11/14/24, 10\:49 AM Polycythaemia Vera

Polycythaemia Vera

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Polycythaemia vera\: a myeloproliferative disorder with excess erythrocyte production; >98% cases due to JAK2 mutation.
Incidence\: 2 per 100,000; prevalence\: 50 per 100,000; usually presents in patients aged 60-70.
Primary polycythaemia\: excess RBC production due to JAK2 mutation.
Secondary polycythaemia\: high RBC production due to chronic hypoxia, local renal hypoxia, or excess EPO production
(e.g., EPO-secreting tumours).
Risk factors\: advancing age, history of Budd-Chiari syndrome.
Symptoms\: headaches, dizziness, sweating, myalgia, weakness, fatigue, tinnitus, pruritis (after hot shower), erythromelalgia,
blurred vision, dyspepsia, gout. Thrombosis (stroke, MI, DVT, PE, Budd-Chiari syndrome).
Clinical
Investigations\:
FBC\: Hb >185 g/L (men), >165 g/L (women); Hct >0.52 (men), >0.48 (women); neutrophilia, thrombocytosis.
Other labs\: blood
Imaging\: abdominal ultrasound, further imaging (CT head/neck/chest/abdomen/pelvis) for EPO-secreting tumours.
Diagnosis (JAK2-positive)\: high Hct or raised red cell mass, JAK2 mutation. (JAK2-negative)\: raised red cell mass or high Hct,
absence of JAK2 mutation, no secondary erythrocytosis cause, consistent bone marrow histology, possible splenomegaly.
Management\:
Cardiovascular risk factor optimisation.
Phlebotomy\: maintain Hct \<0.45 (200-500ml venesected as needed).
Aspirin\: low dose to reduce thrombotic risk.
Cytoreductive therapy\: indicated for progressive splenomegaly, leucocytosis, thrombocytosis, poor venesection tolerance,
age ≥60, thrombosis history; hydroxycarbamide
Complications\: ischaemic stroke, MI, PE, progression to myelo
Prognosis\: median survival ~14 years, mortality commonly due to thromboembolic events; 15% progression to myelo
at 15 years, 10% transformation to leukaemia at 20 years.
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Introduction

Polycythaemia vera is a myeloproliferative disorder characterised by the excess production of erythrocytes. In over 98%
of cases, it is caused by a genetic mutation in the JAK2 gene.
1
Polycythaemia vera is a rare condition with an incidence of 2 per 100,000 and a prevalence of 50 per 100,000. It tends to
present in patients aged 60 - 70 years old.
2
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Aetiology

Myeloproliferative disorders result in the excess production of myeloid cells\: erythrocytes (red blood cells), platelets or
granulocytes (neutrophils, eosinophils and basophils). When excess red blood cells are produced resulting in a raised
haemoglobin concentration and haematocrit this is known as polycythaemia.
Polycythaemia vera is a primary polycythaemia. In almost all cases, the driver of the excess erythrocyte production is a
mutation in the JAK2 (Janus Kinase 2) gene.
1
This contrasts with secondary polycythaemia where a high number of erythrocytes are produced in a physiological
response to chronic hypoxia (i.e. secondary to smoking or chronic lung disease), local renal hypoxia (e.g renal artery
stenosis) or excess erythropoietin (EPO) production (i.e. secondary to EPO secreting tumours).
2

Risk factors

Risk factors for polycythaemia vera include\:
Advancing age\: median age at diagnosis is 60-70 years
History of Budd-Chiari syndrome\: a proportion of people with what had previously been identi
Chiari syndrome (or other splanchnic vein thromboses), will in fact have a JAK2 mutation even if they had initially normal
blood counts

Clinical features

History

Typical symptoms of polycythaemia vera may include\:
2,3
Headaches\: usually associated with dizziness and sweating
Myalgia and weakness
Fatigue
Tinnitus
Pruritis\: particularly after a hot shower or bath
Erythromelalgia\: burning pain, warmth and redness in the hands and feet
Blurred vision\: temporary loss of vision due to hyper-viscosity
Dyspepsia\: peptic ulceration
Gout\: due to increased cell turnover
A third of patients
embolism, Budd-Chiari syndrome. In patients with polycythaemia vera, 75% of thromboses are arterial, and 25% are venous.
Figure 1. Patient with erythromelalgia.
4

Clinical examination

2,3
Typical clinical
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A 'ruddy' (reddish) complexion
Splenomegaly\: present in one-third of patients at the time of diagnosis
Abdominal masses\: benign and malignant uterine, renal and hepatic tumours which can secrete EPO may be palpable
Hypertension

Di

In the context of a raised haemoglobin, di
5
Hypoxia driven\: including COPD, smoking, carbon monoxide poisoning, sleep apnoea, left to right cardiac shunts
(Eisenmenger’s syndrome) and high altitude
Local renal hypoxia\: for example, secondary to renal artery stenosis
Pathological erythropoietin production\: secondary to EPO secreting tumours; including a clear cell renal carcinoma,
Wilms’ tumour, hepatocellular carcinoma, cerebellar haemangioblastoma, pheochromocytoma, uterine myoma,
parathyroid carcinoma and meningioma

Investigations

Full blood count

Polycythaemia is de
2,5
Haemoglobin (Hb) >185 g/L and/or haematocrit (Hct) > 0.52 in males
Hb >165 g/L and/or Hct > 0.48 in females
Red cell mass >25% above predicted
If the patient is dehydrated, apparent polycythaemia may be present in which the Hb/Hct is raised because of a reduced
plasma volume. These patients will have a normal red cell mass.
5
One-o
In addition, neutrophilia and thrombocytosis are commonly seen in patients with polycythaemia vera.

Other laboratory investigations

Other relevant laboratory investigations include\:
Blood
U&E/LFTs\: to assess for renal/hepatic causes (including tumours) of secondary polycythaemia or complications
(including Budd-Chiari syndrome) of polycythaemia vera
Serum ferritin\: normal or low in polycythaemia vera due to increased demand for iron
Arterial blood gas\: may identify hypoxia or raised carboxyhaemoglobin levels secondary to smoking or carbon
monoxide poisoning
5
Serum erythropoietin\: suppressed levels suggest polycythaemia vera whilst raised levels in the context of
polycythaemia suggest a secondary cause; inappropriate EPO production and the possibility of an EPO-secreting
tumour.
JAK 2 V617F mutational analysis\: positive in 95% of patients with polycythaemia vera. Around 5% of cases involve other
JAK2 mutations.

Bone marrow biopsy

A bone marrow biopsy may be helpful in distinguishing polycythaemia vera from secondary polycythaemia. In
polycythaemia, a biopsy may show hypercellularity, increased erythropoiesis, granulopoiesis and megakaryopoiesis, and
variable megakaryocyte size.

Imaging

Relevant imaging investigations include\:
Abdominal ultrasound\: to assess for splenomegaly and exclude secondary causes of polycythaemia including renal
and hepatic pathology.
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Further imaging\: CT head/neck/chest/abdomen/pelvis looking for rarer tumours which may secrete EPO. This is not
always required if a cause for the polycythaemia is found with the above initial tests.

Diagnosis

Table 1. A summary of the diagnostic criteria as per the British Society of Haematology.
5
JAK2‐positive polycythaemia vera (requires both criteria)
A1
High haematocrit (>0·52 in men, >0.48 in women) OR raised red cell mass
(>25% above predicted)
A2 Mutation in J A K 2
JAK2‐negative polycythaemia vera (requires A1‐A4 plus another A or two
B criteria)
A1
Raised red cell mass (>25% above predicted) OR haematocrit ≥0.60 in men,
≥0.56 in women
A2 Absence of mutation in J A K 2
A3 No cause of secondary erythrocytosis
A4 Bone marrow histology consistent with polycythaemia vera
A5 Palpable splenomegaly
A6
Presence of an acquired genetic abnormality (excluding B C R_‐_A B L 1 ) in the
haematopoietic cells
9
B1 Thrombocytosis (platelet count >450 × 10 /L)
B2
Neutrophil leucocytosis (neutrophil count >10 × 10 9
≥12·5 × 10 9
/L in smokers)
/L in non‐smokers,
B3 Radiological evidence of splenomegaly

Management

Patients with polycythaemia vera are at increased risk of arterial and venous thrombosis and therefore initial management
involves cardiovascular risk factor optimisation (i.e. hyperlipidaemia, diabetes, hypertension and smoking status is
assessed and managed as appropriate).
Further treatment options aim to signi
can be seen despite high platelet counts) and symptom burden.
2,5

Phlebotomy

Intermittent long-term phlebotomy is performed to maintain Hct \<0.45. Approximately 200-500mls of blood is venesected
at intervals suitable to the patient.
5

Aspirin

the risk of haemorrhage.
Low dose aspirin reduces the risk of thrombotic events and death in patients with polycythaemia vera. It does not increase

Cytoreductive therapy

Cytoreductive therapy is indicated in those with\:
Progressive splenomegaly
Progressive leucocytosis (WCC>15)
Progressive thrombocytosis (platelets >1500)
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Poor tolerance to venesection (increased frequency of venesection required to maintain Hct\<0.45)
Age of 60 years and above
History of thrombosis
Hydroxycarbamide is the
hydroxycarbamide is contraindicated, not tolerated or ine
Interferon Alfa is particularly useful in women of childbearing age as it is not teratogenic which is a concern with
hydroxycarbamide.
2

Complications

Complications of polycythaemia vera include\:
3
Ischaemic stroke
Myocardial infarction
Pulmonary embolism
Progression to myeloacute myeloid leukaemia
Gastrointestinal haemorrhage
Budd-Chiari syndrome

Prognosis

The median survival is approximately 14 years. Mortality is commonly related to thromboembolic events (ischaemic stroke
and myocardial infarction).
3
Progression to myelo
2
years.

References

TeLINK]
NICE CKS. P o l y c y t h a e m i a / e r y t h r o c y t o s i s . Revised in 2020. Available from\: [LINK]
Patient UK. P o l y c y t h a e m i a R u b r a V e r a . Revised in 2016. Available from\: [LINK]
Herbert L et al. E r y t h r o m e l a l g i a . Licence\: [CC-BY]
McMullin MF et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology
Guideline. Published in 2019. Available from\: [LINK]

Reviewer

Dr Alex Langridge
Haematology Registrar

Related notes

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Chronic Myeloid Leukaemia
Disseminated Intravascular Coagulation (DIC)
Haemolytic anaemia
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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
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