Sickle cell disease (SCD) is one of those Step topics where the stem is usually straightforward—but the answer choices are designed to punish sloppy physiology. If you can explain why each distractor is wrong (or only “sometimes true”), you’ll stop losing points on hematology questions that all feel the same at 2 a.m.
Tag: Heme/Onc > RBC Disorders & Anemias
The Clinical Vignette (Q-bank style)
A 17-year-old boy with a history of multiple hospitalizations for pain crises presents with severe pain in his back and legs after a recent respiratory infection. He is afebrile. Exam shows scleral icterus and splenomegaly is absent. Labs:
| Test | Result |
|---|---|
| Hemoglobin | 7.9 g/dL |
| MCV | 88 fL |
| Reticulocyte count | Increased |
| Total bilirubin | Increased (predominantly indirect) |
| LDH | Increased |
| Haptoglobin | Decreased |
Peripheral smear shows sickled erythrocytes and target cells. Hemoglobin electrophoresis shows no HbA, increased HbS, and increased HbF.
Question: Which mechanism best explains the underlying cause of his disease?
Answer choices:
A. Point mutation causing substitution of valine for glutamic acid in the -globin chain
B. Decreased synthesis of -globin chains causing microcytosis
C. Defect in RBC membrane spectrin leading to spherocytes and splenomegaly
D. Autoantibodies against RBCs causing extravascular hemolysis with a positive Coombs test
E. Low G6PD activity causing episodic hemolysis with Heinz bodies and bite cells
Correct Answer: A. Point mutation causing substitution of valine for glutamic acid in the -globin chain
Why it’s correct (the “core” concept)
Sickle cell disease is caused by a missense point mutation in the HBB gene (β-globin). Specifically:
- Glutamic acid → valine at position 6 of the β-globin chain
- DNA codon: classically remembered as GAG → GTG
- The valine is hydrophobic, which creates a “sticky patch” on deoxygenated HbS → polymerization → sickling.
What this explains in the stem
- Normocytic anemia (MCV normal) with high reticulocytes → chronic hemolysis with marrow compensation
- Indirect hyperbilirubinemia, ↑ LDH, ↓ haptoglobin → hemolysis
- Asplenia/autosplenectomy → absence of splenomegaly in an older child/teen with severe disease
- No HbA on electrophoresis → consistent with HbSS (not trait)
High-yield clinical consequences to keep in your head
- Sickling is promoted by: low O₂, dehydration, acidosis, cold, infection
- Two major pathology buckets:
- Hemolysis → jaundice, pigmented gallstones, high retic
- Vaso-occlusion → pain crises, acute chest syndrome, stroke, avascular necrosis, dactylitis
- Functional asplenia → infections with encapsulated organisms
- Strep pneumoniae, H influenzae, Neisseria meningitidis
- Prevention: vaccination + penicillin prophylaxis in kids
Distractor Breakdown: Why every other choice is tempting—and wrong
B. Decreased synthesis of -globin chains causing microcytosis
Why it tempts you: “β-globin problem” sounds right.
Why it’s wrong: This describes β-thalassemia, not SCD.
- Thalassemias are quantitative defects (reduced globin production), whereas SCD is a qualitative defect (abnormal globin structure).
- β-thalassemia classically causes:
- Microcytosis (low MCV)
- Target cells
- Increased HbA₂ (and often increased HbF depending on severity)
- Many β-thal patients have splenomegaly due to extramedullary hematopoiesis (contrast with autosplenectomy in SCD).
Step tip: If the stem shows normal MCV + hemolysis + pain crises/acute chest, think SCD. If it’s microcytic with target cells and big spleen, think thalassemia.
C. Defect in RBC membrane spectrin leading to spherocytes and splenomegaly
Why it tempts you: Hemolytic anemia + spleen involvement is a common pattern.
Why it’s wrong: This is hereditary spherocytosis.
- Membrane cytoskeleton defects: spectrin, ankyrin, band 3, protein 4.2
- Leads to spherocytes, which get trapped in spleen → extravascular hemolysis
- Classic findings:
- ↑ MCHC
- Spherocytes on smear
- Splenomegaly
- Negative Coombs (non-immune)
- ↑ osmotic fragility (older test)
Contrast with SCD: SCD smear shows sickled cells and often target cells, not spherocytes. Plus, longstanding SCD tends toward functional asplenia, not splenomegaly.
D. Autoantibodies against RBCs causing extravascular hemolysis with a positive Coombs test
Why it tempts you: Indirect bilirubin up + hemolysis labs = “maybe autoimmune?”
Why it’s wrong: This describes autoimmune hemolytic anemia (AIHA).
- Would expect:
- Positive direct antiglobulin (Coombs) test
- Often spherocytes (from partial phagocytosis in spleen)
- Associations:
- Warm AIHA (IgG): SLE, CLL, methyldopa
- Cold agglutinin disease (IgM): Mycoplasma pneumoniae, EBV; agglutination and acrocyanosis
Key discriminator: SCD is not immune-mediated; it’s a hemoglobin structural disorder. No Coombs positivity required/expected.
E. Low G6PD activity causing episodic hemolysis with Heinz bodies and bite cells
Why it tempts you: Hemolysis after stress/infection can mimic a sickle crisis story.
Why it’s wrong: This is G6PD deficiency, an oxidative hemolysis problem.
- Path: ↓ NADPH → ↓ glutathione regeneration → hemoglobin oxidation → denatured Hb (Heinz bodies) → splenic macrophages “bite” them out (bite cells)
- Triggers to memorize:
- Sulfa drugs, dapsone, primaquine
- Fava beans
- Infections (big one)
- Pattern is typically episodic, not chronic vaso-occlusive pain crises with sickling and autosplenectomy.
Step nuance: During an acute hemolytic episode, G6PD testing can be falsely normal (older, enzyme-deficient RBCs are destroyed first). That’s a classic trap—but it’s still not this vignette if you have sickled cells and Hb electrophoresis showing no HbA.
Mini High-Yield SCD Toolbox (Quick recall for Step stems)
Hemoglobin electrophoresis patterns (high-yield)
| Condition | HbA | HbS | HbF | HbA₂ |
|---|---|---|---|---|
| Normal | +++ | 0 | + | + |
| Sickle trait (HbAS) | ++ | + | + | + |
| Sickle disease (HbSS) | 0 | +++ | ↑ | variable |
| β-thalassemia | ↓ | 0 | ↑ | ↑ |
The “why” behind hydroxyurea
Hydroxyurea increases HbF, which:
- Does not sickle
- Dilutes HbS concentration and decreases polymerization
- Leads to fewer pain crises and acute chest episodes
Common board-style associations:
- Hydroxyurea can cause myelosuppression
- Increases MCV (macrocytosis) due to effects on RBC production—don’t let that throw you.
Acute chest syndrome (don’t miss this on Step 2)
- New pulmonary infiltrate + chest pain/fever/hypoxia in SCD
- Causes: infection, fat embolism, pulmonary infarction
- Treatment often includes:
- Oxygen, analgesia, IV fluids (judicious), antibiotics
- Simple or exchange transfusion depending on severity
The One-Liner You Should Be Able to Say Out Loud
Sickle cell disease is a missense point mutation in β-globin (Glu→Val) that makes deoxygenated HbS polymerize, causing hemolysis and vaso-occlusion—and the distractors are usually thalassemia (microcytosis), hereditary spherocytosis (spherocytes + splenomegaly), AIHA (Coombs+), or G6PD deficiency (Heinz bodies/bite cells after oxidative stress).