Haemoglobin and Thalassaemia

Question 1

when does the synthesis of Hb begin?

Answer 1

• in RBC pro-erythroblast stage
• 65% in erythroblast stage
• 35% in reticulocyte stage

Question 2

where is haem/globin synthesized?

Answer 2

Haem - in mitochondria

Globin - in ribosomes

Question 3

describe the synthesis of haem?

Answer 3

• 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

Question 4

describe the synthesis of globin

Answer 4

amino acids are used in ribosomes to create globin chains

Question 5

what proteins are haem contained within?

Answer 5

• myoglobin

- cytochromes

Question 6

what is haem?

Answer 6

• combination of a proto-porphyrin ring

- and central ferrous

Question 7

how may functional globin chains are there

Answer 7

8 arranged in 2 clusters

Question 8

describe the beta cluster

Answer 8

beta, gamma, delta, epsilon

encoded on Chr 11, p-arm

Question 9

describe alpha cluster

Answer 9

alpha, zeta

encoded on Chr 16, p-arm

Question 10

describe levels of alpha (globin gene expression/switching)

Answer 10

made relatively early

stays high throughout

Question 11

describe levels of beta (globin gene expression/switching)

Answer 11

equal and opposite to gamma

becomes dominant after birth

Question 12

describe levels of gamma (globin gene expression/switching)

Answer 12

• equal and opposite to beta

- becomes dominate pre natal

Question 13

describe levels of delta

Answer 13

• production begins mid-natal

- remains low forever

Question 14

describe levels of epsilon and zeta

Answer 14

• equal and opposite to alpha

- levels drop to 0 after 8 weeks

Question 15

describe the Hb abundances

Answer 15

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%

Question 16

describe the primary structure of globin

Answer 16

alpha (141aa)

non-alpha globins (146aa)

Question 17

describe the secondary structure of globin

Answer 17

75% of alpha and beta chains show helical arrangement

Question 18

describe the tertiary globin structure

Answer 18

• approx sphere with a hydrophillic surface and a hydrophobic core
• contains a haem pocket

Question 19

when does Hb have the highest affinity for oxygen?

Answer 19

• when binding is loose
• cooperativity
• more oxygen means greater binding of oxygen
• 2,3-DPG made by muscle cells to inc. dissociation of oxygen

Question 20

what does the sigmoid shape of ODC allow?

Answer 20

greater unloading across a range of low pressures

Question 21

what does the position of ODC depend on?

Answer 21

• 2,3-DPG conc
• pH
• Co2 conc
• structure of Hb

Question 22

what would cause a right shift?

Answer 22

• high H+
• high 2,3-DPG
• high CO2
• HbS

Question 23

what are haemoglobinopathies?

Answer 23

• genetic disorder characterized by a defect of globin chain synthesis

Question 24

how is thalassaemia classified?

Answer 24

• globin type affected
• clinical severity: minor or trait, intermedia, major
• 4 alpha clusters in total but only 2 beta

Question 25

what is beta-thalassaemia?

Answer 25

autosomal recessive | deletion or mutation in beta-globin chains

Question 26

what is beta 0?

Answer 26

deletion of one beta globin encoding gene

Question 27

what is beta +?

Answer 27

mutation of one beta globin encoding gene

Question 28

what are the lab diagnosis characteristics of thalassaemia?

Answer 28

- FBC: microcytic hypochromia, inc. RBCs | - film: target cells, poikilocytosis but no anisocytosis

Question 29

what would you see in the levels of Hb in alpha thal?

Answer 29

normal HBA2 and HbF

Question 30

what would you see in the levels of Hb in beta thal?

Answer 30

raised HbA2 and HbF

Question 31

what is beta-thalassaemia trait?

Answer 31

- carrier trait | - often asymptomatic

Question 32

how is beta thala trait diagnosed?

Answer 32

- by blood film - shows macrocytic blood cells - raised HbA2 and HbF

Question 33

what is beta thalassaemia major?

Answer 33

- carry 2 abnormal copies of beta-globin gene - severe anaemia - require regular blood transfusions - clinical representation after 4-6 months

Question 34

what would you see on a blood film?

Answer 34

- anaemia - irregularly contracted cells - hypochromic cells - alpha chain precipitates - nucleated RBCs

Question 35

what is the clinical representation?

Answer 35

- severe anaemia after 4 months - hepatosplenomegaly - bone marrow - erythroid hyperplasia - hypochromia, poikilocytosis - extra medullary haematopoiesis

Question 36

what are the clinical features?

Answer 36

- chronic fatigue - failure to thrive - jaundice - late puberty - splenomegaly - skeletal deformity - iron overload

Question 37

what are the complications?

Answer 37

- cholelithiasis - biliary sepsis - cardiac/live failure - endocrinopathies

Question 38

what is the treatment?

Answer 38

- regular blood transfusions - iron chelation therapy - splenectomy - supportive medical care

Question 39

what are patients who have high iron content more prone to?

Answer 39

- yersinia infection | - other gram -ve infections

Question 40

when is iron chelation therapy started?

Answer 40

after 10-12 transfusions when serum ferritin >1000mcg/L audiology and opthalmology screening needed before starting

Question 41

what are the 3 forms of iron chelating drugs?

Answer 41

- DFO - Deferiprone - Deferasirox

Question 42

how do you monitor iron overload?

Answer 42

- serum levels of ferritin - liver biopsy - MRI T2 cardiac and hepatic - ferriscan

Question 43

what complication can beta thal be coinherited with?

Answer 43

- sickle beta thalassaemia | - HbE beta thalassaemia

Question 44

what is alpha thalassaemia?

Answer 44

- deletion/mutation in alpha globin genes - affected both foetus and adults --> alpha is in ALL globin variants - severity depends on no. of chains affected