249: 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

4 gamma globins

Hemoglobin Bart disease is a severe form of alpha thalassemia

• Complete alpha-globin deficiency (0 working copies) usually results in hydrops fetalis→ cannot form fetal hemoglobin*
• 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

Produced starting at ~10 weeks

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

Can’t make normal HbA (required beta globins)

• Newborn screening:
  
  • HbF only
    ​
• Post-neonatal testing:
  
  • HbF
  • More HbA₂ than normal (made of alpha and delta globins)

Question 6

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

Answer 6

Alpha-thalassemia

Question 7

On which chromosome is the beta-globin locus found?

Answer 7

Chromosome 11

2 copies of beta globin gene (1 on each chromosome)

Question 8

List 4 treatments for thalassemia

Answer 8

• Transfusions
• Iron chelation
• Splenectomy
• Bone marrow/stem cell transplant

Must manage both anemia and iron overload

Question 9

What causes chronic hemolysis in beta-thalassemia?

Answer 9

Unpaired alpha-globin forms hemichromes in RBCs that induce apoptosis

Question 10

Composition of normal adult hemoglobin:

Answer 10

Hemoglobin A: 2 alph achains, 2 beta chains

• Mutation in beta chain -> more production of HbA2 or HbF*
• HbA2- two alpha, two delta*

Question 11

Composition of hemoglobin H:

Answer 11

4 beta globins

Hemoglobin H Disease: more severe form of alpha thalassemia, 3 of 4 alpha globins are delete

-> HbH disease, in some normal hemoglobin (HbA, with 2 alpha, 2 beta) and some HbH (4 beta)

Question 12

What are the two primary mechanisms for anemia in beta thalassemia?

Answer 12

• 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 13

What test is commonly used for diagnosing thalassemias?

Answer 13

Hemoglobin Electrophoresis

Also helpful in sickle cell

Question 14

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

Answer 14

The extra chains form hemichromes which induce RBC apoptosis

Question 15

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

Answer 15

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

Question 16

What causes hepatosplenomegaly in thalassemia?

Answer 16

Globin chain imbalance, extra chains form hemichromes

• > Tags RBCs for apoptosis
• > Sequestered in spleen

Also exramedullary hematopoiesis -> hepatosplenomegaly

Thank you @Zach Cross!

Question 17

How many copies of the alpha globin gene are there? Where are they located?

Answer 17

4 copies, chromosome 16

(2 copies on each chromosome)

Question 18

In alpha-thalassemia, the alpha globin genes are __________________.

Answer 18

In alpha-thalassemia, the alpha globin genes are DELETED.

Severity of disease determined by number of deletions

2 deletions→ Alpha Thal Minor/Trait

3 Deletions→ Hemoglobin H Disease

4 Deletions→ Hemoglobin Bart Disease, incompatible with life

Question 19

In beta-thalassemia the beta globin genes are __________

Answer 19

In beta-thalassemia the beta globin genes are MUTATED

Beta Thal Minor: one gene mutated

Beta Thal Major: both genes mutated

Gene variants can be B+ (some function) or B0 (non-functional)

Wide variance in presentation

Question 20

What globin genes make up each Hemoglobin molecule?

HbA

HbA2

HbF

HbH

HbBart

Answer 20

• HbA: 2 alpha, 2 beta
• HbA2: 2 alpha, 2 delta
  
  • increased in beta-thalassemia
• HbF: 2 alpha, 2 gamma
• HbH: 4 betas
  
  • seen in Hemoglobin H, severe kind of alpha thalassemia (1 functional alpha gene)
• HbBart: 4 gamma
  
  • seen in Hemoglobin Bart, most severe kind of alpha thalassemia (no functional alpha globin genes)
  • cannot make any functional fetal hemoglobin
  • incompatible with life