251 - Thalassemia

Question 1

What defines thalassemia major vs. intermedia?

Answer 1

• Major: ≥8 transfusions in the last 12 months
• Intermedia: <8 transfusions in the last 12 months

Genotype does not accurately affect phenotype; classify operationally instead of genetically

Question 2

Composition of hemoglobin Bart:

Answer 2

gamma-globin tetramer

• Formed during gestation due to deficient functional alpha-globin*
• Hb Bart decreases quickly after birth -> beta tetramers form instead (HbH)*
• Complete alpha-globin deficiency (0 working copies) usually results in hydrops fetalis; 1 working copy can survive, has HbH disease*

Question 3

Composition of fetal hemoglobin:

Answer 3

2 alpha chains, 2 gamma chains

Higher O2 affinity than adult hemoglobin

Question 4

What kind of anemia is present in beta-thalassemia?

Answer 4

Microcytic anemia with extravascular hemolysis

Hyercellular marrow

Question 5

What types of hemoglobin will be present in beta-thalassemia during…

• Newborn screening:
• Post-neonatal testing:

Answer 5

• Newborn screening:
  
  • HbF only
    ​
• Post-neonatal testing:
  
  • HbF
  • More HbA₂ than normal

Question 6

What is the significance of Hemoglobin E?

(Severe phenotype?)

Answer 6

Point mutation in beta-globin splice site

• Homozygous HbE
  
  • Benign clinical course; alpha/beta interface less stable under oxidative stress
• BUT: heterozygous for HbE and beta-thalassemia
  
  • -> Severe phenotype

Question 7

Is acute hemolysis more prominent in alpha-thalassemia or beta-thalassemia?

Answer 7

Alpha-thalassemia

Question 8

On which chromosome is the beta-globin locus found?

Answer 8

Chromosome 11

Question 9

List 4 treatments for thalassemia

Answer 9

• Transfusions
• Iron chelation - initiate as soon as Hb is consistently low
• Splenectomy
• Bone marrow/stem cell transplant

Must manage both anemia and iron overload

Question 10

What causes chronic hemolysis in beta-thalassemia?

Answer 10

Unpaired alpha-globin forms hemichromes in RBCs that induce apoptosis

Question 11

Composition of normal adult hemoglobin:

Answer 11

2 alph achains, 2 beta chains

• Mutation in beta chain -> more production of HbA2 or HbF*
• (HbF is functional, HbA2 is not)*

Question 12

Composition of hemoglobin H:

Answer 12

Beta-globin tetramer

• Only 1 working copy of alpha-globin (alpha-thalassemia)*
• -> HbH disease, where 1 working copy results in some normal hemoglobin (HbA, with 2 alpha, 2 beta) and some HbH (4 beta)*

Question 13

What are the two primary mechanisms for anemia in thalassemia?

Answer 13

• Ineffective erythropoiesis
  
  • Reduced or absent beta globin
  • -> unpaired alpha-globin, immature RBCs
• Chronic hemolysis
  
  • Unpaired alpha-globin forms hemichromes that induce RBC apoptosis
  • -> sequestered in the spleen

Question 14

For thalassemias, what testing is used for:

• Newborn screening (3):
• Postnatal testing (2):

Answer 14

• Newborn screening:
  
  • HPLC
  • Isoelectric focusing
  • Hemoglobin electrophoresis
• Postnatal testing:
  
  • CBC
  • Hemoglobin electrophoresis

Question 15

What is the consequence of globin chain imbalance within the cell?

Answer 15

The extra chains form hemichromes which induce RBC apoptosis

Question 16

Which complications of thalassemia can be mitigated by transfusions? (5)

Answer 16

• Facial deformity
• Hypersplenism
• Anemia
• Pathological fractures
• Premature closure of the lower femoral epiphysis

Question 17

What types of hemoglobin will be present in alpha-thalassemia during…

• Newborn screening:
• Post-neonatal testing:

Answer 17

• Newborn screening:
  
  • Hb Bart’s
  • HbH
    ​
• Post-neonatal testing:
  
  • Increased HbF
  • HbH

Honestly not sure what this part of the lecture was trying to say - I think the key is that we see different things on neonatal screening vs. later on

Question 18

What causes hepatosplenomegaly in thalassemia?

Answer 18

Globin chain imbalance, extra chains form hemichromes

• > Tags RBCs for apoptosis
• > Sequestered in spleen

Also exramedullary hematopoiesis -> hepatosplenomegaly

Thank you @Zach Cross!