Summary of Hematological and Biochemical Changes Induced by Lead Toxicity 546
92 Common Karyotypic Abnormalities and Molecular/Functional Correlates 549
93 Causes of Leukemoid Reactions 555
94 Causes of Leukoerythroblastic Anemia 559
95 Phenotypes and Genotypes of the Lewis Blood Group System 560
96 Characterizing Markers of Mature Resting Lymphocytes 572
97 Genotypic and Cytogenetic Changes of Lymphoproliferative Disorders 582
98 REAL Classification of Lymphoid Tumors 584
99 Comparison of Commonly Used Lymphoma Classifications 585
100 WHO Classification of Tumors of Lymphoid Tissue 585
101 Predominant Sites of Selected Lymphoproliferative Disorders at Presentation 587
102 Ann Arbor Staging System of Lymphomas 587
103 Immunophenotypes of Lymphoproliferative Disorders 588
104 Febrile Illness Depending upon Type of Plasmodium 595
105 Microscopic Differentiation of Malaria Plasmodia 596
106 Hematological Changes Associated with Malignancy 598
107 Causes of Megaloblastosis 607
108 Causes of Microcytosis 614
109 Phenotypes and Genotypes of the MNS Blood Group System 617
110 Therapeutic Use of Monoclonal Antibodies 623
111 Causes of Monocytosis 629
112 Forms of Mucopolysaccharidosis 631
113 FAB Classification of Myelodysplasia 634
114 Targets of Interaction and Drugs under Trial in Treatment of Myelodysplasia 638
115 Causes of Secondary Myelofibrosis 639
116 Clinical and Laboratory Features of Myeloproliferative Disorders 647
117 Reference Ranges of Common Neonatal Blood Parameters 652
118 Causes of Neonatal Thrombocytopenia 654
119 Causes of Neutropenia 658
120 Antineutrophil Antibodies 661
121 Content of Neutrophil Granules 663
122 Killing Mechanisms of Neutrophils 665
123 Causes of Neutrophilia 670
124 Non-Hodgkin Lymphoma Grading According to the Working Formulation 674
125 Disorders Induced by Parvovirus B19 Infection 694
126 Phenotypes of the P and Associated Blood Group Systems 695
127 Important Platelet Membrane Glycoproteins 708
128 Disorders of Platelet Function 712
129 Guidelines for Transfusion of Platelets 719
130 Diagnostic Scoring System for Polycythemia Rubra Vera 725
131 Laboratory Features of the Porphyrias 727 3393_C000.fm Page xv Monday, November 19, 2007 1:58 PM
Trang 17132 Association of Enzyme Deficiency with Clinical Porphyria 728
133 Drug Groups Associated with Acute Porphyria 729
Individual Drugs Associated with Acute Porphyria 729
134 Protozoan Infections Causing Hematological Disorders 753
135 Causes of Pure Red Cell Aplasia 755
136 Major Red Blood Cell Membrane Proteins 768
137 Ideal Characteristics of Blood Substitutes 781
138 Available Hematology Reference Materials 783
139 Causes of Reticulin Fibrosis of Bone Marrow 790
140 Genotypes and Phenotypes of the Rh Blood Group System 793
141 Coagulation Changes Induced by Various Snake Venoms 817
142 Clinical Phenotypes and Genotypes of Thalassemias 837
143 α-Thalassemia Syndromes 838
144 Severity of β-Thalassemias 839
145 Genotypes of β-Thalassemia Syndromes 839
146 Causes of Thrombocytopenia 844
147 Drugs Associated with Thrombocytopenia 845
148 Causes of Thrombocytosis 846
149 Forms of ADAMTS 13 Deficiency 851
150 Microorganisms Transmissible by Blood Transfusion 862
151 Risk of Transmission of Certain Viruses 863
152 Classification of Vascular Purpura 880
153 Syndromes of Vasculitis 881
154 Ranges for Normal and Abnormal Levels of Viscosity 892
155 Classification of Von Willebrand Disease 895
156 Classification of Von Willebrand Disease Type 2 897
157 Management of Hemorrhage Due to Excess Warfarin 901
Reference Range Tables I Reference Ranges of Hematological Values for Adults 945
II Hemoglobin Concentrations (g/dl) for Iron-Sufficient Preterm Infants 946
III Hemoglobin F and Hemoglobin A2 in the First Year of Life (Measured by Electrophoresis) 947
IV Red Blood Cell Reference Ranges on First Postnatal Day during the Last 16 Weeks of Gestation 947
V Red Blood Cell Reference Ranges from Birth to 18 Years 947
VI Mean Serum Iron and Iron Saturation Percentage 948
VII Values of Serum Iron, Total Iron-Binding Capacity, and Transferrin Saturation from Infants during the First Year of Life 948
VIII Red Blood Cell Enzyme Activities 949
IX Peripheral Blood Leukocytes Reference Ranges (×109/l) 949
X Reference Ranges of Platelets in Peripheral Blood 950
XI Reference Ranges for Folic Acid (μg/l) 950
XII Bone Marrow Cell Populations of Normal Infants in Tibial Bone Marrow (mean % ± SD) 951 3393_C000.fm Page xvi Monday, November 19, 2007 1:58 PM
Trang 18XIII References Ranges for Coagulation Tests in Healthy Full-Term Infants
during First 6 Months of Life 952XIV Reference Ranges for Coagulation Tests in Healthy Premature Infants
(30–36 Weeks Gestation) during the First 6 Months of Life 952
XV Reference Ranges for Inhibitors of Coagulation in the Healthy Full-Term
Infant during the First 6 Months of Life (mean ± 1 SD) 953XVI Reference Ranges for Inhibitors of Coagulation in Healthy Premature
Infants during the First 6 Months of Life 9533393_C000.fm Page xvii Monday, November 19, 2007 1:58 PM
Trang 19ADCC antigen-dependent cellular cytotoxicity
AML acute myeloid leukemia; acute myeloblastic leukemia
ANCA antineutrophilic cytoplasmic antibodies
APC antigen-presenting cell; activated protein C
APRT adenine phosphoribosyltransferase (transaminase)
APSAC acylated plasma streptokinase activator complex
APTT activated partial thromboplastin time
ARAM antigen-recognizing activation motif
3393_C000.fm Page xviii Monday, November 19, 2007 1:58 PM
Trang 20AT/AT-III antithrombin-III
BCR break-point cluster region (genetics)
CDA congenital dyserythropoietic anemia; 2′-chlorodeoxyadenosine
CFU-GEMM colony forming unit-granulocytes/erythroid/macrophages/
megakaryocytesCFU-GM colony forming unit-granulocytes/macrophages
CFU-Meg colony-forming unit-megakaryocyte
3393_C000.fm Page xix Monday, November 19, 2007 1:58 PM
Trang 21CHAD cold hemolytic anemia disease
CHOP cyclophosphamide, adriamycin, vincristine, and prednisone or
CLEVER common lymphatic and endothelial vascular endothelial receptor
CML chronic myeloid leukemia; chronic myelogenous leukemia
CNSHA congenital nonspherocytic hemolytic anemia
CNTFR ciliary neurotrophic factor receptor
CSF colony stimulating factor; cerebro-spinal fluid
CSHH congenital self-healing histiocytosis
DILS diffuse infiltrative lymphocytosis syndrome
3393_C000.fm Page xx Monday, November 19, 2007 1:58 PM
Trang 22DLBCL diffuse large B-cell lymphoma
EACA/EAPA epsilon-aminocaproic acid
EDRF endothelial-derived relaxing factor
FAB French-American-British (classification of leukemia)
FCAS familial cold-associated autoinflammatory disorder
FISH fluorescence in situ hybridization
FMAIT fetomaternal alloimmune thrombocytopenic purpura
rFVIII;c recombinant factor VIII coagulation
G-CSF granulocyte colony stimulating factor
3393_C000.fm Page xxi Monday, November 19, 2007 1:58 PM
Trang 23G-CSFR granulocyte colony stimulating factor receptor
GM-CSF granulocyte/macrophage colony stimulating factor
HAART highly active antiretroviral therapy
HAT/HIT heparin-associated/induced thrombocytopenia
acidified serum test
HGPRT hypoxanthine-guanine phosphoribosyltransferase
Trang 24HPA human platelet antigen
HPFH hereditary persistent fetal hemoglobin
HPP hereditary infantile pyropoikilocytosis
HPP-CFC high-proliferative-potential colony forming cell
HSCT hematopoietic stem cell transplantation
ICSH International Council for Standardization in Hematology
INR international normalized ratio (for prothrombin time)
IPSID immunoproliferative small intestinal disease
ISBT International Society of Blood Transfusion
ISTH International Society of Thrombosis and Hemostasis
3393_C000.fm Page xxiii Monday, November 19, 2007 1:58 PM
Trang 25IVT intravascular fetal transfusion
J-CML juvenile chronic myelocytic leukemia
LCAT lecithin cholesterol acyltransferase
LIFR leukocyte migration inhibiting factor receptor
3393_C000.fm Page xxiv Monday, November 19, 2007 1:58 PM
Trang 26MRI magnetic resonance irradiation
MTP microsomal triglyceride transfer protein
NADPH nicotinamide adenine dinucleotide phosphate reduced
NAPTT nonactivated partial thromboplastin time
NHFTR nonhemolytic febrile transfusion reaction
NOD nucleotide-binding oligomerization domain protein
NRTi nonnucleoside reverse transcriptase inhibitor
PAS para-aminosalicylic acid; periodicacid-Schiff
PBSCT peripheral blood stem cell transplantation
PCI protein C inhibitor; percutaneous coronary artery intervention
PCR-SSCP polymerase chain reaction-single stranded conformational
polymorphisms
3393_C000.fm Page xxv Monday, November 19, 2007 1:58 PM
Trang 27PG prostaglandin (e.g., PGE1)
PIVKA protein-induced vitamin K absence (or antagonist)
POEMS polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes
PTTK partial thromboplastin time with kaolin
PUVA psoralen and ultraviolet-A radiation therapy
RAEB refractory anemia with excess blasts
rFVIII;c recombinant factor VIII coagulation
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Trang 28RNI reactive nitrogen intermediate
SAG-M saline, adenine, glucose, and mannitol
S-phase cells in DNA-synthesis phase of cycle
STATS signal transducers and activators of transcription
TAFI thrombin-activatable fibrinolysis inhibitor
TA-GVHD transfusion-associated graft-versus-host disease
TAP transporters in antigen presentation; T-cell antigen presentation
TC-I, TC-II, TC-III transcobalamin I, II, III
TEC transient erythroblastopenia of childhood
Th/TH/TH T-lymphocyte helper cell
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Trang 29TIL tumor-infiltrating lymphocytes
TRALI transfusion-related acute lung injury
TRAP tartrate-resistant acid phosphatase
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Trang 30Preface ivNotice vContributors viList of Comprehensive Entries viiList of Illustrations xList of Tables xiiiAbbreviations xviiiA–Z 1APPENDIX I: WHO Classification of Tumors of Hematopoietic and
Lymphoid Tissues 911APPENDIX II: FAB Classification of Leukemia/Myelodysplasia 915Reference Range Tables 919References 929Internet References 951Bibliography 953Index 9553393_C000.fm Page xxix Monday, November 19, 2007 1:58 PM
Trang 313393_C000.fm Page xxx Monday, November 19, 2007 1:58 PM
Trang 32A monoclonal antibody that binds to glycoprotein IIb/IIIa (GpIIb/IIIa) on platelets andconsequently inhibits platelet function It is a Fab fragment of a human–mouse chimericmonoclonal antibody It has a very high affinity for (but a slow dissociation rate from) theGpIIb/IIIa Although it has a short half-life of 10 to 30 min, it has a long biological half-life due to its strong affinity to the GpIIb/IIIa receptor, which remains bound in circulationfor up to 15 days However, this prolonged presence has minimal residual activity, andplatelet function returns to baseline 12 to 36 h after therapy More than 80% of GpIIb/IIIamust be blocked to inhibit platelet function It has provided robust, consistent, and highlysignificant reductions in death or myocardial infarction in several large protein C inhibitor(PCI) trials; it is a preferred drug used during coronary interventions such as percutaneoustransluminal stenting Adverse drug reactions are those associated with hemorrhage and
hypersensitivity It should not be given to patients receiving drugs for activation of
fibrinolysis
ABETALIPOPROTEINEMIA
(Bassen-Kornweig syndrome) An autosomally recessive disorder caused by mutations of themicrosomal triglyceride transfer protein (MTP), resulting in defective synthesis of apoproteinB-100 in the liver and apoprotein B-48 in the interstitial cells Lipids, principally triglyceride,cholesterol, and cholesterol esters, are normally surrounded by a stabilizing coat of phospho-lipid Apoproteins are embedded in the surface of the complex of lipids and phospholipids
to form lipoproteins, which in this condition cannot be synthesized Low-density lipoproteins,such as chylomicrons, are absent from serum, leading to defective mobilization of triglycer-ides from the intestines and liver Plasma cholesterol and phospholipids are reduced, and theenzyme lecithin cholesterol acyltransferase (LCAT) is greatly reduced Triglycerides accumu-late in the absorptive cells of the small intestine, resulting in malabsorption in infancy withfailure to develop Fat intolerance and fat-soluble vitamin deficiency result in progressivecerebellar ataxia with peripheral neuropathy and retinitis pigmentosa Acanthocytes are seen
in the peripheral blood, their shortened red blood cell survival giving rise to a mild chronic
hemolytic anemia No specific treatment is available
ABO(H) BLOOD GROUPS Blood groups arising from two specific antigen–antibody systems located on red blood cells (RBCs) and platelets.
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Trang 332 ABO(H) BLOOD GROUPS
Biochemistry
The ABH antigens are carbohydrates, the A and B determinants being found at the termini
of the oligosaccharide chains of glycoproteins and glycolipids
Most ABH antigens on RBCs are glycoproteins, the carbohydrate portion usually beinglinked to protein, e.g., the anion transport protein (AE1 or Band 3) Because the ABH bloodgroup antigens are not localized to a particular protein, the antigens are also found widelydistributed in body tissues and occur in soluble form in secretions The presence or absence
of ABH substances in saliva determines the “secretor” status of the person (see Lewis blood groups)
Genetics and Phenotypes
The ABH antigens of RBCs are determined by genes belonging to the ABO and Hh bloodgroup systems Blood group genes in these systems specify glycosyl transferases thatcatalyze the transfer of monosaccharides from nucleotide sugars onto carbohydrate pre-cursors The product of the H gene is an alpha 1,2-L-fucosyl transferase The H antigenthat is produced is the biosynthetic precursor of the A and B antigens: the A gene specifies
an alpha 1,3-N-acetyl-D-galactosaminyltransferase, and the B gene specifies an D-galactosyltransferase (see Figure 1)
(alpha)1,3-FIGURE 1
Diagrammatic representation of ABH blood group biochemistry.
GalNAc Gal Carbohydrate Lipid or protein
Fuc L–fucose
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Trang 34ABO(H) BLOOD GROUPS 3
The O gene is a common allele at the ABO locus on chromosome 9 and does not result
in the production of A or B antigens A number of alleles at the ABO locus result in aweakened or altered expression of A and B antigens For example, RBCs of the A3 and
Ax phenotypes react with some anti-A antibodies, but not with others Weak phenotypes
may also have a nongenetic cause, e.g., old age and disease (particularly leukemia) Table 1shows the incidence of the major ABO phenotypes These frequencies vary significantlybetween different ethnic groups; for example, the incidence of blood group B is muchhigher in Africans and in Vietnamese ABO polymorphisms have been claimed to haveputative relationships with disease.1
A very rare allele at the H locus on chromosome 19 is the h gene, which results in noexpression of H, and since H is the precursor for A and B, people with the genotype hhhave no A, B, or H antigens on their RBCs These people are said to have the “Bombay”(Oh) null phenotype, because of its relatively high frequency in Bombay, India
Antibodies and Their Clinical Significance
Alloantibodies to the A, B, and H antigens are naturally occurring They are found in theplasma of people who lack the corresponding antigen and who have had no known RBCstimulus, e.g., transfusion or pregnancy (see Table 1) Exposure to widely distributedbacteria carrying ABH-determinant structures accounts for the production of anti-A andanti-B in infants Maternal ABO antibodies are often found in the plasma of newborns.Anti-A and anti-B (and anti-H found in Bombay persons) are often active at 37°C andbind complement, and may give rise to severe hemolytic transfusion reactions if incom-patible RBCs are transfused (see Red blood transfusion) ABO antibodies may cause
hemolytic disease of the newborn, but this is rarely severe, because:
ABO antigens are not fully developed on fetal RBCs
ABO antigens are present on tissues other than RBCs, allowing neutralization of theantibody to occur
Maternal ABO antibodies may be partly or wholly IgM
Weak examples of anti-A, anti-H, and, occasionally, anti-B are sometimes found in theplasma of persons who have weak or altered expressions of the relevant antigens Forexample, anti-A1 may be found in people with the phenotypes A2B and Ax These anti-bodies are rarely of clinical significance, but may cause problems in pretransfusion testing
ABO Blood Grouping
Determination of ABO groups is an essential requirement of pretransfusion testing
Anti-A and anti-B reagents are used to define the antigens on the patient’s RBCs, and the
TABLE 1
Frequencies of the Major ABO Blood Groups
Phenotype Genotype
Frequency in Caucasians (%)
ABO Antibody Regularly Present in Plasma
Trang 35(Spur cells) Abnormal red blood cells (RBCs) characterized by having 2 to 20 irregularlyplaced spicules or thornlike projections of unequal length These spicules are caused bychanges in the lipid content of the red blood cell membrane, possibly from reduction ofglycophospholipids with relative increase of sphingomyelin Once produced, the change
is usually irreversible Acanthocytes are associated with other disorders in some patients.Hereditary
• Abetalipoproteinemia
• Surface antigen polymorphisms:
McLeod phenotype of the Kell blood group – X-linked anomalyInhibition of Lutheran blood groups Lua and Lub – somatic dominantanomaly
• Red blood cell membrane disorders
High RBC membrane phosphatidylcholineAbnormal RBC membrane Band 3 protein
Laboratory Determination of ABO Blood Groups
Patient’s Blood Group
anti-A + – – + Cell or forward group
(reagent antibody tested against patient’s RBCs)
A cells – + + – Serum or reverse group
(patient’s serum or plasma tested against reagent RBCs)
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Trang 36ACIDIFIED SERUM LYSIS TEST 5
Acquired
• Liver disorders, particularly alcoholic cirrhosis
• Malnutrition
HypobetalipoproteinemiaAnorexia nervosa, cystic fibrosis
• Hypothyroidism and panhypopituitarism
• Infantile pyknocytosis
• Vitamin E deficiency in premature newborns
• Splenic hypofunction and splenectomy
Acanthocytes have a reduced red blood cell survival This may give rise to a mild chronic
hemolytic anemia (spur cell hemolytic anemia, Zieve’s syndrome)
ACETYLCHOLINESTERASE
(AChE) An enzyme of the erythrocyte (red blood cell) membrane that has greater activity
in young erythrocytes and decreases progressively with age This decrease in membraneAChE activity is a consistent erythrocyte abnormality in paroxysmal nocturnal hemoglo- binuria (PNH), reflecting defects in the phosphotidyl-inositol anchor
ACIDIFIED GLYCEROL LYSIS TEST
A screening test for hereditary spherocytosis In symptomless relatives of known cases,
it has a higher detection rate than the conventional osmotic fragility test of red blood cells, although the same principles apply, but it is also positive in other causes of sphero-cytosis It requires less blood than the osmotic fragility test and can be performed morerapidly Measurement is carried out in a recording spectrophotometer with the wavelengthset at 625 nm
ACIDIFIED SERUM LYSIS TEST
(Ham test) A test used for the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH).2
Red blood cells from defibrinated, oxalated, citrated, or ethylenediamine tetraacetate(EDTA) anticoagulated patient’s blood are treated at 37°C with normal or patient’s serumacidified to pH 6.5 to 7.0 Normal serum known to be strongly lytic to PNH cells should
be used, but the test should be repeated with the patient’s own serum to exclude a form
of congenital dyserythropoietic anemia — HEMPAS (hereditary erythroblastic clearity associated with a positive acidified serum test) — in which lysis occurs in onlyabout 30% of cells with normal serum and not at all with the patient’s own serum.HEMPAS patients have a negative sucrose lysis test, but this test is positive in those withPNH The lytic potency of normal serum varies and is destroyed by mild heat, even atlow temperature within a few days, so the serum should be used fresh Lysis is measured
multinu-as liberated hemoglobin in a spectrophotometer at the wavelength of 540 nm In PNH, 10
to 15% lysis is usually obtained, with a range of 5 to 80% If the patient has been recentlytransfused, the degree of hemolysis will be reduced Confirmation of the diagnosis ofPNH requires the demonstration of GPI-linked molecules within the red blood cell mem-brane by flow cytometry
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Trang 376 ACQUIRED APLASTIC ANEMIA
ACQUIRED APLASTIC ANEMIA
(Idiopathic aplastic anemia) An uncommon disorder, with an incidence of 1 to 2 per millionper year in Western countries and perhaps twice or three times as common in China,Southeast Asia, and Japan.3 All ages are affected, with a peak incidence in young adultsand again in older patients In children and young adults, acquired aplastic anemia must
be distinguished from congenital types; in the elderly, it must be distinguished frommyelodysplastic syndrome The majority of cases (70%) are idiopathic; 15% follow expo-sure to drugs, which only rarely cause blood dyscrasias, and about 10% follow a hepaticillness, presumed to be viral, although no specific agent has yet been identified Theremaining cases follow other known viral infections or exposure to industrial or domesticagents Drugs associated with aplastic anemia are shown in Table 3
Pathogenesis
The disease is the result of dysfunction in the hematopoietic stem cell population There
is reduction in the number of CD34+ hematopoietic precursors Remaining cells have aproliferative defect The most convincing evidence suggests that the damage is caused byautoimmune cytotoxic T-cell attack In vitro evidence to support the autoimmune hypoth-esis has been summarized3–5a:
60 to 80% respond to immunosuppressive therapy using ATG and ciclosporin
Increased levels of cytokines that inhibit hematopoiesis (IFN-γ, TNF-α)
Increased Fas-antigen expression on bone marrow CD34+ cells
Activated cytotoxic CD8+ T-cells present in blood and bone marrow
quinacrine Nonsteroidal anti-inflammatory drugs phenylbutazone
indomethacin naproxen diclofenac ibuprofen piroxicam Antirheumatic gold salts
D-penicillamine
methylthiouracil propylthiouracil Psychotropic/antidepressants phenothiazines
mianserin dothiepin Anticonvulsants carbamazepine
phenytoin Antidiabetics chlorpropamide Carbonic anhydrase inhibitors acetazolamide
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Trang 38ACQUIRED APLASTIC ANEMIA 7
Oligoclonal expansion of CD8+ T-cells
Upregulation of apoptosis and immune response genes
Human leukocyte antigen (HLA) restriction with overrepresentation of HLA-DR15
In acquired aplastic anemia, activated cytotoxic T-cells secrete cytokines such as tumornecrosis factor (TNF)-α and interferon (IFN)-γ, which inhibit hematopoietic progenitorcells (HPC) TNF-α and IFN-γ upregulate the expression of the Fas receptor on HPCs,triggering apoptosis Increased production of interleukin-2 results in expansion of T-cells.TNF-α and IFN-γ also increase nitric oxide (NO) production by marrow cells, which maycontribute to immune-mediated cytotoxicity and elimination of HPCs This is summarized
in Figure 2
Laboratory Features
The laboratory diagnosis depends upon the peripheral-blood cell levels, film examination, and bone marrow aspirate and trephine Other conditions that lead topancytopenia, particularly acute leukemias, must be excluded In the peripheral bloodthere is anemia, granulocytopenia, and a low platelet count Lymphocytes are normal innumber or reduced Typically there is some red blood cell macrocytosis and the reticulocytecount is low, either absolutely or in proportion to the degree of anemia Fetal hemoglobinlevels may be normal or slightly elevated, but these are not helpful in the differentialdiagnosis There may be some variation in size and shape of red cells, although this is notusually marked The presence of nucleated red cells raises the possibility of paroxysmalnocturnal hemoglobinuria (PNH) or myelodysplastic syndrome (MDS) Neutrophils arereduced, but their morphology is normal apart from some increase in granulation, so-called toxic granulation There is typically no shift to the left Platelet numbers are reduced,and the platelets are mostly small in size Abnormal cells including blasts or hairy cellsare significantly absent The diagnosis ultimately rests on bone marrow examination.Aspiration in typical cases is “easy.” The marrow films contain many fragments that are
peripheral-blood-of hypocellular, “lacy” appearance, and the cell trails are hypocellular, with mainly phocytes and nonhematopoietic cells remaining The bone marrow trephine is the keyinvestigation There is usually overall hypocellularity, with hematopoietic marrow
lym-FIGURE 2
Schematic diagram of proximal events in immune-mediated marrow failure: IFN- γ = interferon- γ ; IRF-1 = IFN regulatory factor-1; NOS = nitric oxide synthase; TNF = tumor necrosis factor (From Young, N.S., Rev Clin Exp Haematol., 4, 426–459, 2000 With permission.)
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Trang 398 ACQUIRED APLASTIC ANEMIA
replaced by fat cells, although cellular, or even hypercellular islands (“hot spots”), may
be found Reticulin is not increased, and no abnormal cells are seen Cytogenetic analysis
of the marrow is difficult, but it is usually normal, although abnormal clones, particularly
of trisomy 8 or monosomy 7, are occasionally found The significance is uncertain,
some-times indicating progression to MDS or acute leukemia There is no increased
chromo-somal instability in response to clastogens, as is seen in Fanconi anemia Mutations in
telomeres, with alterations in the ribonucleic protein complex responsible for synthesis
and maintenance of telomere repeats, has been reported.6
Clinical Features
The pancytopenia develops slowly, such that symptoms, which are the consequence of
the cytopenias, may be delayed.7 Purpura, easy bruising, or repeated epistaxis that is
difficult to control are common presentations Persistent sore throat with or without fever
and pallor, tiredness, or other effects of anemia may also be presenting features The course
of the untreated disease depends upon the severity of the bone marrow failure, as reflected
in the peripheral blood The degree of hypoplasia may remain stable over the ensuing
months or years or become more severe, necessitating therapeutic intervention
Paroxys-mal nocturnal hemoglobinuria and myelodysplasia, which may further progress to acute
myeloid leukemia, develop in 10 to 20% of patients Spontaneous recovery rarely occurs
Treatment
General Supportive Measures
Before specific treatment became available, only about 10% of patients with SAA or VSAA
(see Table 4) survived more than 1 year Current management depends on red blood cell
transfusion and platelet transfusion to correct the cytopenias and on prevention and
treatment of infection consequent upon any neutropenia. Definitive treatments to restore
stem cell function rely either on immunosuppression to allow partial or complete recovery
of peripheral blood pancytopenia, or stem cell transplantation to replace stem cells.8
Immunosuppression (IS)
The standard therapy is with intravenous immunoglobulin, antilymphocyte globulin
(ALG), given daily for 5 days (Some preparations are labeled antithymocyte globulin, or
ATG.) Ciclosporin, started after the ALG, may increase the rate and incidence of remission,
and some remissions are ciclosporin dependent About 65% of patients will achieve
remis-sion as defined as freedom from transfuremis-sion dependence Response is similar at all ages,
TABLE 4
Definition of Disease Severity of Aplastic Anemia (AA)
Severe (SAA) bone-marrow cellularity <25%, or 25–50% with <30% residual hematopoietic cells;
with 2/3 of the following:
neutrophils <0.5 × 10 9 /l platelets <20 × 10 9 /l reticulocytes <20 × 10 9 /l Very severe (VSAA) as for severe AA but with neutrophils <0.2 × 10 9 /l
Nonsevere (NSAA) patients not fulfilling the criteria for severe or very severe AA; with a hypocellular
marrow with 2/3 of the following:
neutrophils <1.5 × 10 9 /l platelets <100 × 10 9 /l hemoglobin <10 g/dl
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Trang 40ACQUIRED IMMUNODEFICIENCY SYNDROME 9
and IS remains the treatment preferred for patients over the age of 40 years with severe
or very severe aplastic anemia, even if a suitable donor is available Improvement is slow,counts rarely improving before 6 weeks following ALG and may be delayed for 6 months
or more Second or third courses of IS may be effective in inducing remission in a fewpatients Relapse, defined as a return to transfusion dependence, occurs in up to 40% ofresponders over 10 years
High-dose cyclophosphamide, with or without ATG, apart from its use as a conditioningtherapy prior to transplantation, can be particularly useful when a suitable donor is
not available Monoclonal antibody therapy with anti-CD20 (rituximab) and anti-CD52 (alemtuximab) is being evaluated for refractory cases.
Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT) See also Allogeneic stem cell transplantation; Hematopoietic stem cell assays When a human leukocyte antigen (HLA)-compatible sibling donor is available, HSCT is
the treatment of choice for children with SAA or VSAA and for adults under 40 years ofage with VSAA HSCT from unrelated, HLA-matched volunteer donors has become moresuccessful with the development of less-toxic conditioning regimens and is offered fol-lowing failure of IS treatment for younger patients Event-free survival is about 70% and
is age dependent, as with all HSCT Survivors do not have a higher incidence of abnormalclones of PNH or MDS cells arising Children have normal growth and fertility so long
as irradiation is avoided in conditioning for transplant
ACQUIRED HEMOLYTIC ANEMIA
See Hemolytic anemias.
ACQUIRED IMMUNODEFICIENCY SYNDROME
(AIDS) A clinical disorder arising from immunodeficiency following infection, usually by the human immunodeficiency virus-1 (HIV-1), less commonly by HIV-2, and rarely by
an undetermined cause The first patients to be infected were identified in 1981 Sincethen, the incidence has rapidly increased throughout the world; by 2003, an estimated
20 million had died from the disease Early diagnosis by HIV screening is recommended.20
Clinical Features
These occur in stages over a number of years Due to differences in immunologicalresponse, they must be considered separately for adults and infants
Adults
The best indicator of progression is the level of CD4 lymphocytes, as measured by flow
cytometry (see Figure 3)
Acute Seroconversion Syndrome
During the prodromal stage (10 to 40 days), evidence of viremia can be detected At theend of this time, approximately 50% of individuals develop an inflammatory illness similar
to infectious mononucleosis with transient lymphadenopathy, fever, pharyngitis, myalgia,
arthralgia, maculopapular skin eruptions, aphthous ulcerations, diarrhea, nausea, vomiting,and headache Neuropathic symptoms such as peripheral neuropathy or asymptomatic