As a primary care physician (PCP), should I order serum erythropoietin (EPO) and JAK2 mutation tests myself or refer the patient to a hematologist (heme) for evaluation of suspected polycythemia vera (PV)?

As a PCP, You Should Order Both EPO and JAK2 Testing Yourself

As a primary care physician, you should initiate the diagnostic workup by ordering serum erythropoietin (EPO) and JAK2 mutation testing yourself when polycythemia vera is suspected, rather than waiting for hematology referral. 1, 2, 3

Why PCPs Should Order These Tests Directly

The Diagnostic Algorithm Starts in Primary Care

• The first step when PV is suspected (hemoglobin/hematocrit above 95th percentile for sex and race, or documented sustained increase ≥2 g/dL above baseline) is to measure serum EPO level 4, 1
• JAK2 mutation testing has dramatically simplified the diagnostic approach and should be performed upfront to assess clonality 2, 5
• These two tests together can distinguish PV from secondary polycythemia in most cases without requiring immediate specialist referral 2, 3

Practical Diagnostic Interpretation

Low EPO (the most common scenario in PV):

• A low serum EPO level has >90% specificity for PV, making it highly suggestive of the diagnosis 4, 1
• EPO remains low even during phlebotomy treatment 4
• However, sensitivity is only <70%, so normal EPO does not rule out PV 4

Normal EPO:

• PV remains a diagnostic consideration with normal EPO levels 4
• JAK2 mutation testing becomes essential in this scenario 6

High EPO:

• Suggests secondary polycythemia and warrants evaluation for hypoxia-driven causes, pathologic EPO production, or congenital causes 4
• However, rare cases of PV can present with elevated EPO (though this is atypical), so JAK2 testing may still be warranted if clinical suspicion is high 6

JAK2 Mutation Testing is Highly Diagnostic

• JAK2 mutations (V617F or exon 12) are present in >95% of PV patients 2, 5
• The presence of JAK2 mutation combined with low or normal EPO strongly supports PV diagnosis 4, 3
• JAK2 testing from peripheral blood is readily available and does not require bone marrow biopsy 2, 3

When to Refer to Hematology

Refer after obtaining EPO and JAK2 results when:

• Both tests support PV diagnosis (low/normal EPO + positive JAK2) - hematologist will determine need for bone marrow biopsy and initiate treatment 4, 1
• Results are equivocal (normal EPO with negative JAK2, or discordant findings) - specialized testing may be needed including bone marrow examination, c-mpl immunohistochemistry, or endogenous erythroid colony assays 4, 1
• JAK2 is positive but EPO is unexpectedly high - requires expert evaluation to confirm diagnosis 6

Do not refer before ordering these tests - this causes unnecessary delays in diagnosis, as the hematologist will order the same initial workup 3

Critical Pitfalls to Avoid

• Do not order red cell mass (RCM) measurement - it is costly, rarely changes management, and a normal RCM does not rule out PV 4, 1
• Do not rely on traditional markers alone (splenomegaly, leukocytosis, thrombocytosis, elevated alkaline phosphatase, vitamin B12) - these lack sensitivity and specificity 4, 1
• Check for iron deficiency first - low MCHC (<32%) suggests iron deficiency that can mask true erythrocytosis; if present, the diagnosis requires demonstration of elevated hemoglobin/hematocrit after iron replacement 4, 7
• Exclude dehydration - the most common cause of falsely elevated hematocrit 7
• Document the patient's baseline - a sustained increase of ≥2 g/dL hemoglobin warrants investigation even within normal reference ranges 1, 7

The Evidence Supporting PCP-Initiated Testing

Recent case reports specifically highlight the critical role of primary care in early PV detection, emphasizing that timely identification and appropriate testing from primary care settings are essential to avoid diagnostic delays 3. The diagnostic approach has been "greatly simplified" by genetic testing, making it feasible for PCPs to initiate the workup 2, 5. The American Society of Hematology guidelines support EPO-based algorithms that can be implemented in primary care, with EPO <2 U/L strongly favoring PV and >12 U/L favoring secondary causes 1.