Microcytic Anemias: Thalassemias Flashcards

1
Q

alpha globin locus is on chromosome ____

beta globin locus is on chromosome ___

A

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)

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2
Q

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

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

—> unpaired globin chains damage developing erythroblasts

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3
Q

single _______ allele is thought to protect against falciparum malaria

what is this genetic problem usually due to?

A

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

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4
Q

what is Hemoglobin H

A

beta4 globin tetramer of hemoglobin

when alpha globin is decreased, excess free beta globulin accumulates

less soluble than HbA

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5
Q

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

A

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

gamma4 tetramer behaves like myoglobin

less soluble than HbA

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6
Q

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

A

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

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7
Q

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?

A

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

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8
Q

target cells (codocytes)

A

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)

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9
Q

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?

A

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

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10
Q

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

A

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

presents right at birth

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11
Q

hydrops fetalis

A

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

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12
Q

heterozygotes for beta thalassemia are thought to be protective against

A

most lethal/severe form of malaria

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

[note that beta+ means LESS beta globin made]

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13
Q

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

A

alpha (2 copies):
alpha alpha / alpha alpha

beta (1 copy):
beta / beta

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14
Q

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

A

alpha: gene deletion

beta: altered gene transcription or translation

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15
Q

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

A

alpha chains do not form tetramers like beta chains

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

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16
Q

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

A

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)

17
Q

Cooley’s anemia

when does it present, and why?

A

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)

18
Q

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

A

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

19
Q

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

A

only hemoglobin F (fetal - alpha/gamma)

not HbA being made

larger portion of HbA2 (alpha/delta)

20
Q

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?

A

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

21
Q

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

A

iron chelation due to iron overload from frequent blood transfusions

bind iron so it can be excreted in urine

22
Q

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

A

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