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Haemaglobinopathies Flashcards

1
Q

what is the structure of haemoglobin

A

Tetramer made up of 2 alpha globin like chains and 2 beta globin like chains

One haem group attached to each globin chain = 4 haem groups

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2
Q

what are the major forms of haemoglobin

A

HbA (two alpha chains and two beta chains, α2β2 )

HbA2 (two alpha and two delta, α2δ2)

HbF (two alpha and two gamma, α2γ2)

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3
Q

what type of haemoglobin is most common

A

HbA

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4
Q

what chromosome is the alpha like genes on

A

chromosome 16

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5
Q

how many alpha genes are present per chromosome

A

2

i.e. 4 per cell

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6
Q

what chromosome is the beta like genes on

A

chromosome 11

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7
Q

how many beta genes are present per chromosome

A

1

i.e. 2 per cell

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8
Q

expression of globin genes stays the same throughout life - true or false

A

false

- changes during embryonic life and childhood

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9
Q

what are haemoglobinopathies

A

Hereditary conditions affecting globin chain synthesis

behave as autosomal recessive disorders

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10
Q

what are the 2 main groups of haemoglobinopathies

A

1 - Thalassaemias; decreased rate of globin chain synthesis

2 - Structural haemoglobin variants; normal production of structurally abnormal globin chain

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11
Q

what is thalassaemias

A

Hereditary disorders of globin chain synthesis resulting in impaired haemoglobin production

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12
Q

what are the 2 forms of thalassaemia

A

Alpha thalassaemia; α chains affected

Beta thalassaemia; β chains affected

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13
Q

what type of anaemia is seen in thalassaemia

A

microcytic hypochromic

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14
Q

what goes wrong in thalassaemia

A

Inadequate Hb production → microcytic hypochromic anaemia

Unbalanced accumulation of globin chains → ineffective erythropoiesis and haemolysis

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15
Q

what happens in alpha thalassaemia to cause Sx

A

Mutations affecting α globin chain synthesis

Reduced or absent synthesis of α chains

Results from deletion of one (-α) or both (- -) alpha genes from ch 16

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16
Q

why does alpha thalassaemia tend to present more severely

A

alpha chains present in all adult forms of Hb therefore HbA, HbA2 and HbF all affected

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17
Q

what are the types of alpha thalassaemia

A

Unaffected individuals have 4 normal α genes (αα/αα)

Alpha thalassaemia trait; one or two genes missing (-α/αα), (–/αα) or (-α/-α)

HbH disease; only one alpha gene left (–/-α )

Hb Barts hydrops fetalis; no functional α genes (–/–)

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18
Q

what are features of Alpha thalassaemia trait

A

Usually (–/αα) or (-α/-α)

Asymptomatic, no Rx needed

Microcytic, hypochromic red cells with mild anaemia

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19
Q

what can alpha thalassaemia trait be mistaken for and how can you tell it apart

A

iron deficiency anaemia

in trait = ferritin normal, RBC raised

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20
Q

what is HbH disease

A

Severe form of α thalassaemia

Only one α gene per cell (–/-α )

α chain production < 30% of normal

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21
Q

what blood results are seen in HbH disease

A

anaemia with very low MCV and MCH

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22
Q

why is it called HbH disease

A

Excess β chains form tetramers (β4) called HbH which cannot carry oxygen

Red cell inclusions (HbH bodies) can be seen with special stains

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23
Q

what are Sx of HbH disease

A

From mild anaemia to transfusion dependant

Splenomegaly due to extramedullary haematopoiesis

Jaundice due to

  • Haemolysis
  • Ineffective erythropoiesis
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24
Q

what is the Tx of HbH disease

A

Severe cases splenectomy+/-transfusion

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25
where is HbH disease prevalent
S.E. Asia, Middle East and the Mediterranean
26
what is the most severe form of alpha thalassaemia
Hb Bart's hydrops fetalis syndrome
27
what happens in Hb Bart's hydrops fetalis syndrome
No α genes inherited from either parent (--/--) Minimal or no α chain production →HbA can’t be made
28
what is the majority Hb at birth
Hb Barts (γ4) and HbH (β4)
29
what are Sx of Hb Bart's hydrops fetalis syndrome
Severe anaemia Cardiac failure, oedema Growth retardation Severe hepatosplenomegaly Skeletal and cardiovascular abnormalities Most die in utero
30
what is beta thalassaemia
Disorder of beta chain synthesis Reduced, or absent beta chain production Only β chains and hence only HbA (α2β2) affected
31
what causes beta thalassaemia
usually a point mutation
32
what are the 3 forms of beta thalassaemia
beta thalassaemia trait beta thalassaemia intermedia beta thalassaemia major
33
what are the features of beta thalassaemia trait
asymptomatic no/mild anaemia low MCV/MCH
34
what are the features of beta thalassaemia intermedia
moderate severity requiring occasional transfusion
35
what are the features of beta thalassaemia major
severe, lifelong transfusion dependency
36
what are lab features of beta thalassaemia major
severe anaemia Reticulocytosis very low MCV/MCH Film; microcytosis, hypochromia, anisopoikilocytosis and target cells
37
what is seen on HPLC in beta thalassaemia major
mainly HbF present | small amounts of HbA
38
what are features of beta thelassaemia major
Presents aged 6-24 months Failure to thrive Pallor Extramedullary haematopoiesis causing: - Hepatosplenomegaly - Skeletal changes - Organ damage
39
what are complications of extra medullary haematopoiesis
can cause spinal cord compression
40
what is Mx of beta thal major
Regular transfusion programme to maintain Hb at 95-105g/l - suppress ineffective erythropoiesis - inhibit over-absorption of iron Allows for relatively normal growth and development
41
what can tx cause in beta thal major
iron overload > can lead to mortality
42
what are consequences of iron overload
Endocrine dysfunction - Impaired growth and pubertal development - Diabetes - Osteoporosis Cardiac disease - Cardiomyopathy - Arrhythmias Liver disease - Cirrhosis - Hepatocellular cancer
43
what is the Mx of iron overload
Desferrioxamine - iron chelating drug
44
how does desferrioxamine work
Chelators bind to iron, complexes formed are excreted in urine or stool
45
what does iron overload make you susceptible too
bacterial infection
46
how is diagnosis of thalassaemia made
exclude iron deficiency first Blood film; hypochromia, target cells, anisopoikilocytosis HPLC: Raised HbA2 diagnostic of beta thal trait. Will be normal in alpha thal trait so DNA testing needed to confirm
47
what is the pathophysiology of sickle cell disease
Point mutation in codon 6 of the β globin gene that substitutes glutamine to valine Alters the structure of the resulting Hb→ HbS HbS polymerises if exposed to low oxygen levels for a prolonged period This distorts the red cell, damaging the RBC membrane
48
what are the two from of sickle cell disease
``` sickle trait (HbAS) sickle cell anaemia (HbSS) ```
49
what are features of sickle trait
One normal, one abnormal β gene (β/βs) | Asymptomatic carrier state
50
what are Sx of sickle trait
Few clinical features as HbS level too low to polymerise May sickle in severe hypoxia eg high altitude, under anaesthesia
51
what are lab results of sickle trait
Blood film normal | Mainly HbA, HbS <50%
52
what are features of sickle cell anaemia
Two abnormal β genes (βs/βs) autosomal recessive HbS > 80%, no HbA
53
what is sickle crisis
Episodes of tissue infarction due to vascular occlusion
54
what are symptoms of sickle cell anaemia
Symptoms depend on site and severity - Digits (dactylitis), bone marrow, lung, spleen, CNS - Pain may be extremely severe Hyposplenism (due to repeated splenic infarcts) Chronic haemolysis
55
what is uncommon in sickle cell anaemia
iron overload
56
what are precipitants of sickle crisis
Hypoxia ‏(can be caused by chest infection) Dehydration (makes HbS more likely to polymerise) Infection Cold exposure Stress/fatigue
57
what is the Tx of a sickle crisis
``` Opiate analgesia Hydration Rest Oxygen Antibiotics if evidence of infection ``` Red cell exchange transfusion in severe crises eg chest crisis or neurological symptoms (venesect >> transfuse)
58
what are long term effects of sickle cell anaemia
Impaired growth Risk of sepsis Risk of organ damage - pulmonary hypertension - renal disease - avascular necrosis - leg ulcers - stroke
59
what is long term treatment of sickle cell anaemia
splenectomy folic acid supplementation hydroxycarbamide
60
what would a patient need if they had a splenectomy
prophylactic penicillin vaccination; pneumococcus, meningococcus, haemophilus
61
why does a patient with sickle cell need folic acid supplementation
↑ RBC turnover so ↑demand
62
how does hydroxycarbamide work
reduces severity of disease by inducing HbF production
63
what is sickle cell disease
heterozygosity for HbS and another β chain mutation | e.g. HbS/β thalassaemia; mild if β+, severe if β0

Haematology SB (19 decks)

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