What is the initial workup for a patient presenting with polycythemia?

Initial Workup for Polycythemia

The initial diagnostic workup for polycythemia should begin with confirming elevated hemoglobin/hematocrit values, followed by serum erythropoietin (EPO) level measurement and JAK2 mutation testing. 1

When to Initiate Diagnostic Evaluation

• Diagnostic evaluation should be initiated when hemoglobin/hematocrit is higher than the 95th percentile of normal distribution adjusted for sex and race 1, 2
• Evaluation is also warranted when there is a documented increase in hemoglobin/hematocrit above the patient's baseline, regardless of where the specific value falls within the reference range 1
• Presence of PV-related features with borderline-high hematocrit values should prompt investigation, including:
  • Thrombocytosis or leukocytosis 1
  • Microcytosis from iron deficiency 1
  • Splenomegaly 1, 3
  • Aquagenic pruritus 1, 2
  • Unusual thrombosis including Budd-Chiari syndrome 1, 2
  • Erythromelalgia 1, 2

Step-by-Step Diagnostic Algorithm

Step 1: Initial Laboratory Testing

• Complete blood count (CBC) with differential to confirm erythrocytosis and assess for additional features 1
• Serum EPO level is the first recommended specialized test 1, 2
  • Low EPO is highly suggestive of polycythemia vera (PV) with specificity >90% 1, 2
  • Normal EPO does not rule out PV (sensitivity <70%) 1, 2
  • High EPO indicates the need to evaluate for secondary polycythemia 1, 2

Step 2: JAK2 Mutation Testing

• JAK2 mutation testing should be performed, as more than 95% of PV patients have JAK2 mutations (JAK2V617F or exon 12 mutations) 3
• This helps distinguish PV from secondary causes of erythrocytosis 3

Step 3: Bone Marrow Examination

• Indicated after abnormal serum EPO results (low or normal) 1
• Assess for:
  • Hypercellularity 1, 2
  • Increased number of megakaryocytes with cluster formation 1, 2
  • Giant megakaryocytes with pleomorphic morphology 1, 2
  • Bone marrow iron stores (decreased in PV) 1

Step 4: Evaluation for Secondary Causes (if EPO elevated)

• Assess for hypoxia-driven causes:

  • Measure arterial hemoglobin-oxygen saturation 1
  • Check carboxyhemoglobin level (especially in smokers) 1, 4
  • Evaluate for chronic lung disease and sleep apnea 1, 3

• Assess for hypoxia-independent causes:

  • Imaging studies of kidney, liver, and central nervous system to rule out EPO-producing tumors 1
  • Consider high oxygen-affinity hemoglobinopathy 5
  • Review medications (EPO doping, androgen preparations) 2

Additional Specialized Testing for Unclear Cases

• In approximately 10% of cases where diagnosis remains unclear, consider: 1
  • Megakaryocyte TPO receptor (c-mpl) expression assessment 1, 2
  • Peripheral blood neutrophil assay for PRV-1 expression 1, 2
  • Spontaneous (endogenous) erythroid colony assays (when available) 1, 2

Common Pitfalls and Caveats

• Red cell mass measurement is generally not necessary in modern practice and does not rule out PV 1, 2
• Don't miss iron deficiency, as it can mask the degree of erythrocytosis; low MCHC may indicate iron deficiency 2
• Traditional markers such as splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity for PV 2
• Remember that smoker's polycythemia is a real entity secondary to chronic carbon monoxide exposure 1
• Be vigilant for unusual presentations of PV, such as thrombosis in atypical sites (e.g., renal vein thrombosis, Budd-Chiari syndrome) 6
• Consider PV in patients presenting with thrombotic events, as these are often the initial manifestation of the disease 4