The Haemoglobin Molecule and Thalassaemia COPY

Question 1

What is the role of red blood cells, what is it’s normal concentration and what does it contain

Answer 1

Carrys oxygen from lungs to tissue and CO2 from tissue to lungs
3.5-5 x 10^12/L
Contains haemoglobin (each cell= 640mil molecule)
No nucleus or mitochondria

Question 2

Describe haemoglobin

Where is haemoglobin found, what is its normal concentration and how much is produced/destroyed every day

Answer 2

Found only in RBCs
normal conc. = 120-165g/L
Approx 90mg/kg produced and destroyed in the body every day

Question 3

When does haemoglobin synthesis occur

Answer 3

During development of RBC and begins in pro-erythroblast
65% erythroblast stage
35% reticulocyte

Question 4

Describe the structure of haemoglobin

Answer 4

4 polypeptide subunits of 2 alpha chains and 2 beta chains with a prosthetic haem group
4 haem+4 globin chains = 1 Hb molecule

Question 5

Describe the synthesis of haemoglobin

Answer 5

haem - mitochondria

global - ribosomes

Question 6

Describe the structure of haem

Answer 6

Same in all types of Hb
Combination of protoporphyrin ring with central iron atom (ferroprotoporphyrin)
Iron is usually in the ferrous form (Fe2+)
Able to reversibly bind to oxygen

Question 7

Where else may haem been found

Answer 7

myoglobin
cytochromes
peroxides
catalase
tryptophan

Question 8

Describe the synthesis of haem

Answer 8

Mainly in the mitochondria which contains the ALAS enzyme
more haem made = -ive feedback on enzyme activity
Iron is brought to the mitochondria (via transferrin) for haem synthesis

Question 9

When are the genes coding for the globin in foetal haemoglobin switched off?

Answer 9

It is decreased towards birth and in the first year after birth.
After 1 year of life, the normal adult pattern of haemoglobin synthesis would have been established.

Question 10

Describe the global gene clusters

Answer 10

Eight functional globin chains, arranged in two clusters:
beta - cluster (b, g, d and e globin genes) on the short arm of chromosome 11
alpha- cluster (a x2 and z globin genes) on the short arm of chromosome 16

Question 11

Describe the gene expression and switching of globin

Answer 11

Main site of RBC production at first is the yolk sac, then liver, then spleen
After birth, main production is the bone marrow
1. zeta and epsilon globin chains immediately
2. switch to alpha and gamma (3-6 months of life)
3. Then alpha and beta
Little delta globin synthesis

Question 12

What makes up Hb A and what is the normal percentage

Answer 12

alpha2,beta2

96-98%

Question 13

What makes up Hb A2 and what is the normal percentage

Answer 13

alpha2,delta2

1.5-3.2%

Question 14

What makes up Hb F and what is the normal percentage

Answer 14

alpha2,g2

0.5-0.8%

Question 15

Describe the secondary structure of globin

Answer 15

75% alpha and beta chains in helical arrangement

Question 16

Describe the tertiary structure of globin

Answer 16

approx sphere
Hydrophilic surface (charged polar side chains) and a hydrophobic core
Haem pocket

Question 17

Describe the oxygen-haemoglobin dissociation curve

Answer 17

Sigmoid shape
Binding of one molecule facilitate the second molecule binding (cooperativity)
P 50 (partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg

Question 18

What does position of the Hb-oxygen dissociation curve depend on

Answer 18

Concentration of 2,3-DPG
H+ ion concentration (pH)
CO2 in red blood cells
Structure of Hb

Question 19

What causes right shift on the oxygen-dissociation curve

Answer 19

High 2,3-DPG
High H+
High CO2
HbS

Question 20

What causes left shift on the oxygen-dissociation curve

Answer 20

Low 2,3-DPG
Low H+
Low CO2
HbF

Question 21

What are haemoglobinopathies

Answer 21

Structural variants of haemoglobin
or
Defects in globin chain synthesis (thalassaemia)

Question 22

Describe beta thalassaemia and where it is prevalent

Answer 22

Deletion or mutation in beta globin gene(s)
Reduced or absent production of b globin chains

Mainly Mediterranean countries (Greece, Cyprus, Southern Italy).

Question 23

Explain how beta thalassaemia is inherited

Answer 23

Autosomal recessive

Carriers are aymsymptomatic but to have microcytic hypo chromic indicies

Question 24

What investigations should be done for thalassaemia

Answer 24

FBC
Rilm
Hb EPS/HPLC
Globin chains synthesis/ DNA studies

Question 25

What causes thalassaemia major, what does it result in and when does it clinically present

Answer 25

2 abnormal copies of the beta globin gene Severe anaemia, incompatible with life without regular blood transfusions Clinical presentation usually after 4-6 months of life

Question 26

What will show on the film for a beta thalassaemia major

Answer 26

Extreme hypochromia Microcytosis Poikilocytosis Howell jolly bodies and nucleated RBCs (from splenectophy and hyper plastic bone marrow)

Question 27

Which are the 2 major inclusion bodies seen in beta thalassaemia

Answer 27

``` Alpha globin precipitates Pappenheimer bodies (Perls stain - inky blue granules) ```

Question 28

Describe the clinical presentation of thalassaemia major

Answer 28

(after 4. months) Hepatosplenomegaly Facial changes, frontal bossing and thickening of maxillary bones (Bone marrow - erythroid hyperplasia) Extra-medullary haematopoiesis (spleomegally)

Question 29

What are the clinical features of beta thalassaemia

Answer 29

``` Chronic fatigue Failure to thrive Jaundice Delay in growth and puberty Skeletal deformity Splenomegaly Iron overload ```

Question 30

What are some complications of beta thalassamia

Answer 30

Cholelithiasis and biliary sepsis (gall stone formation) Cardiac failure Endocrinopathies Liver failure

Question 31

What is the treatment for thalassaemia major

Answer 31

``` Regular blood transfusions Iron chelation therapy (Splenectomy Supportive medical care Hormone therapy Hydroxyurea to boost HbF Bone marrow transplant) ```

Question 32

Describe the transfusions needed for thalassaemia major treatment

Answer 32

Phenotyped red cells Aim for pre-transfusion Hb 95-100g/L Regular transfusion 2-4 weekly If high requirement, consider splenectomy

Question 33

Describe the management of infection for thalassaemia major treatment

Answer 33

Yersinia Other gram negative sepsis (infections thrive in iron overload) Prophylaxis in splenectomised patients - immunisation and antibiotics

Question 34

Describe iron chelation therapy

Answer 34

Start after 10-12 transfusions or when serum ferritin >1000 mcg/l Audiology and ophthalmology screening prior to starting due to toxicity of iron removing drugs

Question 35

What are the types of iron chelation therapies

Answer 35

Deferasirox (Exjade) Desferrioxamine (deferral) Deferiprone (ferriprox)

Question 36

Describe Deferasirox (Exjade)

Answer 36

Oral Dose 20-40mg/kg unwanted effects: rash, GI symptoms, hepatitis, renal impairment

Question 37

Describe desferrioxamine

Answer 37

Sc infusion 8-12 hours 5-7 days per week (or IV in cardiac iron overload) Dose 20-50 mg/kg/day Compliance Vitamin C

Question 38

What are the unwanted effects of desferrioxamine

Answer 38

``` Vertebral dysplasia pseudo-rickets genu valgum retinopathy high tone sensorineural loss increased risk of Klebsiella and Yersinia infection ```

Question 39

Describe deferiprone and its unwanted effects

Answer 39

Oral Dose 5-100 mg/kg/day Effective in reducing myocardial iron Unwanted effects: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy

Question 40

What are the advantages and disadvantages of desferrioaxamine

Answer 40

2 decades experience Survival benefit Heart failure prevented and recersed ``` Parenteral administration (limits compliance) Toxicity (dose-dependent) - ocular, auditory, skeletal ```

Question 41

What are the advantages and disadvantages of deferiprone

Answer 41

Oral administration Cardiac protection Frequency of administration is high due to short plasma half life Unpredictable control of body iron toxicity - agranulocytosis, arthropathy, zinc deficiency

Question 42

What are the advantages and disadvantages of deferasirox

Answer 42

Oral admin Once daily Control of body iron specific Short clinical experience Cardiac protection uncertain toxicity limited but little data

Question 43

How is serum ferritin used to monitor iron overload

Answer 43

>2500 associated with significantly increased complications Acute phase protein Check every 3 months if transfused, otherwise annually

Question 44

How may a MRI be used for iron overload monitoring

Answer 44

Cardiac and hepatic MRIs <20ms = increased risk of impaired LF function Check annually or 3-6 monthly if cardiac dysfunction

Question 45

How may a ferriscan be used to monitor iron overload

Answer 45

``` R2 MRI Non-invasive quantitation of LIC Not affected by inflammation or cirrhosis <3mg/g normal >15mg/g associated with cardic disease Check annually or 6monthly if result >20 ```

Question 46

What would be seen in a blood film for sickle beta thalassamia

Answer 46

``` Sickled cells Target cells Microcytosis Hypochromia (As little or no HbA is being produced, HbS will be the dominant haemoglobin and will precipitate as it does in homozygote sickle cell patients) ```

Question 47

Describe HbE beta thalassaemia

Answer 47

Very common combo in south east Asia | Variable in expression - may be as severe as beta thalassaemia major

Question 48

Describe alpha thalassaemia

Answer 48

deletion or mutation in alpha globin genes Reduced or absent production of a globin chains Affects both foetus and adult Excess beta and gamma chains form tetramers of HbH and Hb Barts respectively Severity depends on number of alpha globin genes affected

Question 49

What is special about alpha globin genes

Answer 49

There are TWO alpha globin genes from each parent so there are FOUR alpha globin genes in total.