Session 8 ILO's Haemolytic anaemias and Haemoglobinopathies Flashcards
Why might anaemia develop?
What is a haemoglobinopathy?
- A condition where there is abnormal synthesis of the globin chain
- Inherited disorders typically autosomal recessive
- Globin gene mutations alter
structure/function/stability
of the haemoglobin tetramer
DOUBLE CHECK
What do globin chain mutations do?
Globin gene mutations reduce expression of specific individual globin proteins resulting in an imbalance in the composition of the haemoglobin tetramer
What is the science behind sickle cell disease?
Abnormal globin chain variants with altered stability and/or function
What is the science behind thalassaemia?
Reduced or absent expression of normal globin chains
Explain the significance of sickle cell anaemia and
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
Appreciate the clinical manifestations of sickle cell anaemia
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
To be able to classify haemolytic anaemias into acquired and inherited types, and explain the underlying causes in each division
Inherited haemolytic anaemias (caused by a defective gene - come back to the causes when watch lecture):
- Glycolysis defect
- Pentose P pathway
- Membrane protein
- Haemoglobin defect
Acquired haemolytic anaemias (caused by damage to cells):
- Mechanical damage
- Antibody damage
- Oxidant damage
- Heat damage
- Enzymatic damage
Name the 4 major types of myeloproliferative neoplasm
- Essential Thrombocythaemia
- Polycythaemia Vera
- Myelofibrosis
- Chronic Myeloid Leukaemia
Describe Polycythaemia vera and explain how these arise
- 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
* Diagnostic criteria = High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass
* JAK2 V617F mutation is present in approximately 95% PRV patients
* No reactive cause found
* Some patients also have high platelets & neutrophils
* Median age 60 yrs
* Male=Female - Essential thrombocythaemia
- ET is associated with a proliferation of platelet precursors in the bone marrow, leading to increased platelet production - 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 - 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
Describe Essential thrombocythaemia and explain how these arise
Describe Myelofibrosis and explain how these arise
Describe Chronic myeloid leukaemia and explain how these arise
Explain how acquired thrombocytopenia may arise and appreciate the clinical signs of this condition
There are 3 ways in which acquired thrombocytopenia may arise
- Decreased platelet production
- B12 or folate deficiency
- Acute leukaemia or aplastic anaemia
- Liver failure
- Sepsis
- Cytotoxic chemotherapy - Increased platelet consumption
- Massive haemorrhage
- DIC
- Thrombotic thrombocytopenia purpura - 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
Explain the haematological abnormalities of patients with haemoglobinopathies - alpha and beta thalassaemia trait
Explain the complications of sickle cell disease
