haemoglobinopathies And Haemolytic anaemia

Question 1

What is haemoglobinpathies

Answer 1

Faulty synthesis of the haemoglobin chains

Question 2

What are the two classes of haemoglobinopathies?

Answer 2

1) reduced or absent expression of normal globin chains

2) Abnormal globin chain produced with altered stability and or function.

Question 3

When does HbA begin to form ?

Answer 3

Commences before birth and steadily increases to become dominant after birth

Question 4

Where are the alpha genes located - on which chromosomes and how many alpha genes do we have ?

Answer 4

Humans have 4 alpha genes ( 2 on maternal and 2 on paternal) on chromosome 16

Question 5

How many beta genes do we have ? And on which chromosones would we find beta globin gene.

Answer 5

B globin gene is on chromosomes 11.

• We have a total of two beta globin genes ( 1 on maternal and 1 on paternal)

Question 6

What ratio at alpha-globin chain proteins and non-alpha globin chains in a normal haemoglobin?

Answer 6

1:1 ratio

Question 7

What is beta— thalassaemia?

Answer 7

B globin gene expression is affected - often causing either a reduction in beta globin chain production or simple the absent of beta globin chains.

Question 8

Where is Beta thalassaemia more prevalent in ? What ethnicities

Answer 8

South Asian

Mediterranean

Middle East

Question 9

What does B0 and B+ denote?

Answer 9

B0 = total absence of gene

B+ reduced production of the beta globin chain

Question 10

What is beta thalassaemia often caused by ?

Answer 10

Gene mutation , rather than deletition

Question 11

What are the three types of B thalassaemia?

Answer 11

1) B thalassaemia minor / Beta thalassaemia trait
2) B thalassaemia intermedia
3) B thalamassaemia major

Question 12

What is the severity of B thalassaemia trait/minor ?

Answer 12

Usually Asymptomatic with mild anaemia

• microcytic / hypochromic RBC

-

Question 13

What is genotype of B thalassaemia minor / trait

Answer 13

Heterezygous with 1 normal and one abnormal gene

Eg B / B0 or B/B+

Question 14

What is the severity of B thalassaemia intermedia?

Answer 14

Severe anaemia

But not enough to require blood transfusions

Question 15

What is the genotype of B thalassaemia intermedia ?

Answer 15

Mild variants of homozygous B thalassaemia

• severe variants of heterozygous ( B0 / B) or BB
• some double HereroYgosity for the Bo/B genes.

GENERALLY HETEROGNEOHS

Question 16

Severity of B thalassaemia major

Answer 16

Severe transfusion dependant

Becomes manifest 6-9 months after birth as synthesis switches from HBF to HBA

Question 17

Genotype of B thalassaemia major

Answer 17

Homozygous : B0/B0 or B+B+

Question 18

What are the four different types of A thalassaemia?

Answer 18

1) silent carrier state
2) A thalassaemia trait
3) Haemoglobin H disease ( HbH)
4) . Hydrops fetalis

Question 19

What is the severity of silent carrier state

Answer 19

• this is when one alpha gene is affected
• this is Asymptomatic
• person is a carrier of the disease but with no symptoms

Question 20

Severity of a thalassaemia trait

Answer 20

• this is when two alpha genes are affected ( either both genes on one chromosome 16 are affected or one gene on each paternal / maternal chromosome 16)
• minimal or No anaemia.
• microcytosis and hypochromia in RBC

Question 21

Severity of haemoglobin H disease

Answer 21

Moderately severe

• this is where there are 3 alpha genes affected
• tetramers of B globin chains form resulting in microcytic , hypichromic anaemia with target cells and Heinz bodies.

Question 22

Hydrops fetalis severity

Answer 22

• SEVERE
• usually results in intrauterine death
• all 4 alpha genes deleted. Excess Y-globin forms tetramers in fetus ( HB Bart) that is unable to deliver oxygen to tissues.

Question 23

On a peripheral blood smear , what would a patient with severe thalassaemia show ?

Answer 23

Hypochromic and microcytic cells due to low haemoglobin

• ANISOPOIKILOCYTOSIS ( variance in shape and size of red blood cells) - frequent target cells ( looks like a bulls eye) , and circulating nucleated red blood cells and Heinz bodies

Question 24

Relative excess of the unaffected globin chains also contribute to the defective nature of red cells ( eg in B thalassaemia aggregates of alpha chains would form) . Haemoglobin aggregates get oxidised and result in what two things ?

Answer 24

1) premature death of erythroblast precursors within bone marrow leading to ineffective erythopoiesis
2) excessive destruction of mature red cells in spleen leading to shortened red blood cell survival

Question 25

What are the consequences of thalassaemia?

Answer 25

1) Extramedullary haemopoiesis: this occurs in an attempt to compensate for the red blood cells that are being destroyed / premature death. But instead this results in splenomegaly , hepatomegaly and expansion of haemopoiesis in the bone cortex ( cortical bone) which impairs growth and causes skeletal abnormalities.
2) Reduced oxygen delivery leads to stimulation fo EPO which further contributes to the drive to make more defective red cells.
3) iron overload is the major cause of premature death.

Question 26

What causes the iron overload in thalassaemia?

Answer 26

1) excessive absorption of dietary iron due to ineffective haemopoiesis
2) repeated blood transfusion which is required to treat anaemia

Question 27

How to treat thalassaemia?

Answer 27

1) red cell transfusion from childhood
2) iron chelation ( substances that bind to iron to reduce excess iron overload)
3) folic acid which helps to support erthyropoiesis
4) immunisation as patients are much greater risk of infection
5) holistic care ( endocrine , cardiology )
6) pre conception counselling for at risk couple S.M.
7) stem cell implantation to replace the defective red cell production,

Question 28

How is sickle cell disease inherited ?

Answer 28

Autosomal recessive

Question 29

What is the cause of sickle cell disease ( eg what mutation , on what chronometer)

Answer 29

• mutation of the B-globin gene on chromosome 11.
  2. GAG codon changed fo GTG resulting in glutamic acid being substituted by valine.
  3. Mutant haemoglobin molecule contains this mutated B-globin protein referred to as HBS.

( point mutation)

Question 30

What is the sickle cell trait ?

Answer 30

Carriers for sickle cell disease .

Causes mild Asymptomatic anaemia

Question 31

Can HBS be co inherited ?

Answer 31

It can be co inherited with another abnormal HB - HbC

Question 32

Where is HBS most Prevalent?

Answer 32

30% of west African population as it confers protection against malaria

Question 33

Is anaemia usually mild or severe in sickle cell disease ?

Answer 33

Mild and well tolerated because HbS readily gives up oxygen in comparison to HbA.

Question 34

Why do problems arise when HBS is in its low oxygen state ?

Answer 34

Because deoxygenated HbS forms polymers that cause red cells to form a sickle shape.

Irreversible sickle cells are less deformable and can cause occlusion in small blood vessels.

Question 35

Average life expectancy of someone with sickle cell disease in the Uk ?

Answer 35

67 years old

Question 36

What are the three type of crises that sickle cell disease causes ?

Answer 36

1) Vaso-occlusive crises : this is where micro circulation is obstructed by sickled RBC in the chest , spleen.
2) Apoplastic crisis : bone marrow does not function properly to produce RBC. This is often triggered by parvovirus.
3) Haemolytic crisis.

Question 37

What are common diseases associated with sickle cell disease ?

Answer 37

1) stroke
2) acute chest syndrome
3) skin ulcers
4) kidney infaracts
5) priapism.

Question 38

What are three inherited defects in red cell membrane structure ?

Answer 38

1) hereditary spherocytosis ( spherical shaped , anykin, spectrin , protein 4.2, band 3 defects ) they become easily flexible and more easily damaged.
2) hereditary eliptocytosis - elliptical rather than biconcave shape. Spectrin defect most common defect. Also defects in band 4.1, Band 3 and glycophorin C proteins.
3) hereditary pyropoikilocytosis - spectrin defect. Severe form elliptocytosis. Abnormal sensitivity to red cells to heat. Similar morphology to that seen in thermal burns.

Question 39

What is microangiopathic haemolytic anaemia

Answer 39

Loss. Of blood cells through destruction

For example

1) shear stress : As cells pass through a defective heart valve ( eg aortic valve stenosis)
2) Cells snagging on fibrin strands in small vessels where there is increased activation of clotting cascade.
3) heat damage from severe burns
4) osmotic damage ( drowning in fresh water)

Question 40

What is autoimmune haemolytic anaemias ?

Answer 40

Caused by antibodies binding to red cell membranes,

• this can result from infections or cancers of the lymphoid cancers.
• classified as either ‘warm’( IgG) or ‘cold’ (IgM) basedon temperature antibodies react best at under lab conditions
• spleen recognises antibody bound cells as abnormal and removes them,
• red cell lifespan reduced resulting in anaemia.