Myeloproliferative Disorders Flashcards
What controls haemopoiesis?
Growth factors (e.g. EPO)
Receptors (mainly tyrosine kinases)
- What are Janus Kinases?
A family of four tyrosine kinase receptors associated with haemopoietic cell growth factor receptors
- 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.
Preponderance 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:
a. Myeloproliferative disorder
b. Leukaemia
c. Myelodysplastic syndrome
a. Proliferation with full differentiation
b. Proliferation with little/no differentiation
c. 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 presence 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 < 400 x 109/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)
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 haemopoiesis
- 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 treatment 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 other mutations of JAK 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:
a. Polycythaemia vera
b. Essential thrombocythaemia
c. Myelofibrosis
a. Not needed in PV with JAK 2 mutations
b. May be helpful if JAK 2 negative
c. Always needed
