Is it appropriate for a primary care provider to order JAK2 (Janus Kinase 2) mutation testing in patients with suspected myeloproliferative neoplasms?

JAK2 Mutation Testing in Primary Care

Yes, primary care providers can and should order JAK2 mutation testing when there is clinical or hematologic suspicion of a myeloproliferative neoplasm, as peripheral blood screening for JAK2V617F is recommended as the first-line test in any patient suspected of having a Philadelphia chromosome-negative MPN. 1

When to Order JAK2 Testing

Primary care providers should order JAK2V617F testing in patients presenting with:

• Unexplained erythrocytosis: Hemoglobin >18.5 g/dL in males or >16.5 g/dL in females 1
• Persistent thrombocytosis: Elevated platelet counts without clear secondary cause 1
• Suspected myelofibrosis: Splenomegaly, constitutional symptoms, or leukoerythroblastic blood picture 1
• Splanchnic vein thrombosis: Particularly in younger patients without typical risk factors 2

Testing Algorithm

JAK2V617F should be the first test ordered in patients suspected of any Philadelphia chromosome-negative MPN (polycythemia vera, essential thrombocythemia, or myelofibrosis). 1

Sequential Testing Approach:

1. First-line: Order JAK2V617F mutation testing on peripheral blood 1

   • This mutation is found in ~95% of polycythemia vera cases and 50-60% of essential thrombocythemia and primary myelofibrosis cases 3

2. If JAK2V617F is negative:

   • For erythrocytosis: Test for JAK2 exon 12 mutations 1
   • For thrombocytosis or myelofibrosis: Test for CALR mutations first, then MPL mutations 1

3. Referral timing: If JAK2V617F is positive or clinical suspicion remains high despite negative testing, refer to hematology for bone marrow biopsy and further evaluation 1

Test Sensitivity Requirements

The JAK2V617F detection assay should be sensitive enough to detect a mutant allele burden as low as 1-3%, as sensitive assays increase the detection rate within myeloproliferative neoplasms. 4 Primary care providers should ensure their laboratory uses appropriately sensitive methods (such as quantitative PCR or high-resolution melting analysis). 1

Common Pitfalls to Avoid

Do not order JAK2 testing for every patient with mild thrombocytosis or erythrocytosis. The majority of patients referred from primary care with suspected MPNs actually have secondary conditions such as iron deficiency, inflammatory diseases, infections, malignancy, or hyposplenism. 5 Reserve testing for patients with:

• Persistent unexplained cytopenias or cytoses after excluding common secondary causes 5
• Clinical features suggesting clonal hematopoietic disease (splenomegaly, constitutional symptoms, unusual thrombosis) 1, 5
• Thrombocytosis >1000 × 10⁹/L or extreme thrombocytosis >1500 × 10⁹/L 1, 2

Do not assume a negative JAK2V617F test excludes MPN. Approximately 10-15% of essential thrombocythemia and primary myelofibrosis patients remain "triple negative" for JAK2, CALR, and MPL mutations. 1 These patients still require hematology referral if clinical suspicion is high.

Do not use JAK2 mutation burden for serial monitoring in primary care. Measuring mutation burden serially during follow-up is not recommended except following allogeneic stem-cell transplantation or possibly interferon treatment, and should be managed by hematology. 1

Coordination with Hematology

While primary care providers can appropriately initiate JAK2 testing, bone marrow biopsy remains necessary for definitive diagnosis in most cases (except polycythemia vera with hemoglobin >18.5 g/dL in males or >16.5 g/dL in females). 1 Positive JAK2 results or persistent clinical suspicion despite negative molecular testing warrant prompt hematology referral for:

• Bone marrow examination to assess morphology and fibrosis 1
• Additional molecular testing if triple-negative 1
• Risk stratification and treatment planning 3, 2