Epidemiology

• The incidence of polycythaemia rubra vera (PRV) is 1.8 per 100,000 population in the UK with an equal sex ratio.
• It can be rather more common in some Jewish groups of European descent.
• It presents most commonly between 50 and 70 years of age.
• Familial cases can occasionally occur, often not until about the age of 70.

Presentation

The disease starts with the plethoric stage and then progresses to the spent stage.

• It may be discovered on routine blood count in a person with no related symptoms or there may be nonspecific complaints of lethargy and tiredness.
• About a third present with symptoms due to thrombosis. Three quarters of this is arterial thrombosis and a quarter is venous thrombosis. Features include stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.
• About 30% of patients complain of headaches, dizziness and sweating, in decreasing order of frequency.
• The Budd-Chiari syndrome occurs in about 2 to 10% of cases of polycythaemia rubra vera (PRV) but when it occurs it should always raise suspicion of the condition. It may be in an early stage of the disease before the haemoglobin is markedly raised, and this develops later. Hepatic or splenic vein thrombosis may be unrecognised but cause portal hypertension. Peptic ulceration is also 4 to 5 times more common with PRV.
• Bleeding from gums or easy bruising is usually mild but gastrointestinal haemorrhage can be more severe.
• Pruritus can be quite marked in 40% and is worse after a hot shower or bath. Mast cells are more numerous and histamine levels high. It is quite possible that low iron stores are also involved.^[1]
• Fewer than than 5% of patients have erythromelalgia. This is erythema, warmth, pain, and even sometimes infarction of the distal extremities. The hands and feet have a painful burning sensation. It also occurs in thrombocythaemia, suggesting that high platelets are important.
• A small number may present with myocardial infarction, congestive heart failure, features of compression of the spinal column from extramedullary haematopoiesis or gout from increased cell turnover.

Examination

• The patient may look plethoric with a ruddy complexion. There is a greater chance of cyanosis with a high haemoglobin .
• Splenomegaly is not uncommon (present in about 75% of patients at the time of diagnosis).
• Tenderness of the sternum may indicate transformation to acute myeloid leukaemia.
• Hypertension is common in patients with polycythaemia rubra vera (PRV).

Differential diagnosis

It is important to distinguish 3 causes of raised haemoglobin level:

• In the first, red cell volume is normal but circulating volume is depleted:
  • Apparent or relative polycythaemia occurs when the circulating volume is depleted. This can occur acutely in dehydration or in hypertension, obesity and stress.
• In the second two, circulating volume is normal or raised but red cell mass is elevated:
  • Primary polycythaemia is usually polycythaemia rubra vera (PRV) but a genetic condition has been described in which there is excessive responsiveness to erythropoietin.
  • Secondary polycythaemia is due to hypoxia causing erythropoietin release as in Eisenmenger's syndrome, chronic obstructive pulmonary disorder (COPD) or smoking. It can also result from abnormal production of erythropoietin as with clear cell carcinoma of kidney, Wilm's tumour, hepatocellular carcinoma, cerebellar haemangioma and, occasionally, uterine myomas. Other tumours have been reported to produce erythropoetin or a similar substance.

Investigation

• FBC in polycythaemia rubra vera (PRV) will show not only elevated Hb and packed cell volume but WCC and platelets will be elevated too. In secondary polycythaemia only red blood cells are raised.
• Ferritin is often low in primary polycythaemia because of increased demand for iron. In secondary causes it is usually normal.
• Arterial blood gases will show hypoxia in cyanotic heart disease and lung disease.
• Radioisotopes can be used to measure circulating volumes. Red cells can be labelled with 51Cr and albumin with 131I. This is expensive, needs skill and is not widely available.
• CT, MRI or ultrasound scanning of the abdomen may show enlargement of the spleen as is often found in PRV. It should also check for abnormalities of the renal system.
• Bone marrow and aspirate tend to be hypercellular in PRV. In the plethoric phase, the blood smear shows normal erythrocytes, variable neutrophilia with myelocytes, metamyelocytes, and varying degrees of immaturity, basophilia, and increased platelet counts. In the spent phase, the blood smear shows abundant teardrop cells, leukocytosis, and thrombocytosis. Generally the findings are not specific to PRV and, indeed, the bone marrow can be normal in PRV.
• Serum erythropoietin levels are often low in PRV. This can differentiate secondary erythrocytosis and pseudoerythrocytosis from PRV, but there is overlap in the levels found and it cannot reliably differentiate.
• Cytogenetic studies. Karyotyping can detect fewer than 30% of patients with PRV. An abnormal test is useful, but a normal test does not exclude PRV.
• Clonal assays (using glucose-6-phosphate dehydrogenase (G6PD) markers) are not generally available for clinical use. Even if it were available it is only of use in female patients.
• Research markers include the thrombopoietin receptor MPL expression and the PRV1 mRNA in granulocytes.^[2]
• With development of new techniques for detecting the Janus kinase 2 (JAK2) V617F mutation this may become a clinically useful marker for PRV. It has been recommended as a diagnostic marker.^[2][3]

Diagnostic criteria

The World Health Organization (WHO) criteria require reasonable elimination of secondary and relative polycythaemia and confirmation of true polycythaemia.^[4] An international panel of experts recently recommended a revision of the WHO classification of Myeloid Neoplasms and these have been endorsed and recommended for adoption.^[3] Essentially, this revision recommends that JAK2 mutation analysis should be listed as a major criterion for polycythaemia rubra vera (PRV) diagnosis.^[3]

Apart from the suggestion of adding the JAK2 mutation as a major 'A' criterion, other suggestions have included additions to categories below:

• Category A:
  • Exclusion of secondary causes of erythrocytosis
  • Clonality cytogenetic markers or abnormalities
  • Endogenous erythroid colonies
• Category B:
  • Splenomegaly demonstrated on isotope or ultrasound scanning
  • Reduced serum erythropoietin
  • Bone marrow panmyelosis

As with many haematological conditions, debate over classification and diagnostic criteria is ongoing and can be confusing.

Management

The main concern with the management of the disease is the prevention of thrombosis, which is the main cause of morbidity and mortality. Fibrotic and leukaemic disease also raises mortality and morbidity. A strategy of balancing risk and benefit has been proposed in which, for example, patients at low risk of thrombosis are treated with low-dose aspirin and phlebotomy.^[5][6] Cytotoxic therapy is reserved for patients at higher risk of thrombosis. Hydroxycarbamide is the drug of choice as it is effective at preventing thrombosis and low in leukaemogenicity.^[5][7]

• In the plethoric phase, phlebotomy is performed until the haematocrit is under reasonable control. Removal of a unit of blood (450 to 500 ml) every 2 to 4 days causes little problem. As iron deficiency sets in, the haematocrit becomes easier to control, and phlebotomy becomes less frequent. Phlebotomy controls erythrocytosis but does not affect the leukocytosis and thrombocytosis of the disease.
• Low-dose aspirin produces a small but significant reduction in thrombotic events, including myocardial infarction and stroke, whilst not increasing the risk of haemorrhage.^[8][9]
• If it is not possible to control thrombotic events with phlebotomy alone, then myelosuppression must be considered but this is not without risk. As discussed below, it increases the risk of leukaemic transformation. Risks and benefits have to be balanced. The traditional treatments are chlorambucil and 32P.
• Interferon A seems to have great promise to treat the condition although it is expensive, its mode of action is unknown and side-effects are quite marked. It can even be used in pregnancy as it is not teratogenic.^[6] It tends to produce a flu-like illness.^[10]
• Anagrelide is a new drug that impairs the budding of platelets and so might be very useful in preventing thrombotic complications.^[11]
• Erythromelalgia responds to low-dose aspirin or reduction of the platelet count with low-dose myelosuppressants.
• Pruritus can be quite disabling. Taking baths or showers at lower temperatures and patting the skin dry, to avoid rubbing may help. Antihistamines, including H2 antagonists are useful. In refractory cases, selective serotonin reuptake inhibitors (SSRIs) like paroxetine 20 mg or fluoxetine 10 mg daily may help.
• The object of phlebotomy is iron deficiency and so food rich in iron should be avoided.
• Elevated uric acid may require allopurinol.
• It may be necessary to consider splenectomy when there is painful splenomegaly or repeated episodes of splenic infarction.

Prognosis

• The median survival in polycythaemia rubra vera (PRV) is 9 to 13 years although, without any form of treatment, 50% die within 18 months.
• There is always a risk of conversion to acute myeloid leukaemia at any stage but this is most marked in the spent phase.^[12]
• The mode of treatment affects this risk of conversion to acute myeloid leukaemia.

The PRV study group found that in those treated only with phlebotomy the risk of transformation was 1.5%, in those given 32P it was 10% and in those treated with chlorambucil the risk was 13%. Gastrointestinal and skin cancers are also more common in the condition and are affected by mode of treatment. The figures for phlebotomy alone, with 32P and with chlorambucil were 4%, 9% and 12% respectively. Hydroxycarbamide would seem to be less toxic than chlorambucil but probably still less benign than phlebotomy alone (because of the risk of adverse effects with both drugs).^[13] It is hoped that interferon and anagrelide do not induce leukaemic transformation.^[6][14]

Historical note

It is sometimes called Osler-Vaquez disease after Baronet Sir William Osler and Louis Henri Vaquez. Vaquez described the disease in 'Sur une forme spéciale de cyanose s'accompagnant d'hyperglobulie excessive et persistante' published in Comptes rendus de la Société de biologie, Paris, 1892, 44: 384-388. Osler published 'Chronic cyanosis, with polycythaemia and enlarged spleen: a new clinical entity' in the American Journal of the Medical Sciences, Thorofare, N.J., 1903, 126: 187-201.^[15] ,