Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Polycythaemia Rubra Vera (High Red Blood Cell Count) article more useful, or one of our other health articles.
Synonyms: polycythaemia rubra vera, plethora vera, primary polycythaemia, Osler-Vaquez disease
Polycythaemia vera (PV) is a clonal haematological malignancy characterised by pronounced symptoms, including fatigue, pruritus and symptomatic splenomegaly, along with an increased risk of thrombosis and the potential for evolution to myelofibrosis and secondary acute myeloid leukemia.
PV is classified under myeloproliferative neoplasms (MPNs), according to the 2008 World Health Organization Classification Scheme. These include::
1.1. Chronic myelogenous leukemia, BCR-ABL1-positive.
1.2. Polycythaemia vera.
1.3. Essential thrombocythaemia.
1.4. Primary myelofibrosis.
1.5 Chronic neutrophilic leukaemia.
1.6. Chronic eosinophilic leukaemia, not otherwise specified.
1.7. Mast cell disease.
PV is the most common form of primary polycythaemia. It is caused by somatic mutation in a single haematopoietic stem cell. PV is a myeloproliferative disorder with predominantly erythroid hyperplasia but also myeloid leukocytosis, thrombocytosis and splenomegaly.
- Approximately 2 per 100,000 people are newly diagnosed each year.
- The reported median age at diagnosis ranges from 65-74 years.
- Familial cases are very rare and usually present in elderly patients.
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 PV 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 more common with PV.
- 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 PV.
The World Health Organization reclassified chronic myeloproliferative diseases as myeloproliferative neoplasms in 2008. The criteria for the diagnosis of PV require 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:
- Relative polycythaemia is characterised by a decrease in plasma volume which causes an apparent increase in the red blood cell mass. Any condition causing fluid loss, such as any cause of dehydration and severe burns, will result in relative polycythaemia.
- In the second two, circulating volume is normal or raised but red cell mass is elevated:
- Primary polycythaemia:
- Usually PV 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 PV. It should also check for abnormalities of the renal system.
- Bone marrow and aspirate:
- Tend to be hypercellular in PV.
- 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 PV. The bone marrow can be normal in PV.
- Serum erythropoietin levels are often low in PV. This can differentiate secondary erythrocytosis and pseudoerythrocytosis from PV but there is overlap in the levels found and it cannot reliably differentiate.
- Cytogenetic studies. An abnormal test is useful but a normal test does not exclude PV.
- Clonal assays (using glucose-6-phosphate dehydrogenase (G6PD) markers) are not generally available for clinical use. Even if they were available they are only of use in female patients.
With the development of new techniques for detecting the Janus kinase 2 (JAK2) V617F mutation this may become a clinically useful marker for PV. It has been recommended as a diagnostic marker.
JAK2-positive PV 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 PV 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 cornerstone of therapy of low-risk patients remains strict control of cardiovascular risk factors, the use of phlebotomy and low-dose aspirin. Higher risk patients should also receive cytoreductive treatments. Hydroxycarbamide and interferon alfa represent standard first-line options for newly diagnosed high-risk PV patients.
For patients who fail first-line cytoreductive therapy (hydroxyurea and/or interferon), existing treatment options include alkylating agents, (eg, busulfan, chlorambucil or pipobroman) and P-32. However, there is evidence that these agents are associated with an increased incidence of leukaemic transformation in patients with PV.
The discovery of mutations in JAK2 as the underlying molecular basis of PV has led to the development of several targeted therapies, including JAK inhibitors - eg, ruxolitinib, which is a selective inhibitor of the Janus-associated tyrosine kinases JAK1 and JAK2 and is licensed in the UK for the treatment of disease-related splenomegaly or symptoms in patients with primary myelofibrosis, post-PV myelofibrosis, or post-essential thrombocythaemia myelofibrosis.
- 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[11, 12].
- 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.
- Median survival is about 14 years (24 years for younger patients). Risk factors for survival include advanced age, leukocytosis and thrombosis.
- Leukaemic transformation rates at 20 years are estimated at less than 10% but fibrotic transformation rates are slightly higher.
- High risk for recurrent thrombosis is defined by the presence of age over 60 years or presence of thrombosis history; low risk is defined by the absence of both of these two risk factors.
- The most common causes of death are ischaemic stroke and myocardial infarction. Other life-threatening complications may include:
- Pulmonary embolism.
- Progression to myelofibrosis or acute myeloid leukaemia.
- Increased risk of gastrointestinal haemorrhage.
Further reading and references
Stein BL, Oh ST, Berenzon D, et al; Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F. J Clin Oncol. 2015 Nov 2033(33):3953-60. doi: 10.1200/JCO.2015.61.6474. Epub 2015 Aug 31.
Tefferi A, Thiele J, Vardiman JW; The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009 Sep 1115(17):3842-7.
Polycythemia vera, PV; Online Mendelian Inheritance in Man (OMIM)
Polycythaemia/erythrocytosis; NICE CKS, July 2010 (UK access only)
Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2015)
Zhang H, Yang Y, Cui J, et al; Gaining a comprehensive understanding of pruritus. Indian J Dermatol Venereol Leprol. 2012 Sep-Oct78(5):532-44. doi: 10.4103/0378-6323.100516.
Assi TB, Baz E; Current applications of therapeutic phlebotomy. Blood Transfus. 2014 Jan12 Suppl 1:s75-83. doi: 10.2450/2013.0299-12. Epub 2013 Oct 3.
Falchi L, Newberry KJ, Verstovsek S; New Therapeutic Approaches in Polycythemia Vera. Clin Lymphoma Myeloma Leuk. 2015 Jun15 Suppl:S27-33. doi: 10.1016/j.clml.2015.02.013.
Griesshammer M, Gisslinger H, Mesa R; Current and future treatment options for polycythemia vera. Ann Hematol. 2015 Jun94(6):901-10. doi: 10.1007/s00277-015-2357-4. Epub 2015 Apr 2.
Polycythemia Vera Treatment Overview; 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 304: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 Apr32(3):251-9.
Tefferi A, Barbui T; Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015 Feb90(2):162-73. doi: 10.1002/ajh.23895.
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