Polycythaemia Vera
Summary
Polycythaemia Vera (PV) is a Myeloproliferative Neoplasm (MPN) characterised by clonal proliferation of haematopoietic stem cells leading to increased red cell mass (erythrocytosis), often with concurrent leukocytosis and thrombocytosis. The pathognomonic molecular driver is the JAK2 V617F mutation (present in >95% of cases). The major clinical risks are thrombosis (arterial and venous) and transformation to Myelofibrosis or Acute Myeloid Leukaemia. Treatment aims to reduce haematocrit to less than 0.45 (venesection) and reduce thrombosis risk (Aspirin, cytoreduction). [1,2]
Clinical Pearls
The "Ruddy Complexion": Patients classically present with a plethoric (red) face, conjunctival injection, and engorged retinal veins.
Aquagenic Pruritus: Itching after a warm bath or shower is highly characteristic (~40%) and often precedes diagnosis by years. It is due to histamine release from mast cells.
Budd-Chiari Syndrome: PV is the single most common cause of Hepatic Vein Thrombosis. Any young patient presenting with Budd-Chiari should be screened for JAK2.
Erythromelalgia: Burning pain in the hands and feet with warmth/erythema. Pathognomonic of MPNs. Responds dramatically to low-dose Aspirin.
Demographics
- Incidence: ~2 per 100,000 per year.
- Age: Median age at diagnosis is 60-65 years. Rare less than 40 years.
- Sex: Slight male predominance.
- Ethnicity: More common in Caucasians.
Risk Factors
- Acquired: No clear environmental risk factors.
- Genetic: JAK2 mutation is acquired, not inherited. However, familial clustering suggests predisposition.
Mechanism
- JAK2 V617F Mutation: A somatic (acquired) point mutation in the Janus Kinase 2 gene on chromosome 9p24.
- Constitutive Activation: The mutation causes the JAK2 tyrosine kinase to be permanently "switched on", even in the absence of Erythropoietin (EPO).
- Downstream Signalling: JAK2 phosphorylates STAT5, leading to uncontrolled erythroid precursor proliferation.
- Clonal Expansion: A single mutant stem cell clonally expands, producing excess Red Cells (primarily), but also White Cells and Platelets.
- Hyperviscosity: The increased red cell mass increases blood viscosity, causing sluggish flow and increased thrombosis risk.
- Transformation: Over time (10-20 years), the clone can acquire further mutations, leading to progression to Myelofibrosis (spent phase) or Acute Myeloid Leukaemia.
JAK2 Exon 12
- ~3-4% of JAK2 V617F-negative PV patients have mutations in JAK2 Exon 12.
- These present with isolated erythrocytosis and younger age.
| Condition | Key Features |
|---|---|
| Secondary Polycythaemia | EPO appropriately elevated (Hypoxia: COPD, Sleep Apnoea, High altitude) or inappropriately elevated (EPO-secreting tumours: Renal cell Ca, Hepatoma). |
| Relative (Apparent) Polycythaemia | Normal red cell mass but reduced plasma volume (Dehydration, Gaisbock syndrome in obese smokers). |
| Essential Thrombocythaemia (ET) | Another MPN. Primarily elevated Platelets. JAK2/CALR/MPL mutations. |
| Primary Myelofibrosis (PMF) | MPN with marrow fibrosis. Tear-drop poikilocytes on film. Dry tap on aspirate. |
Symptoms
Signs
Thrombotic Events (Major Risk)
Blood Tests
- FBC: High Hb (>165 g/L M, >160 g/L F) and High Hct (>0.49 M, >0.48 F). Often also raised WCC and Platelets (Panmyelosis).
- JAK2 V617F: Positive in >95%. Essential for diagnosis.
- JAK2 Exon 12: Check if V617F is negative but PV still suspected.
- EPO Level: Low or Normal (distinguishes from secondary polycythaemia where EPO is High).
- Ferritin: Often low (marrow iron is consumed by erythropoiesis).
Bone Marrow Biopsy
- Not always required if JAK2 is positive, but helpful for WHO criteria.
- Shows Hypercellularity (Panmyelosis), Megakaryocyte pleomorphism, Absent stainable iron.
Red Cell Mass Study
- Historically used but now rarely needed with JAK2 testing.
Management Algorithm
POLYCYTHAEMIA VERA DIAGNOSED
(JAK2+, Raised Hb/Hct, Low EPO)
↓
RISK STRATIFY PATIENT
┌────────────┴────────────┐
LOW RISK HIGH RISK
(Age less than 60, No (Age >60 OR
Thrombosis Hx) Prior Thrombosis)
↓ ↓
VENESECTION VENESECTION
+ ASPIRIN + ASPIRIN
↓ + CYTOREDUCTION
Target Hct less than 0.45 (Hydroxycarbamide)
↓ ↓
MONITOR MONITOR
- FBC monthly - FBC monthly
- Watch for symptoms - Watch for
of transformation transformation
1. Venesection (Phlebotomy)
- Target: Haematocrit < 0.45 (reduces thrombosis risk by 50-60%).
- Method: Remove 400-500ml blood per session, initially weekly/fortnightly until target achieved. Then PRN.
- Iron Deficiency: Induced deliberately. Do NOT give Iron supplements.
2. Aspirin
- Low Dose (75-100mg daily): For all patients unless contraindicated.
- Evidence: ECLAP Trial showed significant reduction in thrombosis.
3. Cytoreduction (High Risk Patients)
- Hydroxycarbamide (Hydroxyurea): First-line. Inhibits ribonucleotide reductase.
- S/E: Leg ulcers, Skin hyperpigmentation, Macrocytosis.
- Concern: Theoretical leukaemic transformation risk (debated).
- Interferon-Alpha (Pegylated): Preferred in younger patients and pregnancy.
- S/E: Flu-like symptoms, Depression.
- Ruxolitinib: JAK2 inhibitor. Second-line for resistant/intolerant patients.
4. Pruritus Management
- Avoid hot baths.
- Antihistamines (often ineffective).
- Ruxolitinib is highly effective for refractory pruritus.
Thrombotic Events (Main Risk)
- Incidence: ~30% of untreated patients.
- Sites: Arterial (Stroke, MI) and Venous (DVT, PE, Budd-Chiari, Portal Vein Thrombosis).
Haemorrhage
- Acquired von Willebrand Disease: In patients with extreme thrombocytosis (>1000 x 10^9/L), large vWF multimers are depleted, causing bleeding.
Transformation (Late)
- Myelofibrosis ("Spent Phase"): ~15% at 15 years. Marrow becomes fibrotic. Cytopenias develop.
- Acute Myeloid Leukaemia (AML): 5-10% lifetime risk. Associated with prior Alkylating agents.
- Median Survival: >15-20 years with current treatment.
- Major Cause of Death: Thrombosis (30-40%), Transformation (10-20%), Secondary malignancy.
- Prognostic Factors: Age, Thrombosis history, Leukocytosis.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| MPNs | BSH (2018) | Target Hct less than 0.45. Aspirin for all. Hydroxycarbamide for high risk. |
| PV | ELN (European LeukemiaNet) | Risk stratification based on age and thrombosis history. |
Landmark Evidence
1. CYTO-PV Trial (NEJM 2013)
- Compared Hct target less than 0.45 vs 0.45-0.50.
- Result: Lower target significantly reduced cardiovascular death and major thrombosis (HR 0.41).
- Impact: Established less than 0.45 as the universal target.
2. ECLAP Trial (NEJM 2004)
- Low dose Aspirin vs Placebo in PV.
- Result: 60% reduction in risk of thrombosis.
- Impact: Aspirin is standard of care.
What is Polycythaemia Vera?
It is a type of blood cancer where your bone marrow makes too many red blood cells. This makes your blood thick and "sticky", which raises the risk of clots (like stroke or heart attack).
What causes it?
Almost all cases are caused by a specific change (mutation) in a gene called JAK2. This isn't something you are born with; it happens during life.
How do we treat it?
- Venesection: We regularly remove blood (like blood donation) to thin it down. The target is to keep your blood thickness (haematocrit) below 0.45.
- Aspirin: A small daily dose helps stop clots.
- Tablets: If you are at higher risk (older, or had a clot before), we add a tablet (Hydroxycarbamide) to slow down the marrow.
What is the outlook?
With treatment, most people live many years (often 15-20+). The main risks are clots and the blood cells changing further over time.
Primary Sources
- McMullin MF, et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol. 2019.
- Marchioli R, et al. Cardiovascular events and intensity of treatment in polycythaemia vera (CYTO-PV). N Engl J Med. 2013.
- Landolfi R, et al. Efficacy and safety of low-dose aspirin in polycythemia vera (ECLAP). N Engl J Med. 2004.
Common Exam Questions
- Diagnosis: "JAK2 negative but PV suspected?"
- Answer: Check JAK2 Exon 12 mutations.
- Target: "Haematocrit target?"
- Answer: less than 0.45 (CYTO-PV Trial).
- Pharmacology: "Side effect of Hydroxycarbamide?"
- Answer: Leg ulcers, Skin hyperpigmentation, Macrocytosis.
- Pathology: "Distinguishing feature from Secondary Polycythaemia?"
- Answer: EPO is Low/Normal in PV, High in Secondary.
Viva Points
- Budd-Chiari: PV is the most common cause. Screen for JAK2 in any patient with hepatic vein thrombosis.
- Acquired vWD: With very high platelets (>1000), large vWF multimers are absorbed/degraded, causing paradoxical bleeding.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.