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IMED2002 > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

What are haemoglobinopathies

A

Generic term for abnormalities of globin chain synthesis
Genetic disorders of Hb synthesis
Leading to reduced RBC survival

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2
Q

What are the size of RBCs with haemoglobinopathies?

A

Microcytic

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3
Q

What is thalassaemia?

A

It is the reduced production of alpha or beta globin chains due to genetic defects
Thalassaemia can be of alpha or beta types

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4
Q

What are structural haemoglobinopathies

A

Abnormal globin chain structures

eg. HbS (sickle cell disease)

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5
Q

Thalassaemia genetic defect is in

A

Single-gene (monogenic) disorder

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6
Q

Thalassaemia syndromes involve

A

the reduced synthesis of 1 or more globin chains which leads to imbalanced globin-chain synthesis & Hb production… leading to an abnormality in making Hb

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7
Q

Is RBC damage the result of the effects of the decreased globin chains or excess globin chains?

A

Excess globin chains

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8
Q

What is alpha thalassaemia due to?

A

Reduced alpha-globin chain synthesis

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9
Q

What is beta thalassaemia due to?

A

Reduced beta-globin chain synthesis

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10
Q

What are structural haemoglobinopathies the result of (gene wise)

A

Point mutations, which result in amino acid substitutions

These are structurally abnormal Hb

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11
Q

What are common examples of structural haemoglobinopathies?

A

Sickle haemoglobin: HbS

and target cells: HbE, HbC

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12
Q

What is the normal Hb structure?

A

2 alpha and 2 non alpha chains

These can be 2 beta (HbA)
or 2 delta (HbA2)
or 2 gamma (HbF)

However, 2 alpha & 2 beta is the most common (98%)

The 2 pairs of globin chains, each contain Haem structures within them, which each contain iron molecules in them

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13
Q

What is fetus Hb synthesis?

A

It begins with zeta and epsilon globin chains

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14
Q

By birth the majority of haemoglobin is of which kind?

A

HbF (alpha and gamma)

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15
Q

How long does it take to switch from HbF to HbA

A

6 months

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16
Q

Up until birth, which globin chains are synthesised? Then

A

zeta and epsilon are made first in the foetal Hb synthesis (then soon decline)

alpha and gamma are synthesised until birth

then after birth, the beta chains are made and they increase with age

the gamma declines after birth

the alpha chain stays constant

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17
Q

where are the alpha-globin chains encoded?

A

on chromosome 16

2 alpha genes are encoded on chromosome 16, and each is responsible for 25% of the normal total alpha chain synthesis

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18
Q

where are the non-alpha globin chains encoded?

A

one beta chain gene on each chromosome 11

the beta gene is part of a complex containing both the gamma and the delta

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19
Q

Thalassaemia involves, and is classified by…

A

involves the deficient synthesis of globin chains of Hb

it is classified by clinical severity

20
Q

In terms of genetic mechanisms, what is the difference between alpha and beta thalassaemia, and structural haemoglobinopathies? What does it result in?

A

Alpha thalassaemia involves gene deletions

Beta thalassaemia involves mutations causing nucleotide substitutions

this results in a reduced amount of globin chain (thalassaemia), which then leads to reduced RBC survival (haemolytic anaemia)

As a result, we get an increased BM erythropoietic response

this is of variable severity (mild - transfusions - fatal)

Structural haemoglobinopathies are mutations which cause nucleotide substitutions

21
Q

Clinical features of haemoglobinopathies:

A

highly variable severity

in severe cases, it is incompatible with life (Barts hydrops)

It can cause variable anaemia:

1) Transfusion dependent (B-thalassaemia major)
2) Stunted growth, endocrine, iron overload
3) Can be mild or asymptomatic (thalassaemia minor)

Can cause splenomegaly, and hepatomegaly (as these organs help the bone marrow to make red cells, but these are also the site of destruction for defective red cells)

Can cause infections & folate deficiency

Bone deformities, fractures, stunted growth are common

Iron overload can cause cardiac problems and endocrine failure

22
Q

Beta thalassaemia causes

A

causes mutations in the Beta globin gene on chromosome 11

leading to reduced beta chain production

23
Q

What is homozygous thalassaemia

A

Is thalassaemia major

this is present at 3-6 months when HbF ceases to be made and the body is unable to make HbA due to lack of B-globin chains (reduced as a result of mutations)

This causes severe anaemia, and the person becomes transfusion-dependent, and has to go through bone marrow transplant

24
Q

What is heterozygous thalassaemia

A

It is thalassaemia intermedia or minor

Usually asymptomatic, but can become symptomatic when stressed

Usually these cases are borderline anaemic, and the MCV is slightly reduced

25
Q

There are different mutations in the beta-globin gene in different parts of the world. True or false

A

True

26
Q

Explain the types of beta thalassaemia

A

Decreased beta chain production is B+ thalassaemia

Absent beta chain production is B0 thalassaemia

If there is only one gene abnormality in the Beta chain genes, then it is Beta thalassaemia minor

Either BB+ or BB0

But if there are 2 gene abnormalities in the genes then it is beta thalassaemia major
B0B0 is the most severe
B0B+ is moderately severe (intermedia)
B+B+ then there is increased HbF and HbA2

27
Q

When is beta thalassaemia major diagnosed?

A

At 3-6 months

28
Q

What causes the disease in Beta thalassaemia major?

A

The excess alpha chains precipitate and cause haemolysis

no two cells look the same in Beta thalassamia

all cells die in less than 120 days

29
Q

What are the symptoms of beta thalassaemia major

A

symptomatic severe anaemia

extramedullary erythropoiesis

splenomegaly

transfusion-dependent, iron overload

Iron chelation therapy

Long survivors develop secondary problems like osteopenia (bone thins, and fractures)

Enlargement of the maxilla

Hair on end in scull x-ray shows that skull increased BM activity (erythroid hyperplasia)

30
Q

Thalassaemia intermedia patients are asymptomatic always true or false

A

false

they have symptomatic anaemia when stressed as a result of sepsis, hypoxia

They rarely require transfusions or splenectomy

31
Q

What is beta thalassaemia trait?

A

it is borderline anaemia

there are microcytic red blood cells

patients are usually asymptomatic

it is usually unremarkable in the peripheral blood film or poikilocytosis (refers to an increase in abnormal red blood cells of any shape that makes up to 10% or more of the total population)

There is also elevated HbA2 (alpha and delta)

Borderline elevated HbF (alpha and gamma)

It is usually BB+ or BB0 thalassaemia

32
Q

Alpha thalassaemia

A

There are 4 alpha globin chain genes (2 on chromosome 16, and 2 copies)

Gene deletions involve 1, 2, 3, or 4 alpha genes deletion

Thalassaemia minor involves 2 or 3 functional genes (with 1 or 2 gene deletions)
eg. - a / a a or - a / - a or - - / a a

Haemoglobin H disease involves only 1 gene (with 3 gene deletions)

eg. - - / - a

Hb barts hydrops fetalis involves 0 genes (all alpha chain genes deleted)

eg. - - / - -

33
Q

Gene deletion sizes

A

There are different sizes of alpha chain gene deletions in different parts of the world

34
Q

Hb barts hydrops fetalis - what is it, what are the outcomes, what are symptoms, what are parent’s genes like?

A

No alpha globin chain genes on chromosome 16 (all deleted), none can be produced

Fatal in utero, or premature delivery at 30-34 weeks

Hydropic infant (severe swelling of unborn child) due to cardiac failure from severe anaemia

The blood has erythroblasts, and is anaemic

Parents are - - / aa (thalassaemia minor), both carriers

35
Q

Why was the white blood cell count elevated in the Hb Bart’s Hydrops Fetalis child?

A

The WBC count is elevated as the machinery started counting the red cell progenitors as white blood cells

36
Q

Hb H disease

A

Loss of 3 alpha globin genes ( - - / - a)

This is thalassaemia intermedia

symptomatic when stressed

is moderately severe

chronic haemolytic anaemia (hence you get erythroid hyperplasia)

splenomegaly, hence, splenectomy

Leg ulcers

37
Q

Alpha thassaemia trait

A

Deletion of 1 or 2 alpha globin chain genes

2 gene deletions is a0
1 gene deletion is a+

3.7 - 4.2 kb deletions are the most common

38
Q

What is the haematology of alpha thalassaemia trait?

A

Normal/ mild anaemia

Microcytic RBCs

Blood film is normal/ mild poikilocytosis

39
Q

Structural haemoglobinopathies what are they, how are they caused, where are they common

A

Are point mutations causing structural abnormalities in a globin chain

HbS: occurs in people of Black African heritage

HbS forms crystals, and sickle shaped RBC

40
Q

Hbs results in (symptoms)

A

Hbs causes sickling crises, including painful & occluded vessels

This results in chest pain, bone pain, tissue infarction and stroke

A stroke happens when blood flow to your brain is stopped.

Auto-splenectomy is the infarction of the spleen

Tissue infarction = Infarction is tissue death due to inadequate blood supply to the affected area.

41
Q

Where is the point mutation located in HbS

A

at codon 6 in the Beta globin gene

This causes insolubility of the HbS when deoxygenated

Insoluble chains of HbS crystallise in the red cells causing the cells to “sickle”

Homozygous: Sickle cell disease
Heterozygous: Sickle cell trait

42
Q

HbSS (homozygote) = sickle cell disease causes

A

Causes haemolytic anaemia and sickling crises

Causes vaso-occlusive events due to the sickling (blood vessels are blocked)

gall stones, reduced splenic function

by the age of 3, there is no spleen left (hence, lowered resistance to salmonella, pneumococcus, infections and meningitis)
no blood flow to the spleen = infarction

lots of pain, tissue infarction, leg ulcers, bone pain, stroke, acute chest syndrome, congestive heart failure and aplastic crises like marrow failure & anemia

43
Q

Laboratory features of sickle cell anaemia are:

A

Anaemia, and sickle shaped cells on the blood film

44
Q

Treatment of sickle cell disease

A 
Avoid dehydration, infections
Vaccination for pneumococcus and haemophilus
Oral penicillin (indefinite)
Folic acid: to prevent folate deficiency
Transfusions: for severe anaemia
Oral hydroxycarbamide: increases HbF
Stem cell transplant
45
Q

Sickle cell trait

A

HbAS (carriers, heterozygous for HbS)

this is a benign condition, there is normal Hb (no anaemia)

need genetic counselling

naturally resistant to malaria

High frequency in populations in the tropics

IMED2002 (12 decks)

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