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Investigations and diagnosis

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

Persistently raised haematocrit M >0·52, F >0·48

Clinical history/examination/1st line investigaions includes EPO

May identify Clear secondary cause - if not then check JAK2 V617F mutational analysis (PB) - if positive then diagnose PV

  • significant, JAK2-unmutated erythrocytosis.
  • consider red cell mass to confirm (if Hct<0·6/0·56)
  • consider USS abdomen

Is there a likely secondary cause from clinical history, stage 1/2 investigations, USS abdomen

statify by serum erythropoietin

  • if serum erythropoetin is normal or low then JAK2 exon 12 mutation analysis; consider bone marrow biopsy

Stage 1 Investigations


Full blood count/blood film, Renal and liver function, Arterial oxygen saturation (SaO2)/carboxyhaemoglobin, Serum ferritin, Serum erythropoietin, JAK2 V617F mutational analysis

  • Full blood count/blood film
    • full blood count analysis will not only confirm a raised Hct but will also identify neutrophilia and thrombocytosis - are common in JAK2 V617F-positive PV and part of
      the criteria for JAK2-negative PV
      • smokers have a significantly higher neutrophil count than non-smokers - neutrophilia is defined as>12.5x 10^9/l in this patient group

  • blood film
    • if confirmed PV, abnormalities, such as circulating blasts, leucoerythroblastic features and monocytosis, would be indications for bone marrow assessment

  • renal, liver function, bone profile
    • various renal and hepatic diseases can cause erythrocytosis
    • serum calcium levels should also be determined to exclude a parathyroid adenoma/carcinoma - rare causes of secondary erythrocytosis

Erythropoetin

  • high EPO levels
    • may occur in hypoxic conditions or when erythrocytosis is secondary to exogenous administration or endogenous overproduction
  • EPO levels are typically low in PV

Serum ferritin

  • low serum ferritin levels are common in PV patients and iron deficiency can mask the presentation of PV > giving a misleadingly low Hct because iron deficiency limits erythropoiesis and hypochromic microcytosis develops.

JAK2 V617F mutational analysis

  • identification of JAK2 mutations in almost all PV patients has revolutionised the diagnosis of PV. The JAK2 V617F mutation can be found in over 95% of PV patients and an exon 12 mutation in most remaining patients
    • testing for JAK2 V617F in peripheral blood is sensitive and bone marrow samples are not required to identify this
    • testing for JAK2 V617F is advised as a stage 1 investigation and should confirm the diagnosis the vast majority of PV patients.

2) Further investigations in JAK2 V617F-negative erythrocytosis

Further investigations are warranted in those patients with a persistent, significant erythrocytosis if JAK2 V617F studies are negative and a secondary cause is not immediately apparent. Secondary causes must be considered because PV is rare in the absence of a JAK2 V617F mutation

Red cell mass studies

  • patients with Hct >0.60 (males) or >0.56 (females) can be assumed to have an absolute erythrocytosis, but in others RCM studies can be helpful to confirm an absolute erythrocytosis
  • an RCM more than 25% above the mean predicted value is diagnostic of an absolute erythrocytosis

Those with a raised Hct but an RCM within the normal range have an apparent erythrocytosis.

  • a relative erythrocytosis, found in states of dehydration, can be confirmed when the RCM is within the normal range and plasma volume is below normal
  • patients with a relative or apparent erythrocytosis require no further investigation

Abdominal ultrasound

  • radiological splenomegaly is a minor criterion for JAK2 V617F-negative PV and ultrasound is the simplest method for detection
  • can also exclude secondary causes of erythrocytosis, particularly renal and hepatic pathology, including hepatocellular carcinoma

Further testing can be stratified according to the EPO level measured during stage 1 investigations

Normal or low EPO level

JAK2 exon 12 analysis

  • compared with JAK2 V617F, patients with exon 12 mutated- PV tend to be
    • younger,
    • with higher haemoglobin concentrations,
    • lower white blood cell (WBC) and platelet counts, and
    • an isolated increase in erythropoiesis without granulocytic or megakaryocytic morphological abnormalities

In contrast to JAK2 V617F testing, a discrepancy between exon 12 mutant allele burden in bone marrow and peripheral blood has occasionally been described.

High EPO level

A raised EPO level should lead to a thorough search for secondary causes of erythrocytosis, which may require additional supplementary investigations.

  • CT head and neck
    -Cerebellar haemangioblastoma
    -Meningioma
    -Parathyroid carcinoma/adenoma

  • consider further investigaion for secondary cause if clinically suspected
    -referral to respiratory/renal, sleep studies

Reference:

McMullin MF et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005 Jul;130(2):174-95

McMullin MF et al. A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline.British Journal of Haematology, 2019, 184, 176-191


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