Myeloproliferative Disorders

Question 1

What controls haemopoiesis?

Answer 1

Growth factors (e.g. EPO)

Receptors (mainly tyrosine kinases)

Question 2

2. What are Janus Kinases?

Answer 2

A family of four tyrosine kinase receptors associated with haemopoietic cell growth factor receptors

Question 3

3. Describe what happens when growth factors bind to Janus Kinase receptors.

Answer 3

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

Question 4

4. What is a chronic myeloproliferative disorder?

Answer 4

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

Question 5

5. Outline the usual presentation of myeloproliferative disorders.

Answer 5

Preponderance to thrombosis

Splenomegaly

Haemorrhage

Question 6

6. List some chronic myeloproliferative disorders.

Answer 6

Polycythaemia vera

Essential thrombocythaemia

Idiopathic myelofibrosis

Idiopathic erythrocytosis

Chronic granulocytic leukaemia

Question 7

7. What are the key differences between:
   a. Myeloproliferative disorder
   b. Leukaemia
   c. Myelodysplastic syndrome

Answer 7

a. Proliferation with full differentiation
b. Proliferation with little/no differentiation
c. Abnormal proliferation and abnormal differentiation

Question 8

8. What is polycythaemia vera?

Answer 8

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

Question 9

9. Describe the clinical presentation of polycythaemia vera.

Answer 9

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

Question 10

10. Outline the typical investigation findings in polycythaemia vera.

Answer 10

High haemoglobin, Hct, MCV, plasma volume and platelets

NO circulating immature cells

Question 11

11. Describe the appearance of a bone marrow biopsy in polycythaemia vera.

Answer 11

Increased cellularity (mainly erythroid cells)

Slight reticulin fibrosis and megakaryocyte abnormalities

Question 12

12. What investigation finding is considered diagnostic of polycythaemia vera?

Answer 12

Presence of JAK 2 V617F mutation

Question 13

13. How is red cell mass and plasma volume measured?

Answer 13

Isotope dilution

Red cells are incubated with radioactive chromium

Plasma is incubated with radioactive iodine

Question 14

14. What is pseudopolycythaemia?

Answer 14

Reduced plasma volume in the presence of a normal amount of haemoglobin results in an apparently raised Hb

Question 15

15. On which exon is the JAK2 V617F mutation found?

Answer 15

Exon 14

Question 16

16. Which other JAK mutation is a significant finding and which condition is it associated with?

Answer 16

Exon 12 mutation

It is associated with idiopathic erythrocytosis

Question 17

17. What are some causes of JAK 2 V617F negative polycythaemia?

Answer 17

Pseudopolycythaemia

True polycythaemia that is secondary to increased EPO (e.g. hypoxia, renal disease, tumours)

Question 18

18. Outline the principles of treatment of polycythaemia vera.

Answer 18

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)

Question 19

19. What is idiopathic erythrocytosis?

Answer 19

Isolated erythrocytosis with low EPO

Treated with venesection only

NO JAK 2 V617F mutation, but some cases will have an exon 12 mutation

Question 20

20. Outline the prognosis of idiopathic erythrocytosis and polycythaemia vera.

Answer 20

Idiopathic erythrocytosis – no adverse prognosis if Hct is maintained

Polycythaemia vera – most survive 10 years, causes of death include thrombosis, leukaemia and myelofibrosis

Question 21

21. What is essential thrombocythaemia?

Answer 21

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)

Question 22

22. Describe the typical clinical presentation of essential thrombocythaemia.

Answer 22

Incidental finding

Thrombosis (e.g. CVA, DVT, gangrene)

Bleeding

Headaches, dizziness and visual disturbances

Question 23

23. What proportion of essential thrombocythaemia patients have JAK 2 mutations?

Answer 23

50%

Question 24

24. Outline the treatment options for essential thrombocythaemia.

Answer 24

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)

Question 25

25. What factor is important in determining risk level in patients with essential thrombocythaemia?

Answer 25

Age (old age = higher risk) Also platelet count and whether symptomatic or not

Question 26

26. Describe the prognosis of essential thrombocythaemia.

Answer 26

Normal life span Leukaemic transformation in about 5% of patients after 10 years Myelofibrosis is uncommon

Question 27

27. Define chronic idiopathic myelofibrosis.

Answer 27

A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haemopoiesis

Question 28

28. Describe the typical clinical presentation of myelofibrosis.

Answer 28

Incidental finding Cytopaenias Thrombocytosis Splenomegaly (can be MASSIVE) Hepatomegaly FLAWS Gout

Question 29

29. Describe the two stages of myelofibrosis.

Answer 29

Pre-fibrotic = blood changes are mild with hypercellular marrow Fibrotic = splenomegaly, blood changes, dry tap, prominent fibrosis and later osteosclerosis

Question 30

30. Describe the appearance of myelofibrosis on a blood film.

Answer 30

Leukoerythroblastic picture Tear drop poikilocytes

Question 31

31. What are some features of the bone marrow in myelofibrosis?

Answer 31

Dry tap Trephine biopsy will show increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and new bone formation

Question 32

32. Outline the treatment options for myelofibrosis.

Answer 32

Symptomatic treatment (e.g. transfusions for anaemia) Splenectomy Cytoreductive therapy (hydroxycarbamide and thalidomide) Bone marrow transplant (in younger patients)

Question 33

33. Describe the prognosis of myelofibrosis.

Answer 33

Median 3-5 year survival

Question 34

34. Describe the structure of janus kinases.

Answer 34

They have a kinase domain and a catalytically inactive pseudokinase domain with regulatory function

Question 35

35. What effect does the JAK 2 V617F mutation have on janus kinases?

Answer 35

It inactivates the pseudokinase domain thereby removing inhibition of activation so it becomes constitutively activated

Question 36

36. Which other mutations of JAK have been associated with myeloproliferative diseases?

Answer 36

Exon 12 mutation of the JAK2 gene Mutations in thrombopoietin receptors NOTE: many patients have NO known mutations

Question 37

37. Describe the use of bone marrow examination in: a. Polycythaemia vera b. Essential thrombocythaemia c. Myelofibrosis

Answer 37

a. Not needed in PV with JAK 2 mutations b. May be helpful if JAK 2 negative c. Always needed