Polycythaemia vera
Description
- JAK2-driven MPN with panmyelosis - red cells dominate, but WCC and platelets rise too
- The management target is thrombosis, not the haematocrit for its own sake
- Presentation
- Incidental raised Hb/Hct on an FBE (commonest)
- Aquagenic pruritus after a hot shower - near-pathognomonic
- Erythromelalgia, plethora, conjunctival suffusion, headache, tinnitus, blurred vision
- Thrombosis at an unusual site - Budd-Chiari, portal or splanchnic vein, cerebral venous sinus
- Gout, peptic ulceration (histamine), splenomegaly (~30-40%)
- *Post-PV myelofibrosis and AML are the two ways it ends*
Epidemiology
- Incidence ~1-3/100,000/yr; prevalence ~50/100,000 (long survival)
- Median age at diagnosis ~60-65; M>F slightly
- <5% present under 40
- Ashkenazi Jewish ancestry over-represented; familial clustering with ~5x inc risk in first-degree relatives (germline JAK2 46/1 haplotype)
Aetiopathogenesis
- JAK2 V617F (exon 14) in ~95%
- Valine -> phenylalanine at codon 617 in the JH2 pseudokinase autoinhibitory domain
- -> loss of autoinhibition -> constitutive JAK-STAT signalling, erythropoietin-independent erythroid colony growth
- JAK2 exon 12 mutation in ~3%
- Isolated erythrocytosis, younger patients, lower WCC/platelets, very low EPO
- *JAK2-negative polycythaemia vera essentially does not exist* - a negative JAK2 with a true raised red cell mass means look elsewhere
- Allele burden correlates with pruritus, splenomegaly, thrombosis and fibrotic transformation
- Additional mutations (ASXL1, SRSF2, IDH1/2, TP53, RUNX1) drive transformation
Why thrombosis happens
- inc haematocrit -> exponential rise in blood viscosity and margination of platelets to the vessel wall
- Leucocytosis - activated neutrophils, NETs, platelet-leucocyte aggregates
- JAK2-mutant endothelium is itself prothrombotic
- This is why leucocyte count and JAK2 status predict thrombosis independently of haematocrit
Diagnosis
Distinguish from the differential first
| Feature | |
|---|---|
| Relative/apparent (Gaisbock) | Plasma volume contraction - diuretics, alcohol, smoking, obesity, hypertension. Normal red cell mass |
| Secondary - hypoxia driven | inc EPO: COPD, OSA, high altitude, right-to-left shunt, high-affinity haemoglobin, smoking (carboxyhaemoglobin) |
| Secondary - EPO producing | Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma, phaeochromocytoma, uterine fibroids, renal artery stenosis, post-renal transplant |
| Drug | Testosterone, EPO abuse, SGLT2 inhibitors |
| Congenital | VHL (Chuvash), EPOR mutation, 2,3-BPG deficiency, high-affinity Hb |
WHO criteria - all 3 major, or first 2 major + minor
| Criterion | |
|---|---|
| Major 1 | Hb >165 g/L (M) / >160 g/L (F), or Hct >0.49 (M) / >0.48 (F), or raised red cell mass >25% above predicted |
| Major 2 | Marrow: hypercellular for age with trilineage growth (panmyelosis), pleomorphic mature megakaryocytes of differing sizes |
| Major 3 | JAK2 V617F or JAK2 exon 12 mutation |
| Minor | Subnormal serum erythropoietin |
- Marrow biopsy may be omitted if Hb >185 (M)/>165 (F) with JAK2 mutation and low EPO - but it is the only way to detect baseline fibrosis, which is prognostic
- Masked PV - iron deficiency from GI loss or prior venesection lowers Hb into the ET range. Check ferritin; a low MCV with thrombocytosis and JAK2 positivity is PV until proven otherwise
Baseline workup
- JAK2 V617F; if negative and clinically suspicious, JAK2 exon 12
- Serum EPO (low supports PV; normal/high points to secondary)
- Ferritin, iron studies, UEC, LFT, urate, LDH
- Abdominal ultrasound - spleen size, portal/hepatic vein patency
- Oxygen saturation, consider sleep study and carboxyhaemoglobin in smokers
- Marrow trephine with reticulin grading and cytogenetics
Risk stratification for thrombosis
- High risk: age >60 OR prior thrombosis
- Low risk: neither
- Leucocytosis >11 and high JAK2 allele burden are additional adverse markers
Management
A. Every patient
- Venesection to keep haematocrit <0.45 - in men and women alike
- CYTO-PV: Hct <0.45 vs 0.45-0.50 gave a 4-fold reduction in cardiovascular death and major thrombosis
- Induces iron deficiency deliberately - *do not replace iron*; the microcytosis is the mechanism, not a complication
- Low-dose aspirin 100 mg daily in everyone (unless contraindicated)
- Twice-daily dosing for persistent microvascular symptoms or high-risk features
- Check for acquired von Willebrand syndrome if platelets >1000 before starting aspirin
- Aggressive cardiovascular risk factor control - smoking cessation, BP, lipids, diabetes, weight
B. Cytoreduction
Indications
- Age >60 or prior thrombosis (i.e. high risk), OR
- Poor venesection tolerance / high venesection requirement
- Progressive splenomegaly, symptomatic disease, extreme leucocytosis or thrombocytosis
| Agent | Position |
|---|---|
| Hydroxyurea | First line, especially >60. Oral/leg ulcers, skin cancer, macrocytosis; teratogenic |
| Interferon (peg-IFN alfa-2a, ropeginterferon alfa-2b) | Preferred in younger patients and in pregnancy. Only agent with consistent molecular responses and JAK2 allele burden reduction; superiority over hydroxyurea emerges after ~2-3 years |
| Ruxolitinib (JAK1/2 inhibitor) | Hydroxyurea-resistant or intolerant disease (RESPONSE). Improves symptoms and pruritus, reduces spleen size, corrects counts. *Does not reduce leukaemic transformation risk*. Watch for herpes zoster, non-melanoma skin cancer, weight gain, and a withdrawal syndrome on abrupt cessation |
| Busulfan / P-32 | Elderly only - leukaemogenic |
- Hepcidin mimetics (rusfertide) control erythrocytosis and reduce venesection requirement - under regulatory review, not yet standard therapy
C. Symptom-directed
- Aquagenic pruritus - antihistamine, SSRI (paroxetine), phototherapy, interferon or ruxolitinib if refractory
- Erythromelalgia - aspirin, often dramatic
- Gout - allopurinol
- Splanchnic vein thrombosis - lifelong anticoagulation + cytoreduction
D. Anticoagulation and procedures
- Prior venous thrombosis -> indefinite anticoagulation alongside haematocrit control
- Optimise Hct and platelets before any elective surgery - perioperative thrombosis and bleeding rates are both raised
- Thromboprophylaxis for immobility, travel, pregnancy
Associations
- Budd-Chiari syndrome and portal/mesenteric vein thrombosis - test JAK2 V617F in any splanchnic vein thrombosis, even with a normal FBE
- Cerebral venous sinus thrombosis
- Erythromelalgia and aquagenic pruritus
- Gout and urate nephropathy
- Peptic ulcer disease
- Other MPNs - ET, primary myelofibrosis (shared JAK2 biology)
- Familial MPN; germline JAK2 46/1 haplotype
- Acquired von Willebrand syndrome at extreme platelet counts
Natural history & complications
- Median survival ~14-20 years; ~24 years if diagnosed under 60
- Untreated, median survival ~1.5 years - almost all from thrombosis
The three outcomes that matter
1. Thrombosis - the main cause of death and morbidity; arterial (stroke, MI) more than venous
2. Post-PV myelofibrosis - ~10-20% at 15-20 years
- Anaemia, progressive splenomegaly, weight loss, rising LDH, leucoerythroblastic film
- Paradoxically the Hb normalises then falls - a falling venesection requirement is a warning sign, not success
3. AML/MDS - ~5-10% at 15-20 years; *prior alkylator or P-32 exposure inc risk*. Almost uniformly fatal
Adverse markers
- Age >60, prior thrombosis, leucocytosis >11-15 x10^9/L
- Abnormal karyotype, marrow fibrosis at diagnosis
- High JAK2 V617F allele burden
- Adverse mutations - ASXL1, SRSF2, IDH1/2, RUNX1, TP53
Monitoring
- FBE + haematocrit at least 3-monthly (more often during venesection)
- Symptom score (MPN-SAF), spleen size, cardiovascular risk factors
- Rising LDH, new anaemia, spleen growth, blasts on film -> repeat marrow for transformation
- Annual skin surveillance on hydroxyurea and ruxolitinib
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