Sickle cell disease and hemoglobin variants

19 DOH Abu Dhabi (HAAD) lab licensing practice questions on Sickle cell disease and hemoglobin variants, part of Hematology. The first 19 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

1. Question 1 · Hard

   A 41-year-old man from Ghana working in Dubai has mild jaundice and a palpable spleen. Hemoglobin 112 g/L (11.2 g/dL), MCV 78 fL, MCHC 372 g/L (reference 320-360), reticulocytes 4.5% (reference 0.5-2.5%). The film shows many target cells, some microspherocytes and a few red cells that each contain a dense, hexagonal or rod-shaped crystal. The sickle solubility test is negative. Cation-exchange HPLC: 93% in the Hb C window, Hb A2 3.8%, Hb F 2.6%, no Hb A and no Hb S. Both of his parents were tested in Ghana and have Hb C trait with normal hemoglobin. What is his most likely genotype?

   1. AHb C/beta-zero thalassemia
   2. BHomozygous Hb E (Hb EE)
   3. CHomozygous Hb C (Hb CC)
   4. DHb SC disease

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   Answer: C · Homozygous Hb C (Hb CC)

   A single dominant peak in the C window with no Hb A or Hb S means that neither beta gene makes normal beta chains. Both parents carry Hb C with a normal beta gene, so each can pass on only beta-A or beta-C; inheriting beta-C from both gives Hb CC, whereas Hb C/beta-zero thalassemia would need a parent who carries beta-zero thalassemia. Hb C is less soluble than Hb A, so it forms the intracellular crystals seen on the film, and the cells lose water, which raises the MCHC and produces microspherocytes and target cells. Hb SC would give a positive solubility test and an S peak, and Hb E elutes in the Hb A2 window, not the C window, and does not form crystals. Hb CC usually causes only mild hemolysis with splenomegaly.

   • A: Both parents have Hb C trait with a normal beta gene, so neither can pass on beta-zero thalassemia.
   • B: Hb E elutes in the Hb A2 window and does not form crystals.
   • D: Hb SC gives a positive solubility test and an Hb S peak.

2. Question 2 · Hard

   A 6-year-old boy whose family comes from Pakistan has had three painful crises and one episode of acute chest syndrome; he has never been transfused. Hemoglobin 84 g/L (8.4 g/dL), MCV 81 fL, reticulocytes 9%, and the film shows sickle cells and target cells. The sickle solubility test is positive. Alkaline (pH 8.6) electrophoresis shows one heavy band at the Hb S position and no band at Hb A. Cation-exchange HPLC: 45% in the Hb S window, 43% in the Hb D window, Hb F 8%, Hb A2 2.6%, no Hb A. His father has sickle cell trait, and his mother has a normal CBC with a 38% peak in the Hb D window. The most likely diagnosis is:

   1. ASickle cell trait (Hb AS)
   2. BHb S/beta-plus thalassemia
   3. CHb SS (sickle cell anemia)
   4. DCompound Hb S/D-Punjab disease

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   Answer: D · Compound Hb S/D-Punjab disease

   On alkaline electrophoresis Hb D-Punjab moves with Hb S, so a single band at the S position can look like Hb SS. HPLC separates the two, showing nearly equal Hb S and Hb D with no Hb A, and the parents' results show one Hb S carrier and one Hb D carrier. Hb D-Punjab (beta 121 Glu→Gln) joins Hb S polymers, so the compound state causes a sickling disorder about as severe as Hb SS, which fits his crises and acute chest syndrome. Hb S/beta-plus thalassemia would show some Hb A, a raised Hb A2 and microcytosis, and sickle cell trait has more Hb A than Hb S and no crises. On acid (pH 6.2) agar Hb D runs with Hb A, separate from Hb S, which is another way to confirm it.

   • A: In sickle cell trait Hb A exceeds Hb S, and crises do not occur.
   • B: Hb S/beta-plus thalassemia shows some Hb A, a raised Hb A2 and microcytosis.
   • C: Hb SS gives a single peak in the S window; here a second peak sits in the D window.

3. Question 3 · Medium

   Hb E trait often shows mild microcytosis, like a thalassemia carrier. Why?

   1. AHb E binds iron poorly, so heme synthesis is reduced
   2. BHb E is unstable and forms Heinz bodies that the spleen removes
   3. CThe Hb E gene lies next to a deleted alpha-globin gene
   4. DIts mutation activates a splice site that lowers beta-E output

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   Answer: D · Its mutation activates a splice site that lowers beta-E output

   The Hb E mutation (codon 26, glutamic acid to lysine) also activates a cryptic splice site in exon 1. Part of the beta-E messenger RNA is spliced abnormally and makes no globin, so beta-E chains are produced in reduced amounts, as in a mild beta-plus thalassemia. That is why Hb E is only about 25-30% of the total in trait and why carriers have a low MCV. Combined with a beta-thalassemia gene, it can cause severe Hb E/beta-thalassemia.

   • A: Hemoglobin variants do not change iron binding or heme synthesis.
   • B: Hb E is only mildly unstable and does not cause Heinz body hemolysis in carriers.
   • C: Hb E is a beta-chain variant on chromosome 11; the alpha genes are on chromosome 16.

4. Question 4 · Medium

   A healthy 30-year-old from Thailand working in the UAE has Hb 128 g/L (12.8 g/dL), MCV 66 fL, many target cells and a normal ferritin. HPLC: 92% in the Hb A2/E window, Hb F 4%, no Hb A. Sickle solubility is negative. The most likely diagnosis is:

   1. AHomozygous Hb C (Hb CC)
   2. BHomozygous Hb E (Hb EE)
   3. CHb E trait
   4. DHb E/beta-zero thalassemia

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   Answer: B · Homozygous Hb E (Hb EE)

   Almost all the hemoglobin is in the Hb A2/E window, with no Hb A, a small Hb F and only mild anemia: this fits homozygous Hb E. People with Hb EE are usually well, with microcytosis and many target cells. Hb E/beta-zero thalassemia also lacks Hb A, but has much more Hb F (often 30-60%) and moderate to severe anemia. Hb E trait has about 25-30% Hb E with mostly Hb A.

   • A: Hb C elutes in its own window on HPLC, not in the Hb A2/E window.
   • C: Hb E trait still has mostly Hb A.
   • D: Hb E/beta-zero thalassemia has a much higher Hb F and significant anemia.

5. Question 5 · Medium

   In sickle cell trait without thalassemia, Hb S is usually about 35-40% of the total rather than 50%. What explains this?

   1. AAlpha chains pair more readily with beta-A than beta-S
   2. BRed cells containing Hb S are removed early by the spleen
   3. CHb S is partly lost when the blood sample is stored
   4. DA promoter defect lowers expression of the beta-S gene

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   Answer: A · Alpha chains pair more readily with beta-A than beta-S

   Alpha chains carry a positive charge and combine faster with the more negatively charged beta-A chains than with beta-S chains, which have lost a glutamic acid. Less Hb S therefore forms, usually about 35-40% of the total. When alpha chains are short, as in coexisting alpha-thalassemia, this preference lowers Hb S further, often below 30%. An apparent carrier with more Hb S than Hb A needs another explanation, such as Hb S/beta-plus thalassemia.

   • B: Trait red cells have a normal life span.
   • C: Hb S is stable in stored samples.
   • D: The beta-S gene has a normal promoter; the difference arises when the chains assemble.

6. Question 6 · Hard

   Which couple has a 25% risk, in each pregnancy, of a child with a significant sickling disorder?

   1. AHb AC man and Hb AE woman
   2. BHb AE man and alpha-thalassemia trait woman
   3. CHb AS man and silent alpha carrier woman
   4. DHb AS man and beta-thalassemia trait woman

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7. Question 7 · Medium

   Compared with Hb SS, Hb SC disease usually shows:

   1. AA higher hemoglobin and many target cells
   2. BA raised Hb A2 and marked microcytosis
   3. CAn Hb F above 20% and no target cells
   4. DMore severe anemia and more sickle cells

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8. Question 8 · Hard

   An adult with Hb SS starts hydroxyurea. Six months later the MCV has risen from 86 to 104 fL, Hb F from 7% to 21%, and the reticulocyte count has fallen. These changes most likely show:

   1. ADeveloping folate deficiency from hemolysis
   2. BThe expected response to hydroxyurea
   3. CDilution by a recent red cell transfusion
   4. DAn aplastic crisis from parvovirus B19

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9. Question 9 · Medium

   Which change makes Hb S polymerize faster inside the red cell?

   1. AA rise in the proportion of Hb F
   2. BA higher blood pH (alkalosis)
   3. CCell dehydration that raises the MCHC
   4. DCoexisting two-gene alpha-thalassemia

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10. Question 10 · Hard

    A 9-year-old has Hb 95 g/L (9.5 g/dL), MCV 71 fL, normal ferritin and HPLC Hb S 91%, Hb F 6%, Hb A2 3.4%, no Hb A. Both parents have Hb AS with Hb S about 30%, MCV 70-72 fL, normal ferritin and normal Hb A2. The child's most likely diagnosis is:

    1. AHb SS with iron deficiency
    2. BHb S/beta-zero thalassemia
    3. CHb SS with alpha-thalassemia trait
    4. DHb S/HPFH

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11. Question 11 · Hard

    A 32-year-old is found to have Hb S at a pre-employment check and has never had a crisis. Hb 142 g/L (14.2 g/dL), MCV 82 fL. HPLC: Hb S 70%, Hb F 28%, Hb A2 1.8%, no Hb A. Flow cytometry shows Hb F evenly spread in all red cells. What is the most likely diagnosis?

    1. AHb S/HPFH
    2. BHb S/delta-beta thalassemia
    3. CHb SS on hydroxyurea
    4. DHb S/beta-zero thalassemia

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12. Question 12 · Hard

    A 7-year-old from Bangladesh needs a transfusion every 4 weeks. Before her first transfusion, HPLC showed 50% in the Hb A2/E window, Hb F 48% and no Hb A. Her father has Hb E trait and her mother has beta-thalassemia trait. The most likely diagnosis is:

    1. AHb E/beta-zero thalassemia
    2. BHomozygous Hb E (Hb EE)
    3. CBeta-thalassemia major
    4. DHb H disease with Hb E

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13. Question 13 · Easy

    A healthy adult with sickle cell trait (Hb AS) usually has:

    1. AChronic hemolytic anemia
    2. BMarked microcytosis
    3. CA normal CBC and blood film
    4. DMany sickle cells on the film

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14. Question 14 · Hard

    A 35-year-old man from Bangladesh working in the UAE has mild anemia and occasional bone pain. Hb 112 g/L (11.2 g/dL), MCV 72 fL. HPLC: Hb S 63%, 30% in the Hb A2/E window, Hb F 3%, no Hb A. Sickle solubility is positive. The most likely diagnosis is:

    1. AHb S/E disease
    2. BHb SC disease
    3. CSickle cell trait
    4. DHb S/beta-plus thalassemia

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15. Question 15 · Easy

    Which amino acid change in the beta-globin chain produces Hb S?

    1. AGlutamine replaces glutamic acid at position 121
    2. BLysine replaces glutamic acid at position 26
    3. CLysine replaces glutamic acid at position 6
    4. DValine replaces glutamic acid at position 6

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16. Question 16 · Medium

    Which genotype behaves clinically most like sickle cell anemia (Hb SS)?

    1. AHb S/HPFH
    2. BHb A/D-Punjab
    3. CHb S/G-Philadelphia
    4. DHb S/D-Punjab

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17. Question 17 · Medium

    Many patients with Hb SS from the Arabian Gulf have Hb F of 15-25% and a milder course. Hb F protects them mainly because it:

    1. ARaises the MCHC of each red cell
    2. BBinds 2,3-BPG more strongly than Hb S
    3. CHas a lower affinity for oxygen
    4. DIs not incorporated into Hb S polymers

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18. Question 18 · Hard

    A 6-year-old has Hb 82 g/L (8.2 g/dL), MCV 67 fL and a palpable spleen. HPLC: Hb S 85%, Hb F 9%, Hb A2 6.0%, no Hb A. Father: Hb A 60%, Hb S 37%, normal MCV. Mother: MCV 63 fL, Hb A2 5.3%, no Hb S, normal ferritin. What is the child's most likely diagnosis?

    1. AHb S/beta-plus thalassemia
    2. BHb SS with alpha-thalassemia
    3. CSickle cell trait with iron deficiency
    4. DHb S/beta-zero thalassemia

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19. Question 19 · Easy

    Which blood film findings are typical of sickle cell anemia (Hb SS)?

    1. ASickle cells, target cells and Howell-Jolly bodies
    2. BTeardrop cells and leukoerythroblastosis
    3. CSchistocytes, microspherocytes and few platelets
    4. DSpherocytes alone, with polychromasia

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