Bit · Heme/Onc
Intrinsic Hemolytic Anemias — HS, G6PD, PNH, Sickle Cell
Four hemolytic anemias caused by something wrong inside the RBC. Membrane, enzyme, surface protein, or hemoglobin.
Mechanism
Intrinsic (RBC-side) hemolytic anemias fall into four mechanistic buckets:
- Hereditary spherocytosis (HS) — defect in membrane proteins (ankyrin, spectrin, band 3). RBCs lose membrane → become spherical → trapped in spleen. Autosomal dominant. Coombs negative. Classic: jaundice, splenomegaly, gallstones, ↑ MCHC. Diagnosis: eosin-5-maleimide flow cytometry or osmotic fragility. Splenectomy curative.
- G6PD deficiency — X-linked, enzyme of pentose phosphate pathway. Without G6PD, RBC has no NADPH → no glutathione regeneration → oxidant stress destroys RBC. Triggered by oxidants (fava beans, sulfa, primaquine, infection). Heinz bodies, bite cells. Mediterranean/African ancestry.
- Paroxysmal nocturnal hemoglobinuria (PNH) — acquired mutation in PIGA → no GPI anchor → no CD55/CD59 on RBCs → complement-mediated lysis. Intravascular hemolysis, dark morning urine, thrombosis (esp. hepatic veins → Budd-Chiari). Flow cytometry: low CD55/59. Treat: eculizumab.
- Sickle cell disease — HbS (β-chain Glu→Val). Polymerizes when deoxygenated → sickling → vaso-occlusion. Autosomal recessive. Heterozygotes protected from malaria. Crises: vaso-occlusive pain, acute chest syndrome, splenic sequestration, autosplenectomy, dactylitis, stroke. Howell-Jolly bodies (functional asplenia).
Differentiator Table
| Disease | Defect | Coombs | Hemolysis location | Distinctive |
|---|---|---|---|---|
| HS | Membrane (ankyrin, spectrin, band 3) | NEG | Extravascular (spleen) | Spherocytes, ↑ MCHC, AD, splenectomy curative |
| G6PD | Pentose phosphate enzyme | NEG | Mostly intravascular during oxidant stress | Heinz bodies, bite cells, X-linked, triggers (sulfa, fava) |
| PNH | Acquired PIGA mutation → no GPI anchor | NEG | INTRAvascular (complement) | Dark morning urine, thrombosis (Budd-Chiari), low CD55/59 |
| Sickle cell | HbS (β-Glu→Val) | NEG | Both | Sickling on deox; vaso-occlusion; autosplenectomy |
The Pivot
Three questions:
- Spherocytes on smear + family history + AD inheritance? → HS.
- Hemolysis after sulfa/fava beans/infection in male of Mediterranean or African descent? → G6PD.
- Dark morning urine + venous thrombosis (especially hepatic)? → PNH.
- African ancestry + childhood pain crises + dactylitis? → Sickle cell.
All are Coombs-NEGATIVE. Positive Coombs = extrinsic (autoimmune hemolytic anemia).
NBME-Style Stem
A 28-year-old man presents with dark urine on awakening, fatigue, and a painful swollen leg. Doppler ultrasound confirms iliofemoral deep vein thrombosis. Hemoglobin is 9 g/dL, LDH is 980 U/L, haptoglobin is undetectable. Flow cytometry shows decreased CD55 and CD59 on red blood cells. Which of the following is the most likely diagnosis?
Concept Anchor
Four ways an RBC can be defective from the inside: bad membrane (HS), bad enzyme (G6PD), missing surface shield (PNH), bad hemoglobin (SCD). All Coombs negative — antibody hemolysis is a different category.