Haem: Myeloproliferative Disorders Flashcards
What controls haemopoisesis?
Growth factors (e.g. EPO)
Receptors (mainly tyrosine kinases)
What are Janus Kinases?
A family of four tyrosine kinase receptors assocaited with haemopoietic cell growth factor receptos
Describe what happens when growth factors bind to Janus Kinase receptors.
- Binding of the growth factors leads to activation of JAK, which activates the STAT pathway
- STAT is a transcription factor that moves to the nucleus and promotes the transcription of genes associated with cell growth and proliferation
What is a chronic myeloproliferative disorder?
- A group of clonal disorders of haemopoietic stem cells characterised by the overproduction of one or more mature myeloid cellular elements in the blood
- There is a trend towards increased fibrosis in the bone marrow
- Some cases will develop into acute leukaemia
Outline the usual presentation of myeloproliferative disorders.
- Predisposed to thrombosis
- Splenomegaly
- Haemorrhage
List some chronic myeloproliferative disorders.
- Polycythaemia vera
- Essential thrombocythaemia
- Idiopathic myelofibrosis
- Idiopathic erythrocytosis
- Chronic granulocytic leukaemia
What are the key differences between:
- Myeloproliferative disorder
- Leukaemia
- Myelodysplastic syndrome
- Myeloproliferative disorder = proliferation with full differentiation
- Leukaemia = proliferation with little/no differentiation
- Myelodysplastic syndrome = abnormal proliferation and abnormal differentiation
What is polycythaemia vera?
- A myeloproliferative disorder characterised by increased production of red cells (independent of normal control mechanisms) with a compensatory increase in plasma volume
- Often accompanied by a degree of increased platelets and granulocytic cells
Describe the clinical presentation of polycythaemia vera.
- Incidental finding
- Symptoms of hyperviscosity (headaches, visual disturbances, fatigue, dyspnoea)
- Increased histamine release (Aquagenic pruritus, peptic ulceration)
- Splenomegaly
- Plethora
- Erythromelalgia (red painful extremities)
- Thrombosis
- Retinal vein engorgement
- Gout
Outline the typical investigation findings in polycythaemia vera.
- High haemoglobin, Hct, MCV, plasma volume and platelets
- NO circulating immature cells
Describe the appearance of a bone marrow biopsy in polycythaemia vera.
- Increased cellularity (mainly erythroid cells)
- Slight reticulin fibrosis and megakaryocyte abnormalities
What investigation finding is considered diagnostic of polycythaemia vera?
Presence of JAK 2 V617F mutation
How is red cell mass and plasma volume measured?
- Isotope dilution
- Red cells are incubated with radioactive chromium
- Plasma is incubated with radioactive iodine
What is pseudopolycythaemia?
Reduced plasma volume in the present of a normal amount of haemoglobin results in an apparently raised Hb
On which exon is the JAK2 V617F mutation found?
Exon 14
Which other JAK mutation is a significant finding and which condition is it associated with?
Exon 12 mutation
It is associated with idiopathic erythrocytosis
What are some causes of JAk 2 V617F negative polycythaemia?
- Pseudopolycythaemia
- True polycythaemia that is secondary to increased EPO (e.g. hypoxia, renal disease, tumours)
Outline the principles of treatment of polycythaemia vera.
Reduce viscosity and keep Hct <45%
- Venesection
- Cytoreductive therapy
Aim to reduce risk of thrombosis
- Aspirin
- Keep platelets <400x109/L (same as ET treatment)
What is idiopathic erythrocytosis?
- Isolated erythrocytosis with low EPO
- Treated with venesection only
- NO JAK 2 V617F mutation, but some cases will have an exon 12 mutation
Outline the prognosis of idiopathic erythrocytosis and polycythaemia vera.
- Idiopathic erythrocytosis - no adverse prognosis if Hct is maintained
- Polycythaemia vera - most survive 10 years, causes of death include thrombosis, leukaemia and myelofibrosis
What is essential thrombocythaemia?
Myeloproliferative disorder mainly involving the megakaryocyte lineage (platelet count > 600 x 109/L)
Describe the typical clinical presentation of essential thrombocythaemia.
- Incidental finding
- Thrombosis (e.g. CVA, DVT, gangrene)
- Bleeding
- Headaches, dizziness and visual disturbances
What proportion of essential thrombocythaemia patients have JAK 2 mutations?
50%
Outline the treatment options for essential thrombocythaemia.
- Aspirin
- Anagrelide (specific inhibitor of platelet formation - may accelerate myelofibrosis)
- Hydroxycarbamide (MAIN TREATMENT - may be leukaemogenic)
- Alpha-interferon (may be used in patients < 40 years)
What factor is important in determining risk level in patients with essential thrombocythaemia?
Age (old age = higher risk)
Also platelet count and whether symptomatic or not
Describe the prognosis of essential thrombocythaemia.
- Normal life span
- Leukaemic transformation in about 5% of patients after 10 years
- Myelofibrosis is uncommon
Define chronic idiopathic myelofibrosis.
A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haemopoesis
Describe the typical clinical presentation of myelofibrosis.
- Incidental finding
- Cytopaenias
- Thrombocytosis
- Splenomegaly (can be MASSIVE)
- Hepatomegaly
- FLAWS
- Gout
Describe the two stages of myelofibrosis.
- Pre-fibrotic = blood changes are mild with hypercellular marrow
- Fibrotic = splenomegaly, blood changes, dry tap, prominent fibrosis and later osteosclerosis
Describe the appearance of myelofibrosis on a blood film.
- Leukoerythroblastic picture
- Tear drop poikilocytes
What are some features of the bone marrow in myelofibrosis?
- Dry tap
- Trephine biopsy will show increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and new bone formation
Outline the treamtent options for myelofibrosis.
- Symptomatic treatment (e.g. transfusions for anaemia)
- Splenectomy
- Cytoreductive therapy (hydroxycarbamide and thalidomide)
- Bone marrow transplant (in younger patients)
Describe the prognosis of myelofibrosis.
Median 3-5 year survival
Describe the structure of janus kinases.
They have a kinase domain and a catalytically inactive pseudokinase domain with regulatory function
What effect does the JAK 2 V617F mutation have on janus kinases?
It inactivates the pseudokinase domain thereby removing inhibition of activation so it becomes constitutively activated.
Which mutations, other than JAK 2 V617F, have been associated with myeloproliferative diseases?
- Exon 12 mutation of the JAK2 gene
- Mutations in thrombopoietin receptors
NOTE: many patients have NO known mutations
Describe the use of bone marrow examination in:
- Polycythaemia vera
- Essential thrombocythaemia
- Myelofibrosis
- Polycythaemia vera - not needed in PV with JAK 2 mutations
- Essential thrombocythaemia - may be helpful if JAK 2 negative
- Myelofibrosis - always needed
