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Haematology > Polycythaemia and Myeloproliferative disorders > Flashcards

Polycythaemia and Myeloproliferative disorders Flashcards

1
Q

Define polycythaemia

A

Raised Hb and Hct

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2
Q

What is the difference between true and relative polycythaemia?

A
  • Relative (lack of plasma) - non-malignant
  • True (excess erthrocytes)
    • Secondary - reactive - elevated EPO (non-malignant)
    • Primary - reduced EPO (myeloproliferative neoplasm)
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3
Q

What are the types of myeloproliferative neoplasms (MPDs)?

A
  1. Ph (Philadelphia Chromosome) negative
    1. Polycythaemia vera (PV)
    2. Essential Thrombocythaemia (ET)
    3. Primary Myelofibrosis (PMF)
  2. Ph positive
    1. Chronic myeloid leukaemia (CML)
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4
Q

What is the difference between true and relative polycythaemia? How could we tell the difference historically?

A

True - Red cell mass increases

Relative - Plasma volume decreases

Dilution studies/Fick principle

  • Red cell mass: 51 Cr labelled RBC
  • Plasma Vol: 131 labelled albumin
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5
Q

Who gets relative polycythaemia?

A
  • Alcohol
  • Obsesity
  • Diuretic
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6
Q

What are the secondary true polycythaemias due to?

A

Due to raised EPO

  • Appropriate
    • High Altitude
    • Hypoxic lung disease
    • Cyanotic heart disease
    • High affinity haemoglobin
  • Inappropriate
    • Renal disease (cysts, tumours, inflammation)
    • Uterine myoma
    • Other tumours (liver, lung)
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7
Q

What is the problem in myeloproliferative neoplasms?

A

There is excess cells but no problem in functionality (differentiation)

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8
Q

What happens when you gain a mutation in an erythrocyte precursor?

A

Excess red blood cells - Polycythaemia vera

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9
Q

What happens when you gain a mutation in the granulocytic series?

A

You get excess neutrophils - CML

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10
Q

What processes are disrupted by these mutation? What types of mutations are these?

A

Disruption in type 1 processes (cellular proliferation)

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11
Q

What are the non-phildaelphia MPD (e.g PV) associated with?

A

Associated with JAK 2 (Janus kinase 2) mutation

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12
Q

What occurs in normal EPO signalling?

A
  1. There are JAK 2 on the EPO receptor (which leads to RBC production)
  2. JAK 2 is not usually phosphorylated
  3. EPO binds to the receptors and they dimerise causing phosphorylation of JAK 2
  4. Downstream signalling
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13
Q

What are the consequences of a mutation in the tyrosine kinase?

A
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14
Q

What type of mutation would you see in PV?

A

JAK2 V617F

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15
Q

What type of mutation would you see in ET?

A
  • JAK2 V617F - 60%
  • Calreticulin - 30%
  • MPL - 5%
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16
Q

What type of mutation would you see in PMF?

A
  • JAK2 V617F - 60%
  • Calreticulin - 30%
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17
Q

How would you diagnose MPD (Ph negative)

A

Based on combination of:

  • Clinical features
    • Syptoms
    • Splenomegaly
  • FBC +/- Bone marrow biopsy
  • EPO level
  • Mutation testing
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18
Q

Describe the epidemiology of PV

A
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19
Q

How is PV diagnosed?

A
  • Usually incidental diagnosis routine FBC (HB high and Hct high)
  • Symptoms of hyperviscosity
    • Headaches, light headedness, stroke
    • Visual disturbances
    • Fatigue, dyspnoae
  • Increased histamine release
    • Aquagenic pruritus
    • Peptic ulceration
  • Test for JAK2 V617F mutation
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20
Q

How do you treat PV?

A
  • Aim to reduce Hct –> target Hct <45%
    • Venesection
    • Cytoreductive therapy hydroxycarbamide
  • Aim to reduce risks of thrombosis
    • Control Hct
    • Aspirin
    • Keep platelets below 400 x 109/l
21
Q

What defines ET?

A

Sustained thrombocytosis >600x109/l

22
Q

Describe the epidemiology of ET

A
23
Q

How does ET present?

A
  • Incidental finding on FBC (50% cases)
  • Thrombosis: arterial or venous
    • CVA, gangrene, TIA
    • DVT or PE
  • Bleeding: mucous membrane and cutaneous
  • Headaches, dizziness, visual disturbances
  • Splenomegaly (modest)
24
Q

What is the treatment of ET?

A
  • Aspirin: to prevent thrombosis
  • Hydroxycarbamide: antimetabolite. Suppression of other cells as well
  • Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
25
Q

What is the prognosis of ET?

A
  • Normal life span may no be changed in many pts
  • Leukaemic transformation in about 5% after >10 years
  • Myelofibrosis also uncommon, unless there is fibrosis at the beginning
26
Q

Define PMF

A

Primary Myelofibrosis

A cloncal myeloproliferative disease associated with reactive bone marrow fibrosis

Extramedullary haematopoeieisis

27
Q

Describe the epidemiology of PMF.

A
28
Q

How does PMF present?

A
  • Incidental in 30%
  • Presentation related to:
    • Cytopenias: anaemia or thrombocytopenia
    • Thrombocytosis
    • Splenomgealy: may be massive
      • Budd-Chiari syndrome
    • Hepatomegaly
    • Hypermetabolic state
      • Weight loss
      • Fatigue and dyspnoea
      • Night sweats
      • Hyperuricaemia

Liver and spleen take up haematopoeieisis

29
Q

What are the haematological findings in PMF?

A
  • Blood film
    • Leucoerythroblastic picture
    • Tear drop poikilocytes
    • Giant plateletes
    • Circulating megakaryocytes
  • Liver and spleen
    • Extramedullary haematopoeieisis in spleen and liver
  • Bone marrow
    • “Dry Tap”
    • Trephine:
      • Increased reticulin or collagen fibrosis
      • Prominent megakaryocyte hyperplasia and clustering with abnormalities
      • New bone formation
  • DNA
    • JAK2 or CALR mutation
30
Q

What is the prognosis of PMF?

A
  • Median 3-5 yrs but very variable
  • Bad prognostic signs:
    • Severe anaemia <100g/L
    • Thrombocytopenia <100x109/L
    • Massive splenomegaly
    • Prognostic scoring system (DIPPS)
      • Score 0 - median survival 15 yrs
      • Score 4-6 - median survival 1.3 yrs
31
Q

What is the treatment of PMF?

A
  • Limited range of options:
    • Supportive: RBC and plt transfusion often ineffective because of splenomegaly
    • Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
    • Ruxolotinib: JAK2 inhibitor (high prognostic score cases)
    • Allogeneic SCT (potentially curative reserved for high risk eligible cases)
32
Q

Describe the epidemiology of CML.

A
33
Q

How does CML present?

A
34
Q

Describe the image.

A
35
Q
A
36
Q

What mutation is present in CML?

A

The t(9;22) translocation produces the philadelphia chromosome

37
Q

How is the phildelphia chromosome made? How is it transcribed?

A
  • From Ch22 - breakpoint cluster region taken upstream
  • From Ch9 - ABL gene (Tyrosine kinase) - cell proliferation
  • RNA transcription will make fusion RNA
    • 5 prime exons from BCR gene
    • 3 prime exons from ABL gene
  • Makes BCR-ABL gene
    • Has constitutive tyrosine kinase activity
38
Q

How would you look for the philadelphia chromosome?

A
  • Could also do PCR techniques (much more common)
    • You can use a:
      • 3’ ABL primer
      • 5’ BCR primer
    • In normal cells - no product amplified
    • If cells harbours a BCR-ABL fusion protein - primers will amplify this
39
Q

What are the different phases of CML?

A

Blast crisis- acute leukaemia (differentiation process affected as well)

40
Q

What is imatinib?

A

Oral Abl Tyrosine kinase inhibitor

41
Q

How can we assess response and monitor therapy with imatinib?

A

After 10 months - 0% cells Ph posiitve

42
Q

Why do tyrosine kinase inhibitors not work in some patients?

A
  • Failure to respond
  • Non-compliance
    • Side effects: Fluid retention, pleural effusions
  • Loss of MMR
    • Acquiring abl point mutations leading to resistance
    • Evolution to blast crisis
43
Q

What should we do if TKI therapy (imatinib) does not work?

A
44
Q
A
  • JAK 2 Wild type
  • Raise EPO
45
Q

Name 2 haematological cancers causing massive hepato-splenomegaly with no lymphadenopathy?

A
  1. PMF
  2. CML
46
Q

Why do you no get massive hepatosplenomegaly in acute leukaemias?

A

Patients have sepsis and bleeding before they can build up to massive splenomegaly

47
Q
A

Chronic phase CML

48
Q

What happened on month 24?

A

Blast crisis

49
Q
A

Novel fusion oncoprotein

Haematology (16 decks)

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