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OutiLaine
MarjattaSinisalo

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, haemoglobin < 145 g/l). This prevents cardiovascular deaths and thromboses.
  • Allopurinol is the primary drug for preventing gout symptoms and hyperuricaemic kidney lesions if urate levels are at the upper end of the normal range.
  • At the time of diagnosis, low-dose aspirin (100 mg/day) is given 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 http://www.dynamed.com/condition/polycythemia-vera#GENETIC_TESTING
  • 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
  • Gastrointestinal symptoms, often haemorrhages
  • Arthralgias
  • Neurological symptoms
  • 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.
  • See also diagnostic criteria (above).

Disease progression and prognosis

  • Progression is rather even. When PV is treated, the life expectancy of the patient is nowadays almost equal to the age-matched general population, i.e. 10-15 years. Life expectancy is influenced by age at diagnosis, occurrence of thrombosis and leukocytosis.
  • Provided that the patient avoids vascular catastrophes the disease may progress to myelofibrosis and sometimes eventually to acute leukaemia.

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, haemoglobin < 145 g/l). 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 haematologist, but the treatment may largely be carried out within primary care.
  • Aspirin 100 mg/day is started if there is no contraindication to treatment http://www.dynamed.com/condition/polycythemia-vera#ASPIRIN.
  • The lowering of red cell mass is started with venesections http://www.dynamed.com/condition/polycythemia-vera#PHLEBOTOMY (400-500 ml at a time) at an interval of a couple of 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 the annual number of venesections exceeds 6-8, 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

JAK2 inhibitors

Symptomatic treatment

  • Antihistamines for itching, and H2 receptors blockers (cimetidine) for abdominal symptoms and also itching. A response to itching has also been reached with interferon alpha (is suitable if cytoreductive therapy is also needed), with aspirin and with ruxolitinib.
  • Allopurinol is used to prevent symptoms of gout and kidney damage, if plasma urate concentration is increased.
  • Aspirin may increase the risk of bleeding if the platelet count is high (> 1 000).

Follow-up

  • According to the therapy
    • 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
    • Interferon alpha: in the same way as with hydroxyurea

References

  • 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]