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Textbook of Pediatric Hematology & Hemato-Oncology
MR Lokeshwar, Nitin K Shah, Anupam Sachdeva, Bharat R Agarwal, Mamta Vijay Manglani, Asha Pillai
SECTION 1: PHYSIOLOGY
CHAPTER 1:
Ontogeny of Erythropoiesis
DEVELOPMENT OF HEMATOPOIESIS
Yolk Sac Phase
Onset of Blood Circulation
Transition from Yolk Sac to Hepatic Erythropoiesis
Hepatic Phase
Bone Marrow Phase (Table 1)
CYTOKINE REGULATION OF ONTOGENY AND HEMATOPOIESIS
Hematopoietic Cytokines, Transcription Factors and Lineage Commitment
Close Relation with Endothelium
Transcriptional Regulation of Early Hematopoietic Development (Fig. 5)
Regulation of Self-renewal and Differentiation of HSCs
Commitment to Lymphoid and Myeloid Lineage (Fig. 6)
ONTOGENY OF HEMOGLOBIN
Hemoglobin and Hematocrit Rise in Fetal Period (Fig. 9)7
CHAPTER 2:
Physiology of Blood Coagulation
PLATELET ACTIVATION
THEORIES OF BLOOD COAGULATION
Cell Based Model of Blood Coagulation
Initiation Phase
Amplification Phase
Propagation Phase
The Kallekrein-Kinin System
COAGULATION PROTEASES AND COFACTORS
Blood Coagulation Inhibitors
FIBRINOLYTIC PATHWAY
Platelet Interaction with Coagulant and Anticoagulant Factors
CHAPTER 3:
Structure, Function and Physiology of Platelets
STRUCTURE AND ULTRASTRUCTURE OF PLATELETS
Function of Platelets
Adhesion to Injured Capillary Endothelium and Subendothelium
Shape Change, Aggregation and Secretion
Further Aggregation and Activation of Coagulation
SECTION 2: NEONATAL HEMATOLOGY
CHAPTER 4:
Variation in the RBC Parameters in the Newborn
NORMAL HEMATOLOGICAL VALUES IN THE NEWBORN
Hemoglobin
Anemia
Blood Volume
Hematocrit
RED CELL COUNT AND RED CELL INDICES7,8
Red Blood Cell Count
Mean Corpuscular Volume7,21–24
Reticulocyte Count and Nucleated RBC1,3,14,19,30
CHAPTER 5:
Physiological Anemia of Newborn, Anemia of Prematurity and Role of Erythropoietin in the Management
PHYSIOLOGIC ANEMIA OF INFANCY
ANEMIA OF PREMATURITY
Background
Incidence3
Pathophysiology
Clinical Manifestations11
Diagnosis12
MANAGEMENT OF ANEMIA OF PREMATURITY
Goal of Anemia of Prematurity Therapy
Prevention Strategies
Role of Blood Transfusion
Rationale for not Transfusing Based on Hb Value Alone
Indications for Blood Transfusion
Issues in Blood Transfusion11,12
Why Minimize Transfusions in Neonates? (Table 5)
CLINICAL GUIDELINES FOR TARGETED USE OF ERYTHROPOIETIN22–24
Indications for Erythropoietin
Dose and Route of Administration
CHAPTER 6:
Effect of Maternal Iron Status on Placenta, Fetus and Newborn
CURRENT KNOWLEDGE IN THE DEVELOPMENT OF IRON DEFICIENCY
PREVALENCE OF NUTRITIONAL ANEMIA IN PREGNANT WOMEN (INDIA)
IRON STATUS IN PREGNANCY
PLACENTA IN IRON DEFICIENCY
Histology
FETUS—NEWBORN
Fetal Latent Iron Deficiency (Rat) and Brain Neurotransmitters
SUMMARY
ACKNOWLEDGMENTS
CHAPTER 7:
Developmental Aspects of Hemostasis in the Fetus and Newborn
INTRODUCTION
EARLIEST EVIDENCE OF THE FETAL HEMOSTATIC SYSTEM
COAGULATION SYSTEM
Coagulation Proteins
Regulation of Thrombin
PLATELETS
Bleeding Time
VESSEL WALL
ANGIOGENESIS
FIBRINOLYTIC SYSTEM
CONCLUSION
CHAPTER 8:
Anemia in the Newborn
INTRODUCTION
ANEMIA
Physiological Anemia
Anemia of Prematurity
Nonphysiologic Anemia in Neonate
ETIOLOGY
Hemorrhage12–25
Incidence of Hemorrhage in Newborn12–25
Obstetric Causes of Blood Loss12,13,15,16
Other Causes of Hemorrhage Includes
Fetomaternal Hemorrhage15–19,21,22
Accidental Incision of Placenta or Umbilical Cord During Cesarean Section
CLINICAL FEATURES
Acute Blood Loss
Other Hemorrhages12,13,25
ETIOLOGY
Anemia Due to Increased RBC Destruction (Hemolytic Anemia)
Causes of Hemolytic Anemia of Newborn27–37
Immune Hemolysis26–31
Nonimmune Hemolysis32–36
Hemolytic Disease of Newborn
Causes of Hemolytic Disease of Newborn
MANAGEMENT OF NEONATAL ANEMIA49
Anemia with Shock
Anemia due to Chronic Hemorrhage/Hemolysis
PREVENTION OF ANEMIA
CHAPTER 9:
Polycythemia and Hyperviscosity Syndrome
INCIDENCE OF NEONATAL POLYCYTHEMIA AND HYPERVISCOSITY
PATHOPHYSIOLOGY
INCREASED FETAL ERYTHROPOIESIS (PRIMARY POLYCYTHEMIA)
HYPERTRANSFUSION (SECONDARY POLYCYTHEMIA)
CLINICAL FEATURES
Laboratory Diagnosis
Hematocrit Measurement
MANAGEMENT
PHLEBOTOMY
Routes for Partial Exchange Transfusion
CHAPTER 10:
Vitamin K Deficiency: Bleeding in Newborns
DEVELOPMENT OF HEMOSTATIC SYSTEM
CHEMICAL STRUCTURE OF VITAMIN K
Vitamin K Cycle
CLINICAL FEATURES
Diagnosis
Treatment
ORAL VITAMIN K
The Cochrane Review
The American Academy Recommendation
Vitamin K and Preterm Newborn
Vitamin K and Cholestatic Disorders
Current International Scenario
CONCLUSION
CHAPTER 11:
Bleeding Neonate: Approach and Management
INCIDENCE
NORMAL NEONATAL HEMOSTASIS
MECHANISM OF HEMOSTASIS3–8
Primary Hemostasis
Vessel Wall Contractions and Platelet Plug Formation
Secondary Phase of Hemostasis3,12,14
Fibrinolytic Activity
Hemostasis in Newborn: Salient Features
Primary Phase of Hemostasis
Secondary Phase of Hemostasis5,6,8,10,13,15
Inherited Permanent Abnormality of Coagulation Factors
Fibrinolytic Activity
Antithrombin III, Protein C and Protein S
Local Pathological Lesion
Combined Factors Deficiencies
Approach to Bleeding Disorders in Neonate
History
Maternal History
Detailed Birth History
Family History
Physical Examination
Well Baby—A ‘Healthy’ Baby with Bleeding Indicates
Sick Baby with Bleeding Indicates
Site of Bleeding
Associated Findings
Associated Congenital Anomalies
Laboratory Approach (Table 1)
Apt Test
Screening Tests (Table 2)
Confirmatory Tests
Platelet Disorders
Coagulation Factors Defects
Vitamin ‘K’ and Neonatal Hemostasis (Fig. 3)12–17
Biology of Vitamin K
Vitamin K
Early Vitamin K Deficiency Bleeding
Clinical Presentation
Predisposing Factors
Diagnosis of HDN
Treatment
Prevention
CONCLUSION
CHAPTER 12:
Approach to Neonatal Thrombocytopenia
SECTION 3: RBC AND WBC DISORDERS
CHAPTER 13:
Introduction and Classification of Anemias in Children
PHYSIOLOGY OF HEMOGLOBIN PRODUCTION
CLASSIFICATION OF ANEMIAS
APPROACH TO HEMOLYTIC ANEMIA
CHAPTER 14:
Nutritional Anemia in Infancy, Childhood and Adolescents
IRON DEFICIENCY ANEMIA IN CHILDREN
Historical
Iron Deficiency Anemia
An Estimated Global Prevalence1–30
IDA among Pregnant and Lactating Women42–51
Iron Requirements in Different Age Groups
REPORTED INCIDENCE OF IDA IN CHILDREN (TABLE 2)
SOURCES OF IRON
Heme Iron
Mucosal Cell Control
Hepicidin and its Role in Iron Metabolism57,58
Iron Transport and Storage
Transport of Iron Across the Placenta
Causes of Iron Deficiency
PATHOGENESIS
Stages of Iron Deficiency
Clinical Features of IDA
Patients with Mild to Moderate Anemia (Hb 6–10 gm%)1,71
Severe IDA < 5 gm%
Diet History
Growth Retardation
Exercises Intolerance80,81
Effects on Pregnancy Outcome42–46,48,50,51
Regulation of Iron Transfer to the Fetus
Diagnosis of Iron Deficiency Anemia (Flow Chart 1)84–90
Screening Tests85–91
Differential Diagnosis of Microcytic Hypochromic Anemia (Table 4)
Confirmatory Tests (Table 3)
Free Erythrocyte Protoporphyrin
Response to Therapy
Laboratory Tests in Iron Deficiency Anemia
TESTS FOR THE STORAGE COMPARTMENT
TESTS FOR PLASMA IRON COMPARTMENT
When to Suspect IDA?
When to Suspect β-thalassemia Trait?
Screening Tests
Bone Marrow Examination
Response to Therapy
Treatment of Iron Deficiency Anemia
IRON THERAPY
Oral Iron Therapy
Dose
Various Forms of Iron Preparation
Daily versus Weekly Supplementation99–104
Response to Therapy
Parenteral Iron Therapy
Intravenous Iron
Indications
Types of Parenteral Iron Preparations
Iron Dextran Complex
Response to Therapy
Side Effects
Prevention of IDA
Current Approaches to Food Based Fortification with Iron
Supplementation of Medicinal Iron
Pregnant Women
Adolescent Girls31–40
Why Concentrate on Adolescents Girls?
Iron Supplementation
Home Fortification with Sprinkles112–123
Control of Viral, Bacterial and Parasitic Infections
CONCLUSION
Did you Know!
CHAPTER 15:
Megaloblastic Anemia
INTRODUCTION
HISTORY1–3
DEFINITIONS
CAUSES OF MEGALOBLASTIC ANEMIA (TABLE 1)
COBALAMIN (VITAMIN B12)
ABSORPTION AND TRANSPORT OF VITAMIN B12
CELLULAR PROCESSING
DEVELOPMENT OF COBALAMIN DEFICIENCY
Inborn Errors of Cobalamin Metabolism20,21
FOLATES
ABSORPTION AND TRANSPORT
Regulation of Folate Homeostasis37–39
Intracellular One-Carbon Metabolism
Compartmentalization and Channeling of Folate Metabolism
Methylfolate Trap41–45
Development of Folate Deficiency
PATHOLOGY OF MEGALOBLASTIC ANEMIA
Hematological Manifestations46–48
Megaloblastosis versus Macrocytosis
Neurological Manifestations
CLINICAL FEATURES
History
Physical Examination
Subclinical Cobalamin Deficiency57–59
DIAGNOSTIC ISSUES AND INVESTIGATIONS
Peripheral Smear and Bone Marrow Aspirate
Masked Megaloblastosis60
Biochemical Evidence56,61
Serum MMA and Homocysteine Level
Tests to Assess Absorption and Transport
Miscellaneous
Positive Therapeutic Response63–66
TREATMENT OF MEGALOBLASTOSIS67–74
Principles
Prophylaxis
Prophylaxis with Cobalamin
Prophylaxis with Folic Acid
Thiamine-responsive Megaloblastic Anemia Syndrome79
CHAPTER 16:
Anemia of Chronic Disease
ANEMIA
PATHOGENESIS
Shortened Erythrocyte Survival
IMPAIRED MARROW RESPONSE
ABNORMAL IRON METABOLISM
Treatment Options
Transfusion
Iron Therapy
Erythropoietic Agents
Monitoring Therapy
ANEMIA OF CHRONIC RENAL INSUFFICIENCY
Clinical Description
Laboratory Findings
Pathogenesis
Management and Course
Side Effects/Adverse Reactions
Erythropoietin Resistance
RENAL REPLACEMENT THERAPY
RENAL TRANSPLANTATION
DIALYSIS
Anemia in Cirrhosis and Other Liver Diseases
PREVALENCE AND CLINICAL MANIFESTATIONS
HEMATOLOGIC FINDINGS
PATHOGENESIS
ANEMIA IN PATIENTS WITH CANCER
Treatment
ANEMIA ASSOCIATED WITH ENDOCRINE DISORDERS
Hypothyroidism
Pathogenesis
Hyperthyroidism
Adrenal Insufficiency
Androgen Deficiency
Hypopituitarism
Hyperparathyroidism
Anorexia Nervosa
CHAPTER 17:
Thalassemia Syndromes
HISTORICAL REVIEW1–6
EPIDEMIOLOGY3,7–17
Thalassemia Incidence: World Scenario
PATHOPHYSIOLOGY (FLOW CHART 1)18–21
CLASSIFICATION3,22,23
Classification of α-thalassemia (Tables 1 and 2)
Molecular Genetics (Figs 3 and 4 and Table 4)5,24–43
Inheritance of Genes (Figs 5A and B)
Clinical Heterogenecity of thalassemia due to Diversity of Mutations
Mild β-thalassemia
Severe β-thalassemia
Management of Thalassemia: Principles of Therapy
Confirmation of Diagnosis
LABORATORY DIAGNOSIS OF β-THALASSEMIA SYNDROMES (TABLE 5)
Thalassemia Major/Intermedia (Figs 7A and B): Complete Blood Count
Thalassemia Minor
Naked-eye Single Tube Red Cell Osmotic Fragility Test (NESTROFT) for Thalassemia Minor44–46
Iron Studies47
Quantitation of Various Hemoglobins (Figs 8 and 9)
Tests Used for Estimating Iron Overload50–53
Clinical Consequences, Diagnosis and Management
ENDOCRINE DYSFUNCTION61–64
BONE DISEASE: OSTEOPENIA AND OSTEOPOROSIS (FIG. 11)65–68
Cardiac Complications69–71
Management of Thalassemia Major72–76
Transfusion Therapy in Thalassemia77–79
Progress in the Concept of Transfusion Therapy for Thalassemia
INITIATION OF TRANSFUSION THERAPY
TYPE OF TRANSFUSIONS (FIGS 12 AND 13 AND TABLE 7)
Amount and Rate of Transfusions
Rate of Transfusion
Adequacy of Transfusions
Advances in Transfusion Therapy
Daycare Transfusion Center
Management of Complications of Transfusion Therapy
Transfusion Related Complications
Iron Overload and Chelation Therapy
Clinical Consequences, Diagnosis and Management
Iron Chelation Therapy80–112
Toxicity of Desferrioxamine
Oral Chelator
Side-effects of Deferiprone
Adverse Events
Newer Iron Chelators
Desferrithiocin102
Hydroxybenzyl-ethylenediamine-diacetic Acid103,104
Pyridoxal Isonicotinoyl Hydrazone105
GT56-252106,107
40SD02 (CHF1540)108,109
Combination Therapy: The Shuttle Hypothesis110,111
Management of Bone Disease in Thalassemia Major: Osteopenia and Osteoporosis (Intervention Recommended Based on BMD Result) (Table 9)65–68
Prevention of Osteopenia/Osteoporosis
Management of Cardiac Complications69–71
Transfusion Transmitted Infections113–126
Hepatitis C
Human Immunodeficiency Virus (HIV)
Hypersplenism (Fig. 18)130–133
Curative Treatment
Stem Cell Transplantation (Fig. 19)134–139
Umbilical Cord Stem Transplantation140–142
Gene Therapy159–161
Prevention162–166
Population Education167
Prenatal Diagnosis168,169
Preimplantation Diagnosis170–174
Preconception Diagnosis175
SUMMARY
CHAPTER 18:
Sickle Cell Anemia in Children
HISTORICAL ASPECT
Types of Sickle Cell Gene Mutations
Incidence and Prevalence of Sickle Cell Disease
Sickle Cell Anemia and Malaria
Pathophysiology
Hb S Polymerization
Increased Adhesion of RBCs to Endothelium
Hemolysis
Genetics of Sickle Cell Anemia
Sickle Cell Syndromes
Sickle Cell Trait or Carrier State
Homozygous Sickle Cell Disease
Compound Heterozygotes
Sickle-β Thalassemia Syndrome
Diagnosis of Sickle Cell Anemia
CBC and Routine Laboratory Testing
Hemoglobin Solubility Test
Sickling Test
Hemoglobin Electrophoresis
Newborn Sickle Cell Disease Screening
Imaging Studies
Prenatal Diagnosis
Clinical Features of Sickle Cell Disease
Manifestation of Sickle Cell Anemia
Anemia
Vaso-occlusive Crisis
Neurological Complications
Acute Chest Syndrome
Avascular Necrosis of the Femoral or Humeral Head
Infection
Unhealed Ulcers (Fig. 6)
Skin Ulcers (Unhealed Ulcers)
Other Complications
Renal Disease
Pulmonary Hypertension
Cholecystitis
Retinopathy
Growth and Development
Cardiac Involvement
Pregnancy
Treatment
Hydroxyurea Therapy
Indications for Hydroxyurea Therapy
Transfusion Therapy
Chelation Therapy
Erythrocytapheresis
Bone Marrow Transplantation
Novel Therapies
Supportive Therapy
Morbidity and Mortality
Patient Education
CHAPTER 19:
Antenatal Diagnosis of Hemoglobinopathies
BACKGROUND
MUTATIONS IN GLOBIN GENES
Alpha Thalassemias
β-Thalassemia5
Sickle Cell Disease5
DNA Techniques Required for Hemoglobinopathies
Detection of Known Mutations
Reverse Dot Blot Analysis
Amplification Refractory Mutation System
Restriction Enzyme PCR
Gap PCR
Detection of Unknown Mutations
Diagnosis Using Indirect Methods
Restriction Fragment Length Polymorphism (Fig. 5)
PRECAUTIONS TAKEN WHILE DOING DNA ANALYSIS
Noninvasive Methods
COUNSELING
CHAPTER 20:
Red Cell Membrane Disorders (Spherocytosis, Elliptocytosis, Stomatocytosis)
HEREDITARY SPHEROCYTOSIS
Prevalence
Etiology
Clinical Features
Diagnosis
Treatment
Indications for Splenectomy
Two to Three Weeks Prior to Splenectomy
HEREDITARY ELLIPTOCYTOSIS
Prevalence
Etiology
Types of Hereditary Elliptocytosis
Treatment
HEREDITARY STOMATOCYTOSIS
Overhydrated Hereditary Stomatocytosis
Treatment
CHAPTER 21:
Red Cell Enzymopathy
G6PD DEFICIENCY
Prevalence
MALARIA HYPOTHESIS
Clinical and Biochemical Variants
Clinical Features
Acute Hemolytic Anemia
NEONATAL JAUNDICE
CHRONIC NONSPHEROCYTIC HEMOLYTIC ANEMIA
Diagnosis
PREVENTIVE STRATEGIES AND TREATMENT
Deficiency of Pyruvate Kinase and Other Enzymes of Glycolytic Pathway
PYRUVATE KINASE DEFICIENCY
Clinical Approach to a Child Suspected to have Enzyme Deficiency
CHAPTER 22:
Autoimmune Hemolytic Anemia
EPIDEMIOLOGY
Lymphoproliferative Disease and Rh-hemolytic Disease
PATHOGENESIS
Cold Agglutinins and Hemolysins—Pathogenic Effects
DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA
Clinical Features
LABORATORY FINDINGS24–27
Anemia
Bone Marrow Examination
Biochemical Tests Suggesting Increased Destruction of Erythrocytes
Antiglobulin (Coombs) DAT Test and Indirect Antibody Test (IAT)
THERAPY17,22, 24,28
Blood Transfusion in Autoimmune Hemolytic Anemia
GLUCOCORTICOIDS
SPLENECTOMY
Immunosuppressive Therapy
RITUXIMAB29,30
CHAPTER 23:
Paroxysmal Nocturnal Hemoglobinuria
MOLECULAR GENETICS OF PAROXYMAL NOCTURNAL HEMOGLOBINURIA
Glycosyl Phosphatidyl Inositol Anchor (GPI-anchor)
PIG-A Gene and its Significance in PNH
Effect of the Defect
INCIDENCE AND NATURAL HISTORY
Indian Perspective
CLINICAL MANIFESTATIONS (TABLE 1)
Intravascular Hemolysis
Pathophysiology of Intravascular Hemolysis
Clinical Effects of Intravascular Hemolysis
Thrombosis
Pathophysiology of Thrombosis
Hematopoiesis Deficient
Classification
WHO SHOULD BE SCREENED FOR PNH? (TABLE 4)
LABORATORY DIAGNOSIS (TABLE 5)
CBC
Urine Hemosiderin
Bone Marrow Examination
Serum Iron Studies and Ferritin
Complement Based Assays
Principle
Acidified Serum Lysis Test (Ham Test)
Sucrose Lysis Test
GPI—Anchor-based Assays
Principle
Advantages
Aerolysin Based Assays
TREATMENT OF PNH
Anemia due to Hemolysis
Eculizumab
Corticosteroids
Androgens
Folate
Chronic Transfusion Therapy
Iron Replacement Therapy
Splenectomy
Treatment of Nonhemolytic Anemia
Management of Thromboembolic Disease
Definitive Treatment of PNH
Stem Cell Transplant for PNH
PEDIATRIC PNH
CHAPTER 24:
Diagnosis and Management of Acquired Aplastic Anemia in Children
DIAGNOSIS OF APLASTIC ANEMIA IN CHILDREN
Clinical Presentations
Laboratory Investigations
RISK STRATIFICATION OF APLASTIC ANEMIA IN CHILDREN
Supportive Care
Transfusion Support
Care of Infections
Prevention of Infections
General Measures
SPECIFIC THERAPY IN APLASTIC ANEMIA
Immunosuppressive Therapy for Aplastic Anemia
Indications
Eligibility
ATG/ALG
Cyclosporine (CsA)
Response to IST (ATG Plus CsA)
Other Drugs
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN APLASTIC ANEMIA
COMPLICATIONS AFTER SUCCESSFUL ENGRAFTMENT
ROLE OF PEDIATRICIAN IN SHARED CARE
FOLLOW-UP AND PROGNOSIS
LONG-TERM COMPLICATIONS
CHAPTER 25:
Inherited Bone Marrow Failure Syndromes
CHAPTER 26:
Benign Disorders of Neutrophils
NEUTROPHILIA
Infection
Sweet's Syndrome (Acute Febrile Neutrophilic Dermatosis)
Familial Neutrophilia
QUALITATIVE CHANGES IN LEUKOCYTES IN INFECTION
Toxic Change in Neutrophils
Phagocytosis by Neutrophils
Cell Death
TRANSIENT NEUTROPENIA
NEUTROPENIA, CHRONIC (MORE THAN 3 MONTHS)
Cyclic Neutropenia
Differential Diagnosis
Kostmann's Syndrome (Infantile Genetic Agranulocytosis)
Lazy Leukocyte Syndrome
Neutropenias with Abnormal Marrow Neutrophils
Myelokathexis (Kathexis = Retention)
Neutropenia with Gigantism and Multinuclearity of Marrow Neutrophils
Neutropenia with Large, Binucleate, Tetraploid Neutrophils and Monocytes in Marrow
Neutropenia as Part of a Genetic Syndrome (Tables 12 and 13)
Antibody-induced Neutropenias
Alloimmune Neutropenias
Autoimmune Neutropenia of Infancy (Chronic Benign)
Viral Infection
Autoimmune Disease
Evan's Syndrome
Marrow Transplantation
Drug-immune Neutropenia (Table 17)
T-Lymphocytosis with Neutropenia
Marrow Infiltration/Replacement (Table 14)
Deficiency of Hematinics
Drugs and Neutropenia
Neutropenia due to Sequestration
GRANULOCYTES: CYTOPLASMIC ANOMALIES (TABLE 18)
Alder Anomaly (Table 19)
Sparse, Coarse Azurophil Granules
Vacuolation
Vacuoles of Neutral Lipid (Jordan's Anomaly)
Ichthyosis and Neutral Lipid Storage Disease
Carnitine Deficiency
Wolman's Disease
Neonatal Hemochromatosis
Other
Pearson's Marrow-Pancreas Syndrome
Döhle-like Bodies
May-Hegglin Anomaly
Fechtner's Syndrome (Alport's Syndrome Variant)
Sebastian Platelet Syndrome
Neutrophil Specific Granule Deficiency
Peroxidase Deficiency and Monocytes
Giant Granulation in Granulocytes and Monocytes
Chediak-Higashi Syndrome
Pseudo-Chediak-Higashi Granulation
Gray-staining Bodies
Other Inclusions
GRANULOCYTES: NUCLEAR ANOMALIES (TABLE 20)
Pelger-Huet Anomaly
Excessive Tags
Hypersegmentation of Neutrophil Nuclei (Table 21)
Nuclear Changes in Toxic States
SECTION 4: BLEEDING DISORDERS
CHAPTER 27:
Approach to a Bleeding Child
HISTORY
Local Versus Systemic
IS THE DEFECT INHERITED OR ACQUIRED?
Inherited Disorders
Acquired Disorders
INDICATIONS FOR EVALUATION
Is the Bleeding due to Vascular, Platelet or a Coagulation Abnormality or a Combination of these?
Family History of Bleeding
X-linked Recessive Pattern
Autosomal Dominant Pattern of Inheritance
ASSOCIATED UNDERLYING DISORDERS
CERTAIN SYNDROMES KNOWN TO BE ASSOCIATED WITH BLEEDING DISORDERS
LABORATORY ASSESSMENT (TABLE 1)
Sample Collection and Technique
Screening Tests
Proper Smear Examination also helps in Evaluating Extent of Thrombocytopenia if Present
Platelet Count
Bleeding Time
Prolonged Bleeding Time with Nearly Normal Platelet Count
Qualitative Platelet Disorders (Table 2)
Prothrombin Time
Activated Partial Thromboplastin Time
Activated Partial Thromboplastin Time is Prolonged
Thrombin Clotting Time
Thrombin Clotting Time is Abnormal in Patients with
Special Confirmatory Tests
CONCLUSION
CHAPTER 28:
Diagnosis and Management of Hemophilia Patients
INTRODUCTION
CLINICAL FEATURES
Grades of Severity
Diagnosis
Investigations
Treatment of Hemophilia
GENERAL PRINCIPLES
To Avoid
To Do
Definitive Treatment
HEMOPHILIC ARTHROPATHY
Pathophysiology
Clinical Features
Acute Bleed in a Relatively Normal Joint
Subacute or Chronic Synovitis
Chronic Hemophilic Arthropathy
Practical Approach to Management of Hemophilia Patients in India
Prompt Replacement
Home Therapy Programs
Advantages
Relief of Pain
Physical and Rehabilitative Therapy
Prophylactic Therapy
Primary Prophylaxis
Secondary Prophylaxis
Tertiary Prophylaxis
Intermittent (Periodic) Prophylaxis
Administration and Dosing Schedules
Muscle Bleeds and Hematomas (Figs 5 and 6)
Treatment
CNS Bleeds
Treatment
Gastrointestinal Bleeds
Treatment
Urinary Tract Bleeding
Treatment
Mucous Membrane Bleeds
Treatment
Chronic Hemophilic Arthropathy
Conservative Treatment
Types of Synovectomy
Pseudotumors (Figs 7A to D)
Treatment
Surgery in Hemophilia
Recommended Dose of Factor
Use of DDAVP in Hemophilia A
Disadvantages
Route of Administration
Pharmacologic Options for Controlling Bleeding
PREVENTION
Carrier Detection and Prenatal Diagnosis
CHAPTER 29:
von Willebrand Disease and Other Rare Coagulation Disorders
COMMON HEREDITARY COAGULATION DISORDERS
von WILLEBRAND DISEASE (VWD)
Pathophysiology
Type of Hemostasis
Prevalence
Inheritance
CLINICAL PRESENTATION
Classification
Type 1 vWD
Laboratory Assays
von Willebrand Disease Type 2
Type 2A von Willebrand Disease Includes Four Subtypes (A, B, M and N)
Laboratory Findings
TYPE 2B von WILLEBRAND DISEASE
Laboratory Assays
Type 2M von Willebrand Disease
Type 2N von Willebrand Disease
Type 3 von Willebrand Disease
Platelet-type vWD (pseudo-vWD)6
Laboratory Findings
DIAGNOSIS OF von WILLEBRAND DISEASE
Accurate Personal and Family Bleeding History
Clinical Evaluation
Laboratory Assays Tests for vWD Include
Factor VIII Activity
Genetic Testing–Mutation in the Patient's vWF
Medical Care
Treatment
Desmopressin Acetate (DDAVP)
Route and Mode of Administration and Dose
Intranasal Preparation
Common Side Effects Include
vWF Concentrates
Cryoprecipitate
Nonreplacement Therapy
Ethinyl Estradiol and Levonorgestel (Levona, Nordette, Lutera, Trivora)
Use of Topical Thrombin
Replacement Therapy Plasma Products
Cryoprecipitate Contains Multimeric von Willebrand Factor
Adjunctive Therapies
Acquired von Willebrand Disease
Often Associated with Underlying Diseases Like
Laboratory Findings
Treatment
Drugs to Avoid
Rare Coagulation Disorders
FIBRINOGEN DEFICIENCIES (F1-5)
Quantitative Defect
Qualitative Defect of the Circulating Fibrinogen
Clinical Features
DIAGNOSIS16,17
Management
Fresh Frozen Plasma or Cryoprecipitate
FACTOR II—PROTHROMBIN DEFICIENCY
Clinical Phenotypes
Clinical Features
Diagnosis
Management22,23
Prothrombin Complex Concentrates are therefore Treatment of Choice
FACTOR V DEFICIENCY (PARAHEMOPHILIA)
Clinical Features
Diagnosis
Management
COMBINED DEFICIENCY OF FACTORS V AND VIII
Clinical Features
Diagnosis
Management
FACTOR VII DEFICIENCY
Clinical Features
Diagnosis
Management
FACTOR X DEFICIENCY
Clinical Features
Diagnosis
Management
FACTOR XI DEFICIENCY (HEMOPHILIA C)
Clinical Features
Diagnosis
Management
FACTOR XIII DEFICIENCY (FIBRIN STABILIZING FACTOR DEFICIENCY)
Clinical Manifestations
Diagnosis
Management
CONCLUSION
CHAPTER 30:
Acquired Inhibitors of Coagulation
ACQUIRED HEMOPHILIA
Pathophysiology
EPIDEMIOLOGY
ETIOLOGY
CLINICAL FEATURES
History
Physical Findings
On Examination
INVESTIGATIONS
DIFFERENTIAL DIAGNOSES
MANAGEMENT
MANAGEMENT OF BLEEDING
Management of Mild Bleeding
Management of Moderate-to-Severe Bleeding
ERADICATION OF THE INHIBITOR
ACQUIRED INHIBITORS TO von WILLEBRAND FACTOR
ACQUIRED INHIBITORS TO FACTOR V
ACQUIRED INHIBITORS TO PROTHROMBIN
ACQUIRED INHIBITORS TO OTHER FACTORS VII, IX, X, XI, XIII
CONCLUSION
CHAPTER 31:
Immune Thrombocytopenic Purpura—Diagnosis and Management
CLASSIFICATION
DIAGNOSIS OF ITP1–9,12–19
Leukocyte Count
Anemia
Antiplatelet Antibody13–25
Bone Marrow Examination27–29
Indication for Bone Marrow Aspiration
Other Investigations23,30,31
Management of ITP2–9,32–53,57,58, 66,69,70–80
Acute ITP2–9
Chronic ITP
SPECIFIC THERAPY IN ACUTE ITP
Corticosteroid Therapy (Oral)32–36
Steroids in ICH
Indications for Steroids in ITP
Dose of Steroids
Intravenous Pulse Methylprednisolone Pulse Therapy37,38,42
Intravenous Immunoglobulin43–48
IVIgG in Chronic ITP
Anti-D in ITP49–53
Splenectomy in ITP54–65
Indication of Splenectomy ITP
Problems after Splenectomy
Role of Nonsteroidal Immunosuppressant Drugs in Chronic ITP
Alpha Interferon70,71
Rituximab72–76
Thrombopoietin in ITP
Dose
CONCLUSION
In Chronic ITP
CHAPTER 32:
Platelet Function Disorders
PLATELET STRUCTURE
Initial Approach to Diagnosing Platelet Dysfunction
Clinical Features of Platelet Defects
Platelet Function Defects may be Hereditary, Acquired or Drug-Induced
CLASSIFICATION OF HEREDITARY PLATELET FUNCTION DEFECTS3
GLANZMANN'S THROMBASTHENIA
Clinical Findings
Laboratory Findings
Therapy
HEREDITARY STORAGE POOL DEFECT (SPD)
Clinical Features
Laboratory Findings
Therapy
ASPIRIN-LIKE DEFECTS
Clinical Features
Laboratory Findings
Therapy
ACQUIRED PLATELET FUNCTION DEFECTS
MYELOPROLIFERATIVE SYNDROMES
UREMIA7
Treatment
PARAPROTEIN DISORDERS
MISCELLANEOUS CAUSES
DRUG-INDUCED PLATELET FUNCTION DEFECTS7
COMMONLY USED DRUGS WHICH INHIBIT PLATELET FUNCTION7
HYPERACTIVE PLATELETS7
Microvesicles and Platelet Procoagulant Activity
PLATELET FUNCTION DEFECTS IN INFANTS AND SMALL CHILDREN1
LABORATORY TESTS FOR PLATELET DISORDERS
Template Bleeding Time
Platelet Function Analyzer PFA-1001
Assay Principle
PFA-100 in vWD 1
PFA-100 in Diagnosis of Hereditary Platelet Function Defects
PLATELET FUNCTION ASSAYS
Platelet Light Transmission Aggregometry (LTA)1
Principle
Preparation of Patient1
Aggregating Agents1
Interpretation (Fig. 6)
Aggregation Patterns in Normal Subjects
SUBSTANCES COMMONLY AFFECTING PLATELET FUNCTION1
FLOW CYTOMETRY1
MEASUREMENT OF NUCLEOTIDES1
WHOLE BLOOD AGGREGOMETRY1
OTHER TESTS USED FOR MEASURING PLATELET AGGREGATION
Rapid Platelet Function Assay by Ultegra– RPFA1
Hemostasis Analysis System
ELISA, RIA and Western Blot
CONCLUSION
CHAPTER 33:
Pediatric Thrombosis
PHYSIOLOGIC CONSIDERATIONS
ETIOLOGY AND RISK FACTORS IN CLINICAL THROMBOSIS
ACQUIRED RISK FACTORS
Neonatal Thrombosis
Risk Factors
VASCULAR ACCESS DEVICES
DEHYDRATION AND SEPSIS
NEPHROTIC SYNDROME
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
THALASSEMIA
MALIGNANCY
FAMILIAL THROMBOPHILIA
Approach to Diagnosis
Radiologic Imaging
Laboratory Evaluation
Acquired or Genetic
Genetic
Therapeutic Approach
ANTITHROMBOTIC AGENTS
Unfractionated Heparin
Low Molecular Weight Heparin
Thrombotic Agents
VITAMIN K ANTAGONIST
Alternative Thrombin Inhibitors
ANTIPLATELET DRUGS
Venacaval Interruption
Surgical Thrombectomy
Treatment of Venous Thromboembolism
DETAILS OF ANTITHROMBOTIC AGENT ADMINISTRATION (TABLES 1 TO 4)
Recommended Durations of Therapy
Neonatal Purpura Fulminans
OUTCOMES
CONCLUSION
CHAPTER 34:
Disseminated Intravascular Coagulation in Neonates
PATHOGENESIS OF DIC
Dysfunctional Physiologic Anticoagulant Pathways
Impaired Fibrinolysis
CLINICAL PRESENTATION
DIAGNOSIS OF ACUTE DIC
MANAGEMENT OF DIC
Transfusion of Platelet Concentrates
Fresh Frozen Plasma
Anticoagulants
Concentrates of Coagulation Inhibitors
Newer Agents
CONCLUSION
SECTION 5: TRANSFUSION MEDICINE
CHAPTER 35:
Blood Components in Pediatric Practice
INTRODUCTION
Why not Whole Blood and why Components?
Which Components?
Storage and Shelf Life
ABO and Rh Compatibility
Whole Blood
Indications
Packed Red Blood Cells
Indications
Chronic Anemia
Platelet Transfusions
Types of Platelets
ABO/Rh Compatibility
Storage
Criteria to Transfuse
Indications
Granulocytes
Leukodepleted Blood Components
Why Leukodepletion?
Fresh Frozen Plasma
Take Home Messages
CHAPTER 36:
Nucleic Acid Amplification Testing
CHAPTER 37:
Transfusion Transmitted Infections
KNOWN TRANSFUSION TRANSMITTED VIRAL INFECTIONS
Viral Hepatitis
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis A
Hepatitis G
TTV and SEN-V
Retroviral Infection
HIV 1 and 2
Human T-cell Leukemia Virus HTLV Types 1 and 2
Human Herpes Virus Infection
Cytomegalovirus
CMV Infection can be Detected by Serologic Assays for AntiCMV Antibodies
Epstein-Barr Virus
Human Herpes Viruses 6 and 8
Parvovirus B19
Bacterial Infections
Syphilis
Malaria
Babesiosis
Trypanosomal Infection
Leishmaniasis
Toxoplasmosis
Microfilariasis
CHAPTER 38:
Noninfectious Hazards of Blood Transfusion
CATEGORIES OF NONINFECTIOUS HAZARDS OF BLOOD TRANSFUSION
Acute
Delayed
ACUTE HAZARDS OF TRANSFUSION
Allergic Reaction
Treatment and Prevention
Immune Mediated Hemolysis
Treatment and Prevention
Nonimmune Mediated Hemolysis
Febrile Nonhemolytic Transfusion Reaction
Treatment and Prevention
Transfusion Related Acute Lung Injury
Treatment and Prevention
Metabolic Complications
Hypothermia
Hyperkalemia
Citrate Toxicity
DELAYED HAZARDS OF TRANSFUSION
Delayed Hemolytic Transfusion Reaction
Treatment and Prevention
Alloimmunization
Treatment and Prevention
Transfusion Related Immunomodulation
Post-transfusion Purpura
Treatment and Prevention
Transfusion Associated Graft versus Host Disease
Treatment and Prevention
Circulatory Overload
Treatment
Iron Overload
Treatment
CONCLUSION
SECTION 6: HEMATO-ONCOLOGY
CHAPTER 39:
Pediatric Acute Lymphoblastic Leukemia
INTRODUCTION
CLINICAL PRESENTATION
LABORATORY DIAGNOSIS OF ACUTE LYMPHOBLASTIC LEUKEMIA
Confirmation of Diagnosis
Flow Cytometry
Cytogenetics of Acute Lymphoblastic Leukemia
Numerical Abnormalities
Structural Abnormalities (Chromosomal Translocations)
Role of Trephine Biopsy
Organ Function Assessment
Other Tests
PROGNOSTIC FACTORS (TABLE 6)
A. Host Biology
Age
Gender
B. Tumor Biology
White Blood Cell Count at Diagnosis
Central Nervous System Status at Diagnosis
Testicular Involvement at Diagnosis
Immunophenotype
Cytogenetics
Numerical Abnormalities
Structural Abnormalities (Chromosomal Translocations)
C. Early Response to Therapy
Peripheral Blood Response to Steroid Prophase
Day 7 and Day 14 Bone Marrow Responses
Peripheral Blood Response to Multiagent Induction Therapy
Induction Failure
Minimal Residual Disease
Newer Factors
Molecular Genetic Abnormalities
Pharmacogenetics
RISK STRATIFICATION OF CHILDHOOD ALL
NCI Risk-grouping
Children's Oncology Group Risk Stratification
MANAGEMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN
Induction Chemotherapy for ALL
Consolidation/Intensification Therapy
Maintenance Therapy
Central Nervous System Therapy
RELAPSE OF DISEASE AND ITS MANAGEMENT
Diagnosing Relapse of ALL
Risk Stratification of Relapsed ALL
Treatment of Marrow Relapse
Reinduction Therapies after Marrow Relapse
Postremission Therapy
Continuation Chemotherapy
Hematopoietic Stem Cell Transplantation
Treatment of Central Nervous System Relapse
Isolated Testicular Relapse
LATE EFFECTS OF THERAPY
SUMMARY
CHAPTER 40:
Pediatric Acute Myeloid Leukemia
BIOLOGY AND PATHOGENESIS
CLASSIFICATION
CLINICAL FEATURES AND DIAGNOSIS
RISK STRATIFICATION AND PROGNOSTIC FACTORS
TREATMENT OF PEDIATRIC AML
Induction Therapy
Postremission Therapy
Maintenance Therapy
Current Status of Stem Cell Transplantation in Pediatric AML
SUPPORTIVE CARE
Novel Therapeutic Agents
TREATMENT OF RELAPSED ACUTE MYELOID LEUKEMIA
ACUTE MYELOID LEUKEMIA IN CHILDREN WITH DOWN SYNDROME
Therapy-related Acute Myeloid Leukemia
ACUTE PROMYELOCYTIC LEUKEMIA
CONCLUSION AND FUTURE DIRECTIONS
CHAPTER 41:
Chronic Myeloid Leukemia
EPIDEMIOLOGY
PATHOPHYSIOLOGY
Biology of CML
Clinical Features
Symptoms and Signs
Investigations
DIFFERENTIAL DIAGNOSIS
Prognostic Factors
Treatment (Fig. 5)
Medical Management
Hydroxyurea
Interferon (IFN)
Tyrosine Kinase Inhibitors (TKI)
Dose of TKI
Response Rates and Response Assessment to TKI
Intolerance and Resistance to TKI
Intolerance
Resistance
Managing Resistance
Toxicity of TKI
Allogenic Stem Cell Transplant (Allo-SCT)
Guidelines for Management of CML in Children
Chronic Phase CML (Flow chart 1)
Accelerated Phase CML (Flow chart 2)
Blast Crisis CML (Flow chart 3)
CHAPTER 42:
Juvenile Myelomonocytic Leukemia
HISTORY AND CLASSIFICATION
EPIDEMIOLOGY
PATHOPHYSIOLOGY AND GENETICS
Molecular Aspects
ONCOGENIC RAS MUTATIONS
CLINICAL FEATURES
HEMATOLOGICAL AND LABORATORY FEATURES
DIFFERENTIAL DIAGNOSIS
Hematopoiesis in Cell Culture Studies
Natural Course and Prognostic Factors
MANAGEMENT OF JMML
Low-dose Conventional Chemotherapy
Intensive Chemotherapy
Other Measures
Experimental Therapeutic Approaches
Hematopoietic Stem Cell Transplantation
CHAPTER 43:
Pediatric Hodgkin Lymphoma
EPIDEMIOLOGY
ETIOLOGY
BIOLOGY
PATHOLOGIC CLASSIFICATION
Classical Hodgkin Lymphoma
Nodular Lymphocyte—Predominant Hodgkin Lymphoma
PRESENTING SYMPTOMS AND SIGNS
Lymphadenopathy
Hepatosplenomegaly
Mediastinal Mass
Systemic Symptoms
DIFFERENTIAL DIAGNOSIS
DIAGNOSTIC EVALUATION
ESTABLISHING THE DIAGNOSIS
LABORATORY STUDIES
IMAGING STUDIES
TREATMENT
Combined Modality Therapy in Children with Hodgkin Lymphoma
Chemotherapy Regimens in Children with Hodgkin Lymphoma
Avoidance of Late Toxicity
Gender-Adapted Chemotherapy
Radiotherapy
Radiation Dose
Radiation Therapy Volume
Radiation Therapy Technique
Response-Adapted Therapy
RECOMMENDATIONS FOR TREATMENT OF PEDIATRIC HODGKIN LYMPHOMA
Treatment of Low-risk Classical Hodgkin Lymphoma
Treatment of Intermediate Risk Classical Hodgkin Lymphoma
Treatment of High-risk Classical Hodgkin Lymphoma
Treatment of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Relapsed or Refractory Disease
Low-risk (Favorable) Group
High-risk Group
FOLLOW-UP AND LATE EFFECTS
SUMMARY
CHAPTER 44:
Non-Hodgkin Lymphoma in Children and Adolescents
EPIDEMIOLOGY AND ETIOLOGY OF CHILDHOOD NHL
CLINICAL FEATURES
Burkitt Lymphoma
Diffuse Large B-cell Lymphoma
Lymphoblastic Lymphoma
Anaplastic Large Cell Lymphoma
Rare Lymphomas in Children
Diagnostic and Staging Evaluation
TREATMENT
Principles of Management
Principles of Chemotherapy in NHL
T-cell Lymphomas (Table 4)
Precursor T Lymphoblastic Lymphoma
B-Precursor LL
B-Cell Lymphoma (Table 5)
Management of Relapse
CONCLUSION
CHAPTER 45:
Langerhans Cell Histiocytosis
EPIDEMIOLOGY
CLINICAL FEATURES
Single-System Disease
Multisystem Disease
DIAGNOSTIC EVALUATION OF LANGERHANS CELL HISTIOCYTOSIS
Tests and Procedures
Fludeoxyglucose F18 (18F-FDG)
TREATMENT OF LANGERHANS CELL HISTIOCYTOSIS
Low-Risk Disease (Single-System or Multisystem)
High-Risk Multisystem Disease
Treatment of Recurrent, Refractory, or Progressive Childhood Langerhans Cell Histiocytosis
CHAPTER 46:
Hemophagocytic Lymphohistiocytosis: Revisited
INTRODUCTION
PATHOGENESIS
Familial Hemophagocytic Lymphohistiocytosis
Genes Associated with Familial Hemophagocytic Lymphohistiocytosis (Table 1, Fig. 2)
Secondary Hemophagocytic Lymphohistiocytosis
Clinical Features
Macrophage Activation Syndrome Associated with Autoimmune Disease
Work-up for Patient of Hemophagocytic Lymphohistiocytosis38
MANAGEMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS31
Principle of Treatment
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 2004 PROTOCOL
Initial Therapy (8 Weeks)
Continuation Therapy (9–40 Weeks)
Indications for BMT
Disease Directed Therapy
CHAPTER 47:
Bone Marrow Transplantation
GRAFT TYPES IN HEMOTOPOIETIC STEM CELLS
Autologous Transplants
SOURCES OF STEM CELLS
Peripheral Blood Stem Cell Apheresis
HUMAN LEUKOCYTE ANTIGEN MATCHING
DONOR REGISTRIES
COLLECTION OF HEMATOPOIETIC STEM CELLS
PREPARATIVE REGIMENS/CONDITIONING REGIMENS
STEM CELL INFUSION
COMPLICATIONS (FIG. 6)
Early Effects
ACUTE GRAFT VERSUS HOST DISEASE
MANAGEMENT OF GVHD
Interstitial Pneumonitis
Infections
DELAYED EFFECTS
Beta Thalassemia
Pesaro Thalassemia Risk Classification
Risk Factors
Risk Classification
APLASTIC ANEMIA
LEUKEMIA
IMMUNODEFICIENCIES
INDIAN SCENARIO
SECTION 7: GENERAL
CHAPTER 48:
Gene Therapy
INTRODUCTION
PROCEDURE OF GENE THERAPEUTICS
Target Tissue
Vectors
Type of Vectors
GENE THERAPY AND ITS USE IN PEDIATRIC HEMATOLOGY AND ONCOLOGY
Gene Therapy for Hemophilia
Gene Therapy for Hemoglobinopathies
Gene Therapy for Immunodeficiencies
Gene Therapy for Hematological Malignancies
Suicide Gene Therapy for Graft Versus Host Disease (GVHD)
CHALLENGES WITH GENE THERAPY
CHAPTER 49:
Monoclonal Antibodies in Pediatric Hematology and Oncology
MONOCLONAL ANTIBODY THERAPY
Mechanism
Adverse Effects of MoAbs
Future
CHAPTER 50:
Biological Response Modifiers
DEFINITION
CLASSIFICATION OF BIOLOGICAL RESPONSE MODIFIERS
Monoclonal Antibodies
Clinical Significance of Monoclonal Antibodies5
Nucleic Acid Based Agents/Antisense Agents
Therapies Targeted to Apoptotic Pathways
Inhibition of Bcl-2 Family Proteins
Molecules Targeting IAPs
TNF-related Apoptosis Inducing Ligand (TRAIL) Receptor Agonism
Therapies Targeted to Extracellular Survival Signaling Pathways
EGFR Inhibitors
KIT and PDGFR Inhibitors
FLT3 Inhibitors
Src Family Kinase Inhibitors
Mammalian Target of Rapamycin (mTOR) Inhibitors
Histone Deacetylase Inhibitors
Protein Farnesyl Transferase Inhibitors
Proteosome Inhibitors
Angiogenesis Inhibitors
Cytokines
Interferons
Interleukins
Tumor Vaccines
SUMMARY
INDEX
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