05: Thalassemias & Hemoglobinopathies

Question 1

2,3-DPG

Answer 1

Binds central hole of Hgb, enhances O₂ release.

↑2,3-DPG –> ↓O₂ avidity

Question 2

Chromosome 16

Answer 2

Alpha globin genes; zeta, 2 alphas

Question 3

Chromosome 11

Answer 3

Beta-globin genes

1 epsilon, 2 gammas, 1 delta, 1 beta

Question 4

Thalassemia

Answer 4

Imbalance in globin synthesis

Question 5

Hemoglobinopathy

Answer 5

Abnormal protein synthesis due to globin gene mutation (Hb S, C, D, O)

Question 6

Alpha Thal Trait

Answer 6

Normal Hb/Hct

Low MCV

Question 7

Alpha Thalassemia

Answer 7

• 3/4 genes effected
• Decreased alpha synthesis
• Gamma₄ tetramer (Hb Barts)
• Beta₄ tetramer (Hb H)
• Excess beta globins –> unstable hemoglobins –> hemolysis
• If 4/4 genes effected, hyrops fetalis (die in utero during 2nd or 3rd trimester)

Question 8

Beta Thalassemia Trait (Minor)

Answer 8

+/- normal Hb/Hct

Low MCV

Question 9

Beta Thalassemia

Answer 9

• Decreased beta synthesis
• Alpha₄ tetramer: toxic, unstable (cells never make it out of bone marrow)
• Excess alpha globins –> ineffective erythropoiesis
• Beta unnecessary in utero, thus no Sx until birth
• Homozygous Beta Thalassemia Major: requires transfusion to survive, BM transplant, iron chelation
  
  • Signs: nucleated RBCs, ↑bone marrow production in skull

Question 10

Sickle cell anemia

Answer 10

• Mutation at beta globin #6 position (GAG–>GTG)
• Glutamic acid (hydrophilic) to valine (hydrophobic)
• Creates sticky hydrophobic patch when Hb deoxygenated
• Predispose to sickling:
  
  • De-oxygenation
  • Cellular dehydration
  • Acidosis
  • Fever
• HbSS RBCs only live 10-20 days
• Life expectancy = mid-50s
• Diagnosis
  
  • Anemia = CBC Hb <8
  • ↑reticulocyte count
  • Peripheral smear: target cells, **Howell-Jolly bodies **(indicates absent spleen function)
• Symptoms:
  
  • Vaso-occlusive crisis (pain)
  • **Dactylitis **(inflammation of entire digit in children 2/2 bone marrow here during infancy)
• Defect in spleen opsonization –> ↑risk for S. pneumo, H influ, N mening, Salmonella
• Acute Chest Syndrome: pulm. infiltrates on CXR; viscious cycle of infarction & infection

Question 11

Hydroxyurea

Answer 11

1. ↑fetal hemoglobin (doesn’t sickle)
2. ↓neutrophils (↓occlusion)
3. ↓adhesion molecules (↓occlusion)
4. Macrocytosis and ↑hydration (↓Hb packing)
5. NO production

Question 12

Trans-Cranial Doppler

Answer 12

Reveals increased flow in cerebral arteries –> suggests narrowing and risk of stroke (occlusion or stenosis).

Question 13

Tricuspid regurgitation

Answer 13

Associated with pulmonary HTN, which leads to worse prognosis for SS patients.

Question 14

Hemoglobin C

Answer 14

Forms crystals, not long fibers.

Question 15

Thalassemic Hemoglobinopathy

Answer 15

• Decreased synthesis of abnormal protein hemoglobin E
• Common in Southeast Asia (40-50%)
• HbE mutation (#26 positon of beta-globin gene) leads to abnormal protein and abnormal splice site –> defective splicing, ↓protein production

Question 16

Beta Thalassemia Intermedia

Answer 16

• Deletion of beta on one chain, mutation of beta to HbE on the other chain.
• Severe anemia, however patient can survive without transfusion (unlike with beta thalassemia major).