Session 5 ILOs - Haemolytic anaemia and haemoglobinopathies and haemopoesis gone wrong

Question 1

Explain the significance (consequences) of sickle cell anaemia and appreciate the clinical manifestations of the disease

Answer 1

The HbS variant has an uncharged valine instead of a charged glutamic acid, making haemoglobin S more prone to polymerise at low oxygen tension. This leads to the formation of long twisted haemoglobin polymers that can result in the deformation the red blood cell membrane leading to the cell taking on a sickle shape.

After repeated episodes of sickling, damage occurs to the red cell membrane causing it to lose elasticity. Such damaged cells fail to return to a normal shape when normal oxygen tension is restored.

Consequences of sickle cell anaemia:

1. Vaso-occlusive episodes due to occlusion of small capillaries from sickle cells getting trapped
2. Anaemia due to sickle cells undergoing haemolysis resulting in a shortened erythrocyte lifespan from ~120 days to ~20-30 days
3. Jaundice and gallstones due to increased bilirubin resulting from chronic haemolysis
4. Splenic atrophy due to splenic infarction with an associated susceptibility to infection by encapsulated bacteria

Clinical manifestations:

• Due to the vasoocclusive episodes, they can have recurrent acute, severe pain and syndromes such as stroke or acute chest syndrome as well as chronic kidney disease and joint damage from avascular necrosis
• Classic symptoms from anaemia (e.g. SOB, pale etc.)
• Jaundice due to increased bilirubin

Question 2

Explain the haematological abnormalities of patients with haemoglobinopathies (e.g. alpha and beta thalassaemia trait) and explain the important clinical features and complications of these disorders

Answer 2

Haematological abnormalities - the thalassaemias:
Result from reduced or absent expression of normal α or β-globin chains. This leads to a reduced level of haemoglobin rather than the presence of an abnormal haemoglobin.

Alpha thalassaemia trait:
α-thalassaemia results from deletion or loss of function of one or more of the four α globin genes (number of affected genes affects the severity of the thalassaemia)
1. Silent carrier state (1 gene deleted = asymptomatic)
2. a-thalassaemia trait (2 genes deleted = minimal or no anaemia)
- Microcytosis and hypochromia of RBCs
3. Haemoglobin H disease (3 genes deleted = moderately severe)
- Microcytic, hypochromic anaemia with target cells and Heinz bodies
4. Hydrops fetalis (4 genes deleted = fatal)
- Excessive y-globin forms tetramers in foetus, unable to deliver oxygen to tissues

Beta thalassaemia trait:
Disease often caused by mutation rather than deletion
1. Beta-thalassaemia minor/trait (heterozygous with 1 normal and 1 abnormal = usually asymptomatic with mild anaemia)
2. Beta-thalassaemia intermedia (heterogenous = severe anaemia, but not enough for transfusions)
3. Beta-thalassaemia major (homozygous = severe transfusion dependent anaemia)

Question 3

Classify the haemolytic anaemias into acquired and inherited types

Answer 3

Inherited haemolytic anaemias:

• Glycolysis defect
• Pentose P pathway
• Membrane protein
• Haemoglobin defect

Acquired haemolytic anaemias:

• Mechanical damage
• Antibody damage
• Oxidant damage
• Heat damage
• Enzymatic damage

Question 4

Describe the 4 major types of myeloproliferative neoplasm and explain how these arise

Answer 4

1. Polycythaemia vera
   - Due to overproduction of RBCs due to abnormality of bone marrow due to JAK2 V617F mutation (present in 95% of patients)
   - Just polycythaemia is either relative (due to a decrease in plasma volume) or absolute (increase in RBCs)
   - Need to figure out if it is primary (polycythaemia vera) or secondary to another condition
2. Essential thrombocythaemia
   - ET is associated with a proliferation of platelet precursors in the bone marrow, leading to increased platelet production
3. Myelofibrosis
   - Characterised by haemopoetic-derived clonal proliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations
   - Starts with proliferative phase when all cell counts are high, then pancytopenia occurs due to bone marrow fibrosis and hypersplenism
   - Can be primary disease or secondary to polycythaemia vera or essential thrombocythaemia
4. Chronic myeloid leukaemia
   - Usually presents with very high white cell count resulting from the uncontrolled proliferation of mature granulocytes and their precursors
   - CML is linked to a genetic abnormality known as the Philadelphia chromosome, which involves a translocation of the chromosome

Question 5

Explain how acquired thrombocytopenia may arise and appreciate the clinical signs of this condition

Answer 5

There are 3 ways in which acquired thrombocytopenia may arise

1. Decreased platelet production
   - B12 or folate deficiency
   - Acute leukaemia or aplastic anaemia
   - Liver failure
   - Sepsis
   - Cytotoxic chemotherapy
2. Increased platelet consumption
   - Massive haemorrhage
   - DIC
   - Thrombotic thrombocytopenia purpura
3. Increase platelet destruction
   - Autoimmune thrombocytopenia purpura
   - Drug induced
   - Hypersplenism (destruction and pooling of platelets)

Clinical signs:

• Only symptomatic after platelet count <30
• Easy bruising
• Petechiae / purpura
• Mucosal bleeding (mouth, back of eye etc.)
• Severe bleeding after trauma
• Intracranial haemorrhage