Polycythemia vera

Polycythemia vera is an uncommon myeloproliferative neoplasm (a type of chronic leukemia) in which the bone marrow makes too many red blood cells.[1] It may also result in the overproduction of white blood cells and platelets.

"erythremia" redirects here. For similar-sounding medical terms, see arrythmia and erythema.
Polycythemia vera
Other namesPolycythaemia vera (PV, PCV), erythremia, primary polycythemia, Vaquez disease, Osler-Vaquez disease, polycythemia rubra vera[1]
Blood smear from a patient with polycythemia vera
SpecialtyOncology

Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the increased red blood cells. It is more common in the elderly and may be symptomatic or asymptomatic. Common signs and symptoms include itching (pruritus), and severe burning pain in the hands or feet that is usually accompanied by a reddish or bluish coloration of the skin. Patients with polycythemia vera are more likely to have gouty arthritis. Treatment consists primarily of phlebotomy.

Signs and symptoms
Erythromelalgia is a rare symptom of PV, here present in a patient with longstanding polycythemia vera. Note reddish limbs and swelling.

People with polycythemia vera can be asymptomatic.[2] A classic symptom of polycythemia vera is pruritus or itching, particularly after exposure to warm water (such as when taking a bath),[3] which may be due to abnormal histamine release[4][5] or prostaglandin production.[6] Such itching is present in approximately 40% of patients with polycythemia vera.[7] Gouty arthritis may be present in up to 20% of patients.[7] Peptic ulcer disease is also common in patients with polycythemia vera; most likely due to increased histamine from mast cells, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori.[8] Another possible mechanism for the development for peptic ulcer is increased histamine release and gastric hyperacidity related with polycythemia vera.

A classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia.[9] This is a burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin. Erythromelalgia is caused by an increased platelet count or increased platelet "stickiness" (aggregation), resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin.[10][11] Patients with polycythemia vera are prone to the development of blood clots (thrombosis). A major thrombotic complication (e.g. heart attack, stroke, deep venous thrombosis, or Budd-Chiari syndrome) may sometimes be the first symptom or indication that a person has polycythemia vera. Headaches, lack of concentration and fatigue are common symptoms that occur in patients with polycythemia vera as well.

Pathophysiology

Polycythemia vera (PCV), being a primary polycythemia, is caused by neoplastic proliferation and maturation of erythroid, megakaryocytic and granulocytic elements to produce what is referred to as panmyelosis. In contrast to secondary polycythemias, PCV is associated with a low serum level of the hormone erythropoietin (EPO). Instead, PCV cells often carry activating mutation in the tyrosine kinase (JAK2) gene, which acts in signaling pathways of the EPO-receptor, making those cells proliferate independent from EPO.[12]

Diagnosis

Physical exam findings are non-specific, but may include enlarged liver or spleen, plethora, or gouty nodules. The diagnosis is often suspected on the basis of laboratory tests. Common findings include an elevated hemoglobin level and hematocrit, reflecting the increased number of red blood cells; the platelet count or white blood cell count may also be increased. The erythrocyte sedimentation rate (ESR) is decreased due to an increase in zeta potential. Because polycythemia vera results from an essential increase in erythrocyte production, patients have normal blood oxygenation and a low erythropoietin (EPO) level.

In primary polycythemia, there may be 8 to 9 million and occasionally 11 million erythrocytes per cubic millimeter of blood (a normal range for adults is 4–6), and the hematocrit may be as high as 70 to 80%. In addition, the total blood volume sometimes increases to as much as twice normal. The entire vascular system can become markedly engorged with blood, and circulation times for blood throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes can cause the viscosity of the blood to increase as much as five times normal. Capillaries can become plugged by the very viscous blood, and the flow of blood through the vessels tends to be extremely sluggish.

As a consequence of the above, people with untreated polycythemia vera are at a risk of various thrombotic events (deep venous thrombosis, pulmonary embolism), heart attack and stroke, and have a substantial risk of Budd-Chiari syndrome (hepatic vein thrombosis),[13] or myelofibrosis. The condition is considered chronic; no cure exists. Symptomatic treatment (see below) can normalize the blood count and most patients can live a normal life for years.

The disease appears more common in Jews of European extraction than in most non-Jewish populations. Some familial forms of polycythemia vera are noted, but the mode of inheritance is not clear.

A mutation in the JAK2 kinase (V617F) is strongly associated with polycythemia vera.[14][15] JAK2 is a member of the Janus kinase family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy.

Following history and examination, the British Committee for Standards in Haematology (BCSH) recommend the following tests are performed:

  • full blood count/film (raised hematocrit; neutrophils, basophils, platelets raised in half of patients)
  • JAK2 mutation
  • serum ferritin
  • renal and liver function tests

If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests:

Other features that may be seen in polycythemia vera include a low ESR and a raised leukocyte alkaline phosphatase.

The diagnostic criteria for polycythemia vera have recently been updated by the BCSH. This replaces the previous Polycythemia Vera Study Group criteria.

JAK2-positive polycythemia vera - diagnosis requires both criteria to be present:

Criteria Notes
A1 High erythrocyte volume fraction (EVF or hematocrit) (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2

JAK2-negative polycythemia vera - diagnosis requires A1 + A2 + A3 + either another A or two B criteria:

Criteria Notes
A1 Raised red cell mass (>25% above predicted) OR hematocrit >0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the hematopoietic cells
B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin

Treatment

Untreated, polycythemia vera can be fatal, with the median survival in patients being 1.5-3 years.[16][17] [18] Data on the effect of life-span of an individual with treated polycythemia vera is inconclusive due to the rarity of the disease. Studies show the median survival rate of controlled Polycythemia Vera ranges from 10 to 20 years.[19]

Frequent blood withdrawals (phlebotomy) is one form of treatment, which often may be combined with other therapies. The removal of blood from the body induces iron deficiency, thereby decreasing the hemoglobin / hematocrit level, and reducing the risk of blood clots. Phlebotomy is typically performed to bring their hematocrit (red blood cell percentage) down below 45 for men or 42 for women.[20] It has been observed that phlebotomy also reduces cognitive impairment.[21]

Medications are also used which reduce the number of red blood cells. These include hydroxyurea and interferon therapy, among others.[22] The tendency of some practitioners to avoid chemotherapy if possible, especially in young patients, is a result of research indicating possible increased risk of transformation to acute myelogenous leukemia (AML). While hydroxyurea is considered a safer chemotherapy in this aspect, there is still some debate about its long-term safety.[23]

There are indications that the lung cancer drug erlotinib may be an additional treatment option for those with certain genetic markers.[24]

Ruxolitinib, a Janus kinase 2 (JAK2) inhibitor, is also used to treat polycythemia.[25]

Ropeginterferon alfa-2b (Besremi) was approved for medical use in the European Union in February 2019,[26] and in the United States in November 2021.[27][28] Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.[27] Interferon alfa-2b is also used.[22]

Epidemiology

Polycythemia vera occurs in all age groups,[29] although the incidence increases with age. One study found the median age at diagnosis to be 60 years,[7] while a Mayo Clinic study in Olmsted County, Minnesota found that the highest incidence was in people aged 70–79 years.[30] The overall incidence in the Minnesota population was 1.9 per 100,000 person-years, and the disease was more common in men than women.[30] A cluster around a toxic site was confirmed in northeast Pennsylvania in 2008.[31]

Notable deaths
  • Phyllis George (1949–2020), American sportscaster and former First Lady of Kentucky[32]
  • Ron Miles (1963–2022), American jazz trumpeter[33]
  • Nell Rankin (1924–2005), American mezzo-soprano[34]

References
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  2. [Polycythemia vera EBSCO database] verified by URAC; accessed from Mount Sinai Hospital, New York
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  4. Steinman H, Kobza-Black A, Lotti T, Brunetti L, Panconesi E, Greaves M (1987). "Polycythaemia rubra vera and water-induced pruritus: blood histamine levels and cutaneous fibrinolytic activity before and after water challenge". Br J Dermatol. 116 (3): 329–33. doi:10.1111/j.1365-2133.1987.tb05846.x. PMID 3567071. S2CID 22068469.
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  31. MICHAEL RUBINKAM (2008). "Cancer cluster confirmed in northeast Pennsylvania". Associated Press. Archived from the original on September 2, 2008.
  32. Yetter, Deborah (May 16, 2020). "Phyllis George, former Kentucky first lady and Miss America, dies at 70". The Courier-Journal. Retrieved May 16, 2020.
  33. Harrington, Jim (March 9, 2022). "'Gifted artist' Ron Miles dies of a rare blood disorder at 58". The Mercury News. Retrieved March 10, 2022.
  34. Allan Kozinn (January 19, 2005). "Nell Rankin Is Dead at 81; Mezzo-Soprano With Met". The New York Times.
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