Microcytic Anemias: Thalassemias Flashcards
alpha globin locus is on chromosome ____
beta globin locus is on chromosome ___
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)
thalassemia syndromes are inherited disorders of alpha or beta globin synthesis that lead to… (2)
- reduced alpha or beta globin synthesis
- excess accumulation of the unaffected chain
—> unpaired globin chains damage developing erythroblasts
single _______ allele is thought to protect against falciparum malaria
what is this genetic problem usually due to?
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
what is Hemoglobin H
beta4 globin tetramer of hemoglobin
when alpha globin is decreased, excess free beta globulin accumulates
less soluble than HbA
when there is no or low alpha globulin production in utero, what happens to hemoglobin?
excess free gamma globulin forms a tetramer (gamma4 tetramer) —> Bart’s hemoglobin (Hb Barts)
gamma4 tetramer behaves like myoglobin
less soluble than HbA
both HbH and HbBart’s can be detected by what molecular method?
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
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?
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
target cells (codocytes)
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)
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?
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
when does Hemoglobin H disease present? (in a patient’s lifetime)
remember that HbH is beta4 tetramer, causing moderate to severe anemia
presents right at birth
hydrops fetalis
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
heterozygotes for beta thalassemia are thought to be protective against
most lethal/severe form of malaria
beta-thalassemia minor:
beta+ / beta
OR
beta0 / beta
[note that beta+ means LESS beta globin made]
what is the normal/expected genotype of alpha globin vs beta globin
alpha (2 copies):
alpha alpha / alpha alpha
beta (1 copy):
beta / beta
alpha globin defects are caused by ______ while beta globin defects are caused by _____
alpha: gene deletion
beta: altered gene transcription or translation
what is the problem with excess alpha chains in beta thalassemia?
alpha chains do not form tetramers like beta chains
excess alpha chains just aggregate (insoluble) and cause destruction of RBC precursors in bone marrow