Hemoglobin Disorders (Thalassemia and Sickle Cell)

Question 1

How many Beta globin genes are present on each chromosome?

Answer 1

one

Question 2

What chromosome is the Beta globin gene located on

Answer 2

chromosome 11

Question 3

What genotypes are considered to be B-thalassemia major?

Answer 3

Bo/Bo or B+/B+

Question 4

What genotypes are considered to be B-thalassemia minor?

Answer 4

B/Bo or B/B+

Question 5

Main sign of B-thalassemia minor

Answer 5

mild microcytic anemia

Thus, you’ll have decreased hepcidin and increased ferroportin to increase duodenal absorption

Question 6

What is Fetal Hemoglobin’s structure (HgF)

Answer 6

Alpha2/Gamma2

Question 7

What is Hemoglobin A2’s stucture

Answer 7

Alpha2/Delta2

Question 8

What is Hemoglobin H’s structure

Answer 8

tetramer of betaglobin

Question 9

Normally, when you’re born what happens to your alpha chain, beta chain, and gamma chain levels

Answer 9

alpha chain levels increase slightly but remains relatively constant compared to fetal levels
beta chain levels (initially 0) increase dramatically, and your gamma chain levels decrease

Question 10

How many alpha globulin genes are on each chromosome?

Answer 10

2

Question 11

What chromosome is the alpha globulin gene located on?

Answer 11

chromosome 16

Question 12

Genetic Mechanism causing Alpha Thalassemias

Answer 12

gene deletions

Question 13

Genetic Mechanism causing Beta Thalassemias

Answer 13

gene point mutations

Question 14

If one of the 4 alpha genes is deleted, what condition do you have?

Answer 14

Alpha Thalassemia silent carrier or Alpha Thalaseemia Trait 1 (-a/aa) but you won’t have anemia because you do have a functional alpha globulin

Question 15

If two of the 4 alpha genes is deleted, what condition do you have

Answer 15

Alpha Thalassemia trait 2 (–/aa) or (-a/-a), in 3% in African Americans

note. you will have some Hb Bart’s in this case

Question 16

If three of the 4 alpha genes are deleted, what condition do you have?

Answer 16

Hemoglobin H Disease (a beta tetramer aka HgH)

Question 17

If 4 of the 4 alpha genes are deleted, what condition do you have

Answer 17

Hydrops Fetalis (from gamma tetramer aka HbBart’s)

Question 18

Microscopic Findings in both Thalassemia’s

Answer 18

target cells

microcytic rbc’s

Question 19

Pathogenesis of Beta Thalassemia Major

Answer 19

you have massive erythroid hyperplasia (overactive bone marrow pushing out immature cells) that just can’t mature before they die

point mutations on both alleles of beta globulin means decreased beta globulin production.

The subsequent accumulation of unpaired Alpha globulins causes a bunch of bad things. These unpaired globulins–>alpha “hemichromes” or clumps–>inclusion bodies–>mess with cytoskeleton, flip membrane so inner proteins like phosphatidylserine are on the outside. leads to:

Thrombotic tendencies
Membrane damage
Autoimmune hemolysis
Ineffective erythropoesis

Question 20

Why is there Iron Overload in Severe Thalassemia?

Answer 20

overactive bone marrow from ineffective erythropoesis reduces hepcidin levels, so you have increased ferroportin, and thus increased serum iron.

you also get excess iron in severe thalassemia when you require chronic blood transfusions (so you should give the blood transfusion with an iron chelator

Iron overload–>cirrhosis–>liver cancer

Question 21

Pathogenesis of Alpha Thalassemia (specfically 3 alpha’s missing)

Answer 21

deletion of alpha genes–>unpaired beta’s form tetramers (HgH), but also these beta hemochromes–>heinz bodies and precipitate out, which leads to hemolysis too

note, you see hemolysis and ineffective erythropoesis, but WAY more hemolysis in peripheral blood, red blood cells can actually develop to maturity before lysing.

Question 22

Clinical Findings of Beta Thalassemia Major

Answer 22

1. Expanded facial features, because of expanded bones
2. Expanded bone marrow–>osteoporosis
3. Splayed teeth from expanded mandible and maxillary
4. hepatosplenegomy
5. skin ulcers (seen in a lot of hemolytic anemias)

Question 23

Clinical Impact of Iron Load in B-Thalassemia Major?

Answer 23

organ damage to...
Liver
Heart
Pancreas
Thyroid
Pituitary gland
Other endocrine organs

Question 24

Why do you not want to do phlebotomy to correct iron overload in Beta Thalassemia Major (you do it in Hemochromatosis)

Answer 24

Because in B-Thalassemia, you’re anemic…you DO NOT want to take out MORE blood cells from the body!

Question 25

CBC indicators of thalasemia

Answer 25

anemia, microcytic conditions, but normal levels of everything else

Question 26

How do you confirm alpha thalasemia with lab test?

Answer 26

you essentially have to first rule out beta thalasemia with a hemoglobin electrophoresis (bc beta thalasemia has elevated HgA2 and HgF) NO iron deficiency next, you can do PCR for a common mutation (Weir didn't specify which one) also in the US you're more likely to see this condition in African Americans

Question 27

How do you confirm suspicion of beta thalasemia?

Answer 27

anemia but no iron deficiency. | hemoglobin electrophoresis checking for elevated HgA2 and HgF

Question 28

Both thalassemia's are microcytic anemias. What lab value differentiates it from other microcytic anemias?

Answer 28

normal (or elevated) iron levels, normal levels of transferrin and ferritin, may have reduced hepcidin IF IRON OVERLOAD, but the MAIN THING: MCV<<<<70!

Question 29

Treatment option for Beta Thalassemia Major

Answer 29

iron chelating (bc of iron overload) chronic blood transfusions from a young age treat osteoporosis treat hypogonadism and other endocrine probz

Question 30

Are allogenic bone marrow transplants successful for thalasemia?

Answer 30

In young people yea!

Question 31

Which has a higher affinity for oxygen, HbA or HbH and Hb Bart's? What's the implication of this?

Answer 31

HbH and Hb Bart's have a higher affinity for oxygen. This is bad because they won't dump the oxygen into tissues like normal hemoglobin You get hypoxiaaa

Question 32

Do you get iron overload?

Answer 32

Not usually...so you don't get all the endocrine and organ problems as you do in beta thalassemia major

Question 33

Microcytic indication of Alpha Thalasemia that WONT be in Beta Thalassemia?

Answer 33

inclusion bodies of HgH (beta globin tetramers) in mature red cells ("golf ball cells" in peripheral blood

Question 34

Genetic cause for Sickle Cell Trait or Disease

Answer 34

point mutation on the 6th amino acid for B globulin, causing glutamic acid to change into valine (to have the disease you need point mutation in both chromosomes) 8% African Americans have the gene

Question 35

Pathogenesis of Sickle Cell Disease

Answer 35

mutated betahemoglobin molecules come together to form polymers, altering skeletal shape of the red blood cells. So they plug shit up and cause ischemic damage Plus, when you have infarctions of bones and other tissues, it is not just due to the clogging of vessels by sickled cells...it is also the resultant inflammatory damage by the white cells and the released nitric oxide (causing vascular spasm)

Question 36

Clinical Findings of Sickle Cells Disease

Answer 36

"Hand-foot syndrome" : Dactylitis in children-->epiphyseal infarction, leading to shortened digits Acute Chest Syndrome: due to fat embolization from the infarcted bone, can clog up pulmonary vessels, causing alveolar edema-->respiratory distress Skin necrosis and ulceration

Question 37

``` On an agar gel, what hemoglobin types would each of the following have a positive result for? Beta Thal. Sickle Cell Disease Sickle Cell Trait Hemoglobin C Normal ```

Answer 37

``` Beta thalassemia: elevation of A2 Sickle Cell :all S Sickle Cell Trait: elevated A and S (more A than S) Hb C: A and C Normal: A ```

Question 38

Clinical Presentation of S/Beta-thal 0?

Answer 38

You would have sickle cell anemia with increased hemoglobin A2 and hemoglobin F levels

Question 39

Sickle Cell Disease Therapy

Answer 39

Aggressively Hydrate Transfuse in certain life threatening situations (Severe anemia, hepatic crisis, acute chest syndrome, priapism, prophylactic transfusions in children with strokes) Pain control Oxygen if hypoxic

Question 40

What do you have to be worried about with chronic transfusions in sickle cell patients

Answer 40

They run an increased risk of developing antibodies to minor antigens in donor blood

Question 41

Mechanism of Action of Hydroxyurea treatment for Sickle Cell Anemia

Answer 41

Preventative treatment Inhibits ribonucleotide reductase It increases fetal hemoglobin and decreases white cells, this is for patients with recurrent crises, so you markedly diminish the crises by decreasing likelihood of flareups