Diagnostic Approach to Polycythemia

Initial Evaluation

The initial diagnostic workup for polycythemia should begin with determining serum erythropoietin (EPO) levels after confirming elevated hemoglobin/hematocrit values, followed by JAK2 mutation testing and bone marrow examination in appropriate cases 1, 2
A diagnostic evaluation for polycythemia should be initiated when hemoglobin/hematocrit is higher than the 95th percentile of normal distribution adjusted for sex and race 1
A diagnostic evaluation for polycythemia should be initiated when there is a documented increase in hemoglobin/hematocrit above the patient's baseline, regardless of where the specific value lies within the reference range 2
A polycythemia vera (PV)-related feature accompanies a borderline-high hematocrit value, such as thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis including Budd-Chiari syndrome, erythromelalgia 2, 3

Serum EPO level is the first recommended test, with low EPO being highly suggestive of PV (specificity >90%) 1, 2
Normal EPO does not rule out PV, as the sensitivity of low EPO for PV is <70% 2
High EPO indicates the need to evaluate for secondary polycythemia 2, 4
Complete blood count with differential should be performed to assess for additional features, such as microcytosis suggesting iron deficiency 1

Bone marrow examination is indicated after abnormal serum EPO results (low or normal) 2
Bone marrow histology should include assessment for hypercellularity, increased number of megakaryocytes, giant megakaryocytes, and pleomorphism in megakaryocyte morphology 4
Bone marrow iron stores should be assessed, with decreased iron stores being a feature of PV 2, 3

If EPO is elevated, investigate for secondary polycythemia causes, including hypoxia-driven causes such as chronic lung disease, sleep apnea, and hypoxia-independent causes such as EPO-producing tumors 5, 6, 7
Arterial hemoglobin-oxygen saturation and carboxyhemoglobin level should be measured to evaluate for hypoxia-driven causes 6
Imaging studies of kidney, liver, and central nervous system should be performed to rule out EPO-producing tumors 6

In approximately 10% of cases where diagnosis remains unclear, additional specialized testing such as megakaryocyte TPO receptor (c-mpl) expression assessment, peripheral blood neutrophil assay for PRV-1 expression, and spontaneous (endogenous) erythroid colony assays may be necessary 2

Red cell mass measurement is generally not necessary in modern practice, as it is a costly redundancy when hematocrit is >60% and does not rule out PV 1, 3
Distinguishing relative polycythemia is important, as most factors causing plasma volume depletion are clinically obvious and do not require specialized testing 5, 8
Smoker's polycythemia is a real entity secondary to chronic carbon monoxide exposure, and polycythemia resolves with smoking cessation 5, 8

Decreased bone marrow iron stores are a characteristic finding on bone marrow examination in polycythemia vera patients, according to the Mayo Clinic Proceedings 9
Microcytosis from iron deficiency is recognized as a polycythemia vera-related diagnostic feature that should prompt evaluation for polycythemia vera even when hematocrit is only borderline elevated, as noted by the Mayo Clinic Proceedings 9

Iron replacement therapy is generally discouraged in polycythemia vera because it may increase red cell mass and worsen polycythemia, as recommended by the Mayo Clinic Proceedings 10 and 11