Haemoglobin and Thalassaemia Flashcards
when does the synthesis of Hb begin?
- in RBC pro-erythroblast stage
- 65% in erythroblast stage
- 35% in reticulocyte stage
where is haem/globin synthesized?
Haem - in mitochondria
Globin - in ribosomes
describe the synthesis of haem?
- transferrin transports ferrous to RBC
- or ferrous is liberated from ferritin
- delta-ALA undergoes few moderations outside mitcocondria
- passes back in as proto-porphyrin
- proto-porphyrin –> haem
describe the synthesis of globin
amino acids are used in ribosomes to create globin chains
what proteins are haem contained within?
- myoglobin
- cytochromes
what is haem?
- combination of a proto-porphyrin ring
- and central ferrous
how may functional globin chains are there
8 arranged in 2 clusters
describe the beta cluster
beta, gamma, delta, epsilon
encoded on Chr 11, p-arm
describe alpha cluster
alpha, zeta
encoded on Chr 16, p-arm
describe levels of alpha (globin gene expression/switching)
made relatively early
stays high throughout
describe levels of beta (globin gene expression/switching)
equal and opposite to gamma
becomes dominant after birth
describe levels of gamma (globin gene expression/switching)
- equal and opposite to beta
- becomes dominate pre natal
describe levels of delta
- production begins mid-natal
- remains low forever
describe levels of epsilon and zeta
- equal and opposite to alpha
- levels drop to 0 after 8 weeks
describe the Hb abundances
HbA (alpha 2, beta 2) - 96-98%
HbA2 (alpha 2, delta 2) - 1.5-3.2%
HbF (alpha 2, gamma 2) - 0.5-0.8%
describe the primary structure of globin
alpha (141aa)
non-alpha globins (146aa)
describe the secondary structure of globin
75% of alpha and beta chains show helical arrangement
describe the tertiary globin structure
- approx sphere with a hydrophillic surface and a hydrophobic core
- contains a haem pocket
when does Hb have the highest affinity for oxygen?
- when binding is loose
- cooperativity
- more oxygen means greater binding of oxygen
- 2,3-DPG made by muscle cells to inc. dissociation of oxygen
what does the sigmoid shape of ODC allow?
greater unloading across a range of low pressures
what does the position of ODC depend on?
- 2,3-DPG conc
- pH
- Co2 conc
- structure of Hb
what would cause a right shift?
- high H+
- high 2,3-DPG
- high CO2
- HbS
what are haemoglobinopathies?
- genetic disorder characterized by a defect of globin chain synthesis
how is thalassaemia classified?
- globin type affected
- clinical severity: minor or trait, intermedia, major
- 4 alpha clusters in total but only 2 beta
what is beta-thalassaemia?
autosomal recessive
deletion or mutation in beta-globin chains
what is beta 0?
deletion of one beta globin encoding gene
what is beta +?
mutation of one beta globin encoding gene
what are the lab diagnosis characteristics of thalassaemia?
- FBC: microcytic hypochromia, inc. RBCs
- film: target cells, poikilocytosis but no anisocytosis
what would you see in the levels of Hb in alpha thal?
normal HBA2 and HbF
what would you see in the levels of Hb in beta thal?
raised HbA2 and HbF
what is beta-thalassaemia trait?
- carrier trait
- often asymptomatic
how is beta thala trait diagnosed?
- by blood film
- shows macrocytic blood cells
- raised HbA2 and HbF
what is beta thalassaemia major?
- carry 2 abnormal copies of beta-globin gene
- severe anaemia
- require regular blood transfusions
- clinical representation after 4-6 months
what would you see on a blood film?
- anaemia
- irregularly contracted cells
- hypochromic cells
- alpha chain precipitates
- nucleated RBCs
what is the clinical representation?
- severe anaemia after 4 months
- hepatosplenomegaly
- bone marrow
- erythroid hyperplasia
- hypochromia, poikilocytosis
- extra medullary haematopoiesis
what are the clinical features?
- chronic fatigue
- failure to thrive
- jaundice
- late puberty
- splenomegaly
- skeletal deformity
- iron overload
what are the complications?
- cholelithiasis
- biliary sepsis
- cardiac/live failure
- endocrinopathies
what is the treatment?
- regular blood transfusions
- iron chelation therapy
- splenectomy
- supportive medical care
what are patients who have high iron content more prone to?
- yersinia infection
- other gram -ve infections
when is iron chelation therapy started?
after 10-12 transfusions
when serum ferritin >1000mcg/L
audiology and opthalmology screening needed before starting
what are the 3 forms of iron chelating drugs?
- DFO
- Deferiprone
- Deferasirox
how do you monitor iron overload?
- serum levels of ferritin
- liver biopsy
- MRI T2 cardiac and hepatic
- ferriscan
what complication can beta thal be coinherited with?
- sickle beta thalassaemia
- HbE beta thalassaemia
what is alpha thalassaemia?
- deletion/mutation in alpha globin genes
- affected both foetus and adults –> alpha is in ALL globin variants
- severity depends on no. of chains affected
