Section 12.1: Anemias (Microcytic, Macrocytic, Hemolytic/Sickle Cell)
Key Takeaways
- Low serum ferritin is the single most specific initial indicator of iron deficiency anemia.
- Neurological symptoms occur in B12 deficiency (subacute combined degeneration) but not in folate deficiency; B12 features elevated methylmalonic acid (MMA) and homocysteine, while folate features normal MMA.
- Sickle cell disease results from an autosomal recessive point mutation in the beta-globin gene, leading to functional asplenia which requires prophylactic penicillin from age 2 months to 5 years.
- G6PD deficiency is an X-linked recessive disorder triggered by oxidative stress (such as sulfa drugs, fava beans, and infections), presenting with Heinz bodies and bite cells on peripheral smear.
PANCE Blueprint & Clinical Significance
Anemias are among the most frequently tested topics in the PANCE hematology blueprint. The exam expects candidates to rapidly differentiate microcytic, normocytic, and macrocytic anemias based on laboratory markers, recognize pathognomonic peripheral smear findings, and establish appropriate management plans while avoiding common diagnostic traps.
Microcytic Anemias: Iron Deficiency Anemia
Pathophysiology
Iron deficiency anemia (IDA) is a microcytic, hypochromic anemia (mean corpuscular volume [MCV] < 80 fL) resulting from inadequate iron stores to support erythropoiesis. Causes include chronic blood loss (e.g., menorrhagia in premenopausal women, occult gastrointestinal bleeding from colorectal cancer in older adults), decreased absorption (e.g., celiac disease, gastric bypass), or increased demand (e.g., pregnancy, infancy).
Clinical Presentation
In addition to classic anemic symptoms (fatigue, exertional dyspnea, pallor), patients may exhibit pica (craving non-nutritive substances), pagophagia (craving ice, which is highly specific for iron deficiency), koilonychia (spoon-shaped nails), angular cheilitis, and glossitis. Plummer-Vinson syndrome represents a high-yield clinical triad of dysphagia, esophageal webs, and iron deficiency anemia, which increases the risk of squamous cell carcinoma of the esophagus.
Diagnostic Workup
An iron panel is the key to diagnosis. A low serum ferritin level is the most specific initial laboratory finding and represents depleted body iron stores. Other findings include low serum iron, elevated total iron-binding capacity (TIBC) reflecting increased transferrin synthesis, and a low transferrin saturation (typically < 15%). The red cell distribution width (RDW) is classically elevated in IDA, distinguishing it from thalassemia (which has a normal RDW and a normal-to-high RBC count). A peripheral blood smear reveals microcytic, hypochromic red blood cells with central pallor, along with occasional pencil cells (elliptocytes).
Management
Treatment centers on identifying and addressing the underlying cause (e.g., colonoscopy in older adults to rule out malignancy) and iron replacement. First-line therapy is oral iron supplementation, typically ferrous sulfate 325 mg (containing 65 mg of elemental iron) taken once daily or every other day. Co-administration with Vitamin C (ascorbic acid) enhances absorption by keeping iron in its soluble ferrous state, while calcium, antacids, and tea impair absorption. Common side effects include dark stools, constipation, and metallic taste. IV iron is indicated for patients with oral intolerance, malabsorption syndromes, or severe ongoing blood loss.
Macrocytic Anemias: Vitamin B12 vs. Folate Deficiency
Pathophysiology & Classification
Macrocytic anemias are defined by an MCV > 100 fL. They are divided into megaloblastic and non-megaloblastic types. Megaloblastic anemia is characterized by impaired DNA synthesis, leading to delayed nuclear maturation relative to cytoplasmic development. The hallmark peripheral smear finding is hypersegmented neutrophils (five or more lobes in > 5% of neutrophils, or a single neutrophil with six or more lobes).
Vitamin B12 (Cobalamin) Deficiency
Dietary B12 is found in animal products. It requires gastric acid to be freed from proteins, intrinsic factor (IF) secreted by gastric parietal cells for ileal absorption, and an intact terminal ileum. Causes of deficiency include vegan diets, pernicious anemia (autoimmune destruction of parietal cells or anti-IF antibodies), Crohn's disease affecting the terminal ileum, and gastric bypass.
Folate (Vitamin B9) Deficiency
Folate is absorbed in the jejunum and is found in green leafy vegetables. Body stores are limited (lasting only a few months, compared to years for B12). Causes include alcoholism ('tea and toast' diet), pregnancy, chronic hemolysis, and drugs like methotrexate, trimethoprim, and phenytoin.
Clinical Distinction
Neurological symptoms are the key differentiator. Vitamin B12 deficiency causes demyelination of the posterior and lateral columns of the spinal cord (subacute combined degeneration), presenting as symmetric paresthesias, loss of vibratory and proprioceptive sensation, and ataxia. Folate deficiency does not cause neurological deficits.
Laboratory Distinction
A serum B12 and folate level are initial steps, but borderline results require secondary markers. Methylmalonic acid (MMA) and homocysteine are intermediate metabolites. In Vitamin B12 deficiency, both methylmalonic acid (MMA) and homocysteine are elevated. In folate deficiency, homocysteine is elevated, but methylmalonic acid (MMA) is normal.
Management & Traps
Vitamin B12 deficiency is treated with cobalamin replacement (typically intramuscular cyanocobalamin 1000 mcg daily for a week, then weekly, then monthly, or high-dose oral replacement if absorption is intact). Folate deficiency is treated with oral folic acid 1 to 5 mg daily. PANCE Trap: Administering folic acid to a patient with unrecognized B12 deficiency will correct the megaloblastic anemia but will allow the irreversible neurological damage to progress.
Hemolytic and Sickle Cell Anemias
Sickle Cell Disease (SCD)
Pathophysiology
SCD is an autosomal recessive hemoglobinopathy resulting from a point mutation in the beta-globin gene (substitution of glutamic acid by valine at position 6), producing abnormal Hemoglobin S (HbS). Under hypoxic, acidotic, or dehydrated conditions, HbS polymerizes, causing red blood cells to assume a rigid, sickle shape. These cells clog microvascular beds, causing vaso-occlusion and tissue infarction, and are prematurely destroyed in the spleen (extravascular hemolysis).
Clinical Presentation
Infants present around 6 months of age as fetal hemoglobin (HbF) levels decline, often with dactylitis (painful swelling of the hands and feet). Vaso-occlusive crises are painful episodes triggered by cold, dehydration, or infection. Acute chest syndrome is a life-threatening complication characterized by chest pain, fever, tachypnea, hypoxia, and a new pulmonary infiltrate on chest X-ray. Splenic sequestration can cause sudden, massive splenic enlargement and cardiovascular collapse. Recurrent splenic infarction leads to functional asplenia (autosplenectomy) by early childhood, predisposing patients to infections from encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). Osteomyelitis in SCD is classically caused by Salmonella species.
Diagnostics
Hemoglobin electrophoresis is the diagnostic standard, showing a predominance of HbS and no normal HbA. Peripheral smear shows sickle cells, target cells, and Howell-Jolly bodies (nuclear remnants indicating functional asplenia).
Management
Long-term management relies on hydroxyurea, which increases the production of fetal hemoglobin (HbF), thereby preventing HbS polymerization and reducing the frequency of painful crises. Folic acid supplementation supports high red cell turnover. Immunizations are critical: patients must receive pneumococcal, meningococcal, and H. influenzae vaccinations, along with prophylactic penicillin from 2 months of age until at least 5 years of age. Acute vaso-occlusive crises are managed with aggressive hydration, oxygen (if hypoxic), and scheduled analgesia (including IV opioids).
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Pathophysiology & Triggers
G6PD deficiency is an X-linked recessive disorder that impairs the hexose monophosphate shunt, preventing the regeneration of NADPH. Without NADPH, red blood cells cannot maintain glutathione in its reduced state, leaving them vulnerable to oxidative stress and subsequent intravascular and extravascular hemolysis. Hemolytic episodes are episodic and triggered by oxidative stress: infections (most common), ingestion of fava beans, or exposure to certain medications (e.g., sulfamethoxazole, nitrofurantoin, dapsone, primaquine, phenazopyridine).
Diagnostics
A peripheral smear during an acute flare reveals Heinz bodies (precipitated denatured hemoglobin) and bite cells (degmacytes, which are RBCs that have had Heinz bodies removed by splenic macrophages). G6PD enzyme activity levels confirm the diagnosis but may be falsely normal during an acute hemolytic episode because the most severely deficient cells have already lysed. Testing should be repeated 2-3 months after the flare resolves.
Management
Avoidance of known oxidative triggers is the cornerstone of management. Supportive care with hydration and blood transfusions is reserved for severe hemolytic anemia.
Laboratory Profiles of Microcytic Anemias
| Condition | MCV | Ferritin | Serum Iron | TIBC | RDW | Key smear/Marrow findings |
|---|---|---|---|---|---|---|
| Iron Deficiency | Low | Low | Low | High | High | Pencil cells, hypochromia |
| Chronic Disease | Normal/Low | Normal/High | Low | Low | Normal | Normal morphology |
| Thalassemia | Very Low | Normal/High | Normal | Normal | Normal | Target cells, microcytosis |
| Sideroblastic | Low/Normal/High | High | High | Low/Normal | High | Ringed sideroblasts in marrow |
A 28-year-old female presents with fatigue and pagophagia. Lab work shows a hemoglobin of 9.2 g/dL and an MCV of 74 fL. Which of the following laboratory findings is most specific for diagnosing the underlying etiology?
A 62-year-old male with a history of alcohol use disorder presents with progressive fatigue and numbness in his feet. Laboratory evaluation reveals macrocytic anemia with an MCV of 112 fL. Which of the following laboratory findings would most reliably distinguish vitamin B12 deficiency from folate deficiency in this patient?
A 4-year-old male with sickle cell disease is brought to the clinic for a routine check-up. The PA discusses preventative care with the child's parents. Which of the following interventions is recommended to reduce the risk of infection by encapsulated organisms in this patient?