S5 Haemiglobinopathies and Haemolytic Anaemias

Question 1

Why might anaemia develop?

Answer 1

1. Linked to the bone marrow - reduced/dysfunctional erythropoiesis, abnormal haem synthesis, abnormal globin chain synthesis
2. Linked to the peripheral RBCs - abnormal structure, mechanical damage, abnormal metabolism
3. Excessive bleeding
4. Linked to removal - increased removal by the RES

Question 2

What are haemoglobinopathies?

Answer 2

Inherited, usually autosomal recessive, globin chain mutations that alter the structure/function/stability of the haemoglobin tetramer

Question 3

What are two examples of haemoglobinopathies?

Answer 3

1. Sickle cell anaemia (abnormal chain variants with altered stability and/or function)
2. Thalassaemias (reduced/absent expression of normal globin chains)

Question 4

What are the 3 major types of haemoglobin in adults (in order of amount present) and what are their globin chains?

Answer 4

1. HbA (2 alpha, 2 beta)
2. HbA2 (2 alpha, 2 delta)
3. HbF (2 alpha, 2 gamma)

Question 5

Why do humans have different Hb expressed at different times in development?

Answer 5

As an adaptive response to variations in oxygen requirements

Question 6

What chromosome are the alpha and beta globin chains on? How many copies of each are on the chromosomes?

Answer 6

Alpha - chromosome 16 - 2 on maternal, 2 on paternal so 4 in total)
Beta - chromosome 11 - 1 on each chromosome so 2 in total

Question 7

In which populations are thalassaemias more prevalent?

Answer 7

South Asian, Mediterranean, Middle Eastern (beta)
Far East (alpha)

Question 8

What are the 4 types of alpha-Thalassaemia? How many genes are deleted from each?

Answer 8

1. Silent carrier state (1 gene)
2. Alpha-Thalassaemia trait (2 genes)
3. Haemoglobin H (HbH) disease (3 genes)
4. Hydros fetalis (4 genes)

Question 9

Describe silent carrier alpha-Thalassaemia.

Answer 9

It is asymtomatic.

The person is a carrier of the disease without symptoms

Question 10

Describe alpha-Thalassaemia trait. What is it’s severity? What are the RBCs like?

Answer 10

Both genes on one chromosome 16, or one gene on each chromosome are deleted.

Minimal/no anaemia

Microcytic and hypochromic

Question 11

Describe Haemoglobin H (HbH) disease. What is it’s severity? What are the RBCs like?

Answer 11

Moderately severe

RBCs are microcytic, hypochromic and there are target cells and Heinz bodies

Question 12

Describe hydrops fetalis. What is it’s severity?

Answer 12

All 4 alpha genes are deleted, so excess gamma-globin forms tetramers in foetus (Hb Bart) - this is unable to deliver oxygen to tissues

Severe - usually results in intrauterine death

Question 13

In beta-Thalassaemias, is the disease often caused by deletion or gene mutation?

Answer 13

Gene mutation

Question 14

What are the 3 types of Beta-Thalassaemia?

Answer 14

1. Beta-Thalassaemia minor/Beta-Thalassaemia trait
2. Beta-Thalassaemia intermedia
3. Beta-Thalassaemia major

Question 15

What is the severity and genotype of Beta-Thalassaemia minor/Beta-Thalassaemia trait?

Answer 15

Severity - usually asymptomatic with mild anaemia (very microcytic and hypochromic RBCs)

Genotype - heterozygous with 1 normal, 1 abnormal gene

Question 16

What do Beta0 and Beta+ mean?

Answer 16

Beta0 - total absence of product

Beta+ - reduction of globin production

Question 17

What is the severity and genotype of Beta-Thalassaemia intermedia?

Answer 17

Severity - sever anaemia (not enough to need regular blood transfusions)

Genotype - heterozygous (can be mild variants of homozygous, severe variants of heterozygous or double heterozygous)

Question 18

What is the severity and genotype of Beta-Thalassaemia major?

Answer 18

Severity - severe transfusion-dependent anaemia (manifests 6-9 months after birth as synthesis switches from HbF to HbA)

Genotype - homozygous

Question 19

What will a blood smear show for a patient with Thalassaemia?

Answer 19

• hypocromic and microcytic RBCs - due to low Hb
• anisopoikilocytosis
• target cells
• nucleated RBCs
• Heinz bodies

Question 20

How do unaffected globin chains contribute to the defective nature of the RBC?

Answer 20

If in excess, insoluble aggregates of alpha chains form in Beta-Thalassaemia.
These Hb aggregates are oxidised and lead to premature death of erythroid precursors in bone marrow (ineffective erythropoiesis) and excessive destruction of mature RBCs i the spleen (shorter RBC survival) - haemolytic anaemia as was all thalassaemia

Question 21

What are the consequences of Thalassaemia?

Answer 21

• extramedullary haemopoiesis occurs to compensate which results in splenomegaly, hepatomegaly and expansion of haemopoiesis into the bone cortex (impairs growth and causes classical skeletal abnormalities)
• reduced oxygen delivery results in stimulation of EPO contributes to the drive to make more defective RBCs
• iron overload due to excessive absorption of dietary iron due to ineffective haemopoeisis and repeated blood transfusions being required to treat the disease
• reduced life expectancy

Question 22

How can you treat Thalassaemia?

Answer 22

• RBC transfusion from childhood
• iron chelation to delay the iron overload
• folic acid to support erythropoiesis
• immunisation
• holistic care to manage complications
• stem cell transplantation for some to replace defective RBC production
• preconception counselling for at risk couples and antenatal screening

Question 23

How does sickle cell disease arise?

Answer 23

Autosomal recessive disease resulting from a mutation of the beta-globin gene - GAG codon changed to GTG - so glutamate is substituted by valine - mutated Hb molecule is called HbS

Question 24

What is the anaemia like if you are heterozygous for HbS?

Answer 24

Mild asymptomatic anaemia

Question 25

Why do about 30% of the West African population have the HbS gene?

Answer 25

It protects against malaria (example of natural selection)

Question 26

What is HbSS?

Answer 26

Homozygous sickle cell anaemia, it is the most common cause of severe sickling syndrome

Question 27

Describe how HbS can be co-inherited?

Answer 27

Can be co-inherited with another abnormal Hb e.g. with beta-Thalassaemia (HbS Beta-Thal) which causes a sickling disorder

Question 28

Why is the anaemia usually mild in someone with sickle cell disease?

Answer 28

As HbS readily gives up oxygen in comparison to HbA

Question 29

When do problems arise if someone has sickle cell disease?

Answer 29

In low oxygen states - deoxygenated HbS forms polymers that cause RBCs to form a sickle shape (usually reversible but if many sickling cycles can become irreversible)

Question 30

What do irreversible sickle cells cause?

Answer 30

They are less deformable and so can cause occlusion in small blood vessels

Question 31

What are the 3 types of crises with sickle cell anaemia?

Answer 31

* vaso-occlusive (most common) * aplastic (often triggered by parvovirus) * haemolytic

Question 32

What 9 things can vaso-occlusion cause?

Answer 32

* retinopathy * splenic atrophy * avascular necrosis * acute chest syndrome * stroke * osteomyelitis * skin ulcers * kidney infarcts * priapism (constant penile erection)

Question 33

How is sickle cell disease treated?

Answer 33

* folic acid * penicillin and vaccinations (due to being hyposplenic) * hydroxycarbamide - increased HbF levels and other effects * red cell exchange

Question 34

What two ways can haemolytic anaemias arise?

Answer 34

* inherited due to a defective gene | * acquired due to damage to cells

Question 35

Where can haemolysis occur?

Answer 35

* in blood vessels - intravascular haemolysis | * in the spleen and wider RES - extravascualr haemolysis

Question 36

Can bone marrow compensate against haemolysis?

Answer 36

It can by increasing production, but only up to a point (6 fold before reaches this point) and then anaemia develops

Question 37

What are 4 ways a defective gene can cause haemolytic anaemia?

Answer 37

* glycolysis defect (pyruvate kinase deficiency limiting ATP production) * pentose phosphate pathway (G6PDH deficiency leads to oxidative damage) * membrane protein (hereditary spherocytosis) * haemoglobin defect (sickle cell disease)

Question 38

What are 5 ways a damage to cells can cause haemolytic anaemia?

Answer 38

* mechanical damage (microangiopathic anaemia) * antibody damage (autoimmune haemolytic anaemia) * oxidant damage (exposure to chemicals/oxidants) * heat damage (severe burns) * enzymatic damage (snake venom)

Question 39

What laboratory findings are found with haemolytic anaemias?

Answer 39

* raised reticulocytes as the bone marrow is trying to compensate * raised bilirubin due to break down of Haem * raised LDH as RBCs are rich in this enzyme

Question 40

What issues arise from bilirubin accumulation?

Answer 40

Jaundice and associated risk of complications like pigment gallstones (made up of bilirubin and calcium salts)

Question 41

How does haemolysis cause cardiac arrest?

Answer 41

If the haemolysis is sudden and massive

Question 42

What are 3 inherited defects in RBC membrane structure?

Answer 42

* hereditary spherocytosis * hereditary eliptocytosis * hereditary pyropoikilocytosis

Question 43

What is hereditary spherocytosis?

Answer 43

Cells take on a spherical shape due to ankyrin, spectrin, protein 4.2 or band 3 defects which disrupt the membrane-cytoskeletal interactions. The cells are less flexible and so are more easily damaged

Question 44

What is hereditary eliptocytosis? What is the most common defect?

Answer 44

Cells are elliptical rather than biconcave disc shape Spectrin defect (but can also have defects in band 4.1, band 3 and glycophorin C proteins

Question 45

What is hereditary pyropoikilocytosis? What do the cells have an abnormal sensitivity to?

Answer 45

A spectrin defect - severe form of hereditary eliptocytosis Cells have an abnormal sensitivity to heat

Question 46

How do microangiopathic haemolytic anaemias result from mechanical damage?

Answer 46

Due to shear stress as the cell passes through a defective heart valve (e.g. aortic valve stenosis) Or cells snag on fibrin strands in small vessels where increased activation of the clotting cascade has occurred (e.g. disseminated intravascular coagulation (DIT))

Question 47

What are schistocytes?

Answer 47

Fragments resulting from mechanical damage It is an indicator that some sort of pathology is present

Question 48

How do autoimmune haemolytic anaemias arise?

Answer 48

Autoantibodies bind to RBC membrane proteins (result from infections or cancers of the lymphatic system). The spleen recognises the antibody bound cells as abnormal and removes them so the RBC lifespan is reduced so anaemia develops

Question 49

How are autoantibodies IgG and IgM classed in haemolysis?

Answer 49

IgG - warm IgM - cold Based off temps antibodies react best at