PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Synonyms: PRV, polycythaemia vera, plethora vera, primary polycythaemia, Osler-Vaquez disease
Polycythaemia rubra vera (PRV) is the most common form of primary polycythaemia. It is caused by somatic mutation in a single haematopoietic stem cell. PRV is a myeloproliferative disorder with predominantly erythroid hyperplasia, but also myeloid leukocytosis, thrombocytosis and splenomegaly.
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 erythropoietin but they are not dependent upon it to multiply. There is a risk of transformation to acute myeloid leukaemia.
- Approximately 2 per 100,000 people are newly diagnosed each year.
- The average age at diagnosis is 60 years.
- Familial cases are very rare and usually present in elderly patients.
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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.
- Budd-Chiari syndrome:
- Occurs in about 2-10% 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 gastrointestinal haemorrhage can be more severe.
- Pruritus can be quite marked in 30-50% and is worse after a hot shower or bath.
- Fewer 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.
The World Health Organization reclassified chronic myeloproliferative diseases as myeloproliferative neoplasms in 2008. The criteria for the diagnosis of PRV requires two major criteria and one minor criterion, or the first major criterion and two minor criteria.
- Major criteria:
- Haemoglobin of more than 18.5 g/dL in men, 16.5 g/dL in women, or elevated red cell mass greater than 25% above mean normal predicted value.
- Presence of JAK2 617V F mutation or other functionally similar mutations, such as the exon 12 mutation of JAK2.
- Minor criteria
- Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
- Serum erythropoietin level below normal range.
- Endogenous erythroid colony formation in vitro.
- Other confirmatory findings no longer required for diagnosis include:
- Oxygen saturation with arterial blood gas greater than 92%.
- Thrombocytosis (>400,000 platelets/mm3).
- Leukocytosis (>12,000/mm3).
- Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).
It is important to distinguish three 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:
- Usually 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 disease (COPD) or smoking.
- It can also result from abnormal production of erythropoietin as with clear cell carcinoma of kidney, Wilms' tumour, hepatocellular carcinoma, cerebellar haemangioma and, occasionally, uterine myomas.
- Other tumours have been reported to produce erythropoetin or a similar substance.
- Primary polycythaemia:
- Initial blood tests:
- FBC in PCV 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..
- 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. 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.
JAK2-positive polycythaemia vera is diagnosed if:
- The JAK2 mutation is identified; and
- The haematocrit is more than 0.48 in women or more than 0.52 in men, or the red cell mass is 25% higher than normal.
JAK2-negative polycythaemia vera is diagnosed if:
- The JAK2 mutation is not identified; and
- The haematocrit is more than 0.56 in women or more than 0.60 in men, or the red cell mass is 25% higher than normal; and
- There is no identifiable secondary cause for polycythaemia; and either
- There is palpable splenomegaly or the presence of an acquired genetic abnormality in the haematopoietic stem cells or both; or
- Any two of the following clinical features are identified: an abnormally increased platelet count, an abnormally increased neutrophil count, radiological evidence of splenomegaly, and abnormally low serum erythropoietin.
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.
- Intermittent long-term phlebotomy to maintain the haematocrit below 45% (lower target level may be appropriate for women). Phlebotomy may cause progressive and sometimes severe thrombocytosis and iron deficiency. Splenomegaly and pruritus may persist despite control of the haematocrit by phlebotomy.
- Low-dose aspirin produces a small reduction in thrombotic events, including myocardial infarction and stroke, whilst not increasing the risk of haemorrhage.
- If it is not possible to control thrombotic events with phlebotomy alone then myelosuppression must be considered. However, this is not without risk and increases the risk of leukaemic transformation. Risks and benefits have to be balanced.
- Chemotherapy options include:
- For people younger than 40 years of age: first-line is interferon; second-line is hydroxycarbamide or anagrelide.
- For people 40-75 years of age: first-line is hydroxycarbamide; second-line is interferon or anagrelide.
- For people older than 75 years of age: first-line is hydroxycarbamide; second-line is radioactive phosphorus or busulfan.
- 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 receptor antagonists (H2RAs), are useful in refractory cases.
- Selective serotonin reuptake inhibitors (SSRIs) - eg, paroxetine or fluoxetine.
- Elevated uric acid may require allopurinol.
- It may be necessary to consider splenectomy when there is painful splenomegaly or there are repeated episodes of splenic infarction.
- Without treatment, life expectancy is 6-18 months.
- The most common causes of death are ischaemic stroke and myocardial infarction.
- With treatment to maintain a normal haematocrit, life expectancy increases to an average of 20 years but is still reduced compared with the general population.
- Other life-threatening complications may include:
- Pulmonary embolism.
- Progression to myelofibrosis or acute myeloid leukaemia.
- Increased risk of gastrointestinal haemorrhage.
Further reading & references
- Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2015)
- Polycythemia vera; Online Mendelian Inheritance in Man (OMIM)
- Polycythaemia/erythrocytosis; NICE CKS, July 2010
- Zhang H, Yang Y, Cui J, et al; Gaining a comprehensive understanding of pruritus. Indian J Dermatol Venereol Leprol. 2012 Sep-Oct;78(5):532-44. doi: 10.4103/0378-6323.100516.
- Tefferi A, Thiele J, Vardiman JW; The 2008 World Health Organization classification system for myeloproliferative Cancer. 2009 Sep 1;115(17):3842-7.
- Tutaeva VV, Misurin AV, Michiels JJ, et al; Application of PRV-1 mRNA expression level and JAK2V617F mutation for the differentiating between polycytemia vera and secondary erythrocytosis and assessment of treatment by interferon or hydroxyurea. Hematology. 2007 Jun 25;:1.
- Tefferi A, Thiele J, Orazi A, et al; Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007 Aug 15;110(4):1092-7. Epub 2007 May 8.
- Chronic Myeloproliferative Disorders Treatment, Polycythemia Vera; National Cancer Institute (US)
- Squizzato A, Romualdi E, Passamonti F, et al; Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev. 2013 Apr 30;4:CD006503. doi: 10.1002/14651858.CD006503.pub3.
- Landolfi R, Di Gennaro L, Novarese L, et al; Aspirin for the control of platelet activation and prevention of thrombosis in essential thrombocythemia and polycythemia vera: current insights and rationale for future studies. Semin Thromb Hemost. 2006 Apr;32(3):251-9.
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Dr Richard Draper
Dr Colin Tidy
Dr John Cox