Thalassemias

Question 1

How many Hb alpha genes are there and how many Hb beta genes are there?

Answer 1

alpha-4

beta-2

Question 2

Hb gamma is the fetal hemoglobin chain. a2y2 is fetal Hb. What is special about fetal Hb?

Answer 2

It does not give up oxygen as readily

Question 3

Where are the alpha Hb genes located in the genome? The other Hb genes?

Answer 3

Alpha is on chromosome 16, the others are all on chromosome 11

Question 4

How can you get iron overload with Beta-thalassemia?

Answer 4

Transfusions. RBCs get stuck in microcirculation/die so the body says make more RBCs. These die too and transfusions are needed. However, the transfusions can cause iron overload bc even though the RBCs die, the iron in the heme is continually recycled.

Question 5

What is thalassemia MAJOR?

Answer 5

Beta-thalassemias

Question 6

What are some clinical presentations of Beta-thalassemia?

Answer 6

Severe osteoporosis, malformed bones, flattened nose, boxed forehead, VERY LARGE SPLEEN due to hemolytic anemia (filled with dead RBC material), ankle ulcers

Question 7

In general, why do we get iron overload? (big picture)

Answer 7

We do not have a mechanism to eliminate it from our bodies

Question 8

Why do patients with thalassemias get iron overload?

Answer 8

Decreased Hepcidin bc the body senses dead RBCs and tells itself we need to make “new iron”

Question 9

Why are patients with Beta-thalassemias in a hypercoaguable state?

Answer 9

Phosphatidylserine is exposed on the outside of the cell due to membrane damage and this is a recognition site for cell removal during apoptosis + it increases thrombin production (increased platelet activation)

Question 10

What are the two types of Beta-thalassemias?

Answer 10

B^0 (no beta chains)

B^+(very few beta chains)

Question 11

If A2 (meaning alpha2/delta2) levels are above 3.5%, what is this an indicator of?

Answer 11

Beta-thalassemia

Question 12

What is a histological feature of RBCs that can help make a dx of B-thalassemia?

Answer 12

Target cells

Question 13

What is a histiological feature of all hemolytic anemias?

Answer 13

Basophilic stippling

Question 14

What are the main prognostic indicators of a transplant failure in pts with Beta-thalassemia?

Answer 14

Portal fibrosis, Hepatomegaly, Inadequate chelation

Question 15

What is HPFH? (Hereditary Persistence of Fetal Hemogloblin)

Answer 15

Decrease in beta globin synthesis compensated by an increase in gamma chain synthesis. Could be co-deletion of delta/beta genes. Produces a favorable sickle syndrome.

Question 16

What is Hemoglobin E disease?

Answer 16

A point mutation on the Beta globin gene (26 Glu to Lys) that presents w/ Beta-thalassemia minor in heterozygotes

Question 17

What is Hemoglobin Lepore?

Answer 17

A delta/beta fusion chain which leads to diminished non-alpha chains (85-95% reduction) leading to thal-intermedia in heterozygotes and thal-major in homozygotes

Normal alpha chains present

Question 18

How do you make a dx of Hemoglobin S/Beta-thalassemia?

Answer 18

HPLC- tells you what chains are present

Check out chart on page 97 of hematology book. Should see an increased A2 band, S band, increased F band

Question 19

If you lose 4 alpha globin genes what happens?

Answer 19

You’re dead (you have Barts Hb which is gamma4). Also known as hydrops fetalis.

Question 20

What is HbH disease?

Answer 20

Alpha-thalassemia where 3 alpha globin genes are mutated. This is less severe than Beta-thal major and affects older RBCs.

Question 21

Where do you find cells that look like “golf balls”?

Answer 21

Tiger Woods’s blood, or HbH disease (either is acceptable, I asked Chesney)

Question 22

What is alpha0 trait?

Answer 22

Two knockouts on one chromosome

Question 23

What is alpha1 trait?

Answer 23

Two knockouts, each on separate chromosomes

Question 24

What is the Hemoglobin Spring Constant?

Answer 24

A base substitution on the terminal sequence of the alpha globin chain mRNA that adds 31 bases and makes the mRNA unstable decreasing its translation (less alpha chains). Presents as severe alpha-thalassemia in homozygotes.

Question 25

What does the carrier state of thalassemias, sickle cell anemia and other Hg disorders often provide a selective advantage against?

Answer 25

Malaria

Question 26

Soon after birth, what happens to globin production?

Answer 26

Gamma globin production decreases and beta globin production increases

Question 27

What do alpha thalasemias typically arise from? Beta thalasemias? (think genetics)

Answer 27

Alpha: gene deletions
Beta: point mutations

Question 28

What geographical location are beta thalasemias common?

Answer 28

Mediterranean

Question 29

What geographical location are alpha thalassemias common?

Answer 29

Far east

Question 30

What do the bones look like in thalasemia Pts?

Answer 30

Thin bones due to BM expansion/hyperplasia as BM is trying to produce more cells

Osteoporosis

Question 31

What other clinical signs/abnormalities are seen in B thalasemia major?

Answer 31

Splayed teeth due to widening of the maxilla and mandible

Facial bone abnormalities (use sunny as a reference)

Hepatosplenomegaly

Skin pigmentation

Ulcers due to decreased wound healing

Question 32

What can you see on liver biopsy in Pts with beta thalasemia major?

Answer 32

Fibrosis and iron deposition in macrophages

Question 33

What is a potential complication in a pt with beta thalasemia and pre existing hep c infection/hepatic cirrhosis?

Answer 33

Hepatocellular carcinoma

Question 34

In the silent carrier and trait alpha thalasemias, what do you see on RBC indices?

Answer 34

Microcytic with mild anemia (book says MCV and MCH are low)

Question 35

What regulates the globin switch (from gamma to beta) 3-6 months after birth?

Answer 35

BCL11A (a transcriptional regulator)