Thalassemia (complete)

Question 1

What is the normal structure of Hb?

Answer 1

Made of 2 alpha-globin chains and 2 beta/delta/gamma chains

Hba1: 2a/2b (95%)
Hba2: 2a/2delta (3.5%)
HbF: 2a/2gamma (2%)

Question 2

Describe how the composition of globin chains in Hb changes during fetal development and after birth

Answer 2

Think of that token graph

Fetal: mainly alpha/gamma, a little alpha/beta

After birth: changes to primarily alpha/beta – a little alpha/delta develops

Question 3

Describe thalassemia and explain its molecular basis

Answer 3

Definition: underproduction of Hb chains b/c of mutations in globin gene (poor/absent function)

Two common types:

1) alpha-thal
2) beta-thal

Question 4

What are the consequences of thalassemia generally speaking?

Answer 4

1) Free excess chains binding to RBC membrane
2) Membrane oxidative injury
3) increase membrane rigidity
4) Decreased membrane stability

Question 5

What is the genetic mutation for alpha-thal?

Answer 5

Absence of 1-4 of 4 genes that control alpha-globin production

Chromosome 16

OVERALL: Alpha-globin underproduced

Question 6

What is the genetic mutation of beta-thal?

Answer 6

Point mutations that result in dysfunctional gene (either moderate or severe)

Chromosome 11

OVERALL: Beta-globin underproduced

Question 7

What is thalassemia minor (beta-thal trait)?

Answer 7

Beta gene: 1 normal, 1 moderately abnormal

Anemia: none-mild

MCV: normal-low

Tranfusion dpdt: No

Question 8

What is thalassemia intermedia?

Answer 8

Beta gene: 2 moderately abnormal

Anemia: Mild-moderate

MCV: Low

Tranfusion dpdt: Sometimes

Question 9

What is thalassemia major (Cooley’s anemia)?

Answer 9

Beta gene: 2 severely abnormal

Anemia: Severe

MCV: Low

Tranfusion dpdt: Always

Question 10

What is alpha-thal trait (silent carrier)?

Answer 10

Alpha gene: - a / a a

Anemia: None

MCV: Normal

Transfusion dpdt: No

Question 11

What is alpha-thal trait (2-gene deletion)?

Answer 11

Alpha gene: - a / - a or - - / a a

Anemia: None - mild

MCV: Normal - low

Transfusion dpdt: No

Question 12

What is HbH disease?

Answer 12

Alpha gene: - - / - a

Anemia: Moderate - severe

MCV: Low

Transfusion dpdt: Sometimes

Question 13

What is hydrops fetalis?

Answer 13

Alpha gene: - - / - -

Incompatible w/ life

Question 14

What are the clinical manifestations of a pt w/ thalassemia?

Answer 14

1) Chronic hemolytic anemia
2) Expand bone marrow and extramedullary hematopoiesis
3) Increase iron absorption
4) Delayed growth and development
5) Pulmonary HTN

Question 15

What are the abnormalities found on a CBC of a pt w/ thalassemia?

Answer 15

• Increased reticulocyte count
• Low MCV
• Low MCHC

Question 16

What are the abnormalities found in the chemistry profile of a pt w/ thalassemia?

Answer 16

• Increased bilirubin
• Increased LDH
• Increased AST

B/c of lysed cells

Question 17

What abnormalities are seen in the peripheral blood smear of a pt w/ thalassemia?

Answer 17

• Microcytosis
• Target cells
• Polychromasia
• mild Anisocytosis
• Sombrero shaped RBCs

Question 18

Describe chronic hemolytic anemia as it relates to thalassemia

Answer 18

• Fragile RBC has short half-life
• Destroyed in marrow or reduced in spleen
• Splenomegaly b/c of so many damaged RBCs

Question 19

Describe expanded bone marrow and extramedullary hematopoiesis as it relates to thalassemia

Answer 19

• Bone marrow expands to try and produce enough RBC
• Fills w/ RBC precursors (but they are fragile, easily destroyed)
• Causes frontal bossing, osteopenia, hepatomegaly, splenomegaly

Question 20

Describe increased iron absorption as it relates to thalassemia

Answer 20

• Iron comes from diet and transfusions (instead of only one)
• Leads to high iron burden/overload

Chelation required

Question 21

Describe delayed growth and development as it relates to thalassemia

Answer 21

Short stature and delayed puberty

Caused by:

1) anemia
2) increased metabolism
3) endocrinopathies

Question 22

Describe endocrinopathies as they relates to thalassemia

Answer 22

2/3 of pts w/ Cooley’s anemia have this

Pituitary gland affected —> hypogonadotrophic hypogonadism

Hypothyroidism in 40-60% of pts w/ B-thal major

Question 23

Describe pulmonary HTN as it relates to thalassemia

Answer 23

chronic hemolytic anemia increases risk for hypertension

Question 24

Describe geographic distribution of thalassemia.

Answer 24

Most common in SE Asia, Africa, Meditarranean

Heterozygotes protected from malaria

Question 25

Why are SE Asians w/ a-thal more likely than Africans w/ a-thal to have a child w/ hydrops fetalis?

Answer 25

SE Asians genes: - - / a a

African genes: a - / a -

Think of mode of inheritance

Question 26

What treatments are available for pts w/ thalassemia?

Answer 26

1) Transfusion support
2) Increase fetal Hb production
3) Bone marrow transplant

Question 27

Describe transfusion support as a treatment for pts w/ thalassemia

Answer 27

• Used in severe thalassemia
• Start in first 2 yrs
• Maintain normal Hb levels
• Avoids bone marrow expansion and extramedullary hematopoiesis

Chelation used to prevent Fe overload

Question 28

Describe increased fetal Hb production as a treatment for pts w/ thalassemia

Answer 28

Agents: Hydroxyurea, butyrate, decitabine

• Induce gamma chain formation for excess alpha chains to bind with
• Reduces negative impact on RBCs

Question 29

Describe bone marrow transplantation as a treatment for pts w/ thalassemia

Answer 29

• Used to cure thalassemia

- Only 30% of pts have been matched w/ an eligible sibling

Question 30

Which method is used to screen newborns for thalassemia?

Answer 30

Same process/purpose as sickle cell disease screening

Heel prick