Macrocytic & Hemolytic Anemias
A Step 1 high-yield lesson linking macrocytic and hemolytic anemias by mechanism, walking pathophysiology → smear buzzwords → confirmatory labs/markers → next-best-step, with B12-vs-folate and hemolytic-anemia comparison tables and classic G6PD and pernicious-anemia vignettes.
Framework: sort by MCV, then by mechanism
Every anemia work-up starts with the MCV and the reticulocyte count.
Macrocytic (MCV >100):
- Megaloblastic = impaired DNA synthesis (B12, folate, drugs) → nuclear–cytoplasmic asynchrony.
- Non-megaloblastic = liver disease, alcohol, hypothyroidism, MDS, brisk reticulocytosis.
Hemolytic anemias are usually normocytic (reticulocytosis can nudge MCV up). Classify by:
- Intrinsic — membrane (spherocytosis), enzyme (G6PD, PK), hemoglobin (sickle), or acquired (PNH).
- Extrinsic — immune (AIHA), mechanical/MAHA, infection.
The two families overlap: megaloblastic anemia produces intramedullary hemolysis (ineffective erythropoiesis), so it shares the hemolysis signature of ↑LDH and ↑indirect bilirubin. Boards reward three moves: recognize the smear buzzword, name the confirmatory lab/marker, and pick the next-best step.
- Megaloblastic = impaired DNA synthesis → macro-ovalocytes + hypersegmented neutrophils (>5 lobes); can progress to pancytopenia.
- Ineffective erythropoiesis → ↑LDH, ↑indirect bilirubin, ↓haptoglobin (intramedullary hemolysis).
- B12 (cobalamin): pernicious anemia (anti-IF / anti-parietal-cell Ab, atrophic gastritis), terminal-ileum disease (Crohn, resection), Diphyllobothrium latum, vegans, chronic metformin/PPI. Neuro = subacute combined degeneration (dorsal columns → ↓vibration/proprioception; lateral corticospinal → spasticity; spinocerebellar → ataxia). ↑Methylmalonic acid AND ↑homocysteine.
- Folate: alcoholics / "tea-and-toast" elderly, pregnancy, ↑demand (hemolysis), drugs (methotrexate, trimethoprim, phenytoin). ↑homocysteine, NORMAL methylmalonic acid. NO neuro signs.
- Discriminator = MMA (high in B12, normal in folate).
- Treat B12 first: giving folate alone corrects the anemia but lets neurologic damage progress.
Vignette: A 62-year-old woman has months of fatigue, a sore beefy-red tongue (glossitis), tingling feet, and an unsteady wide-based gait with ↓vibratory sense. She also has vitiligo and treated hypothyroidism. Hgb 8.9, MCV 118; smear shows hypersegmented neutrophils; LDH and indirect bilirubin are high.
Diagnosis: B12 deficiency from pernicious anemia (autoimmune atrophic gastritis).
Confirm: low serum B12, ↑MMA + ↑homocysteine, anti-intrinsic-factor antibodies (specific).
Next best step: parenteral (IM) B12 replacement. Do not give folate alone — it can mask the anemia while the subacute combined degeneration worsens.
Trap: pancytopenia + hypersegmented PMNs can mimic marrow failure; the smear and MMA keep you out of a needless bone-marrow chase.
Macrocytic anemia comparison
| Feature | B12 deficiency | Folate deficiency | Non-megaloblastic |
|---|---|---|---|
| Smear | Hypersegmented PMNs, macro-ovalocytes | Same as B12 | Round macrocytes, no hypersegmentation |
| Methylmalonic acid | ↑ | Normal | Normal |
| Homocysteine | ↑ | ↑ | Normal |
| Neuro deficits | Yes (SCD) | No | No |
| Classic cause | Pernicious anemia, ileal disease | Alcohol, pregnancy, MTX | Liver disease, hypothyroid, MDS, alcohol |
- Hemolysis signature: ↑reticulocytes, ↑LDH, ↑indirect bilirubin, ↓haptoglobin, jaundice, pigment gallstones.
- Intravascular: ↓↓haptoglobin, hemoglobinemia/-uria, hemosiderinuria, schistocytes. Causes: MAHA (TTP/HUS/DIC), mechanical valve, PNH, ABO transfusion reaction, cold agglutinin disease.
- Extravascular (spleen): spherocytes, splenomegaly, ↑urobilinogen. Causes: hereditary spherocytosis, warm AIHA, sickle cell.
- Direct antiglobulin (Coombs) test positive = immune hemolysis (AIHA, drug-induced, hemolytic disease of the newborn).
- MAHA = schistocytes/helmet cells + thrombocytopenia:
- TTP — ↓ADAMTS13 (pentad: MAHA, thrombocytopenia, neuro, renal, fever); plasma exchange, do NOT give platelets.
- HUS — Shiga toxin, EHEC O157:H7, children, prominent renal failure (avoid antibiotics).
- DIC — ↑PT/PTT, ↑D-dimer, ↓fibrinogen (usually a sick, bleeding patient).
Hemolytic anemias: defect, smear, and marker
| Disorder | Defect | Smear / marker | Dx / management |
|---|---|---|---|
| Hereditary spherocytosis | Spectrin/ankyrin/band 3 | Spherocytes, ↑MCHC | EMA-binding or osmotic fragility; Coombs neg; folate, splenectomy |
| G6PD deficiency | X-linked ↓NADPH | Bite cells, Heinz bodies | Enzyme assay after episode; avoid oxidants |
| PNH | PIGA → ↓CD55/CD59 | Intravascular hemolysis, thrombosis | Flow cytometry (FLAER / CD55/59); eculizumab |
| Warm AIHA | IgG | Spherocytes, DAT+ (IgG) | SLE/CLL/drugs; corticosteroids |
| Cold agglutinin disease | IgM + complement | Agglutination, DAT+ (C3) | Mycoplasma/EBV; keep warm, rituximab |
| Sickle cell | HbS (β6 Glu→Val) | Sickle + target cells, Howell–Jolly | Hydroxyurea (↑HbF) |
Vignette: A 24-year-old man develops fatigue and cola-colored urine two days after starting trimethoprim–sulfamethoxazole for a UTI (a boards variant substitutes fava beans, dapsone, primaquine, or nitrofurantoin). Exam: scleral icterus. Labs: Hgb dropped, ↑LDH, ↑indirect bilirubin, ↓haptoglobin, hemoglobinuria. Smear shows bite cells; a supravital stain reveals Heinz bodies.
Diagnosis: G6PD deficiency (X-linked recessive) — oxidative stress overwhelms glutathione regeneration.
Next best step: stop the offending oxidant and give supportive care; hemolysis is usually self-limited.
Classic trap: a G6PD enzyme level drawn during the acute episode can be falsely normal (young reticulocytes are enzyme-rich). Repeat the assay 2–3 months later to confirm.
AIHA antibody class (the classic Step 1 split):
- Warm AIHA = IgG → "warm weather is Great." Extravascular splenic clearance → spherocytes, DAT+ for IgG; triggers SLE, CLL, methyldopa/penicillin; treat with steroids. (Warm antibodies do not agglutinate at body temperature.)
- Cold agglutinin disease = IgM → the big pentamer M clumps RBCs in the cold. Fixes complement (C3) → agglutination on smear, acrocyanosis; triggers Mycoplasma pneumoniae, EBV/mono; keep warm, rituximab.
G6PD smear: "Bite into a Heinz ketchup packet" → bite cells + Heinz bodies.
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