Thalassemias and Hemoglobinopathies

Question 1

Describe the % of total globin synthesis for alpha globin from conception to 50 yo.

Answer 1

Rises to max during fetal development and remains at max until end of life.

Question 2

Describe the % of total globin synthesis for gamma globin from conception to 50 yo.

Answer 2

Rises to max during fetal development and drops at birth to minimum levels until end of life.

Question 3

Describe the % of total globin synthesis for beta globin from conception to 50 yo.

Answer 3

Remains at minimum levels during fetal development. Rises rapidly at birth and remains at max until end of life.

Question 4

Where does erythropoiesis predominate during fetal development?

Answer 4

Early: yolk sac
Early-late: liver, spleen
Late: bone marrow

Question 5

Where does erythropoiesis predominate during post natal development?

Answer 5

Bone marrow

Question 6

alpha globin genes are located on which chromosome?

Answer 6

16

Question 7

beta globin genes are located on which chromosome?

Answer 7

11

Question 8

Describe the hemoglobin proteins during embryonic development.

Answer 8

zeta2, epsilon2 (Hb Gower 1)
alpha2, epsilon2 (Hb Gower 2)
zeta2, gamma2 (Hb Portland)

Question 9

Describe the hemoglobin proteins during fetal development.

Answer 9

alpha2, gamma2 (HbF)

Question 10

Describe the hemoglobin proteins during adult development.

Answer 10

alpha2, beta2 (HbA)

alpha2, delta2 (HbA2)

Question 11

“chipmunk facies” are typical of what thalassemia?

Answer 11

Beta Thalassemia major

Question 12

Why do you have anemia in thalassemia?

Answer 12

Ineffective erythropoiesis –> apoptosis

Mechanical & immune removal of misshapen RBCs –> hemolysis

Question 13

A mutation/deletion in chromosome 11 may lead to which thalassemia?

Answer 13

Beta

Question 14

A mutation/deletion in chromosome 16 may lead to which thalassemia?

Answer 14

Alpha

Question 15

Pts with Beta thalassemia major REQUIRE this treatment:

Answer 15

blood transfusions

Question 16

Howell-Jolly bodies would be present following this treatment for Beta thalassemia or hereditary spherocytosis:
What do they represent?

Answer 16

Splenectomy; accumulation of RBCs with remnant nuclei that would normally have been bitten off by macrophages in the spleen.

Question 17

Basophilic stippling can occur in pts from this region of the world with B-thalassemia, but less commonly in other populations with this disorder.

Answer 17

Mediterranean

Question 18

What is a key microscopic finding that can distinguish Beta-thalassemia from Fe deficiency?

Answer 18

basophilic stippling (although not always present in B-thal pts)

Question 19

What is RDW?

Answer 19

Red blood cell distribution width (RDW or RCDW) is a measure of the variation of red blood cell (RBC) volume that is reported as part of a standard complete blood count. Usually red blood cells are a standard size of about 6-8 μm in diameter.

Question 20

Why is there Fe overload in thalassemia?

Answer 20

Transfusion Fe
Increased Fe absorption due to:
Ineffective erythropoiesis
- decreased hepcidin = more absorption, release
Fe taken up into liver, heart, & endocrine cells

Question 21

Why does thalassemia cause endocrine and bone disease?

Answer 21

hypogonadism
Pituitary insufficiency
Osteopenia due to bone marrow expansion (crew cut), endocrine dysfunction, Fe chelators

Question 22

Beta thalassemia causes an excess of which globin?

Answer 22

Alpha

Question 23

excess alpha globin in B-thal results in 4 things that cause anemia. List/describe them.

Answer 23

1) Ineffective erythropoiesis due to inclusion bodies
2) Immune removal due to inclusion bodies and complement activation
3) Mechanical removal due to membrane damage, fragmentation, ^ rigidity, decreased deformability
4) Hypercoagulability due to membrane damage and phosphatidylserine relocation from cytoplasmic leaflet to EC leaflet.

Question 24

What diagnostic techniques are needed to Dx thalassemia?

Answer 24

Family Hx
CBC
blood smear
physical exam
*Observation of elevated HbA2 or HbF for B-thal
*Observation of disproportionately elevated RBC count compared to Hb. Very low MCV with normal ferritin for A-thal
PCR for known mutation
Restriction Fragment Length Polymorphism Analysis for unknown mutation

Question 25

List the supportive therapies for thalassemia.

Answer 25

Leukoreduction and viral testing for repeated transfusions
Drugs for Fe overload (Deferoxamine, Deferiprone, Deferasirox)
Hormone replacement for endocrinopathies
Osteoclast replacement and Vit. D for osteoporosis

Question 26

List the curative therapies for thalassemia.

Answer 26

Hematopoietic stem-cell transplantation

Experimental therapies such as erythropoietin, HbF modifiers (such as hydroxyurea, butyrate) and antioxidant therapy.

Question 27

Have allogenic cellular transplants for thalassemia proven to cure the disease?

Answer 27

yes, in up to 90% of cases. (up to 13% mortality in some cases)

Question 28

What is Hb Bart?

Answer 28

an alpha-thalassemia resulting from an absence of both alpha globins (4 alleles missing from parents). Results in 4 gamma globins. Fetus dies in utero or soon after birth (hydrops fetalis)

Question 29

Does HbH have a high or low O2 affinity

Answer 29

Very high

Question 30

What is HbH?

Answer 30

3 alpha alleles missing from parents. Severe anemia. Unstable hemoglobin present in blood: Hemoglobin H (tetrameric β chains). Very high O2 affinity, can’t unload O2 at peripheral tissues. Results in hepatosplenomegaly.

Question 31

Describe alpha-thal when 2 alpha alleles are missing.

Answer 31

The condition is called alpha thalassemia minor. Two α genes permit nearly normal production of red blood cells, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron.

Alpha thalassemia minor can exist in two forms:

alpha-thal-1 (αα/--), associated with Asians, involves cis deletion of both alpha genes on the same chromosome;
alpha-thal-2 (α-/α-), associated with Africans, involves trans deletion of alpha genes on different (homologous) chromosomes

Question 32

Describe alpha-thal when 1 alpha allele is missing.

Answer 32

This is known as alpha thalassemia minima and with this type there is minimal effect on hemoglobin synthesis. Three α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced mean corpuscular volume and mean corpuscular hemoglobin.

Question 33

Does Hb Bart’s have high or low O2 affinity?

Answer 33

Very high

Question 34

What causes splenomegaly in HbH?

Answer 34

Precipitation of beta globin tetramers as red cells age results in decreased RBC deformability. Can’t make it through sinusoids of spleen, get jammed up, cause splenomegaly.

Question 35

What percentage of African Americans carry the sickle cell trait?

Answer 35

8%

Question 36

what fraction of African Americans are homozygous for the sickle cell trait?

Answer 36

1/625 homozygous

Question 37

What in regions of the world does sickle cell anemia predominate?

Answer 37

Mediterranean, Saudi Arabia, India, (Africa?) < not on list

Question 38

What is the AA substitution in sickle cell anemia?

Answer 38

Valine (hydrophilic) sub’d for Glutamate (hydrophobic)

Question 39

What does the AA substitution in sickle cell anemia cause?

Answer 39

A deoxygenated RBC will cause HbS to polymerize, causing the RBC to assume a sickle shape morphology.

Question 40

Describe a bone pathology associated with sickle cell amenia.

Answer 40

epiphyseal infarcts leading to shortening and flattening of long bones. symptom: dactylitis

Question 41

If your pt has sickle cell disease, they must try to avoid:

Answer 41

infection, fever, dehydration, hypoxemia, & acidosis

Question 42

Under what conditions would you transfuse a sickle cell pt?

Answer 42

Life threatening conditions such as:
severe anemia, hepatic crisis, acute chest syndrome, priapism (persistent erection)
stroke prophylaxis in children with strokes

Question 43

If a sickle cell pt is hypoxic, what do you do?

Answer 43

Administer oxygen!

Question 44

If a sickle cell pt is in severe pain, what do you do?

Answer 44

treat the pain! possibly with narcotics

Question 45

What is going on in HbC disease?

Answer 45

Glutamate replaced with lysine. Results in polymerization similar to HbS (sickle cell) but not as bad

Question 46

Which presents with worse symptoms, HbS or HbSC?

Answer 46

HbS. HbSC has milder symptoms because the pt is only heterozygous for sickle cell disease. Fewer sickled cells, fewer crises. Will see target cells, irregularly contracted cells (sickleish cells), and spherocytes in HbSC.