Polycythaemia vera

Polycythaemia vera (PV) is a myeloproliferative disorder caused by the clonal proliferation of hematopoietic progenitor cells.

PV is characterised by an elevation in the red cell mass, typically manifesting as a raised haemoglobin or haematocrit on a full blood count (FBC). It is often accompanied by elevated platelets and/or neutrophils. Around 98% of cases are linked to an acquired mutation of Janus Kinase 2 (JAK2), a tyrosine kinase important in cell signaling pathways.

It may be diagnosed incidentally or symptomatically with features like headache, visual disturbance and pruritis or with thrombotic/haemorrhagic complications. Treatment involves reducing the red cell mass, either with venesection or cytoreductive therapy.

PV is a rare condition that is uncommon under the age of 40.

PV can present at any age but most commonly presents in the 60’s and is very rare in childhood. It appears to be slightly more prevalent in men.

A study by Moulard et al estimated the yearly incidence to be 0.4-2.8 per 100,000.

Polycythaemia refers to an increase in the red cell mass, it may be divided into primary and secondary causes.

Polycythaemia is a disorder characterised by an elevation in the haemoglobin concentration and/or haematocrit. Polycythaemia can be divided into primary and secondary causes.

Primary polycythaemia

This refers to polycythaemia occurring due to a mutation (inherited or acquired) that results in an increase in the red cell mass. Polycythaemia vera is the main cause but a raised red cell mass may also be seen in other myeloproliferative and congenital diseases.

The focus of this note is polycythaemia vera.

Secondary polycythaemia

In secondary polycythaemia the increased red cell mass occurs due to increased erythropoietin (EPO) production. EPO is the main hormone responsible for controlling erythropoiesis (red blood cell production).

This is most commonly due to appropriate rises in EPO secondary to hypoxia, but can also be due to inappropriate rises:

• Hypoxia-induced EPO rise:
  • Smoking
  • Chronic lung disease
  • Obesity
  • Obstructive sleep apnea
• Inappropriate EPO rise:
  • Tumours:
    • Renal cell cancer
    • Wilms’ tumour
    • Adrenal tumours
    • Others
  • Illicit EPO use
  • Androgen use

Relative polycythaemia

Relative polycythaemia refers to an increase in the haematocrit or haemoglobin count in the presence of a normal red cell mass. This results from a decrease in the plasma volume. Causes include dehydration (e.g. diarrhoea/vomiting) and diuretics use.

Other causes

Polycythaemia may be seen in athletes who are ‘blood doping’. It can also be idiopathic with no underlying cause identified.

A mutation in the JAK2 gene is found in approximately 98% of patients.

JAK2 is a tyrosine kinase important in cell signalling pathways. Two major mutations have been identified:

• V617F in exon 14: a point mutation with substitution of a phenylalanine for valine. Seen in around 95% of cases of PV.
• Mutations of exon 12: a heterogenous group of mutations that cause PV. Seen in around 3-4% of cases of PV.

Its mutation results in the proliferation of hematopoietic precursors. These cells are able to develop into platelets and neutrophils in addition to red cells and as such thrombocytosis and leucocytosis may also be present.

PV may be discovered incidentally on a FBC or present with an often insidious onset and non-specific features.

Patients may be entirely asymptomatic with a raised haemoglobin or haematocrit noted incidentally on blood tests. The diagnosis of PV cannot be made on a single FBC and as discussed above there are other causes of polycythaemia. Cases can be discussed with haematology, with a plan made based on the background history.

In patients presenting symptomatically, there is often a history of a gradual, creeping onset. Many of these symptoms are related to the increased blood viscosity secondary to a rise in the red cell mass. Non-specific features like headache and fatigue are common. Visual disturbance (e.g. blurring, transient blindness) can occur due to impairment of blood flow through ocular vessels. Pruritus (itching) may feature and can be severe - it is often exacerbated when the patient is warm (e.g warm bath). The exact cause of the pruritus is unclear.

Other features reflect complications of the disease. Patients are at risk of both thrombotic and bleeding events. This may include unusual thrombotic events like Budd-Chiari syndrome (obstruction of the hepatic veins) or portal vein thrombosis.

Secondary erythromelalgia (pain and redness of hands and feet) is relatively common. It is thought to result from microvascular thrombotic events in the extremities.

Symptoms

• Headache
• Visual disturbance
• Tinnitus
• Itching (especially in a warm bath)
• Fatigue
• Vertigo
• Paresthesia

Signs

• Plethora
• Bruising
• Excoriation
• Conjunctival injection
• Splenomegaly
• Erythromelalgia

Genetic testing for JAK2 mutations can help to confirm a diagnosis of PV.

Bloods

The full blood count (FBC) is a key investigation. In polycythaemia a raised haemoglobin and/or haematocrit is seen*:

• Male: haemoglobin > 185 g/L and/or haematocrit > 0.52
• Female: haemoglobin > 165 g/L an/or haematocrit > 0.48

*See note on masked polycythaemia vera below.

A similar picture is of course seen in secondary polycythaemia. The combination of polycythaemia with a raised white cell count and platelet count is highly suggestive of PV.

LFTs are typically normal but derangement can indicate Budd-Chiari syndrome or a hepatic tumour (causing EPO production and secondary polycythaemia).

A raised serum EPO is suggestive of secondary polycythaemia. Iron studies should be sent as deficiency can lead to a masked polycythaemia vera (see section below).

• FBC
• Renal function
• LFT
• Serum EPO
• Serum ferritin
• Serum uric acid (often elevated)

Genetics

Genetic testing for the JAK2 V617F in exon 14 or mutations in exon 12 help to confirm a diagnosis of PV.

Other investigations

Additional investigations may be ordered depending on the individual clinical scenario. In particular, thorough investigations are required before defining someone as JAK2-negative (no JAK2 mutation) PV - a very rare occurrence (secondary causes must be excluded first).

A bone marrow biopsy can help distinguish PV from secondary polycythaemia. Patients with PV typically have significantly increased erythropoiesis as well as increased granulopoiesis and megakaryopoiesis.

USS may be organised to identify splenomegaly, and can also be used to identify renal or hepatic tumours. CT, MRI and PET-CT may also be ordered to identify tumours that could be causing secondary polycythaemia.

Masked polycythaemia vera

Masked PV refers to PV where the haemoglobin and haematocrit count are normal despite the presence of the disease. This typically occurs in the setting of iron deficiency where the effect of the JAK2 mutation is blunted.

Patients can still develop symptoms as well as thrombotic or haemorrhagic complications. Suspicion should be raised in patients presenting with unusual syndromes like Budd-Chiari without an identifiable underlying cause.

The diagnosis of PV can be made with the combination of a raised haematocrit and mutation in the JAK2 gene.

The British Society of Haematologists (BSH) published guidelines for the diagnosis and management of PV in 2018.

PV can be diagnosed where both of the following are present:

1. High haematocrit (> 0.52 in men, > 0.48 in women) OR raised red cell mass (>25% above predicted)
2. Mutation in JAK2

They have further guidance on the diagnosis of PV in the absence of a JAK2 mutation. This is very rare, far more complex and beyond the understanding typically required at an undergraduate level. For those interested see the full BSH guidelines for more detail.

The World Health Organisation published criteria for the diagnosis of PV in 2016. For more information see this paper by Barbui et al.

The management of PV aims to reduce both complications and bothersome symptoms and reduce the risk of transformation to myelofibrosis or acute leukaemia.

Treatment is aimed at maintaining a haematocrit < 0.45 (for both men and women). This may be achieved with venesection or cytoreductive therapy. Low-dose aspirin is commonly given to reduce the risk of thrombotic complications.

Here we present a summary of the treatment options. For those interested in more detail please see the BSH guidelines.

Venesection

Venesection involves the removal of the affected patient's blood to reduce their circulating red cell mass. This can be completed 200-500ml at a time at intervals dependent on patient factors (e.g. size). This is completed with the target of maintaining a haematocrit of < 0.45.

Low-dose aspirin

Aspirin, 75mg, once daily has been shown to reduce thrombotic events and death from cardiovascular causes. It is given routinely in the absence of contraindications.

Cytoreductive therapy

Cytoreductive therapy is considered in high-risk patients, defined by BSH as:

• Age ≥ 65 years and/or
• Prior PV-associated arterial or venous thrombosis

It is also considered in low-risk patients with certain features including:

• Thrombocytosis (> 1500 × 10⁹/l)
• Progressive splenomegaly
• Progressive leucocytosis (> 15 × 10⁹/l)
• Poor tolerance of venesection

Hydroxycarbamide (hydroxyurea), a non-alkylating antimetabolite, is commonly used. Second-line options include interferon-alpha, ruxolitinib and busulfan (if limited life-expectancy due to increased risk of leukaemic transformation).

Prompt and appropriate treatment of PV has significantly improved the life expectancy of affected patients.

The median survival of patients with untreated PV is as little as 18 months. With treatment, survival improves significantly and can be several decades depending on age at diagnosis and other risk factors.

Patients with PV are at greater risk of major thrombotic events, cardiovascular disease and death. An estimated 6-15% will develop myelofibrosis within 15 years. Around 5% will undergo transformation to acute myeloid leukaemia.

Last updated: April 2022