In which conditions are Jak 2 (Janus kinase 2) kinase mutation and EPO (erythropoietin) levels typically checked?

JAK2 Mutation and EPO Level Testing in Myeloproliferative Neoplasms

JAK2 mutation and EPO levels are primarily checked in suspected myeloproliferative neoplasms (MPNs), particularly polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). 1, 2

Diagnostic Context for JAK2 Testing

• JAK2V617F mutation is found in approximately 95% of polycythemia vera cases and about 50-60% of essential thrombocythemia and primary myelofibrosis cases 2
• JAK2 exon 12 mutations are detected exclusively in 2-4% of PV patients who are negative for JAK2V617F mutation 1, 3
• JAK2 mutations are critical diagnostic criteria in the WHO classification of MPNs 1
• JAK2 testing should be performed when clinical and laboratory findings suggest an MPN, especially with elevated hemoglobin/hematocrit, thrombocytosis, or unexplained bone marrow fibrosis 1

Diagnostic Criteria Requiring JAK2 Testing

Polycythemia Vera

• JAK2 mutation is a major diagnostic criterion for PV according to WHO 2016 criteria 1
• Diagnosis requires either all three major criteria (elevated hemoglobin/hematocrit, bone marrow hypercellularity, and JAK2 mutation) or the first two major criteria plus subnormal serum erythropoietin level 1

Essential Thrombocythemia

• JAK2, CALR, or MPL mutation is a major diagnostic criterion for ET 1
• Diagnosis requires meeting all four major criteria (platelet count ≥450 × 10^9/L, characteristic bone marrow findings, exclusion of other myeloid neoplasms, and presence of JAK2/CALR/MPL mutation) or the first three major criteria plus evidence of clonal marker 1

Primary Myelofibrosis

• JAK2, CALR, or MPL mutation is required for diagnosis of both pre-PMF and overt PMF 1
• In the absence of these mutations, another clonal marker or absence of reactive bone marrow fibrosis is required 1

Erythropoietin (EPO) Level Testing

• Subnormal serum erythropoietin level is a minor criterion for PV diagnosis 1
• EPO levels should be checked in patients with:
  • Suspected polycythemia vera to distinguish from secondary erythrocytosis 2, 4
  • Idiopathic erythrocytosis with low EPO levels (27% have JAK2 exon 12 mutations) 5
  • Erythrocytosis without JAK2V617F mutation (to identify potential JAK2 exon 12 mutations) 3
  • Evaluation of EPO-independent erythroid colony formation 6, 5

Clinical Scenarios Requiring Both Tests

• Elevated hemoglobin (>16.5 g/dL in men, >16.0 g/dL in women) or hematocrit (>49% in men, >48% in women) 1, 4
• Thrombocytosis (platelet count ≥450 × 10^9/L) without obvious cause 1
• Bone marrow fibrosis without identifiable cause 1
• Unexplained splenomegaly with abnormal blood counts 1
• Thrombotic events with abnormal blood counts, especially in unusual sites 2
• Distinguishing between primary (clonal) and secondary (reactive) erythrocytosis or thrombocytosis 2, 4

Interpretation of Results

• JAK2V617F positive with low EPO: Strongly suggests polycythemia vera 1, 2
• JAK2V617F negative with low EPO: Consider JAK2 exon 12 mutations 5, 3
• JAK2V617F positive with normal/high EPO: May indicate ET or PMF 1, 2
• JAK2V617F negative with high EPO: Suggests secondary erythrocytosis 4, 5

Common Pitfalls and Caveats

• Not all MPNs are JAK2 mutation positive - approximately 10-15% of ET and PMF patients are "triple negative" (no JAK2, CALR, or MPL mutations) 1
• JAK2 exon 12 mutations are often missed if only JAK2V617F testing is performed 5, 3
• Normal EPO levels do not exclude PV, especially in borderline cases 2
• EPO levels should be interpreted in the clinical context, as they can be influenced by various factors including renal function, hypoxia, and medications 4
• JAK2 mutation testing should be performed on peripheral blood granulocytes or bone marrow samples for optimal sensitivity 2, 6