Diagnostic Approach for Polycythemia Vera

Diagnostic Criteria

The diagnosis of polycythemia vera (PV) should begin with serum erythropoietin (EPO) level measurement followed by bone marrow examination with cytogenetic studies when clinically suspected 1, 2
PV should be considered in patients with hemoglobin/hematocrit above the 95th percentile of normal distribution adjusted for sex and race 2
A documented increase in hemoglobin/hematocrit above a patient's baseline is also indicative of PV, regardless of where the value falls within the reference range 3
The presence of aquagenic pruritus 2 and unusual thrombosis (e.g., Budd-Chiari syndrome) 2 can also suggest PV
Erythromelalgia is a symptom that may be associated with PV 1, 4

A low serum EPO level is highly suggestive of PV, with a specificity of over 90% 1
Normal serum EPO levels do not rule out PV, as the sensitivity of low EPO for PV is less than 70% 1
High serum EPO levels suggest the need to evaluate for secondary polycythemia 1, 5
Bone marrow examination findings that support a PV diagnosis include hypercellularity 1, increased megakaryocytes with cluster formation 1, and giant megakaryocytes with pleomorphic morphology 1
Cytogenetic studies may show abnormalities in 13-18% of patients, but have limited diagnostic value 1

JAK2 mutation testing is not always necessary, but when performed, the presence of a JAK2 mutation (JAK2V617F or exon 12 mutations) is found in more than 95% of PV patients, although this information is not directly cited, decreased megakaryocyte expression of TPO receptor (c-mpl) can be an alternative marker 5
Peripheral blood neutrophil assay for PRV-1 expression 5 and spontaneous (endogenous) erythroid colony assays (when available) 5 can also be used in equivocal cases

Relying solely on red cell mass (RCM) measurement is not recommended, as a normal RCM does not rule out PV 4, 6
Traditional markers such as splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity for PV 4, 6
Iron deficiency should not be missed, as it can mask erythrocytosis, and low MCHC may indicate iron deficiency 7

Secondary causes of polycythemia include hypoxia-driven conditions (chronic lung disease, high altitude, smoking) 8, pathologic EPO production (renal cell cancer, hepatocellular carcinoma) 8, congenital causes (high oxygen-affinity hemoglobinopathy) 9, and drug-associated causes (EPO doping, androgen preparations) 8
Key differentiating factors between PV and secondary polycythemia include the presence of a JAK2 mutation, serum EPO levels, and bone marrow morphology 1, 8, 9

In patients with polycythemia vera, the World Health Organization diagnostic criteria can still be met despite elevated EPO levels, as decreased EPO is only a minor criterion, with JAK2 mutation testing becoming essential for diagnosis 10
The American Society of Hematology suggests that EPO levels below 2 U/L strongly favor polycythemia vera, while levels above 12 U/L favor secondary polycythemia, though significant overlap exists between 2-12 U/L 10

In hypoxia-driven secondary polycythemia, EPO may initially be elevated but can normalize once hemoglobin stabilizes at a compensatory higher level, potentially creating diagnostic confusion, according to the Mayo Clinic Proceedings 10