Polycythemia vera is a type of blood cancer called a myeloproliferative neoplasm. It is characterized by the bone marrow producing too many red blood cells. Many people also have increased white blood cells and or platelets. In most cases, polycythemia vera is caused by an acquired genetic change in a gene called JAK2 that sends constant signals to blood cells to grow even when the body does not need them.
Polycythemia vera most often develops slowly and is usually diagnosed after abnormal blood test results or during the investigation of symptoms or an unexpected blood clot.
Where is polycythemia vera found?
Polycythemia vera affects the blood and bone marrow. Over time, excess blood cells can also collect in the spleen and, less commonly, the liver, causing these organs to enlarge.
What are the symptoms of polycythemia vera?
The symptoms of polycythemia vera vary widely. Some people have no symptoms and are diagnosed after routine blood tests show high red blood cell levels. Others develop symptoms related to thicker blood and increased blood cell counts.
Common symptoms include fatigue, headaches, dizziness, difficulty concentrating, night sweats, and itching. The itching is often triggered or worsened by warm water, such as during a bath or shower. Some people experience redness of the skin, especially the face, called plethora. An enlarged spleen can cause discomfort or a feeling of fullness in the upper left abdomen.
Polycythemia vera increases the risk of blood clots. In about one in five people, the first sign of the disease is an unexpected clot, such as a deep vein thrombosis, pulmonary embolus, stroke, or heart attack. Clots in the veins of the abdomen, including the portal, splenic, or mesenteric veins, are particularly suggestive of an underlying myeloproliferative neoplasm, even when blood counts appear normal at the time.
Bleeding can also occur, although it is less common than clotting. Iron deficiency from repeated blood removal or bleeding may mask the degree of red blood cell increase in some people.
How common is polycythemia vera?
Polycythemia vera is uncommon. Large population studies estimate that about 1.5 to 1.6 people per 100,000 are diagnosed each year. It is most often diagnosed in older adults, although it can occur at any age.
What causes polycythemia vera?
The exact cause is unknown. Polycythemia vera is not usually inherited. In most people, the disease is driven by an acquired mutation in the JAK2 gene that develops during life. Rarely, prior exposure to high levels of radiation has been linked to an increased risk.
What genetic changes are involved in polycythemia vera?
Almost all people with polycythemia vera have a mutation in the JAK2 gene. The most common mutation is called JAK2 p.V617F. A smaller number of people have other mutations in exon 12 of the JAK2 gene. These mutations cause the JAK2 protein to remain continuously active, leading to increased production of red blood cells and, in some cases, other blood cells.
Additional mutations in other genes, such as TET2, ASXL1, IDH2, and SRSF2, may also be present. These additional mutations are more common as the disease progresses and may influence long-term outcome.
What are the disease phases of polycythemia vera?
Polycythemia vera usually begins as a chronic disease that can remain stable for many years. Over time, some people develop more advanced disease.
In the chronic phase, red blood cell production increases, and white blood cell and platelet counts may also be elevated. Symptoms are often related to thickened blood or increased cell mass.
About 20 percent of people eventually develop post-polycythaemic myelofibrosis. In this phase, scarring develops in the bone marrow, and the marrow becomes less able to produce normal blood cells. This can lead to anemia, low platelet counts, fatigue, and significant splenic enlargement.
In a smaller number of people, polycythemia vera can progress to acute myeloid leukemia. This is a serious complication and is associated with a much poorer outlook.
How is the diagnosis made?
The diagnosis of polycythemia vera is based on blood tests, bone marrow examination, and molecular testing. These tests help confirm the diagnosis and distinguish polycythemia vera from other causes of elevated red blood cell counts.
Blood tests and peripheral blood findings
Blood tests typically show an increased red blood cell count, hemoglobin level, and hematocrit. White blood cells, especially neutrophils, and platelets may also be increased. In some people, iron deficiency can cause red blood cells to appear smaller and paler than normal, partially obscuring the degree of red blood cell increase.
When the blood smear is examined under the microscope, red blood cells may appear crowded, especially when the hematocrit is high. Neutrophils may be increased, sometimes with a mild shift toward younger forms. Platelets are often increased in number. In advanced disease, particularly post-polycythaemic myelofibrosis, abnormal red blood cell shapes such as teardrop-shaped cells may be seen.
Bone marrow biopsy findings
A bone marrow biopsy is often performed to support the diagnosis and assess disease stage. In untreated polycythemia vera, the bone marrow is usually hypercellular, meaning it contains more blood-forming cells than expected. All three major blood cell lines are increased, a pattern called panmyelosis. Red blood cell precursors are often particularly prominent.
Megakaryocytes, the cells that produce platelets, are increased in number and exhibit abnormal features. They vary in size and often have large, deeply lobed, hyperchromatic nuclei. These cells may form loose clusters and are frequently found near the bone surface. Granulocyte maturation is usually normal, and blasts are not increased.
Special stains typically show little to mild scarring of the bone marrow at diagnosis. Iron stores in the bone marrow are usually reduced.
In post-polycythaemic myelofibrosis, the bone marrow shows moderate to severe scarring. Megakaryocytes are often clustered tightly and show marked atypia. Bone marrow aspirates are frequently challenging to obtain and less informative in this stage.
Molecular and genetic tests
Molecular testing is a key part of the diagnosis. Most tests are aimed at detecting a JAK2 mutation, either JAK2 p.V617F or a mutation in JAK2 exon 12. These tests are usually performed on blood or bone marrow samples and may be part of a larger next-generation sequencing panel.
Some people also have chromosome changes detected by cytogenetic testing. Common abnormalities include deletions of part of chromosome 20 or extra copies of chromosomes 8 or 9. Additional or complex chromosome changes are more common in advanced disease and are associated with a higher risk of progression.
Other conditions to rule out
Polycythemia vera must be distinguished from secondary causes of increased red blood cells, such as chronic lung or heart disease, smoking, living at high altitude, or certain tumors that produce erythropoietin. Blood tests showing low erythropoietin levels and the presence of a JAK2 mutation strongly support a diagnosis of polycythemia vera.
It must also be distinguished from other myeloproliferative neoplasms, such as essential thrombocythaemia and prefibrotic primary myelofibrosis, which can sometimes present with overlapping features.
What happens after the diagnosis?
After polycythemia vera is diagnosed, treatment aims to reduce symptoms and lower the risk of blood clots and disease progression. This often includes regular monitoring, treatment to lower the red blood cell level, and medications to control blood counts when needed.
Follow-up includes regular blood tests and clinical assessments to monitor treatment response and detect any signs of progression, such as increasing bone marrow scarring or changes in blood counts.
What is the prognosis for a person with polycythemia vera?
Polycythemia vera is generally a slow-growing disease, but it does shorten life expectancy compared with the general population. The main risks are blood clots, bleeding, progression to myelofibrosis, and transformation to acute leukemia.
The risk of leukemia increases over time and is influenced by factors such as age, high white blood cell counts, specific genetic changes, and possibly some treatments. Many people live for years or decades with careful monitoring and appropriate therapy.
Questions to ask your doctor
- What features of my blood tests support a diagnosis of polycythemia vera?
- Was a JAK2 mutation found, and which type do I have?
- Do my bone marrow biopsy results show any scarring?
- What is my risk of blood clots or bleeding?
- How will my disease be monitored over time?
- What signs might suggest progression to myelofibrosis or leukemia?
