Quick — a 25-year-old woman with fatigue has Hgb 9.2 and MCV 68. What's the FIRST thing you check?
B12 level
Iron studies
Reticulocyte count
Peripheral smear
The MCV Framework — Your Sorting Hat
MCV tells you how big the red blood cells are. That single number splits all anemias into three buckets. Learn the buckets first — then the contents sort themselves.
MCV < 80 = microcytic (cells too small) ·
MCV 80–100 = normocytic ·
MCV > 100 = macrocytic (cells too big)
Drag each anemia into its MCV bucket. If you get one wrong, it bounces back — try again.
Iron deficiency
B12 deficiency
Thalassemia
Anemia of chronic disease
Folate deficiency
Sideroblastic
Lead poisoning
Aplastic anemia
Hemolytic anemia
Liver disease
Microcytic Anemias — The Small Cells
Small cells = not enough hemoglobin filling them up. The mnemonic:
🔑TAILS — Thalassemia, Anemia of chronic disease*, Iron deficiency, Lead poisoning, Sideroblastic. (*ACD can be micro or normo)
🩸 Iron Deficiency — The #1 Anemia on Earth
Most common anemia worldwide. The body doesn't have enough iron to make hemoglobin, so the cells come out small and pale.
- Smear: microcytic, hypochromic (pencil cells = ovalocytes flattened by low hemoglobin)
🔑Pencil cells = pencil thin on iron — they're writing a letter asking for more
- Iron studies: ↓ ferritinFerritin = storage form of iron. Low ferritin = empty warehouse. Most specific single test for iron deficiency., ↓ serum iron, ↑ TIBCTotal Iron Binding Capacity — how many empty seats are on the transferrin bus. High TIBC = lots of empty seats = body desperate for iron., ↓ % saturation
- Causes: Blood loss (#1 in adults — menstruation, GI bleed), poor intake (infants, vegans), poor absorption (celiac, gastrectomy)
🧬 Thalassemia — Genes Made Less Hemoglobin
Genetic defect → less globin chain production → small cells. But the body has iron — it just can't use it properly for hemoglobin.
- Smear: microcytic but with target cells (bullseye appearance)
🔑Target cells = Thalassemia. Both start with T. Bullseye = genetic target.
- Iron studies: NORMAL (this is the key differentiator from iron deficiency!)
- Diagnosis: Hemoglobin electrophoresisSeparates hemoglobin types by charge. HbA2 ↑ in beta-thal trait. HbF ↑ in beta-thal major. Normal in alpha-thal (deletion doesn't change Hb type, just quantity).
- Red cell count: Often ↑ (body compensates by making MORE small cells)
The Board's Favorite Trick: Iron Deficiency vs Thalassemia
Both are microcytic. Both have low MCV. The split:
Iron deficiency: ↓ ferritin, ↑ TIBC, ↑ RDW (cells are all different sizes because some were made when iron was okay)
Thalassemia: Normal iron studies, normal RDW (cells are uniformly small — the genetic defect is consistent), ↑ RBC count
⚠️ Board Trap: "Microcytic anemia that doesn't respond to iron supplementation" = think thalassemia. If they gave iron for weeks and the MCV didn't budge, the problem was never iron.
💎 Sideroblastic Anemia — Iron Trapped in the Wrong Place
The body HAS iron. It just can't put it into hemoglobin. Iron accumulates in mitochondriaThe iron deposits form a ring around the nucleus of developing red cells in the bone marrow — "ringed sideroblasts." The iron is literally stuck in the wrong compartment. of developing red cells → ringed sideroblasts on bone marrow biopsy.
- Iron studies: ↑ ferritin, ↑ serum iron (iron is there, just misplaced)
- Causes: Lead poisoning, alcohol, B6 (pyridoxine) deficiency, isoniazid, myelodysplastic syndrome
- Smear: microcytic + basophilic stipplingBlue dots in the red cell from precipitated RNA. Classic for lead poisoning and sideroblastic anemia. The ribosomal RNA that should have been cleared out is stuck because enzyme pathways are broken.
🔋 Lead Poisoning — A Special Sideroblastic
Lead inhibits two enzymes in heme synthesis: ALA dehydrataseFirst enzyme hit by lead. ALA (aminolevulinic acid) builds up in urine. This is the screening marker. and ferrochelataseLast enzyme — inserts iron into protoporphyrin. When it's blocked, free erythrocyte protoporphyrin (FEP) skyrockets. Iron can't get into the ring.. Result: iron can't get into heme → sideroblastic picture.
- Classic presentation: Kid eating paint chips. Or adult with occupational exposure.
- Labs: ↑ free erythrocyte protoporphyrin (FEP), ↑ ALA in urine, basophilic stippling on smear
- Other symptoms: Lead lines on gums/bones, wrist/foot drop, abdominal colic, encephalopathy in kids
Macrocytic Anemias — The Big Cells
Big cells = problem with DNA synthesis (the cell can't divide properly, so it just keeps growing). Split into megaloblastic (B12/folate) and non-megaloblastic (everything else).
🧠 B12 Deficiency — The Neuro One
Megaloblastic anemia + neurological symptoms. B12 is needed for DNA synthesis AND myelin maintenance.
- Smear: macro-ovalocytes + hypersegmented neutrophils (≥5 lobes = pathognomonic for megaloblastic anemia)
- Neuro: Subacute combined degeneration — loss of position sense, vibration sense, ataxia. Affects dorsal columnsPosterior columns of the spinal cord carry proprioception and vibration. B12 deficiency demyelinates these first. Patient can't tell where their feet are without looking. and lateral corticospinal tractsUpper motor neuron tracts. Damage here causes spasticity, hyperreflexia, positive Babinski. Combined with dorsal column loss = "subacute combined degeneration."
- Causes: Pernicious anemia (#1 — autoimmune destruction of parietal cells → no intrinsic factorMade by parietal cells. Binds B12 in the stomach, carries it to the terminal ileum for absorption. No IF = no B12 absorption regardless of intake.), vegan diet, Crohn's/ileal resection, Diphyllobothrium latum (fish tapeworm)
🥬 Folate Deficiency — The Diet One
Same megaloblastic picture as B12 — hypersegmented neutrophils, macro-ovalocytes. But NO neuro symptoms.
- Causes: Poor diet (#1 — alcoholics, elderly), pregnancy (↑ demand), methotrexate/phenytoin/TMP-SMX (folate antagonists)
- Key difference from B12: Folate stores only last ~4 months. B12 stores last ~3-4 years. Folate deficiency develops FAST.
B12 vs Folate — The One Difference That Matters
Both: megaloblastic, hypersegmented neutrophils, macro-ovalocytes, ↑ homocysteine
Only B12: ↑ methylmalonic acid (MMA), neurological symptoms
Only folate: Normal MMA, no neuro
🔑MethylMalonic acid = only in B12 → Myelin problems. Both M's go together.
⚠️ Board Trap: Never give folate alone to a B12-deficient patient. Folate fixes the anemia (hides the blood findings) but the neuro damage KEEPS PROGRESSING silently. Always check B12 before treating with folate.
🍺 Non-Megaloblastic Macrocytic
Big cells but NO hypersegmented neutrophils. DNA synthesis is fine — the cell membrane is just weird.
- Alcohol: Direct toxic effect on RBC membrane + usually folate-deficient too
- Liver disease: Excess cholesterol deposits in RBC membranes → cells swell
- Hypothyroidism, reticulocytosis (reticulocytes are bigger than mature RBCs), myelodysplastic syndrome
Normocytic Anemias — Normal-Sized, Still Broken
MCV is normal. The cells are the right size — there just aren't enough of them, or they're being destroyed. Split by reticulocyte count:
Reticulocyte count = is the bone marrow TRYING?
↑ Reticulocytes (>2%): Marrow is working overtime → cells are being DESTROYED or LOST (hemolysis, bleeding)
↓ Reticulocytes (<2%): Marrow is failing → cells aren't being MADE (aplastic, ACD, renal failure)
💥 Hemolytic Anemias — Cells Dying Too Fast
Red cells are being destroyed before their 120-day lifespan. The marrow tries to compensate → ↑ reticulocytes.
- General labs: ↑ LDHLactate dehydrogenase — released when cells burst. Elevated in any hemolysis. Not specific but very sensitive., ↑ indirect bilirubin, ↓ haptoglobinHaptoglobin binds free hemoglobin released from lysed cells. When lots of cells lyse, haptoglobin gets used up → levels drop. Low haptoglobin = hemolysis until proven otherwise., ↑ reticulocytes
- Intravascular hemolysis (in the blood vessels): hemoglobinuria, hemoglobinemia, schistocytes on smear
- Extravascular hemolysis (in the spleen): splenomegaly, spherocytes on smear
🏭 Anemia of Chronic Disease — The Body's Sabotage
Chronic inflammation → liver pumps out hepcidinHepcidin is the iron gatekeeper. It blocks ferroportin on gut cells and macrophages, trapping iron inside cells. The body HIDES iron from bacteria during infection — but also from your own red cells. → iron gets LOCKED in storage → can't get to the marrow.
- Iron studies: ↑ ferritin (iron is there, just locked up), ↓ TIBC (body isn't looking for more iron), ↓ serum iron
- Usually normocytic but can be mildly microcytic
- Treatment: Treat the underlying disease. Iron supplements won't help — the iron is already there.
Iron Deficiency vs Anemia of Chronic Disease — Boards LOVE This
| Iron Deficiency | Chronic Disease |
|---|
| Ferritin | ↓↓↓ (empty) | ↑ (locked up) |
| TIBC | ↑ (hungry) | ↓ (not looking) |
| Serum iron | ↓ | ↓ |
| % Sat | ↓ | ↓ |
Both have low serum iron. The split is
ferritin (empty vs full warehouse) and
TIBC (desperate vs indifferent).
🌳 The Anemia Algorithm — Work Through It
Patient is anemic. Walk through the decision tree. I'll quiz you at each branch.
Step 1: You get the CBC back. What's the FIRST number you look at?
Reticulocyte count
MCV
Ferritin
Step 2: MCV is 72 (microcytic). What do you order next?
Iron studies (ferritin, TIBC, serum iron)
B12 and folate levels
Bone marrow biopsy
Step 3: MCV is 110 (macrocytic). Smear shows hypersegmented neutrophils. Is this megaloblastic or non-megaloblastic?
Megaloblastic → check B12 and folate
Non-megaloblastic → check liver, thyroid, alcohol
Step 4: MCV is 88 (normocytic). What splits the differential?
Iron studies
Reticulocyte count
Direct Coombs test
✨
You walked the tree.
MCV → bucket → specific workup. That's the algorithm. On test day, don't get fancy. Follow the tree.
🧪 Clinic Hours
Six patients just showed up anemic. Figure out what's wrong with them before they figure out you're nervous.