Disease of the blood(Gashaw)(1) 9
Page 1: Introduction
Title: Disease of the Blood
Author: Gashaw Abebaw
Page 2: Development of the Hematopoietic System
Hematopoiesis: Formation of blood cellular elements.
Divided into 3 anatomic stages:
Mesoblastic Stage:
Occurs in extraembryonic structures, primarily in the yolk sac.
Lasts from the 10th to 14th days of gestation up to 10-12 weeks.
Hepatic Stage:
Occurs from 6-8 weeks to 20-24 weeks of gestation.
Myeloid Stage:
Begins in the 2nd trimester, predominantly in the bone marrow.
Multipotent Cells:
Initiate all hematopoietic tissues, capable of both self-renewal and differentiation into all blood cell lineages.
Progenitor Cells:
Differentiate under influence of transcription factors and hematopoietic growth factors.
Page 3: Hematopoietic Differentiation
Classical Model: Involves differentiation into lineage-specific progenitors.
Long-term Repopulating Hematopoietic Stem Cells (LTR-HSCs):
Self-renew and differentiate into multipotent cells.
Multipotent Progenitors (MPPs):
Reduced self-renewal, differentiate into common lymphoid and myeloid progenitors.
Common Myeloid Progenitors (CMPs):
Differentiate into all blood lineages except lymphoid.
Cytokine Stimulation: Required for commitment to lineage-restricted cells.
Page 4: Hematopoietic Growth Factors
Early-acting Factors:
SCF, IL-3, GM-CSF
Specific Hematopoietic Factors:
Epo, IL-6, M-CSF, G-CSF.
Major Cytokine Sources:
Bone marrow cells such as macrophages and reticular fibroblasts.
Factor Combinations:
Optimal hematopoietic development requires early- and late-acting factors.
Page 5: Fetal Erythrocyte Changes
Erythrocyte Features:
Fetal erythrocytes larger than adult forms.
Hemoglobin concentrations change, increasing hematocrit and blood hemoglobin during gestation.
Page 6: Hematocrit and MCV Changes Over Time
Figures Present: Erythrocyte mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) changes from 22 weeks to term.
Reference Ranges: Denotes developmental trends in erythrocyte indices through gestation.
Page 7: Fetal Granulocytopoiesis
Neutrophil Development:
First seen at 5 weeks as clusters around the aorta.
Bone marrow develops from 8 weeks, with neutrophils not appearing until 10.5 weeks.
Neutrophils become common from 14 weeks to term.
Presence of progenitor cells abundance in fetal blood prior to mature neutrophils.
Page 8: Fetal Thrombopoiesis
Megakaryocyte Progenitors: Burst-forming unit-megakaryocytes (BFU-MK) and colony-forming unit-megakaryocytes (CFU-MK).
Thrombopoietin (TPO): Dominant regulator of megakaryocyte and platelet production.
Additional Growth Factors: SCF, IL-3, Epo support megakaryopoiesis.
Page 9: Fetal Erythropoiesis
Erythropoietin (EPO): Produced in the fetal liver, not crossing the placenta.
EPO Functions: Promotes survival and proliferation of erythroid-committed progenitors.
Mechanism of Production: Oxygen levels regulate EPO expression through hypoxia-inducible factors.
Page 10: Fetal Hemoglobin Structure
Hemoglobin Composition:
A tetramer of globin chains (2α, 2β) with heme.
Gene locations: Chromosome 16 (α) and 11 (β).
Composition changes during development.
Page 11: Types of Hemoglobins in Development
Six Different Hemoglobins: Present at various developmental stages: α, β, γ, δ, ε, ζ.
Page 12: Changes in Hemoglobin Expression
Developmental Changes:
Involves two major switches regulating β-globin gene expression.
Transition from embryonic to fetal forms, and then to adult forms during gestation.
Page 13: Regulation of Globin Expression
Key Regulators:
Transcription factors (e.g., BCL11A) silence γ-globin leading to hemoglobin switching.
β-Globin Switches: Occur around 6 weeks and mid-gestation.
Page 14-15: Clinical Implications of Hemoglobin Changes
Impacts of Fetal Hemoglobin:
Elevated levels in certain disorders such as thalassemia and sickle cell disease postnatally.
Transition to Adult Hemoglobin Levels: Occurs within first year of life.
Page 16: Anemia Overview
Anemia Definition: Reduction of Hb concentration or RBC volume below normal ranges.
Page 17: Physiological Adjustments to Anemia
Response Mechanisms: Increased cardiac output, augmented oxygen extraction, and increased EPO production.
Page 18-20: History, Physical Examination, and Findings
Clinical Presentation: Investigate dietary, family, and medical history.
Physical Signs: Pallor, flow murmurs, kidney enlargement, etc.
Thorough Examination: Necessary for unearthing specific anemias.
Page 21-22: Laboratory and Diagnosis
Lab Tests: CBC with differential, reticulocyte count, peripheral blood smear.
Further Testing: Based on initial findings and clinical signs.
Page 23: Differential Diagnosis of Anemia
Microcytic Anemias: Iron deficiency, thalassemia, chronic disease.
Normocytic Anemias: Chronic disease, RBC aplasia, infections.
Macrocytic Anemias: Vitamin B12 deficiency, folate deficiency, aplastic anemia.
Page 24: Peripheral Blood Morphology
Characteristic Findings: Microcytes, macrocytes, spherocytes, sickled cells reflecting various anemia causes
Page 25: Anemias of Inadequate Production
Example: Diamond-Blackfan Anemia characterized by normochromic macrocytic anemia presenting in early childhood.
Clinical Findings: Skewed profiles leading to decreased red cell precursors.
Page 26: Diamond-Blackfan Anemia Overview
Features: Anemia co-occurs with extrahematopoietic anomalies.
Genetic Mutations: Relate to ribosomal protein coding.
Page 27: Clinical Findings in DBA
Diverse Anomalies: Craniofacial, urogenital, cardiac show various effects.
Page 28: Laboratory Findings in DBA
Key Lab Values: Macrocytosis without corresponding RBC precursors.
Page 29: DBA Diagnostic Criteria
Support for Diagnosis: Age under 1, macrocytic anemia, bone marrow findings.
Page 30: Treatment for DBA
Corticosteroids: First-line treatment in up to 80% of cases.
Page 31: Long-term Considerations for DBA
Cancer Risk: Elevated chances for MDS, AML, and other malignancies.
Page 32: Acquired Pure Red Cell Aplasia
Transient Erythroblastopenia: Most common in young children following viral infections.
Page 33: Parvovirus B19 and RBC Aplasia
Impact on Chronic Hemolysis: Affects RBC progenitors in compromised states.
Page 34: Anemia of Chronic Disease
Associated Factors: Impacts of immune activation with common causes listed.
Page 35: Role of Hepcidin in Iron Homeostasis
Key Player: Connects anemia to disturbances in iron regulation.
Page 36: Management of Chronic Disease Anemia
Approaches: Target underlying disorders and assist with erythropoiesis.
Page 37: Anemia of Renal Disease
Etiology: Primary cause is decreased EPO production due to renal impairment.
Page 38: Laboratory and Clinical Definitions in CKD
Diagnosis Criteria: Specific blood definitions based on age correlating with hemoglobin and reticulocyte counts.
Page 39: Treatment Recommendations for CKD Anemia
Iron Supplementation Required: Alongside ESA treatments.
Page 40: Congenital Dyserythropoietic Anemia Syndromes
Types: Overview on types with hereditary components.
Page 41: Physiologic Anemia of Infancy
Onset: Associated with increased oxygen availability leading to interim RBC recycling.
Page 42: Prematurity and Anemia
Distinct Features: Occurrence of physiologic anemia in newborns and the factors influencing its management.
Page 43: Megaloblastic Anemias
Description: Larger RBC and asynchronous populations—viable indicators of nutrient deficiencies, particularly B12 and folate.
Page 44: Causes of Increased Macrocytosis
Contributing Conditions: Various causes from malnutrition to genetic anomalies.
Page 45: Diagnostic Approach for Megaloblastic Anemias
Clinical Findings: Profound findings on blood tests leading to definitive diagnoses based on RBC morphology.
Page 46-47: Folic Acid Deficiency Impact
Overview of Implications: From malnutrition to specific treatment strategies to minimize effects of deficiency.
Page 48: Vitamin B12 (Cobalamin) Overview
Nutritional Source Reliance: Strong dependence on dietary sources emphasizing dietary considerations.
Page 49: Mechanisms Behind B12 Deficiency
Impact of Absorption Issues: Effects surrounding intrinsic factor and related gastrointestinal diseases.
Page 50: Clinical Findings in B12 Deficiency
Symptoms and Lab Findings: Typical clinical presentations detailing hematological presentations.
Page 51: Evaluation and Treatment of B12 Deficiency
Approaches for Managing Deficiencies: Ranging from supplementation to understanding broader impacts.
Page 52: Iron-Deficiency Anemia Basics
Most Common Nutritional Disorder: Highlighted by the discussions on deficiency management and dietary impact.
Page 53: Etiology and Development of IDA
Long-term Consequences: Observational data outlining the progression and delayed presentations in infants.
Page 54: Clinical Features and Labs for IDA
Signs and Symptoms: Common physical findings with supportive imaging results leading to diagnosis.
Page 55: Laboratory Indicators of Iron Deficiency
Diagnostic Tests: Measures defining definitive anemia diagnosis and appearance.
Page 56: The Dynamic of Macrocytosis
Factors Influencing RBC shape and size: Emergent research on the conditions resulting in significant morphological changes.
Page 57: Non-Hematologic Causes of Microcytosis
Overview: Discussion on conditions outside the hematologic spectrum influencing overall clinical presentations.
Page 58: Genetic Anomalies Leading to Pancytopenia
Key Syndromes: Overview of rare, inherited syndromes contributing to overall blood production concerns.
Page 59: Fanconi Anemia Profiles
Characteristics: Indicative of complex manifestations leading to molecular understanding and approaches to treatment.
Page 60: Treatment of Aplastic Anemia Syndromes
Interventions: Focus on management approaches to mitigate long-term consequences of genetic anomalies.
Page 61: Other Aplastic Anemia Disorders
Conclusion: List of syndromes with associated conditions notable for their clinical features, diagnostic distinctions, and treatment pathways.