Polycythaemia Rubra Vera

Synonyms: PRV, Polycythaemia vera, plethora vera, primary polycythaemia, Osler-Vaquez disease

This is not simply a high haemoglobin value but a myeloproliferative disorder. There is not only excessive production of normal erythrocytes but also increased production of leucocytes and platelets. In PRV, a single clone of erythrocytes, granulocytes, B cells, and platelets arises when a haematopoietic stem cell gains proliferative advantage over other stem cells. T lymphocytes and natural killer cells remain polyclonal. This can be tested only in female patients as it uses polymorphisms on the X-chromosome and takes advantage of its inactivation. The red cells have normal responsiveness to erythropoetin but they are not dependent upon it to multiply.
There is a risk of transformation to acute myeloid leukaemia.

• The incidence of 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 70.

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 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 gastro-intestinal haemorrhage can be more severe.
• Pruritis 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
• Less 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.

• 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 PRV.

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 PRV but a genetic condition has been described in which there is excessive responsiveness to erythropoetin.
  • Secondary polycythaemia is due to hypoxia causing erythropoetin release as in Eisenmenger syndrome, COPD or smoking. It can also result from abnormal production of erythropoetin 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.

• FBC in PRV will show not only elevated Hb and packed cell volume but WCC and platelets will are 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.
• Radio-isotopes 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 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 pseudoeryhtrocytosis from PRV, but there is overlap in the levels found and it cannot reliably differentiate.
• Cytogenetic studies. Karyotyping can detect less than 30% of patients with PRV. An abnormal test is useful, but a normal test does not exclude PRV.
• Clonal assays (using 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 JAK2 V617F mutation this may become a clinically useful marker for PRV. It has been recommended as a diagnostic marker.^3,2

The 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 Janus kinase 2 mutation analysis should be listed as a major criterion for PRV diagnosis.³

• 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.

The main concern with the management of the disease is the prevention of thrombosis that is the main cause of morbidity and mortality. Fibrotic and leukaemic disease also raise 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. Hydroxyurea 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 500ml) every 2 to 4 days cause 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.
• Pruritis 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 SSRIs like paroxetene 20mg or fluoxetine 10mg 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.

• The median survival in 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%. Gastro-intestinal 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. Hydoxyurea would seem to be less toxic than chlorambucil but probably still less benign than phlebotomy alone.¹³ It is hoped that interferon and anagrelide do not induce leukaemic transformation.^6,14

It is sometimes called Osler-Vaquez disease after Sir William Osler baronet 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 American Journal of the Medical Sciences, Thorofare, N.J., 1903, 126: 187-201.¹⁵,