Anemia

Definitions and Reference Ranges

• WHO definition: Hb <13 g/dL (men), <12 g/dL (non-pregnant women), <11 g/dL (pregnant women; <10.5 in 2nd trimester), <10.5 g/dL (children 6 to 23 mo), <11 g/dL (children 24 to 59 mo) (WHO 2024).
• Severity (WHO): mild (men 11.0 to 12.9, women 11.0 to 11.9), moderate 8.0 to 10.9, severe <8.0 g/dL (pregnancy/peds differ). Severity does not define a transfusion threshold (generally <7 in stable adults).
• Caveats: anemia in older adults warrants evaluation and is not a normal consequence of aging (unexplained anemia of aging is a diagnosis of exclusion); lower thresholds may be normal in athletes (dilutional plasma volume expansion), and Black/African ancestry (use race-neutral cutoffs per modern guidelines).
• Hb vs Hct: Hct ~ 3 × Hb in steady state.

MCV-Based Differential Diagnosis

The MCV-based framework is the anchor of the anemia workup: pair it with the reticulocyte response to separate underproduction from loss/hemolysis.

• Microcytic (MCV <80 fL): TAILS mnemonic, Thalassemia, Anemia of chronic disease (sometimes), Iron deficiency, Lead toxicity, Sideroblastic anemia. (Iron deficiency anemia is covered in a separate note.)
• Normocytic (MCV 80 to 100 fL): blood loss (acute), hemolysis, BM failure (early), CKD/EPO deficiency, ACD, mixed deficiencies, primary BM disease (MDS, leukemia, infiltration), hypothyroid, pregnancy.
• Macrocytic (MCV >100 fL):
  • Megaloblastic: B12 deficiency, folate deficiency, drug-induced (MTX, hydroxyurea, AZT), inborn errors of metabolism. Smear: hypersegmented neutrophils (≥6 lobes, or >3% of neutrophils with 5 lobes), oval macrocytes.
  • Non-megaloblastic: liver disease, alcohol, hypothyroid, MDS, reticulocytosis (counts as macrocytes), drugs.

Reticulocyte Count Interpretation

• Absolute reticulocyte count (ARC): normal ~50,000 to 100,000/µL.
• Reticulocyte production index (RPI): % retic × (pt Hct / 45) × (1 / shift correction; 1 if Hct ≥45, 1.5 if 35 to 44, 2 if 25 to 34, 2.5 if <25).
• RPI >2.5: appropriate response, blood loss or hemolysis.
• RPI <2: inappropriately low, underproduction (iron deficiency, B12/folate deficiency, BM failure, infiltration, EPO deficiency in CKD, MDS, ACD).

Iron Physiology and Hepcidin

• Total body iron ~3 to 4 g: ~70% in Hb, ~25% stored as ferritin/hemosiderin (liver, macrophages), remainder in myoglobin and enzymes. Daily intake ~10 to 20 mg with only ~1 to 2 mg absorbed (duodenum) and ~1 mg/day lost; there is no regulated route of iron excretion.
• Hepcidin is the master regulator: it degrades ferroportin (the iron exporter on enterocytes and macrophages), so ↑ hepcidin → ↓ gut absorption and ↓ iron release from stores, and ↓ hepcidin → unrestricted absorption.
• Inflammation: IL-6 → ↑ hepcidin → iron-restricted erythropoiesis (anemia of inflammation); iron is present in the body but sequestered in hemosiderin-laden macrophages and unavailable for use.
• Iron deficiency: ↓ hepcidin allows ↑ absorption; ferritin is the first iron parameter to fall.
• IRIDA (iron-refractory IDA): TMPRSS6 loss-of-function → inappropriately ↑ hepcidin → poor oral iron absorption and blunted IV iron response; autosomal recessive, rare.
• Heme iron (animal sources) is more bioavailable than non-heme (plant); vitamin C enhances, while tannins, phytates, and calcium impair non-heme absorption.

Iron Compartments and Laboratory Thresholds

Iron Studies Interpretation

• IDA: ferritin ↓, Fe ↓, TIBC ↑, saturation ↓; reticulocytes low.
• ACD: ferritin normal/↑ (acute-phase), Fe ↓, TIBC ↓ or normal, saturation ↓; hepcidin ↑.
• Iron overload (hemochromatosis): ferritin ↑↑, Fe ↑, saturation ↑↑ (>45%).
• Mixed IDA + ACD: tricky; sometimes need BM aspirate with iron stain, sTfR (not affected by inflammation), or a therapeutic trial.

Key Smear Findings

• Schistocytes: MAHA, TTP/HUS, DIC, mechanical valve, severe HTN, scleroderma renal crisis.
• Spherocytes: HS, warm AIHA, and G6PD deficiency (occasionally). Board differential also includes cold agglutinin disease, extensive thermal burns, snake/scorpion/brown recluse bites, and clostridial sepsis.
• Sickle cells: SCD.
• Target cells: thalassemia, liver disease, post-splenectomy, HbC, IDA (some).
• Bite/blister cells: G6PD oxidative hemolysis.
• Tear-drop (dacrocytes): BM infiltration/fibrosis, MF.
• Howell-Jolly bodies: post-splenectomy or hyposplenism (SCD, celiac, IBD, amyloidosis, GVHD).
• Heinz bodies: oxidative damage (G6PD), drug-induced.
• Basophilic stippling: lead, thalassemia, sideroblastic, pyrimidine 5' nucleotidase deficiency.
• Rouleaux: ↑ ESR, plasma cell dyscrasia, infection, inflammation.
• Hypersegmented neutrophils: B12/folate deficiency.
• Blasts: leukemia.

Red Cell Membrane Disorders (overview)

• General clues: anemia with or without acute hemolysis; history negative for poor diet or blood loss but positive for neonatal jaundice, intermittent jaundice, or family history (anemia, jaundice, transfusion, splenectomy, cholecystectomy). Exam: scleral icterus, splenomegaly. Retic usually elevated; MCV often normal in HS. Review the smear.
• Hereditary spherocytosis (HS): most common membrane-defect hemolytic anemia (~1 in 2000, ~3/4 autosomal dominant). Defects in vertical associations linking cytoskeleton to bilayer: ankyrin (ANK1, ~50%), band 3 (SLC4A1, ~25%), spectrin (SPTB, SPTA1, ~20%), protein 4.2 (~5%). Membrane loss → ↓ surface-area-to-volume → spherocytes, which are trapped and phagocytosed in the spleen. Diagnosis: osmotic fragility, EMA binding, or genetic testing. Management mostly supportive (transfusion for severe anemia or parvovirus B19 aplastic crisis); splenectomy/cholecystectomy in selected patients (defer splenectomy in young children).
• Hereditary elliptocytosis: African, Mediterranean, Southeast Asian backgrounds; mostly autosomal dominant. Defects in horizontal associations, commonly spectrin (SPTA, SPTB), also protein 4.1R. Usually mild with minimal hemolysis; diagnosis chiefly by smear.
• Southeast Asian ovalocytosis: band 3 (SLC4A1) 27-bp deletion, not a spectrin defect; protective against malaria; usually asymptomatic.
• Hereditary pyropoikilocytosis (HPP): on a spectrum with elliptocytosis (spectrin mutation); variable hemolysis (worse in early childhood); bizarre-shaped, typically microcytic RBCs on smear.

Red Cell Enzyme Disorders (overview)

• Principle: red cells rely on glycolysis; glycolysis supplies RBC ATP (PK and GPI deficiencies cause ATP depletion); G6PD (pentose phosphate pathway) supplies NADPH for antioxidant defense, so its deficiency causes oxidant injury; pyrimidine 5' nucleotidase acts in nucleotide degradation. Key defects: G6PD, pyruvate kinase (PK), pyrimidine 5' nucleotidase, and glucose phosphate isomerase (GPI).
• G6PD deficiency: acute episodic hemolysis (or mild baseline hemolysis). Triggers: infection, oxidant drugs, fava beans; backgrounds Mediterranean, Middle Eastern, African, SE Asian. Smear: blister/bite cells during a crisis. Check G6PD level after hemolysis resolves (reticulocytes have high G6PD and falsely normalize the level during acute hemolysis). Revised WHO variant classes: A (chronic hemolysis, median activity <20%), B (triggered acute hemolysis, median <45%; former classes II and III), C (no hemolysis, >60%), U (uncertain). These classify variants, not a patient's crisis-time activity. Management supportive plus trigger avoidance.
• Pyruvate kinase deficiency: moderate baseline hemolytic anemia with acute worsening (e.g., infection); smear often unimpressive. Prevalence ~1/20,000, autosomal recessive (PKLR), high in Amish. ↓ RBC ATP shortens lifespan; ↑ 2,3-DPG improves O2 offloading. Diagnosis by enzyme activity and sequencing. Management supportive, folate, splenectomy (often indicated; smaller Hb rise than in HS), and mitapivat (oral PK activator; FDA Feb 2022 for adults with PK deficiency). Board pearl: reticulocyte count rises markedly after splenectomy because the spleen preferentially sequesters reticulocytes in PK deficiency.
• Pyrimidine 5' nucleotidase deficiency: autosomal recessive, most common enzymopathy of nucleotide metabolism; diagnosis via ↑ pyrimidine nucleotides in RBCs and molecular testing. Smear: basophilic stippling; hemolysis with occasional neurologic findings.
• Glucose phosphate isomerase (GPI) deficiency: autosomal recessive; second most common glycolytic enzyme defect; chronic nonspherocytic hemolytic anemia; neurologic/neuromuscular involvement is rare, not typical; splenectomy can reduce transfusion need.

Sideroblastic Anemia (overview)

• Inherited and acquired bone marrow disorders of mitochondrial dysfunction (defects in heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial protein synthesis, or oxidative phosphorylation) with pathologic iron accumulation in erythroid mitochondria that ring the nucleus (ringed sideroblasts).
• X-linked sideroblastic anemia (XLSA) from an ALAS2 missense mutation is the most common; SLC25A38 is the most common autosomal recessive congenital form. Men often present in the first 2 decades with microcytic anemia; women in mid-to-late adulthood with normocytic or macrocytic anemia. Congenital forms tend to be microcytic, acquired forms macrocytic.
• Key contrast: behaves like iron deficiency anemia but with elevated iron studies. Many respond to pyridoxine (B6).
• Acquired: clonal (MDS) or secondary to alcohol, drugs (isoniazid, chloramphenicol, linezolid), or copper deficiency.

Copper Deficiency

• Combined hematologic and neurologic picture: anemia, neutropenia, and myeloneuropathy; frequently misdiagnosed as MDS.
• History of bariatric or other GI surgery (also excess zinc intake causing copper malabsorption).
• Smear/marrow: iron-containing plasma cells, hyposegmented hypogranular neutrophils, dyserythropoiesis with cytoplasmic vacuoles, and ringed sideroblasts.
• Treat with copper supplementation.

Special Tests

• B12, folate, MMA, homocysteine: differentiate B12 (↑ MMA + ↑ homocysteine) from folate (↑ homocysteine only) deficiency.
• LDH, indirect bilirubin, haptoglobin, urine hemosiderin/Hb: hemolysis workup.
• DAT (Coombs): warm AIHA (IgG) vs cold (C3d).
• Hgb electrophoresis or HPLC: thalassemia, sickle, HbC.
• Flow cytometry for PNH: FLAER (binds GPI anchor); CD55, CD59 deficiency on RBC and granulocytes.
• Soluble transferrin receptor (sTfR): measures erythropoietic activity, elevated in iron deficiency; not affected by inflammation (helps in ACD overlap); not a reliable iron-status marker in hemolytic anemias.
• BM biopsy: cytopenias, suspected MDS/aplastic anemia/infiltration.

Transfusion Thresholds (general)

• Hb <7 g/dL: transfuse most stable adult patients (TRICC, AABB).
• Hb <7.5 g/dL: cardiac surgery, oncology with symptoms. Hb <8 g/dL: orthopedic surgery or preexisting cardiovascular disease, including stable CAD (chronic coronary disease).
• Hb <10 g/dL: acute MI/ACS with anemia (MINT 2023; 2025 ACC/AHA ACS guideline Class 2b; 2025 AABB conditional).
• Avoid over-transfusion; restrictive strategy generally non-inferior.

High-Yield Pearls

• Always look at the smear: patterns are diagnostic (schistocytes, sickle, target cells, spherocytes, blasts, blister cells, basophilic stippling).
• Hepcidin ties it together: ↑ in inflammation (IL-6), ↓ in iron deficiency; drives the ACD vs IDA distinction.
• Ferritin falls first in iron deficiency; low ferritin is always consistent with iron deficiency.
• Sideroblastic anemia: MCV varies (congenital often microcytic, MDS-associated often macrocytic) with elevated iron studies (contrast with IDA); consider B6 responsiveness.
• Copper deficiency: anemia + neutropenia + neuropathy after GI surgery, mimics MDS.
• Mixed deficiencies (iron + B12) can give normocytic anemia with ↑ RDW.
• Reticulocyte index distinguishes production deficits from blood loss/hemolysis.
• Restrictive transfusion (Hb <7) is standard for most stable adults.