Polycythaemia vera

Polycythaemia vera (PV) is a tumorous disease belonging to the group of myeloproliferative diseases. In the case of polycythaemia vera, production of blood cells, especially red blood cells, has gotten out of control due to gene changes that have occurred during life. As the change has occurred in haematopoietic stem cells, from which red blood cells, white blood cells as well as platelets originate, all three cell lines may exceed normal values in blood analysis. Polycythaemia means ‘many cells’.

A haemoglobin level over 160 g/L in women and over 165 g/L in men may indicate polycythaemia. Polycythaemia vera should be distinguished from secondary or reactive change – an increase in haemoglobin and red blood cells due to a disease or condition. There may be a compensatory increase in the number of red blood cells due to a lack of oxygen or hypoxia, for example, because of smoking, pulmonary diseases, heart failure, sleep apnoea as well as a stay at high altitude. In such a case, it is not a tumorous disease and the causative factor should be treated.

In addition to red blood cell count and haemoglobin level, the doctor evaluates haematocrit value. Haematocrit shows the ratio of blood plasma and red blood cells as percentage. In the case of dehydration, the haematocrit level may increase as there is less fluid and therefore blood plasma in the body.

The level of erythropoiesis-stimulating hormone erythropoietin is low in polycythaemia vera.

Polycythaemia vera is a rare disease: around two cases per 100,000 people are diagnosed annually. Disease may occur in every age group, but mainly people over 50 become ill, men slightly more often than women. The cause of polycythaemia vera is not completely clear. In 95% of the patients, there is a mutation in the Janus-kinase 2 gene (JAK2V617F). Due to the gene change, blood cell production control is impaired and their lifespan is prolonged. The gene change develops in the course of life and its cause is unclear.

This gene change is not hereditary!

Polycythaemia vera cannot be prevented!

Symptoms

There may be no complaints at the time of polycythaemia vera diagnosis. Symptoms occur mainly due to the accumulation of excessively produced red blood cells in the blood. Blood volume increases and blood becomes more viscous or thick, therefore blood movement in small vessels is impaired.

The main problems are as follows:

  • Due to impairment of the cerebral blood supply, headache, visual disorders, dizziness, tiredness, weakness, symptoms of transitory ischaemic attack (or transient disorder of brain blood supply) may occur.
  • Skin itching/pruritus occurs in 40% of patients and may be more pronounced after a warm bath or sauna.
  • Reddish face, hands and feet, auricles, whites of eyes. Cyanosis or blue colour of fingers, toes, nose and lips may also occur.
  • Muscle and/or bone pain.
  • Increased blood pressure, symptoms of heart failure and ischaemic heart disease.
  • General symptoms such as weight loss, tiredness and nocturnal sweating.
  • Tinnitus.
  • Enlarged spleen or splenomegaly occurs in 75% of patients; this may cause discomfort, a feeling of fullness or pain in the upper left abdomen. In some patients, liver enlargement (hepatomegaly) may develop.
  • Thrombosis risk is higher in polycythaemia vera patients than in the general population. Thrombosis may occur in 60% of patients, especially untreated patients, causing life-threatening complications. Thrombi may be located in different places, including superficial and profound leg veins, cardiac blood vessels (causing chest pain, in severe cases myocardial infarction), cerebral blood vessels (causing transitory stroke), lungs (pulmonary artery thromboembolism).
  • Disease signs associated with haemorrhage are bruising, mucosal bleeding, nasal bleeding or gastrointestinal bleeding, occurring in 15-35% of patients, especially in patients with high platelet levels.
  • Gastric ulcer risk is 3-5 times greater than in the general population.
  • In 25% of patients, gout or uric acid metabolism disorder may manifest.

Diagnosis

Polycythaemia vera is diagnosed by a doctor of blood disorders or a haematologist. During diagnosis, other causes of increased number of blood cells, for example secondary polycythaemia, are excluded. In analysis results, higher than normal haemoglobin, haematocrit, platelet count, leukocyte count, uric acid and vitamin B12 and lower than normal erythropoietin (hormone stimulating erythropoiesis) can be found. For diagnosis, determination of gene mutation JAK2V617F, occurring in 95% of polycythaemia vera patients, is important. A bone marrow investigation confirming manifested and intensive erythropoiesis is performed, if required. Enlarged spleen may be felt during abdominal palpation.

Treatment

Polycythaemia vera is a chronic disease that cannot be cured. In treatment planning, disease symptoms and thrombosis or haemorrhage risks are evaluated. Treatment choice depends on several factors: disease severity, general health, age, etc.

Treatment aims are to prevent thrombosis- and haemorrhage-associated complications and maintain quality of life.

With the help of a phlebotomy procedure, 450-500 mL of blood (sometimes less, ca 250 mL) is removed from circulation. The number of erythrocytes can be rapidly reduced with phlebotomy; the aim is to keep haematocrit below 45%. The procedure resembles blood donation and is mostly well tolerated. After the procedure, plenty of fluid should be consumed. In most cases, fluid loss is replaced via the veins.

In younger patients and patients with less manifest disease, regular phlebotomy is the only treatment method. In other patients, it is combined with other treatment options. Iron deficiency develops after blood removal and therefore haemoglobin levels decrease. Phlebotomy does not influence the level of leukocytes and in most cases neither the level of platelets.

Medicinal products used

  • Low-dose aspirin (so-called baby aspirin) is recommended to reduce the risk of platelet aggregation and thrombosis. Aspirin may irritate gastric mucosa, causing gastric discomfort, nausea, pain. Sometimes, anticoagulant or blood-thinning therapy has to be prescribed when the risk of thrombosis is very high due to concurrent diseases.
  • Hydroxycarbamide or hydroxyurea is a chemotherapeutic agent suppressing cell production in bone marrow and is most often used drug for polycythaemia vera. It effectively inhibits the maturation and division of haematopoietic cells and therefore the number of platelets and leukocytes may be reduced in addition to erythrocytes. Due to the effect of the drug, excess reduction in the number of blood cells may develop, therefore regular blood testing is required. The therapeutic dose will be decided on the basis of the blood test result. Hydroxycarbamide will be taken orally as capsules according to the regimen drawn up by the haematologist. Usually, it is well-tolerated; there are few side effects and these are usually mild. Sometimes, the medicinal product may cause tiredness. Skin colour may become darker. There is a higher risk of developing skin tumours (avoid sunbathing). When ulcers develop on oral mucosa or legs during treatment with hydroxycarbamide, the attending doctor should be informed!
  • Interferon-alpha is a substance usually produced in body cells to fight infections and tumour cells. This drug is preferred in younger people who want to have children. Interferon-alpha reduces the number of platelets by inhibiting erythropoiesis and reduces spleen enlargement. Interferon is injected subcutaneously according to the regimen prescribed by the doctor. The main side effects are flu-like symptoms, which manifest at treatment initiation: high fever, whole-body pain and malaise. Therefore, it is recommended to take paracetamol before the injection and to inject the drug in the evening before sleep. The side effects usually disappear with prolonged use.
  • JAK-inhibitors are a group of medicines which reduce the size of the spleen and improve the number of blood cells, reducing symptoms caused by the disease. These medicines are usually well tolerated. Regular blood analyses and correction of drug dose according to the number of blood cells are important. The use of JAK-inhibitors may increase the incidence of infections (e.g. urinary tract infections) or cause exacerbation of an existing infection (e.g. tuberculosis, viral hepatitis). Upon abrupt cessation of the drug, disease-associated symptoms may recur or become markedly worse and general status may worsen. Eating grapefruit and drinking grapefruit juice should be avoided during treatment with JAK-inhibitors.
  • Busulfan and radioactive phosphorus P32 are rarely used.
  • Allopurinol is used to reduce uric acid in blood. Uric acid content in blood damages kidneys and joints. Uric acid content increases due to purine metabolism disorder gout or the release of waste products from the disintegration of large amount of blood cells, including uric acid.
  • The doctor may prescribe anti-allergic drugs (for example antihistamines) to reduce skin itching, if required.

What can the patient do themselves?

  • Avoid dehydration – drink sufficiently, especially in the case of diarrhoea or fever. Eat a healthy, balanced diet.
  • Avoid taking iron-containing food supplements or drugs. Do not smoke.
  • Maintain a normal weight and practice recreational sports.
  • Keep blood pressure, cholesterol and blood glucose under control.

Prognosis

In most patients, the treatment keeps the blood cell number under control for many years. Their quality of life is mostly normal or near normal without significantly influencing their everyday coping.

Nonetheless, disease course may vary. In 15-30% of patients, polycythaemia vera progresses to myelofibrosis. In the case of myelofibrosis, bone marrow is gradually replaced by fibrotic tissue and less and less space will be left for normal haematopoiesis. Blood cell production is partly transferred to the spleen, causing its enlargement. With time, the number of blood cells may reduce significantly; therefore, patients sometimes become dependent on transfusions of blood components.

In 5-10% of patients, the disease may progress to acute leukaemia.

In the case of acute leukaemia, proliferation of blasts (immature tumorous cells) occurs, leading to a worse prognosis.

It is not possible to influence the course of polycythaemia vera as a disease, but it is possible to prevent complications caused by the disease by following the doctor’s recommendations exactly and leading a healthy life.

Compiled by: Dr Marge Rahu, Dr Halliki Kõdar, Dr Maris Pärnat, Dr Kreete Ilves and Dr Mirja Varik, members of the Myeloproliferative Neoplasms Working Group of the Estonian Society of Haematologists