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Haematology > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

structure of haemoglobin?

A

tetramer made of 2 alpha globin like chains and 2 beta globin like chains
one haem group attached to each globin chain

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2
Q

what do globin chains do?

A

keep haem soluble and protect haem from oxidation

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3
Q

what are the major forms of Hb?

A

HbA (2 alpha chains and 2 beta chains)
HbA2 (2 alpha and 2 delta chains)
HbF (2 alpha and 2 gamma chains)

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4
Q

which Hb is the major form present in adults?

A 
HbA = 97%
HbA2 = 2.5%
HbF = 0-0.5%
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5
Q

genetic control of globin chain production?

A

alpha like genes = chromosome 16 (2 alpha genes per chromosome, 4 per cell)
beta-like genes are on chromosome 11 (one beta gene per chromosome, 2 per cell)
expression of globin genes changes during embryonic life and childhood

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6
Q

when does amount of Hb reach adult levels? clinical implication of this?

A

6-12 months of age

beta chain problems wont manifest until then

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7
Q

what are haemoglobinopathies?

A

hereditary conditions affecting globin chain synthesis

mutations behave as autosomal recessive disorders

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8
Q

2 main groups of haemoglobinopathies?

A

thalassaemias (decreased rate of globin chain synthesis)

structural haemoglobin variants (normal production of abnormal globin chain - cariant Hb such as HbS)

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9
Q

what is thalassaemia and what are the types?

A

reduced globin chain synthesis resulting in impaired haemoglobin production

  • alpha thalassaemia (alpha chains affected)
  • beta thalassaemia (beta chains affected)
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10
Q

consequences of thalassaemia?

A

inadequate Hb production leading to microcytic hypochromatic anaemia
if severe can lead to: unbalanced accumulation of globin chains (toxic to cell), haemolysis and ineffective erythropoiesis

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11
Q

where is thalassaemia most common?

A

malaria endemic areas

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12
Q

how does alpha thalassaemia occur?

A

depletion of one alpha or both alpha genes from chromosome 16
results in reduced (alpha+) or absent (alpha0) alpha chain synthesis from that chromosome
all types of Hb are affected as all types have alpha chains

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13
Q

classifications of alpha thalassaemia?

A

based on number of alpha genes
unaffected = 4 normal alpha genes
alpha thalassaemia trait = 1 or 2 alpha genes missing
HbH disease = only one alpha gene left
Hb Barts hydrops fetalis = no functional alpha genes

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14
Q

describe alpha thalassaemia trait?

A 
1 or 2 alpha genes missing
asymptomatic carrier
no treatment needed
causes microcytic hypochromatic red cells with mild anaemia
low iron but normal ferritin
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15
Q

what is HbH disease?

A

more severe form of alpha thalassaemia with only 1 working alpha gene per cell
anaemia with very low MCV and MCH

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16
Q

how is HbH inherited?

A

…

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17
Q

what causes HbH disease?

A

excess beta chains form tetramers (beta4) called HbH

red cell inclusions of HbH can be seen with special stains

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18
Q

how might HbH present?

A

jaundice

splenomegaly

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19
Q

what is Hb Barts Hydrops Foetalis syndrome?

A

most severe form of alpha thalassaemia
no alpha genes inherited from either parent
minimal/no alpha chain production (therefore HbF and HbA cant be made)
no alpha chains to bind to so tetramers of Hb barts (gamma4) and HbH (beta4) produced

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20
Q

clinical features of Hb Barts Hydrops Foetalis syndrome?

A 
profound anaemia
cardiac failure
growth retardation
severe hepatosplenomegaly 
skeletal and cardio abnormalities 
almost all die in utero
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21
Q

blood film in Hb barts hydrops foetalis syndrome?

A

numerous nucleated RBCs in peripheral blood

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22
Q

what causes beta thalassaemia?

A

disorder of beta chain synthesis usually caused by point mutations
reduced (Beta+) or absent (Beta0) beta chain production depending on mutation
only beta chains affected so only HbA affected

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23
Q

classification of beta thalassaemia?

A

based on clinical severity
beta thalassaemia trait
beta thalassaemia intermedia
beta thalassaemia major

24
Q

what is beta thalassaemia trait?

A

Beta+/beta or beta0/beta

asymptomatic, no/mild anaemia, low MCV/MCH, raised HbA2 is diagnostic

25
Q

what is beta thalassaemia intermedia?

A

beta+/beta+ or Beta0/beta+

moderate severity requiring occasional transfusion (similar phenotype to HbH disease)

26
Q

what is beta thalassaemia major?

A

beta0/beta0

severe, lifelong transfusion dependency

27
Q

clinical features of beta thalassaemia major?

A

presents aged 6-24 months (as HbF falls)
pallor and failure to thrive
extramedullary haematopoiesis causing hepatosplenomegaly, skeletal changes and organ damage

28
Q

Hb analysis in beta thalassaemia major?

A

mainly HbF

no HbA

29
Q

complications of extramedullary haematopoiesis?

A

cord compression

30
Q

how is beta thalassaemia major managed?

A

regular transfusion programme to maintain Hb at 95-105g/L (suppresses ineffective erythropoiesis, inhibits over-absorption of iron)
bone marrow transplant may be an option if carried out before complications develop

31
Q

main cause of mortality in treated beta thalassaemia major?

A

iron overload

32
Q

conseqences of iron overload?

A 
endocrine dysfunction (impaired growth and puberty development, diabetes, osteoporosis)
cardiac disease (cardiomyopathy, arrhythmias)
liver disease (cirrhosis, hepatocellular cancer)
33
Q

how is iron overload managed?

A

cant do venesection as already anaemic

iron chelating drugs (e.g desferrioxamine) bind to iron which is then excreted

34
Q

why does iron overload occur in treatment of beta thalassaemia major?

A

250mg of iron per unit of packed red cells

chronic anaemia drives increased iron absorption so a lot of the iron is absorbed

35
Q

other complications of transfusion?

A

viral infection alloantibodies (hard to crossmatch)
transfusion reactions
increased risk of sepsis (bacteria like iron)

36
Q

pathophysiology of sickle cell disease?

A

point mutation in codon 6 of the beta globin gene that substitutes glutamine to valine producing betaS
this alters the structure of the resulting Hb > HbS
HbS polymerises if exposed to low oxygen levels for a prolonged period
polymerised HbS distorts the RBC, damaging the RBC membrane

37
Q

describe sickle cell trait

A

one normal, one abnormal beta gene (beta/betaS)
asymptomatic carrier state with few clinical features as HbS level is too low to polymerise
can happen in severe hypoxia (e.g altitude)
normal blood film

38
Q

Hb components in sickle cell trait?

A

mainly HbA (<50% HbS)

39
Q

describe sickle cell anaemia?

A

two abnormal beta genes (betaS/betaS)

episodes of tissue infarction due to vascular occlusion (sickle crisis)

40
Q

clinical features of sickle cell anaemia?

A

symptoms depend in site and severity of infarction in sickle crisus
pain may be severely severe
chronic haemolysis (short RBC lifespan)
sequestration of sickled RBCs in liver and spleen
hyposplenism due to repeated splenic infarcts

41
Q

other sickling disorders (sickle cell disease)

A

compound heterozygosity for HbS and another beta chain mutation, e.g

  • HbS/Beta thalassaemia
  • HbSC disease (milder but increased risk of thrombosis)
42
Q

what is sickle crisis?

A

sickle vaso-occlusion resulting in tissue ischaemia and pain

43
Q

what can precipitate a sickle crisis?

A 
hypoxia
dehydration
infection
cold exposure
stress/fatigue
44
Q

how is a sickle crisis managed?

A 
opiate analgesia 
hydration
rest
oxygen
antibiotics if infection present
red cell exchange transfusion (alternating venesection and transfusion) in severe crisis (e.g lung crisis or stroke)
45
Q

how are sickle disorders managed long term?

A

hyposplenism (reduce risk of infection) via prophylactic penicillin and pneumococcus/meningococcus/haemophilus vaccination
folic acid supplementation (increased RBC turnover so increased demand)
hydroxycarbamide can reduce severity of disease by inducing HbF production
regular transfusion in selected cases

46
Q

how is haemoglobinopathy diagnosed?

A

bloods (FBC, Hb, RBCs)
blood film
ethnic origin
high performance liquid chromatography (HPLC) or electrophoresis to quantify haemoglobins present

47
Q

what does HPLC show in haemoglobinopathy?

A 
abnormal haemoglobins (e.g HbS)
raised HbA2 = diagnostic of beta thalassaemia trait
48
Q

HPLC in normal patient?

A

HbA >80%
HbF <1%
HbA2 1.5-3.5%

49
Q

commonest monogenic disorders worldwide?

A

haemoglobinopathies

50
Q

inheritance of haemoglobinopathies?

A

AR

carriers unaffected

51
Q

general definition of thalassaemias?

A

decreased rate of globin chain synthesis

52
Q

when should thalassaemia be suspected?

A

microcytic hypochromic anaemia with normal ferritin

53
Q

how is beta thalassaemia trait diagnosed?

A

raised HbA2

54
Q

main structural haemoglobin problem?

A

sickle cell anaemia

55
Q

what causes sickle cell anaemia?

A

point specific mutation in beta globin gene

causes HbS to polymerise and distort RBC shape and cause vaso-occlusion

56
Q

why is lifelong penicillin and vaccinations needed in sickle cell anaemia?

A

hyposplenism

Haematology (26 decks)

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