Polycythaemia is a common finding amongst general medicine and general practice. The vast majority of causes are secondary or reactive to other causes or are due to reduced plasma volume making the blood more concentrate (‘pseudo’ or relative/apparent polycythaemia). As with all diagnoses history and examination can help point where the problem lies. Knowing the underlying causes can help focus this history:
Our patient was a smoker, probably consumed too much alcohol and had vascular problems. He never saw his doctor and likely lived a rather unhealthy lifestyle. The team didn’t ask but he was overweight and had an elevated random glucose and was awaiting HBA1c testing. It may be that his polycythaemia was due to smoking or lung disease and the vascular problems attributable to undiagnosed type II diabetes mellitus and smoking. He did not have any features suggestive of polycthaemia vera such as:
- Night sweats
- Weight loss, lethargy
- Aquagenic pruritis
- Thrombosis (venous/arterial) and bleeding
- Headache/visual disturbance
However post fluids his indices did not correct (the indices in our patient were severe enough to assume that it is an absolute erythrocytosis rather than relative) and due to the ease of testing for polycythaemia vera we decided to perform further analysis. The substitution of phenylalanine for valine at position 617 of the JAK2 gene is responsible for approximately 95% of cases of polycythaemia vera and costs approximately £50.
Polycythaemia vera is a clonal haematopoietic neoplasm which presents usually in the 60s with a slight male predominance. Progenitor cells have increased sensitivity to growth factors as the V617F mutation allows the JAK protein to become active even when no growth factor is bound leading to increased cell survival and proliferation. The incidence is approximately 2-3 per 100 000 per year. When the V617F mutation is not found, mutations in exon 12 should be looked for as these account for a further 2-4% of cases of polycythaemia vera.
Investigations from BCSH (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06741.x/pdf)
- History and examination
- FBC/film (NB film not generally helpful in diagnosing polythaemia but needed to look for signs of myelofibrosis)
- Ferritin, U&E, LFT (frequently patients are iron deficient)
- JAK2V617F mutation
Stage 2 (if JAK2 negative):
- Red cell mass
- ABG (or Sp02 but beware if at risk of carbon monoxide poisoning, sleep apnoea or high affinity haemoglobins as may be normal)
- Abdominal USS (? epo producing mass)
- Serum erythropoietin level
- Marrow aspirate/trephine/cytogenetics (not generally require if polycythaemic indices and JAK2 +ve but new WHO criteria may change this…)
- Erythroid burst colony forming units (ability of erythroid progenitors to proliferate in vitro independent of epo)
- Arterial oxygen dissociation
- Sleep study
- Lung function studies
- Gene mutations EPOR, VHL, EGLN1 (also known as PHD2)
Abdominal vein thrombosis
Patients with abdominal vein thrombosis should be investigated for the JAK2v617F and exon 12 mutations even with a normal FBC.
Polycythaemia vera should be managed with:
- Venesection to keep haematocrit less than 0.45 (in the acute setting this may be needed frequently e.g. alternate days and concomitant fluid replacement may be necessary)
- Aspirin 75mg per day
- Cytoreduction should be considered if poor tolerance to venesection, thrombocytosis, symptomatic splenomegaly, constitutional symptoms. The choice of therapy depends on the patient. Younger patients may prefer interferon (safe in pregnancy), however hydroxycarbamide is well tolerated and does not appear to have an increased risk of malignancy associated. Anegralide, radioactive phosphorus and busulfan are also potential treatments. New JAK inhibitors such as ruxolitinib may also be used, but ideally in a trial situation.
- Manage other cardiovascular risk factors aggresively (cholesterol, glucose, blood pressure)
- Avoid excess of dietary iron
Other causes of polycthaemia can be managed with venesection but there is very little evidence:
- Correct underlying cause (smoking, hypertension, alcohol, respiratory disorder etc.)
- Apparent erythrocytosis – consider venesection if thrombosis or symptommatic or if HCT >0.54
- Hypoxic lung disease: Oxygen therapy. Consider venesection if HCT >0.56 or symptommatic
- Post renal transplant: ACEi or ARB. Consider venesection to aim 0.45.
A recent article from USA has a slightly different management style. This stratifies patients into low/high groups based on thrombotic risk and would favour a cytoreductive approach in our patient. The article suggests that in low risk patients thrombocytosis would not qualify for cytoreductive treatment. Differences in management are common in different countries and represents a lack of randomised controlled trials in this area.
Communicating the diagnosis.
This is a difficult one. PV is a malignancy and classified as one of the myeloproliferative neoplasms according to the WHO. However as haematologists we do not really see it as such although it is treated with chemotherapy. Many patients can have a normal life expectancy but there is the risk of transformation to acute leukaemia or myelofibrosis (approx 5%). Leaflets and information are widely available from Macmillan websites supporting this as a malignant disorder in the public eye. Whether to tell the patient this is up to the clinician. As our followers have said it may not help and may provoke anxiety and stress.
He underwent five venesetions over two weeks and his indices normalised (due to angina and recent TIA we thought it was better to get the Hb/HCT down as a matter of relative urgency). After a week he was found to have the V617F mutation and was formally diagnosed with PV. The diagnosis was a shock and since losing weight his glucose levels and blood pressure have normalised. He remains on venesection every 2 months along with aspirin and a beta blocker and apart from fatigue feels generally well.
How I treat polycythaemia
JAK 2 costings
Easy to read guide