Anemia: Definition and Hemoglobin Synthesis

Definition of Anemia

• Anemia is a decrease in the number of red blood cells (RBCs) or the amount of hemoglobin in the RBCs, resulting in reduced oxygen delivery and tissue hypoxia.
• It's a manifestation of underlying disease processes, not a disease itself.

Hemoglobin Synthesis

• Hemoglobin synthesis involves an orderly progression of embryonic, fetal, and adult hemoglobins.
• Hb F (fetal hemoglobin) comprises 60-90% of total hemoglobin at birth, decreasing to around 3.2% by 16-20 weeks post-birth.
• The switch from Hb F to Hb A (adult hemoglobin) is genetically controlled based on gestational age.
• Normal adult blood contains Hb A (α2β2), Hb F (γ chains), and Hb A2 (δ chains).

Hemoglobin Abnormalities

• Result from abnormal hemoglobin synthesis or reduced synthesis of normal α or β globin chains (α and β thalassemia).

Clinical Features of Anemia

• Considered based on speed of onset, severity, age, and oxygen dissociation curve.
• Rapid progressive anemia causes more symptoms than slow-onset anemia.
• Mild anemia may be asymptomatic.
• Older patients tolerate anemia less than younger individuals.
• Pyruvate kinase deficiency shifts the oxygen dissociation curve to the right.

Symptoms and Signs

• Shortness of breath, weakness, palpitations, and headache are common symptoms.
• Pallor of mucous membranes is a general sign.
• Less frequent signs include tachycardia, cardiomegaly, and cardiovascular impairment.
• Specific signs are associated with different types of anemia (e.g., spoon nails with iron deficiency, jaundice with hemolytic anemia, leg ulcers with sickle cell anemia).

General Classification of Anemia

• Based on Morphology:
  • Macrocytic anemia (MCV > 100 fL)
  • Microcytic hypochromic anemia (MCV < 80 fL)
  • Normocytic normochromic anemia (MCV 80-100 fL)
• Based on Etiology:
  • Impaired erythrocyte production
    • Abnormal bone marrow (e.g., aplastic anemia)
    • Essential factor deficiency (iron, vitamin B12, folic acid)
    • Stimulation factor deficiency (e.g., anemia of chronic disease)
  • Accelerated erythrocyte destruction (hemolytic anemia)
    • Intracorpuscular defect (intrinsic RBC factor)
      • Membrane defect (e.g., hereditary spherocytosis)
      • Enzyme deficiency (e.g., G6PD deficiency)
      • Hemoglobin abnormalities (e.g., thalassemia)
    • Extracorpuscular defect (nonintrinsic RBC factor)
      • Mechanical (e.g., MAHA)
      • Chemical or infectious causes
  • Excess blood loss (e.g., accident, GI bleeding)

General Aspects of Anemia

• Anemia is defined as hemoglobin concentration below normal levels.
• Adult male: < 13.5 g/dL
• Adult female: < 11.5 g/dL
• Newborn infant: < 14 g/dL
• Anemia usually, but not always, involves reduction in red blood cell count and PCV level.

Laboratory Diagnosis

• Complete Blood Count (CBC)
• Reticulocyte count and Reticulocyte Production Index (RPI)
• Peripheral blood examination
• Bone marrow examination
• Other laboratory tests:
  • Iron studies
  • Urinalysis
  • Stool analysis
  • Liver and renal function tests
  • Serum vitamin B12 and folate assays

Other Laboratory Findings

• Leukocytes and Platelets Count: Helps distinguish anemia from pancytopenia (reduction in all blood cells), suggesting general marrow defects like hypoplasia.
• Reticulocyte Count: Normal level is 50-150 x 10^9/L (0.5-2.5%). Increased in anemia due to increased erythropoietin level. A lack of increase in reticulocyte count with anemia may indicate impaired marrow function or erythropoietin synthesis defect.

Morphologic Classification of Anemias and Reticulocyte Count

• Microcytic Anemias:
  • MCV < 80 fL, RBCs < 6 μm.
  • Often associated with hypochromia (increased central pallor in RBCs) and MCHC < 32 g/dL.
  • Caused by reduced hemoglobin synthesis, heme synthesis (iron deficiency, chronic inflammation, sideroblastic anemia, lead poisoning), or globin chain synthesis (thalassemia, Hb E disease).
  • Iron deficiency is the most common cause, manifesting early as reduced iron stores without microcytosis or anemia.
• Macrocytic Anemias:
  • MCV > 100 fL, RBCs > 8 μm.
  • Result from megaloblastic or nonmegaloblastic red cell development in the bone marrow.
  • Megaloblastic anemias are due to impaired DNA synthesis (vitamin B12 and folate deficiency, myelodysplasia), leading to asynchrony between nuclear and cytoplasmic development, resulting in larger cells.
  • Characterized by oval macrocytes, hypersegmented neutrophils, and megaloblasts in bone marrow.
  • Nonmegaloblastic macrocytic anemias are characterized by large, round RBCs, often seen with liver disease, alcohol abuse, and bone marrow failure.
• Normocytic Anemias:
  • MCV 80-100 fL.
  • Need peripheral blood film examination to rule out dimorphic populations (microcytes and macrocytes) which can yield a normal MCV.
  • Can develop from hemolytic anemias (premature destruction of RBCs), characterized by elevated reticulocyte count, and further divided into intrinsic (membrane defects, hemoglobinopathies, enzyme deficiencies) and extrinsic (immune and nonimmune RBC injury) causes.