MCV-Based Classification
Step 1: classify by MCV. Microcytic (MCV <80 fL): iron deficiency anemia (IDA), thalassemia, anemia of chronic disease (ACD — usually normocytic, can be microcytic), sideroblastic anemia, lead poisoning. Mnemonic: TAILS (Thalassemia, ACD/lead, IDA, Lead poisoning, Sideroblastic). Normocytic (MCV 80-100 fL): acute blood loss, hemolytic anemia, aplastic anemia, ACD (most common), kidney disease (↓EPO), mixed deficiency (IDA + B12 can cancel out). Macrocytic (MCV >100 fL): B12 deficiency, folate deficiency (megaloblastic — hypersegmented neutrophils), liver disease, hypothyroidism, drugs (methotrexate, hydroxyurea, AZT), reticulocytosis (reticulocytes are large).
Iron Studies: IDA vs ACD vs Thalassemia
Iron deficiency anemia (IDA): serum iron LOW, TIBC HIGH (upregulated to capture scarce iron), ferritin LOW (ferritin = best single test for IDA — low ferritin is virtually diagnostic), transferrin saturation <15%. Smear: microcytic hypochromic RBCs, pencil cells (elliptocytes), anisocytosis, poikilocytosis. Causes: chronic GI blood loss (most common in adults — workup with colonoscopy + EGD), heavy menstrual bleeding (young women), poor intake (infants/toddlers). Anemia of chronic disease (ACD): serum iron LOW, TIBC LOW (liver downregulates in inflammation), ferritin HIGH (ferritin is an acute-phase reactant), transferrin saturation <15-20%. Mechanism: hepcidin excess (from IL-6) sequesters iron in macrophages. Thalassemia trait: microcytic, but iron studies NORMAL; RBC count HIGH or normal (distinguishes from IDA where RBC count is low); Mentzer index: MCV/RBC <13 = thalassemia, >13 = IDA.
Megaloblastic Anemia: B12 vs Folate
Both B12 and folate deficiency cause megaloblastic anemia: large oval macrocytes + hypersegmented neutrophils (≥5 lobes in >5% of neutrophils, or any neutrophil with ≥6 lobes). Key distinction: B12 deficiency causes neurological symptoms, folate deficiency does NOT. B12 deficiency neuro findings: subacute combined degeneration of the spinal cord — posterior column (loss of vibration/proprioception) + lateral corticospinal tract (upper motor neuron signs) + peripheral neuropathy. Causes of B12 deficiency: pernicious anemia (anti-intrinsic factor antibodies → can't absorb B12 in terminal ileum), terminal ileum resection, gastric bypass, strict veganism. Diagnosis: low serum B12, elevated methylmalonic acid (MMA) + homocysteine (both elevated in B12 deficiency; only homocysteine elevated in folate deficiency). Folate deficiency causes: poor diet (#1 — alcoholics, elderly), pregnancy/hemolysis (increased demand), methotrexate/trimethoprim (dihydrofolate reductase inhibitors). Treatment: folate supplementation; B12 IM injection if malabsorption.
Hemolytic Anemia Approach
Hemolysis = increased RBC destruction → anemia + elevated LDH + elevated indirect bilirubin + low/absent haptoglobin (haptoglobin binds free hemoglobin → consumed during hemolysis). Reticulocytosis (elevated reticulocyte count, >2%) confirms increased RBC production in response to destruction. Intravascular hemolysis: RBCs destroyed within vessels → hemoglobinuria (pink/red urine) + hemoglobinemia + very low haptoglobin; causes: G6PD deficiency (oxidant stress — infections, fava beans, antimalarials + primaquine, dapsone), transfusion reaction (ABO incompatibility), TTP/HUS/DIC (microangiopathic — schistocytes on smear), PNH (paroxysmal nocturnal hemoglobinuria — CD55/CD59 deficiency, venous thrombosis). Extravascular hemolysis: RBCs destroyed in spleen/liver macrophages → NO hemoglobinuria; causes: autoimmune hemolytic anemia (AIHA — warm = IgG, treat with steroids; cold = IgM/complement, avoid cold), hereditary spherocytosis (spectrin defect, spherocytes on smear, positive osmotic fragility test), sickle cell disease.