Haem: CML and myeloproliferative disorders Pt.1 Flashcards
What is polycythaemia?
A condition characterised by raised Hb concentration and raised haematocrit.
What are the two main types of polycythaemia?
Relative - caused by a lack of plasma (associated with alcoholism, obesity and diuretics)
True - caused by an excess of erythrocytes
What is secondary polycythaemia and what can cause it?
- Polycythaemia that occurs due to excessive stimulation by EPO (there is no problem with the bone marrow itself)
- Appropriate causes: high altitude, hypoxic lung disease, cyanotic heart disease, high affinity haemoglobin
- Inappropriate causes: renal disease (cysts, tumours), uterine myoma, other tumours
How can myeloproliferative neoplasms be broadly categorised?
- Philadelphia positive: CML
- Philadelphia negative: polycythaemia vera, essential thrombocythaemia, primary myelofibrosis
What are the two processes that cell undergo as they develop and how are these different in acute and chronic leukaemia?
- Two processes: differentiation + proliferation
- Chronic leukaemia: differentiation is intact (produces mature cells) + proliferation is excessive and abnormal
- Acute leukaemia: differentiation is abnormal (cells have lost the ability to mature) + proliferation is excessive and abnormal
What are the main types of myeloid malignancy?
- Acute myeloid leukaemia (blasts >20%)
- Myelodysplastic syndromes (blasts 5-19%)
- Chronic myeloid leukaemia
- Myeloproliferative disorders
Mutations in which genes are commonly associated with the development of myeloproliferative disorders?
Tyrosine kinase
What is the normal physiological role of tyrosine kinase?
- Transmit cell growth signals from cell surface receptors to the nucleus
- They are activated by transferring phosphate groups to itself and downstream proteins
- They promote cell growth but they do NOT affect maturation
Name three genes that are associated with myeloproliferative disorders.
- JAK2 (V617F)
- Calreticulin
- MPL
Which conditions is defined by the presence of Jak2?
100% of polycythaemia vera has JAK2 V617F mutation
NOTE: it is also found in 60% of primary myelofibrosis and essential thrombocythaemia
What is the normal physiological role of JAK2? How is this different in polycythaemia vera?
- It is a tyrosine kinase that is normally bound to the inactive EPO receptor. When EPO binds to the receptor, the receptor dimersises, autophosphorylates and phosphorylates JA2 which promotes cell proliferation.
- Mutated JAK2 is constitutively active in the absence of EPO thereby driving cell replication in the absence of a stimulus.
What is the diagnosis of myeloproliferative disorders based on?
- Clinical features (splenomegaly is particularly important)
- FBC
- Bone marrow biopsy
- EPO level
- Mutation testing
Outline the typical presentation of polycythaemia vera?
- Often incidental
- Hyperviscosity: headaches, visual disturbance, stroke, fatigue, dyspnoea, light-headedness
- Increased histamine release: aquagenic pruritis, peptic ulceration
Outline the principles of treatment of polycythaemia vera.
- Reduce haematocrit (aim for <45%) - venesection, cytoreductive therapy (hydroxycarbamide)
- Reduce thrombosis risk - control Hct, aspirin, keep platelets < 400x109/L
What is essential thrombocythaemia?
Chronic myeloproliferative disorder mainly involving the megakaryocyte lineage
Characterised by sustained thrombocytosis > 600 x109/L
