Polycythaemia Vera

Question 1

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

Answer 1

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

Question 2

Polycythaemia vera

Answer 2

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.

Question 3

PV is a rare condition that is uncommon under the age of …

Answer 3

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

Question 4

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 …

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

Answer 4

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.

Question 5

Polycythaemia

Polycythaemia refers to an increase in…

Answer 5

Polycythaemia
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.

Question 6

Primary polycythaemia

Answer 6

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.

Question 7

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:

Answer 7

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

Question 8

Relative polycythaemia

Answer 8

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.

Question 9

A mutation in the … gene is found in approximately 98% of patients with PV

Answer 9

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

Question 10

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

Answer 10

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.

Question 11

Clinical features PV

Answer 11

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.

Question 12

Symptoms of PV

Answer 12

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

Question 13

Signs in PV

Answer 13

Plethora
Bruising
Excoriation
Conjunctival injection
Splenomegaly
Erythromelalgia

Question 14

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

Answer 14

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

Question 15

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

Answer 15

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

Question 16

A raised serum … is suggestive of secondary polycythaemia. Iron studies should be sent as deficiency can lead to a masked polycythaemia vera

Answer 16

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).

Question 17

Bloods IN PV

Answer 17

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

Question 18

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

Answer 18

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

Question 19

PV jak2

Answer 19

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.

Question 20

Masked polycythaemia vera

Answer 20

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.

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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

Question 23

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

Answer 23

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.

Question 24

PV treatment - Treatment is aimed at maintaining a haematocrit < … (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.

Answer 24

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.

Question 25

Venesection

Answer 25

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.

Question 26

Low-dose aspirin in PV

Answer 26

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.

Question 27

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

Answer 27

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

Question 28

PV … (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).

Answer 28

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).

Question 29

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

Answer 29

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.

Question 30

The median survival of patients with untreated PV is as little as …

Answer 30

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.