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YEAR 5: Haematology AS > Haem: Myeloproliferative Disorders > Flashcards

Haem: Myeloproliferative Disorders Flashcards

1
Q

What controls haemopoisesis?

A

Growth factors (e.g. EPO)

Receptors (mainly tyrosine kinases)

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2
Q

What are Janus Kinases?

A

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

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3
Q

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

A
  • 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
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4
Q

What is a chronic myeloproliferative disorder?

A
  • 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
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5
Q

Outline the usual presentation of myeloproliferative disorders.

A
  • Preponderance to thrombosis
  • Splenomegaly
  • Haemorrhage
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6
Q

List some chronic myeloproliferative disorders.

A
  • Polycythaemia vera
  • Essential thrombocythaemia
  • Idiopathic myelofibrosis
  • Idiopathic erythrocytosis
  • Chronic granulocytic leukaemia
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7
Q

What are the key differences between:

  1. Myeloproliferative disorder
  2. Leukaemia
  3. Myelodysplastic syndrome
A
  1. Myeloproliferative disorder = proliferation with full differentiation
  2. Leukaemia = proliferation with little/no differentiation
  3. Myelodysplastic syndrome = abnormal proliferation and abnormal differentiation
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8
Q

What is polycythaemia vera?

A
  • 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
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9
Q

Describe the clinical presentation of polycythaemia vera.

A
  • 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
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10
Q

Outline the typical investigation findings in polycythaemia vera.

A
  • High haemoglobin, Hct, MCV, plasma volume and platelets
  • NO circulating immature cells
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11
Q

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

A
  • Increased cellularity (mainly erythroid cells)
  • Slight reticulin fibrosis and megakaryocyte abnormalities
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12
Q

What investigation finding is considered diagnostic of polycythaemia vera?

A

Presence of JAK 2 V617F mutation

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13
Q

How is red cell mass and plasma volume measured?

A
  • Isotope dilution
  • Red cells are incubated with radioactive chromium
  • Plasma is incubated with radioactive iodine
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14
Q

What is pseudopolycythaemia?

A

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

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15
Q

On which exon is the JAK2 V617F mutation found?

A

Exon 14

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16
Q

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

A

Exon 12 mutation

It is associated with idiopathic erythrocytosis

17
Q

What are some causes of JAk 2 V617F negative polycythaemia?

A
  • Pseudopolycythaemia
  • True polycythaemia that is secondary to increased EPO (e.g. hypoxia, renal disease, tumours)
18
Q

Outline the principles of treatment of polycythaemia vera.

A

Reduce viscosity and keep Hct <45%

  • Venesection
  • Cytoreductive therapy

Aim to reduce risk of thrombosis

  • Aspirin
  • Keep platelets <400x109/L (same as ET treatment)
19
Q

What is idiopathic erythrocytosis?

A
  • Isolated erythrocytosis with low EPO
  • Treated with venesection only
  • NO JAK 2 V617F mutation, but some cases will have an exon 12 mutation
20
Q

Outline the prognosis of idiopathic erythrocytosis and polycythaemia vera.

A
  • Idiopathic erythrocytosis - no adverse prognosis if Hct is maintained
  • Polycythaemia vera - most survive 10 years, causes of death include thrombosis, leukaemia and myelofibrosis
21
Q

What is essential thrombocythaemia?

A

Myeloproliferative disorder mainly involving the megakaryocyte lineage (platelet count > 600 x 109/L)

22
Q

Describe the typical clinical presentation of essential thrombocythaemia.

A
  • Incidental finding
  • Thrombosis (e.g. CVA, DVT, gangrene)
  • Bleeding
  • Headaches, dizziness and visual disturbances
23
Q

What proportion of essential thrombocythaemia patients have JAK 2 mutations?

A

50%

24
Q

Outline the treatment options for essential thrombocythaemia.

A
  • 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)
25
Q

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

A

Age (old age = higher risk)

Also platelet count and whether symptomatic or not

26
Q

Describe the prognosis of essential thrombocythaemia.

A
  • Normal life span
  • Leukaemic transformation in about 5% of patients after 10 years
  • Myelofibrosis is uncommon
27
Q

Define chronic idiopathic myelofibrosis.

A

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

28
Q

Describe the typical clinical presentation of myelofibrosis.

A
  • Incidental finding
  • Cytopaenias
  • Thrombocytosis
  • Splenomegaly (can be MASSIVE)
  • Hepatomegaly
  • FLAWS
  • Gout
29
Q

Describe the two stages of myelofibrosis.

A
  • Pre-fibrotic = blood changes are mild with hypercellular marrow
  • Fibrotic = splenomegaly, blood changes, dry tap, prominent fibrosis and later osteosclerosis
30
Q

Describe the appearance of myelofibrosis on a blood film.

A
  • Leukoerythroblastic picture
  • Tear drop poikilocytes
31
Q

What are some features of the bone marrow in myelofibrosis?

A
  • Dry tap
  • Trephine biopsy will show increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and new bone formation
32
Q

Outline the treamtent options for myelofibrosis.

A
  • Symptomatic treatment (e.g. transfusions for anaemia)
  • Splenectomy
  • Cytoreductive therapy (hydroxycarbamide and thalidomide)
  • Bone marrow transplant (in younger patients)
33
Q

Describe the prognosis of myelofibrosis.

A

Median 3-5 year survival

34
Q

Describe the structure of janus kinases.

A

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

35
Q

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

A

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

36
Q

Which mutations, other than JAK 2 V617F, have been associated with myeloproliferative diseases?

A
  • Exon 12 mutation of the JAK2 gene
  • Mutations in thrombopoietin receptors

NOTE: many patients have NO known mutations

37
Q

Describe the use of bone marrow examination in:

  1. Polycythaemia vera
  2. Essential thrombocythaemia
  3. Myelofibrosis
A
  1. Polycythaemia vera - not needed in PV with JAK 2 mutations
  2. Essential thrombocythaemia - may be helpful if JAK 2 negative
  3. Myelofibrosis - always needed

YEAR 5: Haematology AS (20 decks)

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