Thalassemia

Question 1

Review the normal structure of hemoglobin and indicate the globin chains that typically make it up. Describe how the composition of globin chains in hemoglobin changes during fetal development and after birth.

Answer 1

Hemoglobin is a heterodimer made up to 2 alpha-globin chains and another pair of different globin chains (usually beta and delta). Majority of hemoglobin in human RBCs after 4-6 months of age is Hemoglobin A1: 2 alpha chains and 2 beta chains (95%), A2: 2 alpha chains and 2 delta chains (3.5%) and HbF: 2 alpha chains and 2 gamma chains (2%).

Question 2

Describe what thalassemia is and explain in a general way the molecular basis for it.

Answer 2

Thalassemia: underproduction of a hemoglobin chains due to a variety of mutations that result in poor or absent function of the globin gene. Imbalance of the chains leads to: free excess chains binding to RBC membrane, membrane oxidative injury, increased membrane rigidity, decreased membrane stability. Two common types: alpha-thalassemia and beta-thalassemia.

Question 3

Describe the basic genetic differences between alpha-thalassemia and beta-thalassemia.

Answer 3

• Alpha-thalassemia: alpha-globin is under produced, due to an absence of 1+/4 genes that control production on chromosome 16.
• Beta-thalassemia: beta-globin is under produced most often due to point mutations which result in a dysfunctional gene on chromosome 11.

Question 4

Explain the meaning of the terms thalassemia major, thalassemia intermedia, and thalassemia minor.

Answer 4

Major: 2 severely abnormal or absent genes (severe anemia and always transfusion dependent)
Intermedia: 2 mildly-moderately abnormal genes (mild-mod anemia and sometimes transfusion dependent)
Minor: 1 normal gene and 1 abnormal gene (no-mild anemia and never transfusion dependent)

Question 5

Describe the genetic, hematologic, and clinical differences between alpha-thalassemia trait, hemoglobin H disease, and hydrops fetalis.

Answer 5

-a-thal trait (silent carrier): (-a/aa, no anemia, nl MVC, not transfusion dependent)
-a-thal trait (2 gene del): (-a/-a or –/aa, no-mild anemia, low-nl MVC, not transfusion dependent)
-HbH disease: –/-a, mod-severe anemia, low MVC, sometimes transfusion dependent
Hydrops fetalis: –/–. incompatible with life

Question 6

Describe clinical manifestations in patients with thalassemia.

Answer 6

a. Chronic hemolytic anemia: fragile RBC has short half-life and is destroyed in marrow or culled by the spleen from circulation (Splenomegaly: enlarged from removing so many damaged RBCs. )
b. Expanded bone marrow and extramedullary hematopoiesis: bone marrow expands to try and produce adequate RBC mass, it fills with RBC precursors (but they are fragile and destroyed—ineffective erythropoiesis). Leads to frontal bossing, osteopenia, enlargement of liver and spleen.
c. Increased iron absorption: increase absorption of iron from diet, but these patients usually are getting transfused –> high iron burden and iron overload. Must use iron chelation therapy.
d. Delayed growth and development: anemia, increased metabolism and endocrinopathies –> short stature, delayed puberty.
e. Endocrinopathies: 2/3 of Cooley’s anemia patients have abnormal endocrine function. Pituitary gland is often effected and can lead to hypogonadotrophic hypogonadism. Hypothyroidism is present in 40-60% of patients with Beta-thalassemia major.
f. Pulmonary HTN: chronic hemolytic anemia increases risk of pulmonary HTN.

Question 7

Describe findings on the CBC and peripheral blood smear in patients with thalassemia.

Answer 7

i. Anemia with some increase in retic count: varies with severity of thalassemia, Cooley’s anemia  severe anemia (Hgb ˂7 g/dL) that develops within first year of life and requires transfusions to sustain life beyond 2-3 years. Milder thalassemia may require transfusions later in life.
ii. Abnormal peripheral smear: microcytosis (small RBC’s), target cells, polychromasia (blue cells that represent retic’s), mild anisocytosis (variation in RBCs size). RDW is nrml-minimally elevated. Low MCV, low MCHC, sombrero shaped RBC’s
iii. Abnormal chemistry profile increased total/indirect bilirubin, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) as they are released from lysed RBCs.

Question 8

Describe clinical manifestations in patients with thalassemia: Chronic hemolytic anemia:

Answer 8

fragile RBC has short half-life and is destroyed in marrow or culled by the spleen from circulation (Splenomegaly: enlarged from removing so many damaged RBCs. )

Question 9

Describe clinical manifestations in patients with thalassemia: Expanded bone marrow and extramedullary hematopoiesis:

Answer 9

bone marrow expands to try and produce adequate RBC mass, it fills with RBC precursors (but they are fragile and destroyed—ineffective erythropoiesis). Leads to frontal bossing, osteopenia, enlargement of liver and spleen.

Question 10

Describe clinical manifestations in patients with thalassemia: Increased iron absorption:

Answer 10

increase absorption of iron from diet, but these patients usually are getting transfused –> high iron burden and iron overload. Must use iron chelation therapy.

Question 11

Describe clinical manifestations in patients with thalassemia: Delayed growth and development:

Answer 11

anemia, increased metabolism and endocrinopathies –> short stature, delayed puberty.

Question 12

Describe clinical manifestations in patients with thalassemia: Endocrinopathies:

Answer 12

2/3 of Cooley’s anemia patients have abnormal endocrine function. Pituitary gland is often effected and can lead to hypogonadotrophic hypogonadism. Hypothyroidism is present in 40-60% of patients with Beta-thalassemia major.

Question 13

Describe clinical manifestations in patients with thalassemia: Pulmonary HTN:

Answer 13

chronic hemolytic anemia increases risk of pulmonary HTN.

Question 14

Describe the geographic distribution of thalassemia. Describe a situation where people heterozygous for thalassemia may have a survival advantage

Answer 14

most common in SE Asian, African and Mediterranean descent. May have an heterozygote advantage for malaria.

Question 15

Explain why Southeast Asians with alpha-thalassemia are more likely than Africans with alpha-thalassemia to have a child with hydrops fetalis.

Answer 15

The genotype –/αα (both genes on the SAME chromosome are missing) is more common in the SE Asian populations. This person can pass on a chromosome with no functional alpha genes (–) and if the other parent contributes a similar chromosomes theoffpsring will have no alpha genes. The child will be unable to amek any normal hemoglobin (alpha chain is required for all types of Hgb), and the baby will die in utero (Hydrops fetalis). The –α/-α genotype (each chromosome has 1 intact alpha gene) is more common in the African populations and therefore the offspring will inherit a least 1 alpha gene. Less likely to see Hydrops fetalis is this population

Question 16

Describe approaches to treatment for thalassemia

Answer 16

a. Transfusion support: in severe thalassemia, transfusions are started in the first 2 years of life to maintain normal Hgb levels and avoid excess bone marrow expansion and extramedullary hematopoiesis. Chelation therapy must be paired with transfusions to prevent iron overload. Chelation agent: deferoxamine (infused SQ over 8-12 hours, in ABD area, 5-7x/wk, compliance is challenging).
b. Increase fetal Hgb production: Hydroxyurea, butyrate and decitabine can induce the gamma chain to produce providing a pool of globin chains for the excess alpha chains to combine with, thus reducing their negative impact on RBCs.
c. Bone marrow transplant: thalassemia can be cured with BMT, 70% thalassemia-free survival at 20 years for people who receive a HLA-identical unaffected sibling match. Only 30% of patients have a matched sibling.

Question 17

Explain how newborn screens can be used to diagnose thalassemia

Answer 17

Using a heel prick, Virtually all infants born in the United States are screened at birth for hemoglobinopathies, using the blood from a heel stick placed on filter paper, as is done for the PKU and other sponsored newborn screening tests. The purpose is early identification of sickle cell disease, so that parental education and prophylactic penicillin can be provided to prevent early mortality. However, it is also an opportunity to identify children with other forms of hemoglobinopathies, including B-thalassemia major.