Microcytic Anemias: Thalassemias

Question 1

alpha globin locus is on chromosome ____

beta globin locus is on chromosome ___

Answer 1

alpha globin - chr. 16, 2 copies
(zeta is also found here)

beta globin - chr. 11, only 1 copy
(epsilon, gamma, and delta globin is also found here)

*embryonic: zeta and epsilon
*fetal: alpha and gamma
*adult: alpha and beta (small amount alpha and delta)

Question 2

thalassemia syndromes are inherited disorders of alpha or beta globin synthesis that lead to… (2)

Answer 2

1. reduced alpha or beta globin synthesis
2. excess accumulation of the unaffected chain

—> unpaired globin chains damage developing erythroblasts

Question 3

single _______ allele is thought to protect against falciparum malaria

what is this genetic problem usually due to?

Answer 3

alpha-thalassemia: single gene deletion is asymptomatic (silent carrier)

(should have 2 alleles)

*note that alpha globin problem is usually due to gene deletion:
- alpha / alpha alpha (most common)
OR
- - / alpha alpha
OR
- alpha / - alpha
OR
- - / - alpha

Question 4

what is Hemoglobin H

Answer 4

beta4 globin tetramer of hemoglobin

when alpha globin is decreased, excess free beta globulin accumulates

less soluble than HbA

Question 5

when there is no or low alpha globulin production in utero, what happens to hemoglobin?

Answer 5

excess free gamma globulin forms a tetramer (gamma4 tetramer) —> Bart’s hemoglobin (Hb Barts)

gamma4 tetramer behaves like myoglobin

less soluble than HbA

Question 6

both HbH and HbBart’s can be detected by what molecular method?

Answer 6

HbH: beta4 tetramer
HbBart’s: gamma4 tetramer (in utero)

both can be detected via electrophoresis:
Hb H travels farther than > Hb Bart’s, which travels farther than > HbA

Question 7

what alpha-globulin genotype(s) would you suspect for a patient with near-normal hemoglobin, normal RDW (RBC are uniform in size), but significant microcytosis (low MCV) and target cells?

Answer 7

basically mild anemia with small cells

target cells: bump in the middle of RBC due to less hemoglobin

likely a 2 gene deletion of alpha thalassemia

either:
- alpha / - alpha
OR
- - / alpha alpha

Question 8

target cells (codocytes)

Answer 8

RBC with bump in the middle (instead of concave)

excess RBC membrane compared to hemoglobin content

due to low hemoglobin (thalassemia) or increased membrane (splenectomy - don’t have a spleen)

Question 9

what alpha globin genotype would you suspect for a patient with moderate-to-severe anemia, HbH present, significant microcytosis (low MCV) and target cells present?

Answer 9

likely 3 gene deletion of alpha globin (- - / - alpha)

remember that HbH is beta4 tetramers —> makes RBC fragile and leads to RBC lysis

*when beta4 tetramers are stained (oxidant), they look like many small blue dots

Question 10

when does Hemoglobin H disease present? (in a patient’s lifetime)

Answer 10

remember that HbH is beta4 tetramer, causing moderate to severe anemia

presents right at birth

Question 11

hydrops fetalis

Answer 11

4 gene deletion in alpha globin (genotype is - - / - -)

gamma4 tetramers (Hb Bart’s) - behave like myoglobin —> does not release oxygen to tissues (affinity is too high), also causes RBC fragility (new RBC produced are destroyed)

not compatible with life

Question 12

heterozygotes for beta thalassemia are thought to be protective against

Answer 12

most lethal/severe form of malaria

beta-thalassemia minor:
beta+ / beta
OR
beta0 / beta

[note that beta+ means LESS beta globin made]

Question 13

what is the normal/expected genotype of alpha globin vs beta globin

Answer 13

alpha (2 copies):
alpha alpha / alpha alpha

beta (1 copy):
beta / beta

Question 14

alpha globin defects are caused by ______ while beta globin defects are caused by _____

Answer 14

alpha: gene deletion

beta: altered gene transcription or translation

Question 15

what is the problem with excess alpha chains in beta thalassemia?

Answer 15

alpha chains do not form tetramers like beta chains

excess alpha chains just aggregate (insoluble) and cause destruction of RBC precursors in bone marrow

Question 16

what kind of thalassemia does the following describe:
- asymptomatic or mild anemia
- normal or high RBC count
- microcytosis and low MCH
- target cells
- increased hemoglobin A2 (seen in electrophoresis)
- serum iron, ferritin, and transferrin saturation may all be increased

Answer 16

beta-thalassemia minor (heterozygous)

note that increased Hgb A2 (alpha-delta) is due to alpha aggregates

remember ferritin reflects iron storage (they have iron, but it’s not being used to make hemoglobin)

Question 17

Cooley’s anemia

when does it present, and why?

Answer 17

beta-thalassemia major (beta+/0 / beta0)

little to no HbA production, hemolysis —> high EPO

life-long transfusion dependent anemia

at birth, plenty of alpha2/gamma2, so symptoms begin ~6-9 months (late infancy - when you would expect adult hemoglobin HbA to take over)

Question 18

what are the consequences (2) of high EPO production in beta thalassemia major (Cooley’s anemia)? describe physical manifestations

Answer 18

little to no HbA production and hemolysis —> EPO production

too much EPO causes:
1. bone marrow expansion - skeletal deformities —>
develop maxillary bone hyperplasia, frontal bossing (forehead is larger), protrusion of teeth, long bones are fragile, “hair on end” appearance of skull in x-ray
2. extramedullary hematopoiesis - spleen, liver, lymph nodes —>
hepatosplenomegaly

Question 19

what will you seen on electrophoresis at birth for a patient with beta thalassemia major (Cooley’s anemia)?

Answer 19

only hemoglobin F (fetal - alpha/gamma)

not HbA being made

larger portion of HbA2 (alpha/delta)

Question 20

patients with beta thalassemia major (Cooley’s anemia) are transfusion-dependent for life (every 2-4 weeks)

what does this put them at risk for?
what can be done about it?

Answer 20

iron overload (we regulate iron through absorption, not through excretion) —> free iron circulates (toxic)

—> hepatomegaly, cirrhosis (liver), hypogonadism, insulin resistance, early heart failure

treat with iron chelation: deferoxamine (IV) and deferiprone (oral) - binds iron so it can be excreted in urine

Question 21

how are deferoxamine (IV) and deferiprone (oral) used for patients with beta thalassemia major?

Answer 21

iron chelation due to iron overload from frequent blood transfusions

bind iron so it can be excreted in urine

Question 22

how do the following compare in iron deficiency anemia vs beta thalassemia minor?
a. RBC count
b. RDW
c. serum iron
d. serum ferritin
e. transferrin (TIBC)
f. transferrin saturation

Answer 22

iron deficiency:
a. RBC count: LOW
b. RDW: HIGH
c. serum iron: LOW
d. serum ferritin: LOW
e. transferrin (TIBC): HIGH
f. transferrin saturation: LOW

beta thalassemia minor:
a. RBC count: HIGH (more RBC being made)
b. RDW: normal
c. serum iron: normal or HIGH
d. serum ferritin: normal or HIGH
e. transferrin (TIBC): normal or LOW
f. transferrin saturation: normal or HIGH