Polycythaemia Vera
BSH Diagnosis and management of polycythaemia vera. Date: Nov 2018.
Definition
Essential thrombocythaemia is a MPN characterised by clonal proliferation of haematopoietic stem cells in the bone marrow, resulting in:
- Increased red cell mass (erythrocytosis)
- Often with concurrent leucocytosis and thrombocytosis
MPNs are a group of clonal haematopoietic stem cell disorders characterised by overproduction of mature myeloid lineage cells. The 4 classical myeloproliferative neoplasms are:
- Primary myelofibrosis
- Polycythaemia vera
- Essential thrombocythaemia
- Chronic myeloid leukaemia
MPNs share several features:
- Mutations affecting the JAK-STAT signalling pathway (most commonly JAK2, but also CALR or MPL mutations)
- CML is distinct, driven by the Philadelphia chromosome (BCR-ABL fusion gene)
- Bone marrow hypercellularity
- ↑ Risk of thrombosis (particularly in polycythaemia vera and essential thrombocythaemia)
- Risk of transformation to AML
Aetiology
Almost always caused by JAK2 mutation
- JAK2 V617F mutation is found in >95% of patients with polycythemia vera
- JAK2 exon 12 mutations are found in most remaining cases
The mutation causes constitutive activation of the JAK-STAT signalling pathway → EPO-independent RBC production
JAK-2 negative polycythaemia vera is a very rare clinical entity.
Clinical Features
Typically presents at a median age of 60 y/o
| Cutaneous features |
|
| Microvascular disturbances | Due to hyperviscosity
|
| Thrombotic complications |
|
| Other features |
|
Due to the high turnover of cells and associated hyperuricaemia, gout may be present at diagnosis.
Investigation and Diagnosis
| Test | Typical findings |
|---|---|
| FBC |
|
| Red cell mass study |
|
| Biochemistry |
|
| Molecular testing |
|
| Bone marrow biopsy | Typical findings
|
Disclaimer:
No formal diagnostic criteria are included in this section. This is because the diagnostic criteria outlined in the 2018 BSH guideline are now considered outdated and have been replaced by more recent classification frameworks. These newer frameworks (e.g. WHO 2022 and ICC 2022) broadly incorporate many of the key findings listed above.
For UKMLA and non-specialist level learning, it is more important to recognise these key findings than to learn specific diagnostic criteria.
Management
1st Line Therapy – All Patients
The following should be offered to ALL patients, regardless of their risk category:
- Venesection – to maintain a target haematocrit of <0.45
- Low-dose aspirin (75-100 mg daily)
- Cardiovascular risk management (e.g. smoking cessation, treating hypertension / diabetes / hyperlipidaemia)
Cytoreductive Therapy – Selected Patients
Indications:
- High-risk patients (≥65 y/o or history of polycythaemia-associated thrombosis)
- Low-risk patients with
- Persistent leucocytosis
- Extreme / progressive thrombocytosis (≥1500 x 109/L)
- Venesection not tolerated / unable to control haematocrit
- Progressive / symptomatic splenomegaly
- Uncontrolled disease-related symptoms (e.g. weight loss, night sweats)
Choice of cytoreductive therapy:
- Hydroxycarbamide, or
- Interferon-alpha
Differential Diagnosis
Secondary Polycythaemia
Definition
Secondary polycythaemia refers to erythrocytosis caused by increased EPO production, typically in response to chronic hypoxia or pathological EPO secretion.
This contrasts with polycythaemia vera, which is a primary MPN characterised by autonomous red blood cell production that occurs independently of EPO regulation.
Aetiology
| Category | Common causes |
|---|---|
| Central hypoxia |
|
| Renal (local) hypoxia |
|
| Pathological EPO production |
|
| Drug induced |
|
Polycythaemia Vera vs Secondary Polycythaemia
Key factors that differentiate between polycythaemia vera and secondary polycythaemia
| Feature | Polycythaemia vera | Secondary polycythaemia |
|---|---|---|
| Serum EPO | Low (or inappropriately normal) | High |
| White cell and platelet count | Often elevated | Normal |
| Oxygen saturation | Normal | May be low (in hypoxia-driven causes) |
| Splenomegaly | Common | Uncommon |
| JAK2 mutation | Present | Absent |
| Bone marrow biopsy | Hypercellular with trilineage expansion (panmyelosis) | Isolated erythroid proliferation |
Relative Polycythaemia
Definition
Relative polycythaemia refers to an apparent increase in haemoglobin and haematocrit due to reduced plasma volume, in the presence of a normal red cell mass.
In contrast, true polycythaemia refers to an absolute increase in red cell mass, and includes both polycythaemia vera and secondary polycythaemia.
Aetiology
Relative polycythaemia is caused by plasma volume depletion, rather than increased erythropoiesis.
Common causes include: [Ref]
- Dehydration – most common
- Gaisbock syndrome (stress polycythaemia) – haemaoconcentration associated with
- Diuretic use
- Smoking
- Obesity
- Hypertension
Clinical Features
Relative polycythemia is NOT associated with the clinical features of true polycythemia, such as pruritus, leukocytosis, or thrombocytosis. [Ref]
It does NOT carry the same thrombotic risk.
True vs Relative Polycythaemia
True polycythaemia includes both polycythaemia vera and secondary polycythaemia. Characterised by an absolute increase in red cell mass. [Ref1][Ref2]
| Feature | True polycythaemia | Relative polycythaemia |
|---|---|---|
| Red cell mass | Increased | Normal |
| Haematocrit | Increased | |
| Haemoglobin | ||
Relative polycythaemia reflects haemoconcentration, whereas true polycythaemia reflects increased red cell mass.