Haemaglobinopathy

Question 1

what is tetramer made up of

Answer 1

2 alpha global like chains and 2 beta global like chains

Question 2

how many haem groups attach to a global chain

Answer 2

1:1

Question 3

what are the major forms of hb

Answer 3

HbA - 2 alpha 2 beta
HbA2 - 2 alpha, 2 delta
HbF - 2 alpha, 2 gamma

Question 4

what are the commonest forms of hb

Answer 4

HbA - 97%
HbA2 2.5%
HbF 0.5%

Question 5

genetic control of alpha like genes

Answer 5

on chromosome 16

2 alpha genes per chromosome and 4 per cell

Question 6

genetic control of beta like genes

Answer 6

chromosome 11

one beta gene per chromosome - 2/cell

Question 7

when does expression of global genes change

Answer 7

through embryonic life and childhood

Question 8

how are genes arranged

Answer 8

in order of expression

Question 9

which genes in embryo

Answer 9

chromosome 16 - gower1, portland, gower 2

Question 10

foetal hb

Answer 10

hbf

Question 11

adults hb

Answer 11

hba2

hba

Question 12

when are adult levels reached

Answer 12

by 6-12 months of age

Question 13

what are haemoglobinopathies

Answer 13

heredity conditions affecting global chain synthesis

autosomal recessive

Question 14

what are the two main groups pf hbp

Answer 14

thalassaemia - decreased rate of global chain synthesis

structural hb varients - normla production of structural abnormal global chain leading to variant hb such as HbS

Question 15

types of thalassaemias

Answer 15

alpha thalassaemia - alpha chains affected

beta - beta chains affected

Question 16

what does thalassaemia lead to

Answer 16

inadequate hb procuditon leading to microcytic hypochromin anaemia

unbalanced accumulation of global chains leading to ineffective erythropoiesis and haemolysis

Question 17

why are thalassaemias important

Answer 17

commonest monogenic disorders
major cause of morbidity
becoming more common in the uk

Question 18

why is thalassaemia more prevalent in certain areas

Answer 18

selective pressure in malaria endemic areas has allowed these mutations to flourish

Question 19

what happens during alpha thalassaemia

why

which hb is affected

Answer 19

reduced of absence of synthesis of alpha chain

deletion of one or both alpha genes from chromosome 16

alpha chains present in all adult forms of hb are effected - hba, hba2, hbf

Question 20

classification of alpha thalaaaemia

Answer 20

unaffected have 4 normal alpha genes

alpha thal trait - one of two genes missing

HbH disease - only one alpha left

Hb Barts hydrops fetales - no functional alpha genes

Question 21

alpha trait 
symp
rx
signs
why is it important

Answer 21

–/aa or -a/-a
asymp

no rx needed

microcytic hypo chromic red cells with mild anaemia

important as can be mistaken for iron defic but ferratin normal and red blood cell count raised

Question 22

HbH dx
what is it 
chain production 
outcome 
what can be seen on a stain

Answer 22

severe form of alpha thalaeeaemia

only one alpha gene per cell so –/-a

alpha chain production is <30% than normal

anaemia with low MCV and MCH
excess beta chains form tetramers beta4 called HbH which can’t carry oxygen

red cell inclusions (HbH bodies) can be seen w special stains

Question 23

clinical features of HbH dx

Answer 23

mild anaemia -> transfusion dependant
splenomegaly due to extramedullary haemtopoiesis
jaundice due to haemolytic and inffecetive erythropoiesis
growth retardation
gallstones
iron overload
severe cases - splenectomy+/- transfusion

Question 24

where is HbH common

Answer 24

middle east
SE asia
mediterranaean

Question 25

Hb Barts hydrops fetales synd

Answer 25

severest form of alpha thallassaemia no a genes inherited (--/--) minimal or no alpha chain production -? HbA can't be made

Question 26

clinical features of Barts

Answer 26

``` severe anaemia cardiac failure, oedema growth retardation severe hepatosplenomegaly skeletal and cardiovascular abnormalities most die in utero ```

Question 27

b thalassaemia is what caused by what how many mutations have been identified so far

Answer 27

reduced or absent beta chain production only beta chains so only HbA affected usually caused by point mutations over 200 so far

Question 28

classification of BT

Answer 28

beta thalassaemia trait - asymp, no or mild anaemia, low MCV and MCH betal thallasaemia intermdiate - mod serverity requiring occasional transfusion beta thalassaemia major- severe life long transfusion dependency

Question 29

lab features of beta thal major

Answer 29

severe anaemia reticulocytosis, very low MCV/MCH film: microcytosis, hypochromia, anisopoikilocytosis and target cells HPLC: mainly HbF present small amounts of HbA

Question 30

clinical features of beta thal major

Answer 30

presents aged 6-24 months failure to thrive pallor extra medullary haemopoiesis causing: hepatosplenomegaly, skeletal damage, organ damage, cord compression

Question 31

management of beta thal major

Answer 31

regular transfusion programme to maintain Hb at 95-105g/l to suppress ineffective erythropoiesis and inhibit over absorption of iron allows for relatively normal growth and development iron overload from transfusion then becomes the main cause of mortality bone marrow transplant can be an option if carried out before complications develop

Question 32

clinical features of beta thal major

Answer 32

presents aged 6-24 months failure to thrive pallor extra medullary haemopoiesis causing: hepatosplenomegaly, skeletal damage, organ damage, cord compression

Question 33

management of beta thal major

Answer 33

regular transfusion programme to maintain Hb at 95-105g/l to suppress ineffective erythropoiesis and inhibit over absorption of iron allows for relatively normal growth and development iron overload from transfusion then becomes the main cause of mortality bone marrow transplant can be an option if carried out before complications develop

Question 34

consequences of iron overload

Answer 34

endocrine dysfunction - impaired growth and pubertal development, DM, osteoporosis cardiac - cardiomyopathy, arrhythmias liver dx - cirrhosis, herpatocellular cancer

Question 35

management of iron overload

Answer 35

250mg of iron per unit of red cells chronic anaemia -> increased absorption of iron from gut venesection not feasible as already anaemic chelators bind to iron, complexes formed excreted in urine or stool

Question 36

what is the natural mechanism for iron excretion

Answer 36

there is none

Question 37

other transfusion related complications

Answer 37

viral infection - HIV, hep B and C alloantibodies - hard to crossmatch suitable blood transfusion reactions increased risk of bacterial sepsis as bacteria like iron

Question 38

diagnosis of thalassaemia

Answer 38

thal trait usually suspected form red cell indices and ethnic origin - exclude iron defic first blood film: hypochromia, target cells, anisopoikilocytosis HPLC: Hba, Hba2, Hbf, abnormal hb, raised Hba2 diagnostic for beta thal - will be normal in alpha thal so DNA testing needed to confirm

Question 39

screening for haemoglobinopathies

Answer 39

antenatal screening to identify carriers | newborn screening programme for couple at risk