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Polycythaemia Vera (Pv)

Essentials

  • The major goal of the treatment is to prevent thrombotic complications and haemorrhages.
  • The amount of red blood cells is kept within the normal range (haematocrit < 0.45). This prevents cardiovascular events.
  • At the time of diagnosis, usually low-dose aspirin (100 mg/day) is started to reduce the risk of distal ischaemia and transcient ischaemic attacks.Low-Dose Aspirin for Patients with Polycythaemia Vera This dose is sufficient to reduce the risk of thrombosis in cerebral and coronary circulation.

Definition

  • PV is a chronic and progressive haematological disease caused by excessive blood cell production (precursor cells in the bone marrow and mature cells in the peripheral blood) by the hyperplastic bone marrow. Increased erythropoiesis, increased amount of red blood cells (erythrocytosis) and high haemoglobin levels are the prominent features.

Epidemiology

  • Approximately 2 new cases/100 000/year
  • Most common among middle-aged and elderly people: most patients are 50-70 years old.

Aetiology

  • Unknown

Diagnostic criteria

Modified WHO 2016 criteria

  • The diagnosis of polycythaemia vera requires meeting three major criteria, or the two first major criteria and the minor criterion.
  • Major criteria
    1. Hb > 165 g/l (or hematocrit > 0.49) in men, Hb > 160 g/l (or hematocrit > 0.48) in women, or other evidence of increased red cell volume
    2. Bone marrow biopsy: hypercellularity with trilineage growth (panmyelosis)
    3. Presence of JAK2 V617F or JAK2 exon 12 mutation
  • Minor criterion
    • Subnormal serum erythropoietin (EPO) level
  • Bone marrow biopsy may not be required if Hb > 185 g/l in men or > 165 g/l in women and the major criterion 3 and the minor criterionare present. Bone marrow biopsy should generally be performed, however, before starting cytostatic pharmacotherapy. It is recommended to consult a haematologist at the time of diagnosis for defining treatment lines.

Differential diagnosis

  • Secondary erythrocytoses (serum EPO concentration often increased)
    • Often associated with cardiopulmonary diseases, heavy smoking
    • Abnormal O2 affinity haemoglobins, e.g. Hb Helsinki, Hb Linköping
    • Anabolic steroids, erythropoietin, SGLT2 inhibitors
    • In secondary polycythaemias the blood erythrocyte count is only mildly increased.
  • Relative erythrocytoses (red cell mass normal)
    • ”Stress” polycythaemia
    • Dehydration
  • Other myeloproliferative conditions

Symptoms and signs

  • Redness of the skin
  • Hyperaemic conjunctivae
  • Mild splenomegaly
  • Hyperviscosity symptoms
    • Headache, dizziness
    • Numbness of the fingertips and erythromelalgia
  • Thrombotic symptoms
  • Itching, especially after a shower or sauna
  • Gastrointestinal haemorrhage symptoms
  • Arthralgias
  • In many cases, the PV diagnosis is set in patients with very mild or no symptoms after investigating for high haemoglobin concentration that originally was an incidental finding.

Laboratory findings

  • Erythrocytosis; also high haemoglobin and haematocrit unless iron deficiency is apparent. MCV and MCH values are often already decreased at the time of diagnosis.
  • Hypercellular bone marrow
  • Low serum erythropoietin concentration
  • Blood JAK2 gene mutation positive in over 95% of the patients.
  • If PV is suspected on the basis of the blood count, serum erythropoietin concentration andJAK2 gene mutation should be examined in primary health care. If on the basis of these PV is probable, the patient should be referred to specialized care, either an internal medicine or a hematologic clinic, for diagnosis confirmation and treatment planning.
  • See also diagnostic criteria (above).

Disease progression and prognosis

  • Risk classification is influenced by the patient's age and history of thromboses. The risk is classified as low if the patient is 60 years old or younger and has no history of thromboses. Everyone over 60 years of age or with a thrombotic event associated with the disease is classified as a high-risk patient.
  • The life expectancy of a treated patient is almost equal to the age-matched general population.
  • The disease can, however, over time develop into myelofibrosis Myelofibrosis (Mf) and less commonly into acute leukemia Acute Leukaemias in Adults.

Complications

  • Thromboses and haemorrhages

Treatment and follow-up

  • The goal of treatment is to maintain the amount of red blood cells within the normal range (haematocrit < 0.45). When deciding on the treatment, an individual risk assessment which is based on the patient's age and thrombosis history is made. The course of treatment is planned by a specialist in internal medicine or haematology, but the treatment may largely be carried out within primary care.
  • Aspirin 100 mg/day is started if there is no contraindication to treatment.
  • The lowering of red cell mass is started with venesections (400-500 ml at a time) at an interval of one to two weeks. If haemoglobin is > 200 g/l, 400 ml can be taken daily up to the maximum of 1 500-2 000 ml.
  • Venesections do not treat thrombocytosis, which may increase as a result of venesections.
  • If venesections 6-8 times a year are not enough, pharmacological treatments should be considered. In younger patients this treatment should be postponed for as long as possible. If strong leucocytosis and thrombocytosis are present, cytoreductive therapy is often needed.

Cytostatic treatment

  • Given in primary health care in collaboration with an experienced specialist.
  • Hydroxyurea is the drug of choice; radiophosphorus possible for the elderly, interferon alpha http://www.dynamed.com/condition/polycythemia-vera#INTERFERON_ALFA in special circumstances (e.g. pregnancy)
    • With hydroxyurea the response is seen in one week; therapy requires intense follow-up in the beginning. Treatment is often long-lasting. Haemoglobin reduction starts to be seen in about one month. Hydroxyurea causes an increase in the size of red blood cells (macrocytosis).
    • 32 P is given as a single dose. Effect begins in about 2 weeks (first in leucocytes, the in platelets and lastly in red cell counts) and lasts < 2 years. 32 P can be repeated a few times if the response to treatment was good.
    • Check local policies concerning reimbursement of interferon.
  • Busulphanrarely (slow-acting and use requires experience)

Symptomatic treatment

  • Antihistamines for itching, aspirin, for abdominal symptoms and also for itching H2 receptors blockers
  • Allopurinol is used to prevent symptoms of gout and kidney damage, if plasma urate concentration is increased.
  • Aspirin should not be used if the platelet count is high (> 1 000 × 109 /l), increases bleeding.

Follow-up

  • According to the therapy
    • Only venesections: blood count follow-up in primary health care
    • Hydroxyurea: initially every 1-3 weeks, later every 3 months
    • 32 P: first control after 1 month, thereafter every 2-4 months; in stable disease, every 4-12 months
  • In a stabile situation, follow-up can take place in primary health care.
    • Blood count, kidney and liver function, lipids

    References

    • Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol 2023;98(9):1465-1487[PubMed]
    • McMullin MF, Harrison CN, Ali S et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol 2019;184(2):176-191.[PubMed]
    • Barbui T, Passamonti F, Accorsi P et al. Evidence- and consensus-based recommendations for phlebotomy in polycythemia vera. Leukemia 2018;32(9):2077-2081. [PubMed]