Hemoglobinopathies

Question 1

What is the structure of a hemoglobin molecule?

Answer 1

two alpha globin chains
two beta globin chains
iron-porphyrin complexes conjugated to each globin chain

Question 2

Which forms of hemoglobin are present in the fetal stage?

Answer 2

alpha and gamma

Question 3

What forms of hemoglobin are present at the newborn stage?

Answer 3

75% HbF (composed of two alpha chains and two gamma chains) and 25% HbA (composed of two alpha chains and two beta chains)

Question 4

What is the pathophysiology of thalassemias?

Answer 4

alpha and beta globin subunits are unbalanced; excess subunits are toxic and result in damage to erythrocyte precursors and therefore ineffective erythropoiesis

Question 5

What is each different number of functional alpha globin subunits called?

Answer 5

only 3 functional: carrier
2 functional: alpha thalassemia minor
1 functional: HbH disease
1 functional in cis with a point mutation: thalassemia intermedia
0 functional: hemoglobin Bart’s hydrops fetalis

Question 6

What are some complications of thalassemia?

Answer 6

-frontal bossing with prominent cheekbones due to the accumulation of bone marrow
-growth failure
-massive splenomegaly
-iron overload that can lead to cirrhosis, cardiomyopathy, diabetes, growth failure, and other hormonal disturbances

Question 7

What treatments are available for thalassemia?

Answer 7

-transfusions as needed
-iron chelation to eliminate excess iron
-bone marrow transplantation
-TGFbeta signaling inhibitor
-gene therapy (experimental)

Question 8

How does sickle cell relate to solubility?

Answer 8

it has reduced solubility when deoxygenated, causing it to polymerize (become sticky and clumps together)

Question 9

What are some genetic modifiers of sickle cell disease?

Answer 9

alpha thalassemia trait: decreases severity by increasing competition between beta globin chains
BCL11A: transcription factor importance in silencing gamma globin
if gamma level is over 10%, severity of disease is much lower

Question 10

What are the therapeutic options for sickle cell disease?

Answer 10

hydroxyurea to induce gamma globin
blood transfusion to reduce sickle RBC fraction
bone marrow transplantation to replace hematopoietic stem cells

Question 11

What are some complications of stem cell transplantation for those with sickle cell disease?

Answer 11

Chronic graft vs host disease
infertility
organ toxicity
graft failure

Question 12

What are the characteristics of methemoglobinemia?

Answer 12

iron is reduced to Fe3+ state and cannot carry oxygen, resulting in pseudocyanosis but no real symptoms
Typically due to mutations in cytochrome b reductase or exposure to drugs or toxins or neonatal dehydration