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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
There are different mutations in the beta-globin gene in different parts of the world. True or false
True
26
Explain the types of beta thalassaemia
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
When is beta thalassaemia major diagnosed?
At 3-6 months
28
What causes the disease in Beta thalassaemia major?
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
What are the symptoms of beta thalassaemia major
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
Thalassaemia intermedia patients are asymptomatic always true or false
false they have symptomatic anaemia when stressed as a result of sepsis, hypoxia They rarely require transfusions or splenectomy
31
What is beta thalassaemia trait?
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
Alpha thalassaemia
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
Gene deletion sizes
There are different sizes of alpha chain gene deletions in different parts of the world
34
Hb barts hydrops fetalis - what is it, what are the outcomes, what are symptoms, what are parent's genes like?
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
Why was the white blood cell count elevated in the Hb Bart's Hydrops Fetalis child?
The WBC count is elevated as the machinery started counting the red cell progenitors as white blood cells
36
Hb H disease
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
Alpha thassaemia trait
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
What is the haematology of alpha thalassaemia trait?
Normal/ mild anaemia Microcytic RBCs Blood film is normal/ mild poikilocytosis
39
Structural haemoglobinopathies what are they, how are they caused, where are they common
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
Hbs results in (symptoms)
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
Where is the point mutation located in HbS
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
HbSS (homozygote) = sickle cell disease causes
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
Laboratory features of sickle cell anaemia are:
Anaemia, and sickle shaped cells on the blood film
44
Treatment of sickle cell disease
``` 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
Sickle cell trait
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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