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 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 identified as idiopathic Budd-Chiari syndrome (or other splanchnic vein thromboses), will in fact have a JAK2 mutation even if they had initially normal blood counts
Typical symptoms of polycythaemia vera may include:2,3
Headaches: usually associated with dizziness and sweating
Myalgia and weakness
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 first present due to thrombosis including stroke, myocardial infarction, deep vein thrombosis, pulmonary embolism, Budd-Chiari syndrome. In patients with polycythaemia vera, 75% of thromboses are arterial, and 25% are venous.
Typical clinical findings of polycythaemia vera include2,3:
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
In the context of a raised haemoglobin, differential diagnoses to consider include: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
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-off values of Hct >0.6 in males and >0.52 in females require additional investigation.
In addition, neutrophilia and thrombocytosis are commonly seen in patients with polycythaemia vera.
Other laboratory investigations
Other relevant laboratory investigations include:
Blood film: to assess for features of leukaemia which require bone marrow assessment
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 poisoning5
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.
Relevant imaging investigations include:
Abdominal ultrasound: to assess for splenomegaly and exclude secondary causes of polycythaemia including renal and hepatic pathology.
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.
JAK2‐positive polycythaemia vera (requires both criteria)
High haematocrit (>0·52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
Mutation in JAK 2
JAK2‐negative polycythaemia vera (requires A1‐A4 plus another A or two Bcriteria)
Raised red cell mass (>25% above predicted) OR haematocrit ≥0.60 in men, ≥0.56 in women
Absence of mutation in JAK 2
No cause of secondary erythrocytosis
Bone marrow histology consistent with polycythaemia vera
Presence of an acquired genetic abnormality (excluding BCR‐ABL1 ) in the haematopoietic cells
Thrombocytosis (platelet count >450 × 109 /L)
Neutrophil leucocytosis (neutrophil count >10 × 109 /L in non‐smokers, ≥12·5 × 109 /L in smokers)
Radiological evidence of splenomegaly
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 significantly reduce thrombosis risk whilst also reducing the risk of haemorrhage (which can be seen despite high platelet counts) and symptom burden.2,5
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
Low dose aspirin reduces the risk of thrombotic events and death in patients with polycythaemia vera. It does not increase the risk of haemorrhage.
Cytoreductive therapy is indicated in those with:
Progressive leucocytosis (WCC>15)
Progressive thrombocytosis (platelets >1500)
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 first line cytoreductive agent. Interferon-alfa is a second line option or alternative if hydroxycarbamide is contraindicated, not tolerated or ineffective.
Interferon Alfa is particularly useful in women of childbearing age as it is not teratogenic which is a concern with hydroxycarbamide.2