Polycythemia Workup
Initial Diagnostic Approach
Begin the workup by confirming elevated hemoglobin/hematocrit values adjusted for sex and race, then immediately measure serum erythropoietin (EPO) level, followed by JAK2 mutation testing if EPO is low or normal. 1
When to Initiate Workup
Trigger diagnostic evaluation when: 1
- Hemoglobin/hematocrit exceeds the 95th percentile for sex and race
- Documented increase above patient's baseline regardless of absolute value
- Borderline-high hematocrit accompanied by PV-related features: thrombocytosis, leukocytosis, microcytosis, splenomegaly, aquagenic pruritus, unusual thrombosis (Budd-Chiari syndrome), or erythromelalgia
Step 1: Confirm True Polycythemia
Exclude relative (apparent) polycythemia by: 2, 1
- Assessing hydration status and clinical context (dehydration, diuretics, severe burns, diarrhea, vomiting)
- Recognizing that most plasma volume depletion causes are clinically obvious and don't require specialized testing
- Identifying smoker's polycythemia (carbon monoxide-mediated, resolves with cessation)
- Avoiding red cell mass measurement - this is costly, redundant when hematocrit >60%, and doesn't rule out PV 1
Laboratory Testing Algorithm
Step 2: Serum Erythropoietin Level (First-Line Test)
Low EPO is highly suggestive of polycythemia vera with >90% specificity, but sensitivity is only ~70%. 1, 3
Interpretation: 1
- Low EPO: Proceed to JAK2 mutation testing and bone marrow examination
- Normal EPO: Does NOT rule out PV; proceed to JAK2 testing
- High EPO: Evaluate for secondary polycythemia causes
Critical caveat: Rare cases of PV can present with elevated EPO levels, so JAK2 mutation testing remains essential when clinical suspicion is high. 4
Step 3: Complete Blood Count with Differential
Assess for additional features: 1, 3
- Thrombocytosis (present in 53% of PV cases)
- Leukocytosis (present in 49% of PV cases)
- Microcytosis with low MCV/MCH/MCHC - this distinctive pattern strongly suggests PV with iron deficiency, not simple iron deficiency anemia 5
Step 4: JAK2 Mutation Testing
More than 95% of PV patients harbor JAK2 mutations, which distinguishes PV from secondary causes. 3, 6
Step 5: Bone Marrow Examination
Indicated after abnormal EPO results (low or normal): 1
- Assess for hypercellularity
- Evaluate megakaryocyte number, size (giant forms), and pleomorphism
- Check iron stores - decreased stores are characteristic of PV
Evaluation for Secondary Polycythemia (If EPO Elevated)
Hypoxia-Driven Causes
Measure: 1
- Arterial hemoglobin-oxygen saturation
- Carboxyhemoglobin level
- Chronic lung disease
- Sleep apnea
- High altitude exposure
- Cardiac right-to-left shunts
- Hemoglobinopathies with increased oxygen affinity
Hypoxia-Independent Causes
Perform imaging studies of: 1
- Kidneys (renal cell carcinoma)
- Liver (hepatocellular carcinoma)
- Central nervous system (meningioma)
- Adrenal glands (pheochromocytoma)
- Uterus (leiomyoma)
Specialized Testing (When Diagnosis Remains Unclear)
In approximately 10% of cases where standard workup is inconclusive: 1
- Megakaryocyte TPO receptor (c-mpl) expression
- Peripheral blood neutrophil PRV-1 expression assay
- Spontaneous (endogenous) erythroid colony assays
Important limitation: These specialized tests complement but do not substitute for standard diagnostic procedures, and their sensitivity/specificity have not been rigorously validated. 2
Critical Pitfalls to Avoid
Do NOT give iron supplementation before establishing the diagnosis - if PV with iron deficiency is present, iron replacement worsens hyperviscosity and dramatically increases thrombotic risk. 5
Do NOT assume microcytosis always means simple iron deficiency - the combination of elevated RBC count with microcytosis specifically suggests PV with iron deficiency. 5
Do NOT rely solely on EPO levels - normal EPO does not exclude PV given the 70% sensitivity. 1
Do NOT order red cell mass measurements routinely - this test is unnecessary in modern practice when hematocrit is clearly elevated and other diagnostic tools are available. 1