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2.2 Haematology > Haemaglobinopathies > Flashcards

Haemaglobinopathies Flashcards

1
Q

What is a haemoglobinopathy

A

The normal production of structurally abnormal globin chains

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2
Q

What may cause haemoglobinopathies
(4)

A

Point mutations
Deletion of triplets
Mutation of a stop codon
A fusion mutation or due to an insertion

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3
Q

Give some examples of haemoglobin varients

A

Hb C
Hb S/C
Hb E
Hb D

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4
Q

What is Hb C

A

B6 Glu>lys

Results in mild haemolytic anaemia

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5
Q

What is Hb S/C

A

This accounts for 20-50% of patients with sickle cell disease

Causes less severe vaso-occlucive complications

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6
Q

What is Hb E
(3)

A

Most common mutation

B26 Glu.lys

Homozygotes suffer from mild anaemia

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7
Q

What is Hb D
(2)

A

B121 Glu>Gln

Mostly asymptomatic

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8
Q

What percentage of west Africans have sickle cell disease

A

1 in 4

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9
Q

Comment on the severity of sickle cell disease
(6)

A

HbS

Heterozygotes are asymptomatic

Homozygotes have SCD

Haemolytic anaemia of varying severity punctuated by painful sickling crises

Reduced life expectancy with most people suffering in Nigeria dying before 21 years of age

Approximately 20% of children die under 5 in Africa

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10
Q

How does sickle cell disease confer protection against malaria
(3)

A

Hb S shape is difficult for the malaria parasite to use

Macrophages will also continuously break down these sickle cells

Parasites are unable to get to the end of their life cycle before being phagocytosed along with the sickle cell

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11
Q

What causes structural/qualitative defects of Hb

A

Occurs when the amino acid sequence of one globin chain is altered

Mutation may arise due to addition, substitution, deletion or fusion to the base sequence in the globin chain -> this leads to a change in the amino acid sequence

Leads to sickle cell anaemia

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12
Q

How does sickle cell anaemia come about
(5)

A

Due to a change in the base sequence of the B chain

An A is changed to a T

GAG&raquo_space;> GTG

This results in the replacement of glutamic acid by valine at position 6 on the B chain

This causes a change in the overall charge and polarity of the molecule

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13
Q

How is HbS diagnosed in the lab
(7)

A

Positive solubility test

Blood film

Full Blood Count

DNA analysis to confirm genetic mutation

Electrophoresis

HPLC

General bloods

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14
Q

How is a blood film used to diagnosed HbS
(7)

A

Sickle cells
Target cells
Polychromasia
Hypochromic microcytes
Reticulocytes
NRBC
Howel Jolly bodies if hyposplenic

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15
Q

How is a full blood count used to diagnose HbS

A

Haemoglobin is low

MCV is low

MCH is low

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16
Q

How is High Performance Liquid Chromatography used to diagnose Hb
(4)

A

Hb A is absent
Hb S 80-100%
Hb F 5-15%
Increased HbA2

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17
Q

How is the Bio-Rad Varient II used in the primary screening of B-thalassaemia
(6)

A

Analyser utilises ion-exchange HPLC to investigate B-thalassaemia

A B-thalassaemia short program test kit is used with the analyser

Samples are diluted and mixed at the sampling station and then injected into the analytical cartridge

Hb is fractioned by type, based on its ionic interactions with the reagent

Results are shown as a chromatogram

The analyser is usually interfaced to the Laboratory Information System (LIS)

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18
Q

How is the Sebia Capillarys 2 Flex Piercing - Confirmatory Testing used
(3)

A

Analyser uses capillary electrophoresis to confirm thalassaemia and other haemoglobinopathies

Works by separating charged molecules by their electrophoretic mobility in an alkaline buffer when voltage is applied

The Hb fractions are detected at 415nm at the cathode of the capillary and an electrophoretogram is produced, together with quantified fractions of Hb

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19
Q

How is sickle cell anaemia treated
(4)

A

Drug treatments

Allogenic transplant

Ex vivo gene therapy

In vivo gene therapy

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20
Q

How are drugs used to treat sickle cell anaemia

A

These aim to allow more cells to transit the microcirculation before sickling

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21
Q

How are allogeneic transplants used to treat sickle cell anaemia

A

Bone marrow stem cells from a donor without SCD are transplanted

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22
Q

How will Ex vivo gene therapy be used in the future to treat SCD

A

The patients bone marrow cells are modified by adding a B-globin gene using a retroviral vector or with gene editing

This will reactivate foetal haemoglobin (HbF) or correct the disease mutation

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23
Q

How will Ex vivo gene therapy be used in the future to treat SCD

A

The patients bone marrow cells will be modified by adding a B-globin gene

This will be done using either a retroviral vector or with gene editing

This will reactivate foetal haemoglobin or correct the disease mutation

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24
Q

How will In vivo gene therapy be used in the future to treat SCD

A

Direct gene editing in patients could circumvent the need for transplantation of modified patient cells if sufficient efficiency and safety can be achieved

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25
Q

What are quantitative abnormalities of Hb

A

Heterogenous group of genetic disorders which result from a reduced rate of synthesis of the alpha or Beta globin chains

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26
Q

What causes quantitative abnormalities

A

May arise because of:
Inadequate amount of mRNA
Unstable mRNA
mRNA that contains untranslatable nonsense message

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27
Q

What happens when there is quantitative abnormalities of Hb (Thalassaemias)?

A

There is a decrease in one of the globin chains

So the other chain is in excess and thus the molecule is unbalanced and the chain in excess tries to form tetramers and precipitates within the cell

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28
Q

What are quantitative abnormalities of Hb called

A

Thalassaemias

29
Q

Write a note on the types of thalassaemia
(2)

A

Some mutations cause a complete absence of globin chain synthesis -> a0 or B0 thalassaemias

In other mutations the globin chain is produced at a reduced rate and these are known as a+ or B+ thalassaemias

30
Q

What are the three groups of thalassaemias

A

Thalassaemia major

Thalassaemia intermedia

Thalassaemia minor

31
Q

What is thalassaemia major

A

Severe anaemia

Transfusion dependant

32
Q

What is thalassaemia intermedia

A

Phenotype ranging from severe anaemia to mild hypochromic microcytic anaemia

33
Q

What is thalassaemia minor

A

Clinically asymptomatic carrier state

34
Q

What is the most sever thalassaemia genetically

A

B0 B0

35
Q

What haemoglobin is affected by a Thalassaemia?

A

HbA (aB)

A2 (aB)

F (ay)

36
Q

What haemoglobin is affected by B Thalassaemia?

A

HbA (aB)

37
Q

What haemoglobin is affected by y Thalassaemia?

A

HbF (ay)

38
Q

What haemoglobin is affected by d Thalassaemia?

A

HbA2 (ad)

39
Q

What happens in beta thalassaemia
(4)

A

Excess alpha chain produced which are highly unstable and precipitate in red cells

Degradation of excess a chains produce deleterious effects on RC membrane and electrolyte homeostasis - shortened RC survival

alpha chain inclusions in red cell results in haemolysis in spleen

Anaemia becomes apparent after 3-6 months of age when they switch from gamma to beta chain production occurs

40
Q

How is B Thalassaemia diagnosed in the lab
(6)

A

Full Blood Count

Blood film

HPLC

Reticulocytes

DNA analysis to confirm genetic mutation

Family studies

41
Q

How is B thalassaemia diagnosed on a blood film
(7)

A

Hypochromic microcytes

Target cells

Anisopoikloctosis

Polychromasia

NRBC

Pappenheimer bodies

basophilic stippling

42
Q

How is a FBC used to diagnose B Thalassaemia

A

Haemoglobin down

MCV down

MCH down

43
Q

How is HPLC used to diagnose B thalassaemia

A

Reduced or absent HbA peak

Increased Hb F

Increased Hb A2

44
Q

How is B thalassaemia treated
(4)

A

Conventional therapies

Pharmaceutical induction of y-globin

Allogenic HSC transplantation

Gene and cell therapy

45
Q

What conventional therapies are used to treat B thalassamia

A

Transfusions and iron chelation therapy are used

Frequent transfusions are needed which result in high iron which needs to be chelated to prevent overload

46
Q

How is pharmaceutical induction of y-globin used to treat Thalassaemia

A

Drugs given to induce the production of y-globin

47
Q

How is gene and cell therapy used to treat Thalassaemia

A

B or y-globin vectors to bring about the production of the genes

48
Q

How is allogeic HSC transplantation used to treat thalassaemia

A

Haematopoeitic stem cell transplant

49
Q

What percentage of people does thalassaemia affect

A

7%

50
Q

What percentage of thalassaemias are alpha thalassaemia

A

3%

51
Q

What are the different types of a thalassaemia
(4)

A

Carrier: asymptomatic

a-thal minor: only 2 alpha genes -> asymptomatic or mild microcytic anaemia

Hb H disease -> only 1 working a gene -> haemolytic and microcytic anaemia -> splenomegaly

no working alpha gene -> incompatible with life -> hydrops fetalis -> most common occurring type -> excess fluid builds up in the body before birth

52
Q

How is alpha thalassaemia diagnosed in the lab
(8)

A

FBC
Blood film
Reticulocytes
H Prep
HPLC
Family studies
DNA analysis
General blood

53
Q

How is FBC used to diagnose a- thalassaemia

A

Hb down

MCV down

MCH down

54
Q

How is blood film used to diagnose a- thalassaemia

A

Hypochromic microcytes
Target cells
Anispoikilocytosis
Polychromasia
NRBC
Pappenheimer bodies
Basophilic stippling

55
Q

How is general bloods used to diagnose a- thalassaemia

A

LDH and bilirubin up

Haptoglobin down

56
Q

How is H prep used to diagnose a- thalassaemia

A

Incubation with brilliant Cresyl Blue typical golf ball appearance (30-90%)

57
Q

How is HPLC used to diagnose alpha thalassaemia

A

Hb H peak
Hb Barts peak

58
Q

What type of inclusions are seen in thalassaemias

A

Inclusion body

Heinz body

Howell-Jolly body

59
Q

What is an inclusion body and how does it come about
(3)

A

Seen in HbH disease (a type of a thal)

Excess B chains precipitating as haemoglobin H inclusion bodies in the cell

In B thalassaemia major, excess a chains can also precipitate as inclusion bodies

60
Q

What is a Heinz body and how does it come about
(4)

A

Type of inclusion body containing denatured haemoglobin

Classically associated with G6DP deficiency but can be found in thalassaemias as well

Typically larger than inclusion bodies

If functional spleen is present these will lead to bite cells

61
Q

What are Howell-Jolly bodies and how does it come about
(3)

A

Type of inclusion body containing DNA

Usually removed by splenic macrophages like Heinz bodies

Can be seen when red cells fail to mature or when a functional spleen is absent

62
Q

What is hereditary persistence of foetal Hb
(3)

A

Rare, benign condition characterised by continued synthesis of HbF in adults

No clinical symptoms of thalassaemia

Little significance except when combined with other forms of thalassaemia or Haemoglobinopathies

63
Q

What happens if hereditary persistence of foetal Hb is combined with sickle cell anaemi

A

It produces a milder form of disease due to the presence of Hb F

64
Q

What is the one benefit of HbF

A

Its more resistant to denaturation than Hb A

65
Q

How do we identify hereditary persistence of foetal Hb in the lab

A

Can be demonstrated on blood smears using Kleihauer Betke stain

Only cells containing HbF will stain

66
Q

Classify hereditary persistence of foetal Hb

A

Classified according to distribution of Hb F among red cells

Pancellular HPFH

Heterocellular HPFH

67
Q

What is pancellular HPFH

A

Hb F uniformly distributed throughout red cells

68
Q

What is heterocellular HPFH

A

Hb F found in only small number of cells

2.2 Haematology (38 decks)

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