Haem - Polycythaemia & Myeloproliferative disorders

Question 1

Define polycythaemia

Answer 1

Raised haemoglobin concentration and raised haematocrit

Question 2

What are the types of polycythaemia

Answer 2

Relative (lack of plasma)/ pseudopolycythaemia: alcohol, obesity, diuretics

True:
Primary (myeloproliferative neoplasm): philadelphia Chr -ve or +ve
Secondary (non-malignant)

Question 3

What are dilution studies

Answer 3

Measures RBC mass and plasma volume
1. Take components out
2. Radiolabel them (51Cr-RBCs, 131I-Albumin)
3. Reinfuse and measure dilution

Red cell mass N, plasma volume reduced → relative
Red cell mass high, plasma volume N → true polcythaemia

Question 4

What are the causes of true primary polycythaemia

Answer 4

Primary (myeloproliferative neoplasm): suppressed EPO
Philadelphia Chr -ve:
- essential thrombocythaemia (megakaryocyte)
- Polycythaemia vera (erythroid)
- Primary myelofibrosis

Philadelphia chromosome +ve:
CML

Question 5

What are the causes of secondary true polcythaemia

Answer 5

Raised EPO
Appropriate (JAK2 wild type/V617F/Exon12):
- High altitude
- Hypoxic lung disease (COPD)
- Cyanotic heart disease
- High affinity Hb

Inappropriate:
- Renal disease (cysts, tumours, inflammation)
- Uterine myoma
- Other tumours (liver, lung)

Question 6

What is the role of tyrosine kinase

Answer 6

Transmit cell growth signals from surface receptors to nucleus
Activated by transferring phosphate groups
Normally held tightly in inactive state
Promote cell growth but do NOT block maturation

Question 7

Which gene mutations are associated with myeloproliferative disorders

Answer 7

JAK2: single point mutation in polycythaemia vera (100%), essential thrombocythaemia and primary myelofibrosis
Calreticulin:
MPL

Question 8

Describe idiopathic erythrocytosis

Answer 8

a JAK2 V617F -ve (sometimes JAK 2 exon 12) version of PV where there is an isolated expansion of RBCs (not pseudopolycythaemia) / not plts

Question 9

What is the epidemiology of polycythaemia vera

Answer 9

M > F
Mean age at diagnosis = 60yo (5% <40yo)

Question 10

What are the clinical features of polycythaemia vera

Answer 10

Hyperviscosity: headaches, light-headedness, visual disturbances, fatigue, dyspnoea
Histamine release: aquagenic (hot water) pruritus, peptic ulceration
Plethoric (red nose)
Thrombosis, stroke
Retinal vein engorgement
Splenomegaly

Question 11

What are the features of polcythaemia vera on investigation

Answer 11

Blood count: high RBC, Hb, plts, WCC
JAK2 V617F mutation

Question 12

What is the treatment for polycythaemia vera

Answer 12

reduce HCT <45% + reduce risk of thrombosis:
- Venesection (only suitable in younger/healthy patients)
- Hydroxycarbamide (cytoreductive therapy → less DNA synthesis in RBCs): Keep plts <400 x 109/L and Hct <45%
- Aspirin

Question 13

Define essential thrombocythaemia

Answer 13

Chronic myeloproliferative disorder involving megakaryocytic lineage

Question 14

What is the epidemiology for essential thrombocythaemia

Answer 14

Bimodal age distribution: 30 years (minor peak); 55 years
30yo (M = F); 55 years (F > M)

Question 15

What are the clinical features of essential thrombocythaemia

Answer 15

Incidental (50% of cases)

Thrombosis (arterial or venous) – CVA, gangrene TIA, DVT/PE
Bleeding (mucous membrane and cutaneous)
Hyperviscosity (headaches, light-headedness, stroke, visual disturbances, fatigue, dyspnoea)
Splenomegaly (modest)

Question 16

What are the features of essential thrombocythaemia on investigation

Answer 16

Blood count: high plts (Sustained thrombocytosis >600 x 109/L)
Mutations (JAK2, calreticulin, MPL) - 50%
Blood film – large platelets and megakaryocyte fragments
Increased BM megakaryocytes (not reactive)

Note: the Hb is NOT that elevated (differentiates from PV)

Question 17

What is the treatment for essential thrombocythaemia

Answer 17

Aspirin (thrombosis prevention)
Hydroxycarbamide (antimetabolite that suppresses cell turnover)
Anagrelide (inhibits platelet formation but NOT commonly used due to SEs of palpitations and flushing)

Question 18

What is the prognosis for essential thrombocythaemia

Answer 18

Normal life span in many patients
Leukaemic transformation in about 5% over 10 years
Myelofibrosis is also UNCOMMON, unless there is fibrosis at the beginning

Question 19

Define primary myelofibrosis and what is it characterised by

Answer 19

a clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Characterised by extramedullary haematopoiesis (i.e. in liver and spleen)
Other MPD (ET and PV) may transform into PMF

Question 20

What is the cause and epidemiology of primary myelofibrosis

Answer 20

Expansion of the clone → produces fibroblast growth stimulating factor → proliferation and collagen deposition in the bone marrow → bone marrow scarring
Epidemiology = 60-70yo, M=F, 0.5-1.5/100,000/year

Question 21

What are the clinical features of primary myelofibrosis

Answer 21

Incidental in 30%
Presentations related to:
- Cytopaenias (anaemia, thrombocytopaenia)
- Thrombocytosis
- Splenomegaly (MASSIVE) → Budd-Chiari syndrome
- Hepatomegaly (extra-medullary haematopoiesis)
- Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia)

Question 22

What are the features of primary myelofibrosis on investigation

Answer 22

Blood film:
- Leucoerythroblastic picture
- Tear drop poikilocytosis (dacrocytes)
- Giant platelets
- Circulating megakaryocytes

Bone marrow:
- DRY TAP
- Trephine biopsy: increased reticulin/collagen fibrosis, increased clustering and megakaryocytes, new bone formation
JAK2/CALR mutation
Evidence of extramedullary haematopoeisis (liver, spleen)

Question 23

What is the treatment for primary myelofibrosis

Answer 23

Supportive: transfusion of RBC or platelets (often ineffective due to splenomegaly → rapid break down RBCs)
Cytoreductive Therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
HSCT: potentially curative (reserved for high risk eligible cases)
Splenectomy: symptomatic relief but a dangerous operation, often followed by worsening of condition
Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)

Question 24

What is the prognosis for myelofibrosis

Answer 24

Prognostic scoring system = DIPPS (1-6)
Median 3-5 years survival (however, very variable)
BAD prognostic signs:
- Severe anaemia < 100 g/L
- Thrombocytopaenia < 100 x 109/L
- Massive splenomegaly
- High DIPPS score (score 4-6: 1.3 years)