Increase in cell counts - polycythaemia
Description
- Polycythaemia = Hb, red cell count and red cell mass all above the upper limit of normal
- Erythrocytosis = the measured Hb/Hct is raised; the red cell mass may or may not be
Three categories - separate them first
| Red cell mass | Plasma volume | EPO | |
|---|---|---|---|
| Primary (PV) | inc | Normal/inc | dec (subnormal) |
| Secondary | inc | Normal | Normal or inc |
| Relative/apparent (Gaisböck) | Normal | dec | Normal |
- Polycythaemia (rubra) vera = a myeloproliferative neoplasm - autonomous erythropoiesis, EPO-independent
- Relative polycythaemia: diuretics, dehydration, obesity, alcohol, smoking, hypertension - no marrow disease, no cytoreduction
Epidemiology
- PV incidence ~1-2 per 100,000/yr; prevalence rising with incidental FBE detection
- Median age at diagnosis ~60; M slightly > F
- JAK2 V617F in ~95%, JAK2 exon 12 in ~3% - virtually all PV is JAK2-mutated
- Secondary and relative causes are far commoner than PV in an unselected raised Hct
Aetiopathogenesis
Primary
- JAK2 V617F (exon 14) - constitutive JAK-STAT activation -> EPO-independent erythroid proliferation
- Same mutation in ~50-60% of ET and myelofibrosis; allele burden is higher in PV
- JAK2 exon 12 - isolated erythrocytosis, younger, lower EPO
- Rare familial erythrocytosis: EPOR mutation, VHL (Chuvash), HIF2A/EPAS1, PHD2/EGLN1, high-oxygen-affinity haemoglobins, 2,3-DPG mutase deficiency
Secondary - EPO-driven
Appropriate (hypoxia)
- High altitude, COPD, obstructive sleep apnoea, obesity hypoventilation
- Smoking / carbon monoxide (carboxyhaemoglobin - measure it)
- Right-to-left cardiac shunt, cyanotic congenital heart disease
- High-affinity haemoglobin variants
Inappropriate (autonomous EPO)
- Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma, phaeochromocytoma, uterine leiomyoma, parathyroid tumours
- Renal artery stenosis, polycystic kidneys, hydronephrosis, post-renal transplant erythrocytosis
Drug-induced
- Exogenous testosterone/androgens, erythropoietin doping, SGLT2 inhibitors (increasingly common and easily missed)
Diagnosis
WHO 2022 (HAEM5) criteria for polycythaemia vera
Major
1. Hb >165 g/L (men) or >160 g/L (women), OR Hct >49% (men) or >48% (women), OR red cell mass >25% above predicted
2. Bone marrow: age-adjusted hypercellularity with trilineage growth and pleomorphic mature megakaryocytes
3. JAK2 V617F or JAK2 exon 12 mutation
Minor
- Subnormal serum erythropoietin
- Diagnosis = all 3 major, OR majors 1 and 2 + the minor criterion
- Marrow biopsy may be waived where erythrocytosis is sustained and marked (Hb >185 men / >165 women) with JAK2 mutation and low EPO - but then post-PV myelofibrosis cannot be recognised later
Practical work-up of a raised haematocrit
1. Repeat the FBE - exclude a spurious or transient result; assess for dehydration/diuretics
2. JAK2 V617F - the single most useful test
3. Serum EPO - low = PV; normal or high = look for a secondary cause
4. Oxygen saturation, carboxyhaemoglobin, sleep study if symptoms
5. Abdominal ultrasound - spleen size, renal and hepatic lesions
6. Testosterone/EPO/SGLT2 inhibitor use, smoking, altitude, diving
7. Marrow biopsy if PV suspected or JAK2-negative erythrocytosis persists
Clinical features of PV
- Aquagenic pruritus (after a hot shower - histamine from basophils), erythromelalgia, plethora, gout
- Hepatosplenomegaly, hypertension, headache, dizziness, visual disturbance
- Thrombosis - arterial and venous, including splanchnic (Budd-Chiari, portal) - often the presenting event
- Paradoxical bleeding in extreme erythrocytosis or thrombocytosis (acquired von Willebrand syndrome)
- Iron deficiency is usual - from venesection and from expanded erythropoiesis
Management
A. Polycythaemia vera - all patients
- Low-dose aspirin 100 mg daily - unless contraindicated or acquired vWD present
- Twice-daily aspirin considered with high-risk features or persistent symptoms
- Venesection to keep haematocrit <0.45
- CYTO-PV: Hct <0.45 vs 0.45-0.50 reduced cardiovascular death and major thrombosis 4-fold
- Some centres target <0.42 in women
- *Do not give iron* - the induced iron deficiency is therapeutic
- Aggressive management of conventional cardiovascular risk factors, smoking cessation
B. Risk stratification -> cytoreduction
- High risk = age >=60 OR prior thrombosis -> add cytoreduction
- Also consider if: poor venesection tolerance, symptomatic or progressive splenomegaly, platelets >1500, severe symptoms, progressive leucocytosis
| Agent | Comment |
|---|---|
| Hydroxyurea | Long-standing first line. Cytopenias, oral/leg ulcers, skin cancer risk, macrocytosis (a marker of adherence) |
| Ropeginterferon alfa-2b | Now a preferred first-line option - 2-weekly to monthly SC; reduces JAK2 allele burden and improves event-free survival (PROUD/CONTINUATION-PV, Low-PV) |
| Pegylated interferon alfa-2a | Preferred in younger patients and pregnancy |
| Ruxolitinib (JAK1/2) | Hydroxyurea-resistant or intolerant (RESPONSE) - controls Hct, spleen and symptoms |
| Busulfan / P32 | Elderly only - leukaemogenic |
- Rusfertide (hepcidin mimetic) - phase 3 positive; venesection-sparing, in development
C. Secondary polycythaemia
- *Treat the cause* - CPAP for OSA, smoking cessation, resect the EPO-secreting tumour, stop or dose-reduce testosterone or the SGLT2 inhibitor
- Venesection only if symptomatic hyperviscosity or Hct very high
- *Do not venesect cyanotic congenital heart disease routinely* - the erythrocytosis is compensatory; iron deficiency worsens outcomes
- Aspirin is not indicated simply because the Hct is raised
D. Perioperative and pregnancy
- Normalise the haematocrit before elective surgery - very high thrombotic and haemorrhagic risk otherwise
- Pregnancy: aspirin, venesection to trimester-specific Hct, interferon if cytoreduction needed, LMWH post-partum
Associations
- Budd-Chiari syndrome and splanchnic vein thrombosis - test JAK2 in every case, even with a normal FBE (masked PV)
- Other myeloproliferative neoplasms - ET, myelofibrosis, CML (JAK2-negative, BCR::ABL1-positive)
- Gout and hyperuricaemia - high cell turnover
- Peptic ulcer disease (histamine)
- Acquired von Willebrand syndrome with extreme thrombocytosis
- Erythromelalgia, aquagenic pruritus
- OSA, obesity, smoking, androgen use - the secondary causes worth naming
Natural history & complications
- PV median survival now >15-20 years with treatment; untreated, median survival ~1.5 years from thrombosis
- Thrombosis is the dominant cause of morbidity and death - arterial more often than venous
Transformation
- Post-PV myelofibrosis: ~10-20% at 15-20 years
- Suspect with rising spleen, falling Hb, leucoerythroblastic film, weight loss, need for fewer venesections
- AML/MDS: ~5-10% at 20 years - higher with alkylating agents, P32 and advanced age
Adverse prognostic factors
- Age >60, prior thrombosis, leucocytosis >11 x10^9/L, abnormal karyotype
- Non-JAK2 driver mutations (ASXL1, SRSF2, IDH2) on NGS
Complications
- Arterial and venous thrombosis, including at unusual sites
- Haemorrhage - especially with aspirin plus acquired vWD
- Symptom burden: fatigue, pruritus, night sweats, early satiety (use the MPN-SAF TSS)
- Gout, portal hypertension, secondary malignancy
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