Common Types of Anemia
Understanding RBC Morphology
Normocytic and normochromic refer to normal erythrocytes (RBCs). The suffix "-cytic" refers to cell size, while "-chromic" indicates color intensity.
Size Classification (Cytic)
- Macrocytic: Large cells, typically associated with folate/B12 deficiency
- Microcytic: Small cells, typically associated with iron deficiency
Color Classification (Chromic)
- Hypochromic: Pale cells due to low iron content
- Hyperchromic: Darker cells due to high iron concentration
Hereditary Spherocytosis
Cause
Hereditary spherocytosis results from an autosomal dominant defect in RBC membrane proteins, including spectrin and ankyrin. This defect leads to spherically shaped RBCs that are fragile and prone to hemolysis in the spleen.
Clinical Presentation
- Hemolytic anemia with fatigue and pallor
- Jaundice and pigmented gallstones
- Splenomegaly
- May present in neonates with prolonged jaundice
Pathophysiology
Defects in membrane-supporting proteins weaken the connection between the cell membrane and cytoskeleton, transforming the normal biconcave shape into a spherical one. This change reduces cellular flexibility and durability, making these cells unable to pass through splenic sinusoids. They become trapped in the spleen and are destroyed, leading to extravascular hemolysis.
Blood Smear Findings
- Spherocytes: Small, round RBCs with absent central pallor
Diagnostic Workup
- Increased red cell distribution width (RDW)
- Positive osmotic fragility test
- EMA binding test (flow cytometry; most accurate diagnostic test)
Management
- Folic acid supplementation
- Splenectomy if severe (recommended after age 5)
- Pre-splenectomy vaccination for encapsulated organisms (e.g., Streptococcus pneumoniae)
Iron Deficiency Anemia
Causes
- Chronic blood loss (GI bleeding, heavy menstruation)
- Inadequate dietary intake or impaired absorption
Clinical Presentation
- Fatigue, pallor, shortness of breath
- Pica (craving for ice or non-food items like dirt)
- Glossitis and angular cheilitis
- In severe cases: koilonychia (spoon-shaped nails)
Pathophysiology
Iron is essential for hemoglobin synthesis. Without adequate iron, RBCs are produced smaller (microcytic) and contain less hemoglobin, appearing pale (hypochromic).
Blood Smear Findings
- Microcytic, hypochromic RBCs
- Increased RDW due to the release of immature reticulocytes from bone marrow attempting to compensate for anemia (reticulocytes are larger than mature RBCs)
Laboratory Findings
- ↓ Ferritin
- ↓ Serum iron
- ↑ Total iron-binding capacity (TIBC)
- ↓ Transferrin saturation percentage
Diagnostic Workup
- First-line test: Serum ferritin
- For older males or postmenopausal women: Evaluate for occult GI bleeding
Management
- Oral iron supplementation (ferrous sulfate)
- Recheck hemoglobin in 4 weeks
- Treat underlying cause (e.g., colonoscopy for suspected GI blood loss)
Folate and B12 Deficiency
Causes
Folate deficiency:
- Poor diet, alcoholism, pregnancy, methotrexate therapy
B12 deficiency:
- Pernicious anemia (anti-intrinsic factor antibodies)
- Gastrectomy
- Terminal ileum disease (Crohn's disease)
- Strict veganism
Clinical Presentation
- Standard anemia symptoms
- Glossitis
- B12 deficiency only: Neurologic symptoms including ataxia, paresthesias, loss of vibration and proprioception sense, and dementia
- Folate deficiency: No neurologic symptoms
Pathophysiology
Both folate and B12 are required for DNA synthesis. In their absence, nuclear division is impaired while cytoplasmic growth continues, resulting in large cells (macrocytic). Neutrophils are similarly affected, showing delayed nuclear maturation with hypersegmented nuclei.
Blood Smear Findings
- Macrocytic anemia
- Hypersegmented neutrophils
Laboratory Findings
- B12 deficiency: ↑ Methylmalonic acid (MMA) and ↑ homocysteine
- Folate deficiency: ↑ Homocysteine with normal MMA
Diagnostic Workup
- Serum B12 and folate levels
- MMA and homocysteine levels if initial levels are borderline
Management
- Folate deficiency: Oral folic acid supplementation
- B12 deficiency: Intramuscular or oral B12 (depending on underlying cause)
Never give folate alone in B12 deficiency, as this can worsen neurologic symptoms. In B12 deficiency, both DNA synthesis (causing megaloblastic anemia) and myelin synthesis (causing neurologic symptoms) are impaired. Folate supplementation alone bypasses the DNA synthesis block and improves anemia, but does not correct the B12-dependent pathway needed for myelin formation. This allows neurologic damage to continue unchecked and may even worsen silently because the anemia - a key warning sign - appears to improve.
Thalassemia
Causes
Inherited mutations affecting globin chain production:
- Alpha thalassemia: Deletion of alpha-globin genes (common in Southeast Asia and Africa)
- Beta thalassemia: Point mutations in beta-globin genes (common in Mediterranean and Middle Eastern populations)
Clinical Presentation
- Mild to severe anemia
- Microcytic anemia unresponsive to iron therapy
- In severe cases: splenomegaly, skeletal deformities (chipmunk facies), and iron overload due to chronic transfusions
Pathophysiology
Decreased or absent globin chain production (α or β) results in reduced hemoglobin content, producing smaller, paler RBCs (microcytic and hypochromic).
Blood Smear Findings
- Microcytic, hypochromic RBCs
- Target cells: Form due to excess membrane relative to cell volume (common in hemoglobinopathies)
- Basophilic stippling: Represents retained RNA due to ineffective erythropoiesis (especially prominent in β-thalassemia)
Laboratory Findings
- Normal or increased serum iron and ferritin
- Normal/Decreased RDW (distinguishes from iron deficiency, which shows increased RDW)
Diagnostic Workup
- Hemoglobin electrophoresis: Shows ↑ HbA2 and HbF in beta-thalassemia
- Genetic testing: Particularly useful for alpha-thalassemia diagnosis
Management
- Thalassemia minor: No treatment typically required
- Thalassemia major: Chronic transfusions plus iron chelation therapy (e.g., deferoxamine), with consideration for hematopoietic stem cell transplantation (HSCT)