Should a patient with a 7‑year history of persistent hemoglobin 15.8–17 g/dL, low endogenous erythropoietin, and otherwise normal complete blood count be tested for a Janus kinase 2 (JAK2) V617F mutation and, if negative, for JAK2 exon‑12 mutations to rule out polycythemia vera?

Should This Patient Be Tested for JAK2 Mutations?

Yes, this patient should be tested for JAK2 V617F mutation immediately, and if negative, proceed with JAK2 exon 12 mutation testing to evaluate for polycythemia vera. The combination of persistent elevated hemoglobin (15.8-17 g/dL over 7 years) and low endogenous erythropoietin is highly suggestive of a primary erythrocytosis rather than secondary causes, making polycythemia vera the leading diagnostic consideration 1, 2.

Diagnostic Algorithm for This Patient

Step 1: Order JAK2 V617F Testing First

• JAK2 V617F should be the initial molecular test in any patient with unexplained erythrocytosis, as it is present in >95% of polycythemia vera cases 1, 3.
• The test should use a method sensitive enough to detect mutant allele burden as low as 1-3%, such as quantitative PCR or high-resolution melting analysis 2, 4.
• Low serum erythropoietin combined with persistent erythrocytosis strongly suggests a JAK2-driven myeloproliferative neoplasm rather than secondary polycythemia 1, 5.

Step 2: If JAK2 V617F Is Negative, Test for JAK2 Exon 12 Mutations

• JAK2 exon 12 mutations occur in 10-16% of JAK2 V617F-negative polycythemia vera cases and are specifically associated with isolated erythrocytosis 1, 6.
• This sequential testing approach is explicitly recommended by NCCN guidelines: test JAK2 V617F first, then JAK2 exon 12 mutations specifically for patients with erythrocytosis 1.
• Exon 12 mutations can be present at low allelic levels (as low as 2-6%), requiring sensitive detection methods such as clamped PCR or fragment analysis 7, 8.

Step 3: Additional Diagnostic Workup

While molecular testing proceeds, the following should be obtained:

• Bone marrow biopsy with morphology assessment showing hypercellularity with trilineage growth (panmyelosis) supports polycythemia vera diagnosis 1.
• Serum erythropoietin level (already done and low in this patient) is a minor diagnostic criterion for polycythemia vera 1.
• Complete blood count with differential to assess for leukocytosis or thrombocytosis that may accompany polycythemia vera 1.

Why This Testing Sequence Matters

Meeting WHO Diagnostic Criteria

The 2016 WHO criteria for polycythemia vera require:

• Two major criteria plus one minor criterion, OR
• First major criterion plus two minor criteria 1.

Major criteria include:

1. Elevated hemoglobin/hematocrit (>16.5 g/dL in women, >18.5 g/dL in men) OR sustained increase >2 g/dL from baseline
2. Presence of JAK2 V617F or JAK2 exon 12 mutation 1

Minor criteria include:

1. Bone marrow showing panmyelosis
2. Subnormal serum erythropoietin (present in this patient)
3. Endogenous erythroid colony formation 1

This patient already has one minor criterion (low erythropoietin) and borderline hemoglobin elevation, making molecular confirmation critical for diagnosis 1.

Clinical Significance of Early Diagnosis

• Polycythemia vera carries significant thrombotic risk (the main cause of morbidity and mortality), with hyperviscosity from elevated red cell mass contributing to arterial and venous thrombosis 5.
• Early identification allows for risk stratification and initiation of appropriate therapy (phlebotomy, aspirin, and potentially cytoreductive therapy) to prevent thrombotic complications 9, 5.
• The 7-year history of persistent elevation suggests this is not a transient or secondary process, further supporting the need for definitive molecular diagnosis 1.

Important Caveats

• JAK2 exon 12 mutations are more common in younger patients and females compared to JAK2 V617F-positive polycythemia vera 6.
• These mutations less frequently progress to homozygosity (13% vs 69% for V617F), which may affect disease phenotype 6.
• If both JAK2 V617F and exon 12 testing are negative, referral to hematology for bone marrow biopsy becomes essential, as diagnosis can still be made based on characteristic histopathology combined with low erythropoietin 3, 2.
• Approximately 2-5% of true polycythemia vera cases may be JAK2-negative, requiring bone marrow examination and exclusion of secondary causes for definitive diagnosis 3.