Thalassemias and Hemoglobinopathies

Question 1

HbC is common where?
Sickle cell?
HbE?

Answer 1

west africa
central africa
east Asia

Question 2

What globin chains are common in the fetus?

Answer 2

alpha and gamma (HbF) with very little beta. At birth this changes where gamma globin levels are replaced with beta globin (HbA)

Question 3

What is the composition of hemoglobin A2?

Answer 3

2 alpha and 2 delta

Question 4

HbF and HbA2 are increased in what disease?

Answer 4

b-thalassemia

Question 5

What is common in a-thalassemia?

Answer 5

Hgb H (small amounts of alpha chain remaining- most hemoglobin is only beta) or Hgb Bart’s (total absence of alpha chains)

Question 6

Symptoms of B-thalassemia?

Answer 6

expanded facial bony structure due to hematopoietic expansion in the bone marrow in those bones due to ineffective erythropoiesis

• hypercoagulability
• anemia
• hepatosplenomegaly
• ischemic ulcers
• splaying of teeth
• heart failure (from being chronically anemic)

Question 7

What is ineffective erythropoiesis?

Answer 7

as red cells are produced they are destroyed before they can leave marrow causing accumulation and expansion of bone marrow

Question 8

What is a common complication due to treatment of b-thalassemia with prbcs?

Answer 8

red blood cell products contain iron, so continuous transfusions (as is necessary in young patients to enhance growth) can lead to iron overload

causes endocrine dysfunction, heart failure, hemochromatosis, sex hormone maturation is delayed, hypothyroidism, diabetes, etc.

Question 9

How else besides too much iron via infusion can cause iron overload?

Answer 9

increased iron absorption- ineffective erythropoiesis causes decreased levels of hepcidin

When transferrin saturated, NTBI circulates and may be taken up by liver, heart and endocrine cells

Question 10

What happens to a-globin chains in b-thalassemia?

Answer 10

4 things:
1) excess a-globin form inclusion bodies leading to cell apoptosis and ineffective erythropoiesis

2) inclusion body formation stimulates immune removal via IgG and complement binding
3) Membrane damage increases rigidity leading to mechanical removal in the spleen
4) Membrane damage causes phosphatidylserine exposure leading to activation of prothrombinase complex leading to hyper coagulability

Question 11

How are thalassemia diagnosed?

Answer 11

family history, CBC, blood smear (shows stippling and target cells), physical exam, HPLC

Question 12

What will HPLC show in b-thalassemia?

Answer 12

elevated A2 or F hgb

Question 13

What will HPLC show in a-thalassemia?

Answer 13

Normal HPLC and iron levels.

Disproportionately elevated RBC as compared to Hgb, very low mcv with normal ferritin.

Must use other tests:
PCR (known mutation)
Restriction Fragment Length Polymorphism Analysis (unknown mutation)

Question 14

Treatment of b-thalassemia?

Answer 14

supportive therapy- transfusion to keep hemoglobin above 9 during development, (iron chelated therapy to relieve excess iron)

vitamin D to keep bones strong and hormone replacement for endocrinopathies

allogeneic bone marrow transplant can cure disease but not common

Question 15

Where are a-globin genes found?

Answer 15

chromosome 16 (beta on 11)

Question 16

Zero a-globin genes leads to what?

Answer 16

hydrops fetalis- death at birth usually. Have four gamma chains

Question 17

One a-globin gene leads to what?

Answer 17

HbH disease with precipitated beta globin tetramers as red cells age.

Question 18

Why is HbH more consistent with hemolytic anemia than an ineffective erythropoiesis?

Answer 18

many cells make it out of bone marrow

Question 19

Symptoms of HbH?

Answer 19

hypersplenism in 10%, leg ulcers, and gallstones

rarely need transfusions or splenectomy or iron overload

Question 20

What is Hgb E?

Answer 20

type of b-thalassemia caused by a point mutation in the beta globin gene leading to unstable messenger RNA

Question 21

What is Hgb Lepore?

Answer 21

type of b-thalassemia where delta/beta fusion occurs with marked decreased non-alpha chains

Question 22

What is hereditary persistence of fetal hemoglobin?

Answer 22

type of b-thalassemia with marked decrease in beta chain formation compensated by marked increased F hub

Question 23

What is Hgb constant spring?

Answer 23

type of a-thalassemia caused by a base substitution of terminal codon in the alpha gene causing reduced alpha gene levels

Question 24

What causes sickle cell anemia?

Answer 24

substitution of valine for glutamine in b-globin gene

common in 8% of AA (1 in 625 are homozygous)

Question 25

What happens in sickle cell anemia?

Answer 25

In decreased oxygen situations, hemoglobin chains aggregate

Question 26

Symptoms of sickle cell anemia?

Answer 26

Vascular occlusion resulting in:

• Pain crises
• Strokes
• Bone infarction
• Ischemic ulcers (decreased blood flow to skin)
• Acute chest syndrome
• Hepatopathy
• Priapism

Anemia resulting in:

• Heart failure
• Generalized weakness
• Iron overload

Question 27

How else does sickle cell disease cause tissue damage besides damage?

Answer 27

1) increased levels of white cells that increase inflammation
2) reduction of NO via free hemoglobin interaction

Question 28

What is common in small children with sickle cell?

Answer 28

dactylitis leading to shortening of digits

Question 29

How do you diagnose sickle cell?

Answer 29

HPLC/electrophoresis

Question 30

How is sickle cell treated?

Answer 30

hydroxyurea to remove methyl groups to increase HgF

prevent things that lead to sickling- infection, fever, dehydration, hypoxemia, acidosis

aggressively hydrate

transfusion in certain life threatening situations

pain control

oxygen if hypoxic