9. Haemoglobinopathies And Haemolytic Anaemias

Question 1

What are haemoglobinopathies?

Answer 1

Inherited disorders that cause defects in globin chain synthesis
Usually autosomal recessive

Question 2

What are the 2 types of haemoglobinopathies?

Answer 2

Abnormal globin chain variants with altered sability and/or function
Reduced or absent expression of normal globin chains

Question 3

Give an example of each of the haemoglobinopathies

Answer 3

Sickle cell disease

Thalassaemias

Question 4

What is haemoglobin?

Answer 4

Tetramer of 4 globin polypeptide chains
2 alpha and 2 non-alpha chains (beta, delta or gamma)
Each globin chain is complexed with an oxygen binding haem group

Question 5

What are the types of haemoglobin?

Answer 5

A - 2 alpha 2 beta, ~95% in adult
A2 - 2 alpha 2 delta, ~ 3% in adult
F - 2 alpha 2 gamma <1% in adults (fetal haemoglobin)

Question 6

Which chromosomes are the alpha and beta globin genes on?

Answer 6

Alpha - 16

Beta - 11

Question 7

How many of each gene do humans have?

Answer 7

Have 4 alpha genes (2 on maternal and 2 on paternal)

Have 2 beta genes (1 on each chromosome)

Question 8

What does normal expression of globin genes cause?

Answer 8

Under tight control to ensure a 1:1 ratio of alpha to non-alpha globin chain proteins

Question 9

What can defects in the regulation of expression of globin genes result in?

Answer 9

Both relative and absolute amounts of globin chain proteins and can result in beta thalassaemia or alpha thalassaemia

Question 10

Where are the thalassaemias more prevalent?

Answer 10

Beta thalassaemia - south Asian, Mediterranean, Middle East

Alpha thalassaemia - Far East

Question 11

What are the different diseases of alpha thalassaemia caused by different number of alpha globin genes deleted?

Answer 11

1 gene deleted - silent carrier state
2 genes deleted - alpha-thalassaemia trait
3 genes deleted - haemoglobin H disease
4 genes deleted - hydrops fetalis

Increase in severity down the list

Question 12

Describe alpha thalassaemia trait

Answer 12

Minimal or no anaemia
Either both genes on one chromosome 16 or one gene on each chromosome 16 deleted
Microcytosis and hypochromia in RBCs
Resembles beta thalassaemia minor

Question 13

Describe haemoglobin H disease (HbH)

Answer 13

Moderately severe
Tetramer of beta-globin (HbH) form resulting in microcytic, hypochromic anaemia with target cels and Heinz bodies
Resembles beta thalassaemia intermedia

Question 14

Describe hydrops fetalis

Answer 14

Sever, usually results in intrauterine death
All 4 alpha genes deleted
Excess gamma-globin forms tetramer in foetus (Hb Bart) that is unable to deliver oxygen to tissues

Question 15

What are beta0 and beta+?

Answer 15

Beta0 denotes total absence of production

Beta+ denotes reduction of globin production

Question 16

Describe beta thalassaemia minor or beta thalassaemia trait

Answer 16

Usually asymptomatic with mild anaemia (very microcytic and hypochromic RBCs)
Resembles alpha thalassaemia trait
Heterozygous with 1 normal and one abnormal gene (beta0/beta or beta+/beta)

Question 17

Describe beta-thalassaemia intermedia

Answer 17

Sever anaemia but not enough to require regular blood transfusions
Resembles haemoglobin H disease
Genetically heterozygous (can be homozygous, heterozygous or double heterozygous)

Question 18

Describe beta-thalassaemia major

Answer 18

Sever transfusion-dependent anaemia
Becomes manifest 6-9 months after birth as synthesis switches from HbF to HbA
Homozygous

Question 19

What with a peripheral blood smear from patient with severe thalassaemia typically show?

Answer 19

Hypochromic and microcytic RBCs

Anisopoikilocytosis with frequent target cells and circulating nucleated RBCs and Heinz bodies

Question 20

What does aggregation and oxidation of haemoglobin in thalassaemia cause?

Answer 20

Premature death or erthroid precursors within bone marrow leading to ineffective erythropoiesis
Excessive destruction of mature red cells in spleen leading to shortened RBC survival

Question 21

Why does extramedullary haemopoiesis occur in thalassaemia and what does it result in?

Answer 21

Body’s attempt to compensate but results in splenomegaly, hepatomegaly and expansion of haemopoiesis in bone cortex
This impairs growth and causes classical skeletal abnormalities

Question 22

What does reduced oxygen delivery in thalassaemia lead to?

Answer 22

Stimulation of EPO which further contributes to the drive to make more defective red cells

Question 23

Why does iron overload occur in thalassaemia?

Answer 23

Excessive absorption of dietary iron due to ineffective haematopoiesis
Repeated blood transfusions required to treat anaemia
Causes premature death

Question 24

What are the treatments for thalassaemia?

Answer 24

Red cell transfusion
Iron chelation (delays iron overload)
Folic acid (help support erythropoiesis)
Immunisation
Holistic care (cardiology, endocrine, physiological, ophthalmology)
Stem cell transplantation
Pre-conception counselling for at risk couples and antenatal screening

Question 25

What is sickle cell disease?

Answer 25

Autosomal recessive disease resulting from mutation of beta-globin gene GAG codon changed to GTG resulting in glutamic acid being substituted by valine Mutant haemoglobin molecule called Haemoglobin S

Question 26

Where is the HbS gene most commonly found?

Answer 26

Found in ~30% of W African population as it confer protection against malaria

Question 27

When do problems occur with sickle cell anaemia?

Answer 27

In low oxygen state (due to chest infection, when cold, vasoconstriction in peripheries etc) as deoxygenated HbS forms polymers that case red cells to form a sickle shape

Question 28

What is the problem with irreversible sickle red cells?

Answer 28

They are less deformable and can cause occlusion in small blood vessels (sticky)

Question 29

What are the 3 types of sickle cell crises?

Answer 29

Vaso-occlusive - painful bone crises, organ (chest, spleen) Aplastic (often triggered by parvovirus) Haemolytic End organ damage occurs as result of acute thromboses or O2 deprivation

Question 30

What can occlusion in small blood vessels cause?

Answer 30

``` Retinopathy Splenic atrophy Avascular necrosis Acute chest syndrome Stroke Kidney infarcts ```

Question 31

What inherited defects can cause haemolytic anaemia?

Answer 31

Glycolysis defect Pentose-P pathway Membrane protein Haemoglobin defect

Question 32

What acquired factors can cause haemolytic anaemia?

Answer 32

``` Mechanical damage Antibody damage Oxidant damage Heat damage Enzymatic damage ```

Question 33

Where can haemolysis occur?

Answer 33

``` Blood vessels (intravascular haemolysis) Spleen and wider RES (extravascular haemolysis) ```

Question 34

What are the key laboratory findings in haemolytic anaemia?

Answer 34

Raised reticulocytes Raised bilirubin Raised LDH

Question 35

What are the consequences of haemolytic anaemia?

Answer 35

Accumulation of bilirubin leading to jaundice and possible pigment gallstones Overworking red pulp leads to splenomegaly Massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery to tissues and hyperkalaemia due to release of intracellular contents

Question 36

What are the inherited effects in red cell membrane structure?

Answer 36

Hereditary spherocytosis Hereditary eliptocytosis Hereditary pyropoikilocytois

Question 37

Describe hereditary spherocytosis

Answer 37

Many cells take on spherical shape Ankyrin, spectrin, protein 4.2 or band 3 defects disrupt membrane-cytoskeletal interactions Cells less flexible and more easily damaged

Question 38

Describe hereditary eliptocytosis

Answer 38

Many cells elliptical rather than biconcave disc shape Spectrin defect most common Also defects in band 4.1, band 3 and glycophorin C proteins

Question 39

Describe hereditary pyropoikilocytosis

Answer 39

Spectrin defect Severe form of hereditary elliptocytosis Abnormal sensitivity of red cells to heat Similar morphology to that seen in thermal burns

Question 40

What acquired damage can cause haemolytic anaemias?

Answer 40

Microangiopathic haemolytic anaemias result from mechanical damage e.g. - sheer tress as cells pass through a defective heart valve - cells snagging on fibrin strands in small vessles where increased activation of clotting cascade has occurred Heat damage Osmotic damage Forms schistocytes

Question 41

What are autoimmune haemolytic anaemias?

Answer 41

Cause by antibodies brining to red cell membrane proteins Can result from infections or cancers of lymphoid system Classified as either warm (IgG) or cold (IgM) based on temperature antibodies react best at Spleen recognises antibody bound cells as abnormal and removes them Red cell lifespan reduced