Benign Hematologic Disorders in Children: A Clinical Guide

Preface
Contents
Contributors
Part I: Origin of Blood Cells
	Chapter 1: Hematopoiesis
		Introduction
		Cell Development Stages during Hematopoiesis
		Sites of Hematopoiesis
		Mechanisms Underlying Hematopoiesis
		Transcription Factors
		Cytokines
		Cell-to-Cell Interactions
		Conclusion
		References
Part II: Red Blood Cell Disorders
	Chapter 2: Nutritional Anemias: Iron Deficiency and Megaloblastic Anemia
		Iron Deficiency Anemia
		Prevalence
		Pathophysiology
		Iron Deficiency and Neurodevelopment
		Iron Deficiency and Thrombosis and Stroke in Children
		Etiology of Iron Deficiency
		Screening
		Clinical Symptoms and Signs of Iron Deficiency Anemia
		Diagnosis and Treatment
			Laboratory Testing
			Oral Iron Therapy
			Intravenous (IV) Iron Therapy
		Vitamin B12 and Folic Acid Deficiency
		Folate Deficiency
			Pathophysiology
			Etiology
			Diagnosis
			Treatment
		Vitamin B12 Deficiency
			Prevalence
			Pathophysiology
			Etiology
			Signs and Symptoms
			Diagnosis
			Treatment
		Bibliography
	Chapter 3: Lead Poisoning
		Introduction
		Epidemiology of Lead Exposure in Children
			Host Factors
			Chemical Factors Regarding Lead
			Environmental Sources of Lead
		Clinical Manifestations of Elevated Blood Lead Levels
			Neurologic Toxicity
			Hematological Toxicity
			Renal Toxicity
		Approach to Children with Lead Poisoning
			Laboratory and Imaging Studies in Lead Poisoning
			Improving Child Resilience in Lead Poisoning
			Investigation and Mitigation of Sources of Lead Exposure
		Interventions Based on Lead Level
		Chelation Treatment for Lead Poisoning
		Burden of Disease Attributed to Lead Exposure
		Prevention of Lead Exposure in Children
		References
	Chapter 4: Immune and Nonimmune Hemolytic Anemia
		Immune Hemolytic Anemia
			Introduction
			Primary Autoimmune Hemolytic Anemia
				Natural History and Presentation
				Laboratory Evaluation
				Warm Autoimmune Hemolytic Anemia
				Cold Agglutinin Syndrome
				Paroxysmal Cold Hemoglobinuria
				Mixed Autoimmune Hemolytic Anemia
				Treatment
			Secondary Autoimmune Hemolytic Anemia
				Evans Syndrome
		Nonimmune Hemolytic Anemia
			Introduction
			Microangiopathic Hemolytic Anemia
			Thrombotic Thrombocytopenic Purpura
			Hemolytic Uremic Syndrome
				Shigatoxin-Induced Hemolytic Uremic Syndrome
				Atypical Hemolytic Uremic Syndrome
			Paroxysmal Nocturnal Hemoglobinuria
		References
	Chapter 5: Sickle Cell Disease
		Epidemiology
		Etiology and Pathogenesis
			Oxidative Stress
			Inflammation
			Hypercoagulability
		Sickle Cell Trait (SCT)
		Clinical Manifestations
			Acute Complications
			Chronic Complications
		Diagnostic Testing
		Clinical Surveillance Guidelines
		Supportive Therapy
		Hydroxyurea (HU)
		Other Disease Modifying Medications
		Stem Cell Transplant
		Gene Therapy
		Other Issues in SCD (Transition to Adulthood, Adolescent Issues, Living with a Chronic Disease)
		References
	Chapter 6: Thalassemia
		Introduction
		Alpha Thalassemia
		Beta Thalassemia
		Chronic Transfusions and Iron Chelation Therapy
		Stem Cell Transplant for Beta Thalassemia Major
		Pharmacological Advances
		Gene Therapy for Beta Thalassemia Major
		Summary/Conclusion
		References
	Chapter 7: Disorders of RBC Metabolism
		Overview
		Specific RBC Metabolism Syndromes
			Glucose-6-Phosphate Dehydrogenase Deficiency
			PK Deficiency
			Other RBC Enzyme Deficiencies
		Conclusion
		References
	Chapter 8: Red Blood Cell Membrane Defects
		Introduction
		Hereditary Spherocytosis
			Clinical Features
			Laboratory Features and Diagnosis
			Clinical Management
		Hereditary Elliptocytosis
			Clinical Features
			Laboratory Features and Diagnosis
			Clinical Management
		Hereditary Stomatocytosis
			Clinical Features
			Laboratory Features and Diagnosis
			Clinical Management
		Summary
		References
Part III: Platelet Disorders
	Chapter 9: Immune Thrombocytopenia
		Introduction
		Etiology and Pathogenesis
		Clinical Features
		Evaluation
		Management
		Observation-Only Management
		Medical Interventions
			Intravenous Immunoglobulin (IVIG)
			Corticosteroids
			Anti-D Immunoglobulin
		Treatment of Severe Bleeding Events
		Second-Line Therapies
		Splenectomy
		Conclusion
		References
	Chapter 10: Inherited and Congenital Thrombocytopenia
		Introduction
		The Platelet Life Cycle
			Platelet Birth
			Platelet Anatomy and Function
			Neonatal Platelet Variation
		Clinical Evaluation
			History
			Physical Exam
		Laboratory Evaluation
			PFA-100
			Light Transmission Aggregometry
			Flow Cytometry
			Additional Testing
		Inherited Platelet Disorders
			Disorders of Platelet Production
				Congenital Amegakaryocytic Thrombocytopenia
				Thrombocytopenia with Absent Radii
				Amegakaryocytic Thrombocytopenia with Radioulnar Synostosis
				Wiskott-Aldrich Syndrome
				X-Linked Thrombocytopenia
				ANKRD26-Related Thrombocytopenia
				ACTN1-Related Thrombocytopenia
				Bone Marrow Failure Syndromes Associated with Thrombocytopenia
					Fanconi Anemia
					Dyskeratosis Congenita
					Shwachman-Diamond Syndrome
						Familial Platelet Disorder with Associated Myeloid Malignancy
					MYH-9-Related Disorders
						Pearson Syndrome
			Qualitative Platelet Disorders
				Bernard-Soulier
				DiGeorge Syndrome
				Glanzmann Thrombasthenia
				Granule Defects
				Pseudo-von Willebrand Disease
		References
	Chapter 11: Platelet Disorders
		Introduction
		Clinical Features of Platelet Disorders
		General Evaluation for Platelet Dysfunction
		Qualitative Disorders
			Inherited Platelet Disorders
				Receptor Defects
					Bernard-Soulier Syndrome
					Glanzmann Thrombasthenia
					Platelet-Type von Willebrand Disease (Pseudo-von Willebrand Disease)
				Platelet Granule Defects
					Dense Granule Defects
					Alpha-Granule Defects
				Other Rare Platelet Disorders
			Acquired Platelet Disorders
				Drug-Induced Platelet Dysfunction
				Systemic Disease
		Quantitative Disorders
			Inherited Disorders
				Disorders of Platelet Production
					Congenital Amegakaryocytic Thrombocytopenia
					Thrombocytopenia with Absent Radii Syndrome
				Other Inherited Disorders
					Wiskott-Aldrich Syndrome
					Jacobsen Syndrome
					Myosin Heavy-Chain 9-Related Thrombocytopenia
			Acquired Platelet Disorders
				Spurious Thrombocytopenia
				Thrombocytopenia Caused by Sequestration
					Hypersplenism
					Hypothermia
				Thrombocytopenia Secondary to Increased Platelet Destruction
					Immune Thrombocytopenic Purpura
					Thrombocytopenia in Lymphoproliferative Disorders/Autoimmune Diseases
					Neonatal Alloimmune Thrombocytopenia
					Drug-Induced Thrombocytopenia
					Thrombotic Microangiopathic Disorders
					Kasabach-Merritt Syndrome
					Other Causes of Thrombocytopenia Due to Increased Platelet Destruction
				Thrombocytopenia Secondary to Decreased Platelet Production
				Thrombocytosis
		General Management Principles for Platelet Disorders
		Summary
		References
	Chapter 12: Thrombocytosis in Children
		Background/Introduction
		Definition of Thrombocytosis in Childhood
		Classification of Thrombocytosis
		Thrombopoietin and Role in Thrombocytosis
		Secondary, Reactive Thrombocytosis
			Etiologies of Secondary Thrombocytosis
			Rebound Thrombocytosis
			Drug-Induced Thrombocytosis
		MPN and Primary Thrombocytosis/Thrombocythemia
		Primary Thrombocytosis
			Hereditary Thrombocytosis
			Essential Thrombocytosis
			Diagnostic Criteria for ET
			Morphology of ET
			Molecular Characterization in Primary Thrombocytosis
			Clinical Characteristics of Pediatric ET
			Natural History
		Workup for Patients with Thrombocytosis
		Treatment
		Summary
		References
Part IV: WBC Disorders
	Chapter 13: Neutropenia
		Introduction
		Definition and Epidemiology
		Approach to the Neutropenic Child
		Etiologies of Neutropenia
			Inherited Neutropenia
				Severe Congenital Neutropenia (SCN) or Kostmann Syndrome
				Cyclic Neutropenia
				Shwachman-Diamond Syndrome
				Fanconi Anemia
				Dyskeratosis Congenita (DKC)
				Neutropenia and Immunodeficiency
				Neutropenia and Metabolic Diseases
		Acquired Neutropenia
			Neutropenia and Nutritional Deficiencies
			Marrow Suppression/Infection-Related Neutropenia
			Autoimmune Neutropenia (AIN)
			Chronic Idiopathic Neutropenia (CIN)
			Drug-Induced Neutropenia
			Alloimmune and Isoimmune Neonatal Neutropenia
		Vaccination in the Neutropenia Child
		Conclusion
		References
	Chapter 14: Granulocytosis
		Neutrophilia
		Mechanisms for Neutrophilia
		Types of Neutrophilia
			Reactive Neutrophilia
				Acute Neutrophilia
				Chronic Neutrophilia
		Primary Neutrophilia
		Leukemoid Reaction
		Evaluation and Management of Neutrophilia
		Eosinophilia
		Evaluation and Management of Eosinophilia
		Basophilia
		Conclusion
		References
	Chapter 15: Disorders of Granulocyte Functions
		Introduction
		Clinical Presentation of Disorders of Granulocyte Functions
		Chronic Granulomatous Disease (CGD)
			Epidemiology
			Clinical Presentation
			Diagnosis and Management
		Leukocyte Adhesion Deficiencies (LAD)
			Leukocyte Adhesion Deficiency Type 1 (LAD-1)
				Epidemiology
				Clinical Presentation
				Diagnosis and Management
			Leukocyte Adhesion Deficiency Type 2 (LAD-2)
				Epidemiology
				Clinical Presentation
				Diagnosis and Management
			Leukocyte Adhesion Deficiency Type 3 (LAD-3)
				Epidemiology
				Clinical Presentation
				Diagnosis and Management
		Hyperimmunoglobulin E Syndrome (Hyper IgE Syndrome; HIES)
			Autosomal Dominant Hyper IgE Syndrome (AD-HIES)
				Epidemiology
				Clinical Presentation
				Diagnosis
			Autosomal Recessive HIES (AR-HIES)
				Epidemiology
				Clinical Presentation
					Other Characteristics
				Diagnosis
				Management of Hyper IgE Syndrome
		Specific Granule Deficiency (SGD)
		Shwachman-Diamond Syndrome (SDS)
		Chediak-Higashi Syndrome (CHS)
		Neutrophilic Dermatoses
			Pyoderma Gangrenosum (PG)
			Sweet’s Syndrome
		Periodontitis Syndromes
		Summary/Conclusion
		References
Part V: Coagulation Disorders
	Chapter 16: von Willebrand Disease
		Introduction
		Structure and Function of VWF
		Genetics
		Classification of VWD
		Clinical Features
			Acquired von Willebrand Syndrome
		Diagnosis
			Management
		Summary
		References
	Chapter 17: Hemophilia
		Introduction
		Genetics
		Epidemiology
		Pathophysiology
		Clinical Presentation
		Diagnostic Evaluations
		Treatment
		Surgical Considerations
		Inhibitor Antibodies
		Future Therapies
		Conclusions
		References
	Chapter 18: Acquired Disorders of Coagulation in Neonates and Children
		Introduction
		Pathogenesis of Septic Shock
		Organ Injury in Sepsis
		Thrombotic Thrombocytopenic Purpura (TTP) and Thrombocytopenia-Associated Multiple Organ Failure (TAMOF)
		Disseminated Intravascular Coagulation (DIC)
		Platelet Dysfunction in Renal Failure
		Coagulopathy of Liver Failure
		Coagulopathy of Massive Transfusion
		Conclusion
		References
	Chapter 19: Thromboembolism
		Introduction
		Epidemiology
		Pathophysiology
		Risk Factors
			Personal and Family History
			Thrombophilia
				Protein Deficiencies
					Qualitative Genetic Mutations
			Acquired/Inflammatory Markers
			Miscellaneous
			Anatomic
			Central Venous Catheter
			Other Hospital-Related Risks
			Chronic Disease
				Hormonal Therapy
		Types and Symptoms
			Deep Vein Thrombosis
			Pulmonary Embolism
			Superior Vena Cava (SVC) Syndrome
			CVC-Associated VTE
			Cerebral Sinus Venous Thrombosis
		Evaluation
			Laboratory
			Imaging
		Treatment
		Medications Used in Children
			Unfractionated Heparin (UFH)
			Other IV Anticoagulants
			LMWH
			Oral Anticoagulants
			Other
			Thrombolysis
		Prevention
		Complications
			Recurrence
				Post-thrombotic Syndrome
			Chronic Thromboembolic Pulmonary Hypertension
				Mortality
		Conclusions
		References
	Chapter 20: Heavy Menstrual Bleeding and Bleeding Disorders in Adolescents: A Primer for the Primary Care Physician
		Introduction
			Defining Normal Menstruation
			The Etiology of HMB
		Evaluation of Underlying Bleeding Disorders
			Medical and Family History
			Physical Examination
		Laboratory Evaluation
			Initial Evaluation
			Testing for Iron Deficiency Anemia
			Testing for Bleeding Disorders
				Von Willebrand Disease
				Platelet Function Disorders
		Management of Heavy Menstrual Bleeding with Bleeding Disorders
			Management of Acute Bleeding
			Long-Term Management of Menstrual Bleeding
			Management of Secondary Iron Deficiency
		Conclusion
		References
Part VI: Neonatal Hematology
	Chapter 21: Newborn Screening for Hemoglobinopathies
		Introduction
		History of Newborn Screening for Hemoglobinopathies
		Methodology for Identification of Hemoglobinopathy on NBS
			Hemoglobin Electrophoresis
			Isoelectric Focusing (IEF)
			High-Performance Liquid Chromatography (HPLC)
			Molecular Methods for Hemoglobinopathy Diagnosis
		Interpretation of NBS Results
		Genetic Counseling for Hemoglobinopathy Traits on NBS
		Screening Recommendations Beyond the US
		Conclusion
		References
	Chapter 22: Neonatal Immune Hemolytic Anemia
		Introduction
		Pathophysiology
			Rhesus Hemolytic Disease
			ABO Hemolytic Disease
			Minor Blood Group Hemolytic Disease
		Natural History
		Fetal Evaluation and Monitoring
		Prevention
		Newborn Management
			Hyperbilirubinemia Management
			Anemia Management
		Outcomes
		References
	Chapter 23: Neonatal Hemostasis
		Coagulation Factors and Thrombin Generation
		Vitamin K-Dependent Factors
		von Willebrand Factor
		Platelets
		Natural Inhibitors of Coagulation
		The Fetal and Neonatal Fibrinolytic System
		Clinical Aspects of Developmental Hemostasis
			Sampling Challenges
			Clinical Findings
		Common Factor Deficiencies
		Rare Factor Deficiencies
		Liver Disease
		Thrombocytopenia
		Inherited Thrombocytopenia
		External Factors that Compromise Platelet Function
		Neonatal Thrombotic Disorders
		Acquired Prothrombotic Disorders
			Clinical Findings
			Diagnosis
			Treatment
		Renal Vein Thrombosis
		Anticoagulation Therapy
			Unfractionated Heparin Versus Low-Molecular-Weight Heparin
			Oral Anticoagulants
			Direct Thrombin Inhibitors
			Thrombolytic Therapy
		References
	Chapter 24: Disorders of Bilirubin Metabolism
		Normal Bilirubin Metabolism
		Physiologic Jaundice
		Breast Milk Jaundice
		Breastfeeding Jaundice
		Gilbert Disease
			Epidemiology
			Pathophysiology
			Clinical Presentation
			Management
		Crigler-Najjar Syndrome
			Epidemiology
			Pathophysiology
			Clinical Presentation
			Management
		Transient Familial Neonatal Hyperbilirubinemia (Lucy-Driscoll Syndrome)
		Dubin-Johnson Syndrome
			Epidemiology
			Pathophysiology
			Clinical Presentation
			Management
		Rotor Syndrome
			Epidemiology
			Pathophysiology
			Clinical Presentation
			Management
		Progressive Familial Intrahepatic Cholestasis
			Epidemiology
			Pathophysiology
			Clinical Presentation
			Management
		References
Part VII: Bone Marrow Failure Syndrome
	Chapter 25: Failure of Erythrocyte Production
		Introduction
		Decreased Rate of Erythrocyte Production
			Intrinsic Bone Marrow Failure Disorders
				Acquired Aplastic Anemia
					Incidence
					Etiology and Pathogenesis
					Definition and Classifications
					Clinical Features
					Diagnosis and Management
				Diamond-Blackfan Anemia
					Incidence
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Transient Erythroblastopenia of Childhood
					Incidence
					Etiology and Pathogenesis
					Clinical Features
				Parvovirus Infection
					Incidence
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Fanconi Anemia
					Incidence
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
			Defect in Stimuli of Bone Marrow
				Anemia Due to Chronic Renal Disease
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Anemia of Chronic Disease
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
			Disorders of Erythrocyte Maturation and Ineffective Erythropoiesis
				Iron Deficiency Anemia
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Lead Poisoning
				Vitamin B12 Deficiency
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Folic Acid Deficiency
					Etiology and Pathogenesis
					Clinical Features
					Diagnosis and Management
				Congenital Dyserythropoietic Anemia
		References
	Chapter 26: Inherited Bone Marrow Failure Syndromes
		Introduction
		Etiology
		Signs and Symptoms
		Diagnosis
		Treatment
		Outcome
		Long-Term Follow-Up
		Conclusion
		References
	Chapter 27: What Pediatricians Need to Know About Acquired Aplastic Anemia
		Introduction
		Epidemiology
		Etiology
		Pathogenesis
		Clinical Presentation
		Differential Diagnosis
		Diagnosis and Severity Stratification
		Supportive Care
			Transfusion Support
			Infection Prevention and Treatment
		Treatment
			Immunosuppressive Therapy (IST)
			Eltrombopag
			Hematopoietic Stem Cell Transplant
		Summary
		References
Part VIII: Supportive Care
	Chapter 28: Immunizations in the Child with Sickle Cell Disease
		Introduction
		Immune Dysfunction
		Vaccine Schedule
			Haemophilus influenzae Type b (Hib) Vaccine
			Neisseria meningitidis Vaccines
			Streptococcus pneumoniae Vaccines
		Summary
		References
	Chapter 29: Transfusion Medicine for Pediatrics
		The Donation Process
		Processing of Blood Components at the Collection and Processing Facility
		Processing of Blood Components at the Hospital Blood Bank
		Blood Components
			Packed Red Blood Cells
				Source
				Young Versus Old Blood
				Pretransfusion Testing
				Volume and Rate
				Indications
					Basic Principles
					PRBC Transfusion Indications by Disease Category
			Platelets
				Source
				Pretransfusion Testing
				Volume and Rate
				Indication
			Plasma-Based Components
				Source
				Pretransfusion Testing
				Volume and Rate
				Indication
			Granulocytes
		Adverse Effects of Transfusion
		Transfusion-Related Acute Lung Injury (TRALI) and Transfusion-Associated Circulatory Overload (TACO)
		Allergic Reactions
		Febrile Non-hemolytic Transfusion Reaction (FNHTR)
		Transfusion-Associated Graft Versus Host Disease (TA-GVHD)
		Transfusion Avoidance
		Setting Evidence-Based Clinical Guidelines
		Intravenous Iron
		Recombinant Erythropoietin
		References
	Chapter 30: Management of Infections in Neutropenic Patients
		Introduction
		Infections Causing Neutropenia
		Neutropenia in Immunocompromised Hosts
		Neutropenia in Previously Healthy Host
		Pathogens of Concern in the Neutropenic Host
			Bacteria
			Viruses
			Fungal Infections
		Approach to the Patient with Febrile Neutropenia
			Management
		Antimicrobial Therapy
			Empiric Antibacterial Therapy
			Modification and Duration of Antimicrobial Therapy
		Antifungal Therapy
			Consultation
			Control Measures
				Infection Control and Prevention
				Neutropenic Diet
		Summary
		References
Part IX: Miscellaneous
	Chapter 31: Pediatric Vascular Anomalies: Opportunities in Primary Care
		Introduction to Vascular Anomalies
			Overview and Classification
			Approach to a Child with a Suspected Vascular Lesion
		Infantile Hemangioma
			Clinical Presentation
			Complications
			Syndromes That Include Infantile Hemangiomas
				PHACES Syndrome
				LUMBAR Association
			Management
				Observation
				Propranolol
				Timolol
				Other Medical Therapies
				Nonmedical Therapies
		Kaposiform Hemangioendothelioma
			Clinical Presentation
			Coagulopathy
			Management
		Simple Vascular Malformations
			Capillary Malformation
			Venous Malformation
			Lymphatic Malformation
				Common (Cystic) Lymphatic Malformation
				Lymphedema
				Multisystem Disorders of Lymphatics
			Arteriovenous Malformation
		Selected Syndromes Associated with Vascular Malformations
			Overview
			Sturge–Weber Syndrome
			Klippel–Trénaunay Syndrome
			Hereditary Hemorrhagic Telangiectasia
		Resources for Patients and Families
		References
	Chapter 32: Complement Dysregulation Syndromes in Children and Adolescents
		The Complement System
		Shiga Toxin E. coli Hemolytic Uremic Syndrome
		Atypical Hemolytic Uremic Syndrome
		Pneumococcal Hemolytic Uremic Syndrome
		Paroxysmal Nocturnal Hemoglobinuria
		Congenital CD59 Deficiency
		Treatment Considerations of Complement-Mediated Disease
		References
Index