This book is a completely revised new edition of the definitive reference on disorders of hemoglobin. Authored by world-renowned experts, the book focuses on basic science aspects and clinical features of hemoglobinopathies, covering diagnosis, treatment, and future applications of current research. While the second edition continues to address the important molecular, cellular, and genetic components, coverage of clinical issues has been significantly expanded, and there is more practical emphasis on diagnosis and management throughout. The book opens with a review of the scientific underpinnings. Pathophysiology of common hemoglobin disorders is discussed next in an entirely new section devoted to vascular biology, the erythrocyte membrane, nitric oxide biology, and hemolysis. Four sections deal with ? and ? thalassemia, sickle cell disease, and related conditions, followed by special topics. The second edition concludes with current and developing approaches to treatment, incorporating new agents for iron chelation, methods to induce fetal hemoglobin production, novel treatment approaches, stem cell transplantation, and progress in gene therapy.
Author(s): Martin H. Steinberg, Bernard G. Forget, Douglas R. Higgs, David J. Weatherall
Edition: 2nd
Publisher: Cambridge University Press
Year: 2009
Language: English
Pages: 884
Half-title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
List of Contributors......Page 11
Foreword......Page 17
Preface......Page 19
Introduction......Page 21
SECTION ONE THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS......Page 23
Mesoderm......Page 25
Extraembryonic Hematopoiesis: Yolk Sac......Page 26
Intraembryonic Hematopoiesis: Paraaortic Splanchnopleura/Aorta-Gonad-Mesonephros......Page 27
Secondary Hematopoietic Territories: Liver and Bone Marrow......Page 28
The Embryonic Hematopoietic Hierarchy......Page 29
Myelopoiesis......Page 30
Erythroid–Myeloid Progenitors: CFU-C......Page 31
Hematopoietic Stem Cells......Page 32
A Model of the Embryonic Hematopoietic Hierarchy......Page 33
Avian......Page 34
Mammals......Page 35
Signaling Pathways......Page 36
Transcription Factors......Page 38
Epigenetic Factors......Page 39
REFERENCES......Page 40
ZEBRAFISH (Danio rerio)......Page 46
ERYTHROID DEVELOPMENT IN THE CHICKEN (Gallus gallus)......Page 47
ERYTHROID DIFFERENTIATION......Page 48
LIQUID CULTURE OF ERYTHROID CELLS......Page 51
ERYTHROPOIETIN......Page 52
ERYTHROPOIETIN RECEPTOR AND CELL SIGNALING......Page 53
KNOCKOUT PHENOTYPES OF SIGNAL TRANSDUCTION MOLECULES INVOLVED IN ERYTHROPOIESIS......Page 54
ERYTHROBLASTIC ISLANDS ARE THE STRUCTURAL UNITS OF DEFINITIVE ERYTHROPOIESIS......Page 55
STRESS ERYTHROPOIESIS......Page 56
TRANSCRIPTIONAL REGULATION OF ERYTHROPOIESIS TRANSCRIPTION FACTORS REQUIRED FOR THE STEM CELLEARLY PROGENITOR COMPARTMENT AFFECT ERYTHROPOIESIS......Page 57
GATA-1 MUTATIONS IN HUMAN DISEASE......Page 58
EKLF......Page 59
GENE EXPRESSION DURING ERYTHROID MATURATION......Page 60
REFERENCES......Page 61
NUMBER AND CHROMOSOMAL LOCALIZATION OF HUMAN GLOBIN GENES......Page 68
DETAILED CHROMOSOMAL ORGANIZATION OF THE HUMAN GLOBIN GENES......Page 69
GENOMIC CONTEXT OF THE α-GLOBIN AND β-GLOBIN GENE CLUSTERS......Page 72
Common versus Lineage-specific Regulation......Page 73
Basal Promoters......Page 74
Upstream Regulatory Sequences......Page 75
Proximal Enhancers......Page 77
Distal Enhancers......Page 78
REFERENCES......Page 80
GENERAL PRINCIPLES......Page 84
Biochemical Purification......Page 85
MICROARRAY ANALYSIS TO IDENTIFY TRANSCRIPTION FACTOR TARGET GENES......Page 86
DEFINING PHYSICAL INTERACTIONS BETWEEN DISTANT DNA ELEMENTS......Page 87
ELUCIDATING GENE FUNCTION BY TARGETED MUTAGENESIS......Page 88
The GATA Protein Family......Page 89
GATA-1–Interacting Proteins......Page 90
GATA-1 and Human Disease......Page 91
EKLF and Other CACCC Box-binding Proteins......Page 92
Broader Roles for EKLF in Erythroid Development......Page 93
EKLF-related Transcription Factors......Page 94
NF-E2 and Related Proteins......Page 95
Candidate Nuclear Factors Involved in Globin Switching......Page 96
Summary and Perspective......Page 97
REFERENCES......Page 98
Models of Cellular Control......Page 108
The Question of Developmental Clock of Switching......Page 109
Regulatory Elements of the ε-Globin Gene......Page 110
Regulatory Elements of the β-Globin Gene......Page 111
Globin Gene Silencing......Page 112
Control of HbF in the Adult......Page 114
THE CONCEPTUAL BASIS OF PHARMACOLOGICAL INDUCTION OF FETAL HEMOGLOBIN SYNTHESIS......Page 115
Role of the BCL11A Locus......Page 116
REFERENCES......Page 117
Oxygen Transport......Page 123
Transport of Other Gases......Page 126
HbS Polymer......Page 127
Higher Order Aggregation of HbS......Page 128
HbS Thermodynamics......Page 130
Effectors of Polymerization......Page 131
Copolymerization of HbS with Other Hemoglobins......Page 132
Kinetics of Polymerization......Page 133
HbS Polymer Melting......Page 134
HbS Polymerization in Red Blood Cells......Page 135
REFERENCES......Page 136
Functional Properties......Page 141
Modulation of HbF Levels......Page 142
Cellular Heterogeneity of HbF......Page 143
Medical Conditions Associated with Increased HbF......Page 144
Mutations of the γ-Globin Genes (HBG2, HBG1)......Page 145
The δ-Globin Gene and δ Globin......Page 146
Clinical Aspects of HbA2......Page 148
Function......Page 151
Glycated Hemoglobins......Page 152
Other Minor Hemoglobins......Page 154
REFERENCES......Page 155
SECTION TWO PATHOPHYSIOLOGY OF HEMOGLOBIN AND ITS DISORDERS......Page 159
Red Cell Rheology......Page 161
Factors Affecting Vascular Biology......Page 162
Mechanisms of Sickle Red Cell Adhesion......Page 164
Sickle Red Cell Adhesion and the Endothelial Response......Page 168
Vascular Function......Page 169
Red Cell Rheology......Page 172
CONCLUSIONS......Page 173
REFERENCES......Page 174
Membrane Pathobiology......Page 180
The Membrane Skeleton......Page 181
Membrane Lipids......Page 183
ALTERATIONS IN CATION CONTENT AND CELLULAR HYDRATION......Page 186
Deoxygenation-induced Cation Leak, Sodium–Potassium ATPase, Cell Sodium, and Sodium/Hydrogen Exchange in Sickle Erythrocytes......Page 187
Cell Calcium and Calcium-activated Potassium Channel (Gardos Pathway) in Sickle Erythrocytes......Page 189
Potassium Chloride Cotransport in Sickle Erythrocytes......Page 191
MULTITRACK MODEL OF SICKLE CELL VOLUME REGULATION PATHOBIOLOGY......Page 194
Pharmacological Inhibition of Sickle Cell Dehydration......Page 195
SUMMARY......Page 196
REFERENCES......Page 197
Nitric Oxide Synthesis......Page 207
Bioreactivity of Nitric Oxide......Page 208
Bioreactivity of Nitric Oxide with Hemoglobin......Page 209
Nitric Oxide and Hemoglobin–Oxygen Affinity......Page 211
HYPOXIC VASODILATION......Page 212
Vascular Tone......Page 213
Vascular Permeability......Page 214
Apoptosis......Page 215
Platelet Adhesion and Aggregation......Page 216
Leukocyte Adhesion......Page 217
REFERENCES......Page 218
Oxidation of Erythrocyte Proteins and Lipids......Page 223
Membrane Phospholipid Asymmetry......Page 224
Fragility of ISCs to Mechanical and Shear Stress......Page 225
CLEARANCE OF HEMOGLOBIN......Page 226
Hemolysis-associated Vascular Dysfunction: A Unique State of NO Resistance in Hemolytic Diseases......Page 228
Hemolysis, Coagulation and the Spleen......Page 231
Priapism and Hemolytic Anemia......Page 233
Pulmonary Arterial Hypertension in Sickle Cell Disease and Thalassemia......Page 234
Prognosis of Patients with Sickle Cell Disease and Pulmonary Hypertension......Page 235
Pulmonary Hypertension in Children with Sickle Cell Disease......Page 236
Diagnosis, Evaluation and Therapy of Pulmonary Hypertension in Sickle Cell Disease......Page 237
REFERENCES......Page 238
THALASSEMIC MICE......Page 247
Sickle Transgenic Mice......Page 249
Erythrocytes of Transgenic Mice......Page 251
Organ Pathology in Sickle Mice......Page 252
SUMMARY......Page 254
Reference Resources......Page 255
REFERENCES......Page 256
SECTION THREE α THALASSEMIA......Page 261
INTRODUCTION......Page 263
Chromosomal Rearrangements Involving 16p13.3......Page 265
Variation in the Number of Globin Genes......Page 266
Restriction Site Polymorphisms......Page 267
α Thalassemia due to Deletions......Page 268
α0-Thalassemia due to Deletions of the Structural α-Globin Genes......Page 270
α0 THALASSEMIA DUE TO A DELETION OF THE α-1-GLOBIN GENE THAT ALSO INACTIVATES THE α2-GLOBIN GENE......Page 272
α THALASSEMIA DUE TO DELETIONS OF THE α-GLOBIN REGULATORY ELEMENT......Page 273
Mutations Affecting the Poly(A) Addition Signal......Page 274
Mutations Affecting Initiation of mRNA Translation......Page 276
Chain Termination Mutants......Page 277
MOLECULAR DIAGNOSIS OF α THALASSEMIA......Page 278
REFERENCES......Page 279
α/β-Globin mRNA and Globin Synthesis Ratios in α Thalassemia Trait......Page 288
Red Cell Indices and Hematological Findings in α Thalassemia Trait......Page 289
Hemoglobin Analysis in α Thalassemia Trait......Page 292
Management and Genetic Counseling of α Thalassemia Trait......Page 295
α Thalassemia Trait and Pregnancy......Page 296
α THALASSEMIA CAUSING MILD HEMOLYTIC ANEMIA......Page 297
The Pathophysiology of HbH Disease......Page 298
Hemoglobin Analysis in HbH Disease......Page 299
Blood Transfusion......Page 300
Iron Status in Patients with HbH Disease......Page 301
Treatment of Patients with HbH Disease......Page 302
HEMOGLOBIN BART'S HYDROPS FETALIS SYNDROME......Page 303
Developmental Changes in Hemoglobin Composition......Page 304
Maternal Complications......Page 305
Hemoglobin H Hydrops Fetalis......Page 306
Prevention and Management......Page 307
Interactions Between α Thalassemia and α-Globin Structural Variants......Page 308
Interactions Between α Thalassemia and β-Globin Structural Variants......Page 309
α Thalassemia in Homozygotes and Compound Heterozygotes for β-Chain Abnormalities......Page 310
REFERENCES......Page 311
THE ATR-16 SYNDROME......Page 318
Defining the Genetic Abnormalities in Patients with ATR-16 Syndrome......Page 321
How Do Chromosomal Abnormalities Give Rise to the ATR-16 Syndrome?......Page 323
Summary of the ATR-16 Syndrome......Page 325
The Clinical Findings of the ATR-X Syndrome......Page 326
The Hematological Findings of the ATR-X Syndrome......Page 327
Identification of the ATR-X Disease Gene......Page 328
Characterization of the ATRX Gene and Its Protein Product......Page 329
Is There Any Relationship Between the Types of ATRX Mutation and the Phenotype?......Page 330
The Relationship Between the Types of Mutation in ATRX and Thalassemia......Page 331
What is the Normal Functional Role of ATRX?......Page 332
Summary of the ATR-X Syndrome......Page 333
AN ACQUIRED FORM OF α THALASSEMIA ASSOCIATED WITH MYELOID MALIGNANCY (ATMDS SYNDROME)......Page 334
Red Cell Indices and Hematological Findings in ATMDS......Page 335
Hemoglobin Analysis in ATMDS......Page 336
Implications of ATRX Mutations in ATMDS......Page 337
Summary of ATMDS Syndrome......Page 338
REFERENCES......Page 339
SECTION FOUR THE β THALASSEMIAS......Page 343
Nondeletion Forms of β Thalassemia......Page 345
Mutations of Splice Site Consensus Sequence......Page 350
Mutations that Create New Alternative Splice Sites in Introns......Page 351
MUTATIONS AFFECTING THE INITIATION CODON......Page 352
DELETIONS RESTRICTED TO THE β-GLOBIN GENE......Page 353
Missense Mutations......Page 354
Elongated or Truncated Variants with Abnormal Carboxy Terminal Ends......Page 357
Normal HbA2 β Thalassemias......Page 358
Somatic Deletion of β-Globin Gene......Page 359
Classification......Page 360
DELETIONS RESULTING IN HPFH OR δβ THALASSEMIA......Page 362
GγAγ(δβ)0 THALASSEMIAS......Page 363
HEMATOLOGY RESULTS AND HEMOGLOBIN ANALYSIS......Page 364
Intercellular Distribution of HbF in HPFH and δβ Thalassemia......Page 365
Newly Apposed Enhancer Sequences......Page 366
Mutations of the γ Gene Promoters......Page 367
HPFH UNLINKED TO THE β-GLOBIN CLUSTER......Page 369
δβ THALASSEMIA AND HPFH CONCLUSIONS......Page 370
REFERENCES......Page 371
THE SEVERE TRANSFUSION-DEPENDENT FORMS OF β THALASSEMIA: β THALASSEMIA MAJOR......Page 379
Diagnostic Difficulties at Presentation......Page 380
Course Through Childhood in Inadequately Transfused Patients......Page 381
The Well-transfused Thalassemic Child......Page 382
Hypersplenism and Plasma-Volume Expansion......Page 383
Cardiac Complications......Page 384
Lung Disease and Pulmonary Hypertension......Page 387
Endocrine Dysfunction......Page 388
Infection......Page 391
Liver disease......Page 395
Other Vitamin and Trace Metal Deficiencies......Page 397
Intelligence and Behavioral Patterns......Page 398
Peripheral Blood and Marrow......Page 399
Serum Iron......Page 400
Hemoglobin A2......Page 401
How is β Thalassemia Intermedia Defined?......Page 402
Interactions of “Silent” or “Mild” β......Page 403
Interactions of Mild beta Thalassemia Alleles......Page 404
Interactions between α and β Thalassemia......Page 405
Heterozygous β Thalassemia with an Unusually Severe Phenotype......Page 406
Clinical Features......Page 407
Cardiac Function......Page 408
Infection......Page 409
Red Cell Survival, Ferrokinetics, and Erythrokinetics......Page 410
Hematological Findings......Page 411
Life Expectancy......Page 412
Phenotypic Characteristics in Relationship to Different Molecular Forms of β Thalassemia......Page 413
Association with Other Genetic Disorders......Page 414
Isolated Elevated HbA2 Levels: Heterozygous β Thalassemia with α Thalassemia and Related Conditions......Page 415
MANAGEMENT......Page 416
Iron Chelation......Page 417
Assessment and Maintenance of Body Iron Levels......Page 418
Blood-Borne Infections......Page 419
Global Health Issues......Page 420
(δβ)0 and (Aγδβ)0 Thalassemia......Page 421
Hereditary Persistence of Fetal Hemoglobin......Page 422
Symptomatic Forms......Page 439
Pathophysiology......Page 442
Genotype–Phenotype Interaction......Page 443
Clinical Manifestations......Page 446
Complications......Page 447
Conclusions......Page 448
LABORATORY DIAGNOSIS IN ADULTS......Page 449
INTERACTIONS OF HEMOGLOBIN E WITH OTHER β-GLOBIN CHAIN VARIANTS......Page 451
REFERENCES......Page 452
CLINICAL FEATURES......Page 457
Diagnosis......Page 459
Detecting HbS and Measuring Hemoglobin Fractions......Page 460
CLINICAL FEATURES OF SICKLE CELL ANEMIA......Page 461
Assessing the Severity of Sickle Cell Disease......Page 462
THE NEONATE......Page 463
FIRST 10 YEARS......Page 464
Growth and Development: Nutrition......Page 465
Nutrition......Page 466
Epidemiology......Page 467
Diagnosis......Page 468
Acute Splenic Sequestration......Page 472
Aplastic Crisis and B19 Parvovirus Infection......Page 473
Hyperhemolysis......Page 474
Epidemiology......Page 475
Prevention......Page 476
Pathophysiology......Page 478
Clinical Course......Page 479
Prevention......Page 480
Management......Page 481
Hazards of Pregnancy......Page 482
Surgery and Anesthesia......Page 484
Epidemiology......Page 485
Clinical Aspects......Page 486
Sex Hormones......Page 488
Parathyroid and Bone Mineral Metabolism......Page 489
Epidemiology and Diagnosis......Page 490
Pulmonary Function......Page 491
Epidemiology......Page 492
Pathophysiology......Page 493
Clinical Features......Page 494
Pathophysiology......Page 495
Epidemiology and Clinical Features......Page 496
Diagnosis......Page 497
Sickle Cell Liver Disease......Page 498
Neurocognitive Dysfunction in Adults......Page 500
Eye Disease......Page 501
Cardiovascular Complications......Page 502
Pathophysiology......Page 503
Diagnosis......Page 504
Blood Pressure and Hypertension......Page 505
Mortality......Page 506
REFERENCES......Page 507
Transduction......Page 519
Transmission......Page 521
Acute Pain Episodes......Page 523
Objective Signs......Page 524
Blunted Pain Relief......Page 525
Clinical Pharmacology of Analgesics: General Features......Page 526
Codeine......Page 529
Meperidine......Page 530
Adverse Effects and Complications of Opioids......Page 531
Opioid-induced Hyperalgesia......Page 532
MANAGEMENT OF ACUTE SICKLE CELL PAIN......Page 533
Outpatient Pain Treatment in Medical Facilities......Page 534
Inpatient Pain Episode Treatment......Page 535
CHRONIC PAIN IN SICKLE CELL DISEASE......Page 536
Pseudoaddiction......Page 538
SUMMARY......Page 539
REFERENCES......Page 540
HbC and Malaria......Page 547
Biochemical Features of HbC......Page 548
Oxygen Affinity......Page 551
Laboratory Features and Diagnosis......Page 552
Treatment Recommendations......Page 553
Cellular Determinants of Pathophysiology and Severity......Page 554
Hematology and Laboratory Findings......Page 556
Mortality......Page 558
Sickle Retinopathy......Page 559
Acute Chest Syndrome......Page 563
Spleen......Page 564
Genitourinary......Page 565
TREATMENT OF HbSC DISEASE......Page 566
REFERENCES......Page 567
Effects of α Thalassemia......Page 571
Effects of Variant Hemoglobins, β Thalassemia and HPFH......Page 573
Pyruvate Kinase Deficiency......Page 574
Mortality, Rhabdomyolysis, and Sudden Death......Page 575
Pregnancy and Contraception......Page 576
Exercise Capacity......Page 577
Genitourinary System......Page 578
SPLEEN......Page 579
NERVOUS SYSTEM......Page 580
TRANSFUSION OF HbAS BLOOD......Page 581
REFERENCES......Page 582
β Thalassemia Mutations in HbS–β Thalassemia......Page 586
Hematological Evaluation of HbS–β0 Thalassemia......Page 588
Hematological Evaluation of HbS–β+ Thalassemia......Page 589
HbS–β0 Thalassemia......Page 590
HbS–β Thalassemia with α Thalassemia......Page 591
Diagnosis......Page 592
Treatment Recommendations......Page 593
SICKLING HEMOGLOBINS WITH TWO SUBSTITUTIONS IN THE β-GLOBIN GENE......Page 594
Hb Jamaica Plain......Page 595
Examples with a Clinical Phenotype......Page 596
HbSE Disease......Page 598
Treatment Recommendations......Page 599
Cellular Effects......Page 600
Clinical Effects......Page 601
HbS with α-Globin Chain Variants......Page 602
HbS with Other Globin Variants......Page 604
REFERENCES......Page 605
SECTION SIX OTHER CLINICALLY IMPORTANT DISORDERS OF HEMOGLOBIN......Page 609
Mutation Distribution......Page 611
High Oxygen Affinity Hemoglobins......Page 612
Variants with Low Oxygen Affinity......Page 614
UNSTABLE HEMOGLOBINS......Page 615
Pathophysiology......Page 616
Clinical Aspects......Page 618
Pathophysiology......Page 619
Posttranslational Modifications......Page 621
Interesting β-Globin Gene Variants with Point Mutations......Page 622
Interesting α-Globin Gene Variants with Point Mutations......Page 623
Two Point Mutations in a Globin Chain......Page 625
REFERENCES......Page 626
Pathophysiology of Methemoglobinemia......Page 629
Hereditary Methemoglobinemia......Page 630
Acquired Methemoglobinemia......Page 632
Diagnosis of Methemoglobinemia......Page 633
Treatment of Methemoglobinemia......Page 634
Epidemiology......Page 635
Pathophysiology of CO Poisoning......Page 636
Diagnosis and Treatment of CO Poisoning......Page 637
Clinical Presentation, Diagnosis, and Treatment......Page 638
REFERENCES......Page 639
SECTION SEVEN SPECIAL TOPICS IN HEMOGLOBINOPATHIES......Page 645
Why Do the Hemoglobinopathies Occur at Such a High Frequency?......Page 647
Historical Background......Page 648
Malaria in Human Populations......Page 649
Hemoglobin E......Page 651
β Thalassemia (Chapters 16 and 17)......Page 652
Epistatic Interactions Between Protective Polymorphisms......Page 653
POPULATION AND EVOLUTIONARY IMPLICATIONS......Page 654
The Epidemiological Transition and the Frequency of Severe Forms of Hemoglobinopathy......Page 655
Control and Management Issues......Page 656
REFERENCES......Page 657
Haplotypes of the β-Globin (HBB) Genelike Cluster in Sickle Cell Anemia and β Thalassemia......Page 660
Effects of β-Globin Gene Cluster Haplotype on HbF......Page 662
Genetic Modulation of HbF......Page 663
β Thalassemia......Page 666
Genetic Polymorphisms as Predictors of Disease Severity......Page 667
Genetic Polymorphisms as Predictors of Disease Severity......Page 673
REFERENCES......Page 674
Electrophoresis......Page 680
Isoelectric Focusing, Capillary Isoelectric Focusing, and Capillary Electrophoresis......Page 681
Mass Spectrometry......Page 682
Hemoglobin F......Page 683
P50 and Other Measurements of Oxygen Saturation......Page 684
CSAT......Page 685
Manual Methods......Page 686
Reticulocyte Count......Page 687
Measures of Cell Heterogeneity......Page 688
Globin Chain Synthesis......Page 689
Clinical Evaluation of Hemoglobinopathies and Thalassemias using Protein-based and Cellular Diagnostics......Page 690
Amniotic Fluid......Page 691
Preimplantation Diagnosis......Page 692
Diagnosis of Deletion Mutations by PCR......Page 693
Diagnosis of Point Mutations by PCR......Page 694
Allele-specific Oligonucleotide PCR......Page 695
Primer-specific Amplification......Page 696
Restriction Enzyme PCR......Page 697
PCR Methods for Unknown Mutations......Page 699
β-Globin Gene Haplotype Analysis......Page 700
Other Variants......Page 701
ANTENATAL DIAGNOSIS......Page 703
REFERENCES......Page 704
SECTION EIGHT NEW APPROACHES TO THE TREATMENT OF HEMOGLOBINOPATHIES AND THALASSEMIA......Page 709
Hemoglobin Level and Blood Requirements......Page 711
Choice of Blood Product......Page 712
Partial Exchange Transfusion......Page 713
Choice of Blood Product......Page 714
Exchange Transfusion......Page 715
Acute Stroke......Page 716
Perioperative Management......Page 717
Priapism......Page 718
Abnormal Transcranial Doppler Ultrasonography......Page 719
Recurrent Acute Chest Syndrome and Pulmonary Hypertension......Page 720
COMPLICATIONS OF TRANSFUSION THERAPY......Page 721
Sickle Cell Disease......Page 722
Hypersplenism and Increased Transfusion Requirements......Page 723
Rates of Iron Loading......Page 724
Distribution of Excess Iron......Page 725
Clinical Consequences of Transfusional Iron Overload......Page 726
Thalassemia Major......Page 727
Other Transfusion-dependent Anemias......Page 728
Liver Iron Concentration......Page 729
Monitoring of the Heart......Page 730
Urine Iron Excretion......Page 731
Maintenance of Safe Tissue Iron Concentrations......Page 732
Extracellular Iron......Page 733
Intracellular Iron......Page 734
Constraints of Chelator Design......Page 735
Historical Perspective......Page 736
Effects on Iron Balance and Liver Iron......Page 737
Effects on the Heart......Page 738
Injection Site Reactions......Page 739
Miscellaneous Effects......Page 740
Methods of Delivery for Desferrioxamine......Page 741
Sickle Cell Disease......Page 742
Chemistry and Pharmacology......Page 743
Effect on Liver Iron......Page 744
Neutropenia and Agranulocytosis......Page 745
Pharmacology......Page 746
Effect on the Heart......Page 747
Effects on Iron Balance, LIC, and Ferritin......Page 748
Renal Effects......Page 749
Future Perspectives with Chelation Therapy......Page 750
REFERENCES......Page 751
DNA HYPOMETHYLATING AGENTS......Page 767
Clinical Use of Hydroxyurea......Page 770
Mechanisms of Action......Page 771
INHIBITORS OF HISTONE DEACETYLASES......Page 772
COMBINATION THERAPY......Page 773
REFERENCES......Page 774
Sickle Cell Disease......Page 777
β Thalassemia......Page 778
Blockade of Ca2+-activated K+ Channel (Gardos Channel)......Page 779
Inhibition of KCl Transport by Mg2+......Page 780
Sickle Cell Disease......Page 781
Sickle Cell Disease and β Thalassemia......Page 783
Targeting Endothelin-1......Page 784
Nitric Oxide......Page 785
Xanthine Oxidase Inhibitors......Page 786
Oral N-Acetyl-Cysteine Therapy......Page 787
REFERENCES......Page 788
The Pesaro Experience......Page 796
Alternative Donors......Page 798
The Thalassemia Patient Undergoing Bone Marrow Transplantation......Page 799
Effect of Bone Marrow Transplantation on Thalassemia......Page 800
Hepatitis......Page 801
Current Results of Hematopoietic Cell Transplantation for Sickle Cell Disease......Page 802
Effect of Donor Hematopoiesis on Sickle Vasoocclusion......Page 806
Growth and Development after Hematopoietic Cell Transplantation for Sickle Cell Disease......Page 807
Alternative Sources of Donor Hematopoietic Cells......Page 808
SUMMARY......Page 809
REFERENCES......Page 810
THE SCIENCE OF VIRAL VECTORS......Page 813
Murine Retroviral Vectors......Page 814
Lentiviral Vectors......Page 817
Gene Therapy for Hemoglobinopathies Will Require High-Level Gene Transfer into Hematopoietic Stem Cells......Page 820
New Approaches for Transduction of Human Hematopoietic Stem Cells......Page 821
In Vivo Selection Strategies to Enrich for Transduced Hematopoietic Stem Cells......Page 822
The Development of Mouse Models of β Thalassemia and Sickle Cell Disease......Page 823
β-Globin Lentiviral Vectors: Correction of Murine Models of β Thalassemia and Sickle Cell Disease......Page 824
γ-Globin Lentiviral Vectors......Page 825
Successful Treatment of Patients with Immunodeficiencies......Page 826
The Unexpected Occurrence of Insertional Mutagenesis in Immunodeficiency Gene Therapy Trials......Page 827
Moving Forward: Can Insertional Mutagenesis be Avoided?......Page 828
REFERENCES......Page 829
Index......Page 837
