Polycythaemia rubra vera and essential thrombocytosis

Question 1

Polycythaemia rubra vera (PRV) is a chronic myeloproliferative neoplasm (PMN) due to clonal proliferation of haematopoietic stem cells leading to overproduction of RBCs, as well as WBCs and platelets.

Epidemiology
Age: 60 years old
Sex: slight male predominance

Question 2

Secondary polycythaemia are chronic conditions that increases EPO production

A. Hypoxia-driven
1. COPD and heavy smoking
2. Cyanotic heart disease
3. High altitude
4. Obstructive sleep apnoea

B. Pathological EPO production
1. EPO secreting tumours (RCC, HCC, cerebellar haemangioblastoma)
2. Renal artery stenosis
3. Polycystic kidney fisease

C. Exogenous EPO administration
D. Congenital polycythaemia (VHL gene mutation)

Question 3

Pathophysiology of PRV

Answer 3

JAK2 mutation and activation of JAK-STAT pathway
- Uncontrolled proliferation of erythroid precursors even with low EPO levels.

Question 4

Clinical presentation of patients with PRV

Answer 4

1. Aquagenic pruritus - intense itch with exposure to warm water
2. Plethora - face, ears, lips, conjunctivae
3. Erythromelalgia - burning, erythema and warm hands and feet
4. Cell turnover - fatigue, weight loss, night sweat, gout (hyperuricaemia)
5. Haemorrhage (epistaxis, ecchymoses, gingival bleed, BGIT)
   - Acquired VWF syndrome or dysfunctional platelet
6. Splenomegaly +/- hepatomegaly
7. Hyperviscocity syndrome - headache, giddiness, vertigo, tinnitus, visual disturbance
8. Thrombotic events - MI, stroke, arterial occlusion, DVT, pulmonary embolism, Budd-Chiari syndrome, splenic vein thrombosis

Question 5

WHO Criteria for PRV

Answer 5

All 3 major criteria (or) 2 major 1 minor

Major Criteria
1. High Hb / HCT or RBC mass > 25% normal
- Men: Hb > 15.4, HCT > 49%
- Women: Hb > 16, HCT > 48%
2. Bone marrow biopsy - hypercellularity for age with trilineage growth
3. JAK2 mutation

Minor Criteria
1. Abnormal serum erythropoietin level

Question 6

Diagnostic investigations for PRV

Answer 6

Definitive
1. FBC
2. PBF
3. Serum EPO
4. JAK2 mutation analysis
5. Bone marrow aspiration and trephine

Monitoring of complications
1. Uric acid
2. LDH
3. RP - potassium
4. Calcium, phosphate

Supportive
1. Vit B12, folate
2. Iron panel
3. ALP

Question 7

Management of PRV

Answer 7

Definitive management
1. Regular phlebotomy
2. Low dose aspirin
3. Cytoreduction - hydroxyurea, INF-a
4. JAK2 inhibitor - ruxolitinib

Supportive management
5. Pruritus
- Antihistamine
- SSRI
- Gabapentin
- PUVA

Question 8

Prognosis of PRV

Answer 8

Survival: 15-20 years

Causes of mortality:
1. Thromboembolism
2. Transformation to AML/MDS
3. Complications of myelofibrosis

Question 9

Essential thrombocythaemia (ET) is a chronic myeloproliferative neoplasm due to clonal proliferation of megakaryocytes in bone marrow leading to overproduction of platelet

Other names:
1. Essential thrombocytosis
2. Primary thrombocythaemia

Epidemiology
Age: 60 years old (20% diagnosed before age 40)
Sex: female > male (2:1)

Question 10

Pathophysiology of ET

Answer 10

1. Key driver mutations
   - JAK2 V617F
   - CALR
   - MPL
   - Triple negative ET
2. Activation of JAK2 tyrosine kinase

Question 11

Clinical presentation of patients with ET

Answer 11

1. Asymptomatic in 50% patients
2. Constitutional - fever, fatigue, weight loss
3. Thrombotic events
   - Arterial: TIA, stroke, MI, peripheral arterial occlusion
   - Venous: DVT, PE, Budd-Chiari, portal or splenic vein thrombosis
   - Microvascular and vasomotor: erythromelalgia, neurological (headache, giddiness, visual disturbance)
4. Haemorrhage - acquired VWF syndrome
5. Mild splenomegaly
   (Significant enlargement suspicious for PMF)
6. Pregnancy complications - fetal loss, maternal thrombosis

Question 12

WHO Diagnostic Criteria for ET

Answer 12

All 4 major or 3 major 1 minor

Major Criteria
1. Thrombocytosis > 450
2. Bone marrow biopsy - megakaryocytic lineage with enlarged mature megakaryocytes and hyperlobulated nuclei
3. Not meeting criteria for CML, PRV, PMF, MDS, other myeloid neoplasm
4. JAK2 V617F, CALR or MPL mutation

Minor Criteria
1. Alternative clonal marker, absent of reactive thrombocytosis

Question 13

Diagnostic investigations for ET

Answer 13

1. FBC
2. PBF
3. BMAT
4. Driver mutation molecular testing (JAK2, CALR, MPL)
5. Serum ferritin - exclude reactive
6. ESR, CRP - exclude reactive

Question 14

Management of ET

Answer 14

1. Low dose aspirin
2. Cytoreduction - hydroxyurea, INF-a