Approach to Anemia Workup
A board-style algorithmic walkthrough of the anemia workup built on two axes — MCV (cell size) and reticulocyte count (marrow response) — with iron-study interpretation, the microcytic and megaloblastic differentials, hemolysis labs, and the classic \"next best step\" decisions Step 2 CK tests.
The two-axis framework
Anemia is not a diagnosis — it is a lab finding that demands a workup, and Step 2 CK almost always tests the algorithm, not rote recall. Start every case with three tests: a CBC (for the MCV), a peripheral smear, and a reticulocyte count. Two questions then organize everything: (1) What is the cell size (MCV)? and (2) Is the marrow responding (reticulocytes)?
MCV splits anemia into microcytic (<80 fL), normocytic (80–100 fL), and macrocytic (>100 fL). The reticulocyte count separates hypoproliferative anemias (low retic = a production problem) from hemolysis or blood loss (high retic = a destruction/loss problem). WHO defines anemia as Hgb <13 g/dL in men and <12 g/dL in women. Fix these two axes in your head and the 'next best step' answer usually falls out on its own.
- Order first, always: CBC with MCV, peripheral smear, reticulocyte count, and note the RDW
- MCV buckets: micro <80 · normo 80–100 · macro >100 fL
- Reticulocyte production index (RPI) corrects retic% for the severity of anemia: RPI >2–3 = appropriate marrow response (blood loss/hemolysis); RPI <2 = hypoproliferative (production defect)
- ↑RDW (anisocytosis) favors iron deficiency or a mixed/nutritional cause; a normal RDW with microcytosis favors thalassemia or anemia of chronic disease
- Ferritin is the single best test for iron deficiency — a low ferritin is diagnostic — but ferritin is an acute-phase reactant and may be falsely normal or high with inflammation
- New iron-deficiency anemia in an adult man or postmenopausal woman = occult GI blood loss until proven otherwise → endoscopy/colonoscopy
Microcytic anemia — iron studies
| Cause | Serum iron | TIBC | Ferritin | Transferrin sat | Classic clue |
|---|---|---|---|---|---|
| Iron deficiency | ↓ | ↑ | ↓ | ↓ | ↑RDW, pica, koilonychia, GI bleed |
| Anemia of chronic disease | ↓ | ↓ | ↑/nl | nl/↓ | chronic inflammation, ↑ hepcidin |
| Thalassemia | nl | nl | nl | nl | ↑RBC count, target cells, ↑HbA2 (β) |
| Sideroblastic | ↑ | nl/↓ | ↑ | ↑ | ringed sideroblasts; basophilic stippling in lead |
Vignette: A 64-year-old man reports fatigue. Hgb 9.2 g/dL, MCV 74, RDW elevated. Smear: microcytic, hypochromic RBCs. Ferritin 8 ng/mL, low serum iron, high TIBC.
- Diagnosis: Iron-deficiency anemia.
- Next best step: Colonoscopy (often plus EGD) to identify the GI source — occult colorectal cancer must be excluded in any older adult or postmenopausal woman with new IDA. Do not simply start iron and reassure.
- Buzzwords that point to iron deficiency: pica (pagophagia — craving ice), koilonychia (spoon nails), restless legs, and Plummer–Vinson syndrome (dysphagia + esophageal webs + iron deficiency, often with glossitis).
Macrocytic (MCV >100):
- Megaloblastic = impaired DNA synthesis → hypersegmented neutrophils on smear: B12 or folate deficiency, and drugs that block DNA synthesis (methotrexate, hydroxyurea, 5-fluorouracil, zidovudine)
- Non-megaloblastic: alcohol, liver disease, hypothyroidism, myelodysplastic syndrome, reticulocytosis
- B12 deficiency causes neurologic disease (paresthesias, ataxia, subacute combined degeneration); folate deficiency does not
- Replace B12 before folate — giving folate alone can precipitate or worsen irreversible neurologic damage
Normocytic (MCV 80–100) — split by the reticulocyte count:
- Low retic (hypoproliferative): anemia of chronic disease, CKD (↓ EPO), early iron deficiency, aplastic anemia, marrow infiltration
- High retic: hemolysis or acute blood loss → send LDH, haptoglobin, indirect bilirubin, and a direct Coombs
B12 vs folate deficiency
| Feature | Vitamin B12 deficiency | Folate deficiency |
|---|---|---|
| MCV / smear | ↑, megaloblastic, hypersegmented PMNs | ↑, megaloblastic, hypersegmented PMNs |
| Neurologic signs | Yes (SCD, paresthesias, ataxia) | No |
| Methylmalonic acid | ↑ | Normal |
| Homocysteine | ↑ | ↑ |
| Classic setting | vegan diet, pernicious anemia, ileal disease/resection, chronic metformin | alcoholism, pregnancy, methotrexate/phenytoin, goat's-milk diet |
Vignette: A 25-year-old woman with SLE develops fatigue and jaundice. Hgb 8 g/dL, MCV 95, reticulocytes markedly elevated. Labs: ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin. Smear shows spherocytes.
- Diagnosis: Autoimmune hemolytic anemia (warm, IgG) — a high-reticulocyte normocytic anemia with a hemolysis lab pattern.
- Next best step: Direct antiglobulin test (Coombs) — a positive result confirms immune-mediated hemolysis; treat with corticosteroids.
- Smear pearls: schistocytes → MAHA (TTP/HUS, DIC, mechanical valve); bite cells / Heinz bodies → G6PD deficiency; sickle cells → sickle cell disease; spherocytes → AIHA or hereditary spherocytosis.
Microcytic anemia — 'TAILS':
- T — Thalassemia
- A — Anemia of chronic disease (can be micro- or normocytic)
- I — Iron deficiency
- L — Lead poisoning (basophilic stippling)
- S — Sideroblastic anemia
Hemolysis lab triad: ↑ LDH + ↑ indirect bilirubin + ↓ haptoglobin, with reticulocytosis, = hemolysis — then add the direct Coombs to separate immune from non-immune causes.
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