What is the diagnostic approach for an adult patient with suspected polycythemia, considering their complete blood count (CBC) results, medical history of blood disorders, cardiovascular disease, or respiratory issues?

Diagnostic Approach to Polycythemia

Begin by confirming true polycythemia with repeat hemoglobin/hematocrit measurements, then immediately order JAK2 mutation testing and serum erythropoietin (EPO) levels to distinguish polycythemia vera from secondary causes. 1

Initial Confirmation and Laboratory Workup

• Confirm elevated values with repeat measurements: hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), or hematocrit >49% (men) or >48% (women) warrants full diagnostic evaluation 2, 3
• Order complete blood count (CBC) with differential to assess for accompanying thrombocytosis (present in 53% of PV cases) and leukocytosis (present in 49% of PV cases), which strongly suggest polycythemia vera 3, 4
• Check serum ferritin and transferrin saturation immediately, as iron deficiency commonly coexists with polycythemia vera and causes microcytic hypochromic red cells despite elevated RBC count 4, 5, 6
• Measure reticulocyte count to assess bone marrow response 5
• Review peripheral blood smear for red cell morphology abnormalities 5

Distinguishing Primary from Secondary Polycythemia

Serum EPO Level Interpretation

• Low EPO (below reference range): Highly suggestive of polycythemia vera with >90% specificity, though sensitivity is only 64-70% 1, 4
• Normal EPO: Polycythemia vera remains possible; proceed with JAK2 testing 1
• Elevated EPO: Strongly suggests secondary polycythemia; systematically evaluate for hypoxia-driven or hypoxia-independent causes 1, 4

JAK2 Mutation Testing

• Order JAK2 V617F mutation testing (exon 14) first, as it is positive in >95% of polycythemia vera cases 2, 3
• If JAK2 V617F is negative, proceed to JAK2 exon 12 mutation testing, which captures the remaining ~3% of PV cases 2
• Positive JAK2 mutation confirms polycythemia vera diagnosis when combined with elevated hemoglobin/hematocrit 2, 3

Evaluating for Secondary Causes (When EPO is Elevated or Normal and JAK2 Negative)

Hypoxia-Driven Causes

• Obtain detailed smoking history: Smoker's polycythemia from chronic carbon monoxide exposure is the most common cause of secondary polycythemia and resolves with smoking cessation 1, 4, 7
• Measure arterial oxygen saturation or arterial blood gas to detect hypoxemia 4
• Order sleep study if nocturnal hypoxemia from obstructive sleep apnea is suspected 4, 5
• Obtain chest X-ray to evaluate for chronic lung disease (COPD, interstitial lung disease) 4
• Assess for cyanotic congenital heart disease with right-to-left shunting in patients with cardiac history 4, 5
• Consider high-altitude habitation: Physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 4, 2

Hypoxia-Independent Causes

• Order abdominal ultrasound or CT to screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma 1, 4
• Review medication history for exogenous erythropoietin or testosterone use 1, 4
• Assess for post-renal transplant erythrocytosis in transplant recipients 1
• Consider congenital causes: Chuvash polycythemia, high-oxygen-affinity hemoglobinopathy, EPOR mutations (rare) 1, 4

Distinguishing True from Apparent Polycythemia

• Assess hydration status clinically: Severe dehydration, diarrhea, vomiting, diuretic use, burns, and capillary leak syndrome cause relative polycythemia from plasma volume depletion 1
• Do not order red cell mass measurements when plasma volume depletion is clinically obvious 1
• Recognize that Gaisböck syndrome and stress polycythemia are poorly understood entities with little foundation; avoid unnecessary red cell mass studies in these contexts 1
• Red cell mass measurement is reserved only for equivocal cases where diagnosis remains unclear after initial workup 1

Bone Marrow Examination (When Indicated)

• Perform bone marrow biopsy with cytogenetic studies when JAK2 is positive or when diagnosis remains equivocal after initial workup 1, 2
• Characteristic bone marrow findings in PV: Hypercellularity with trilineage growth (panmyelosis), increased megakaryocytes with cluster formation, giant megakaryocytes with pleomorphism, mild reticulin fibrosis (12% of cases), decreased iron stores 1, 2
• Cytogenetic studies show abnormalities in only 13-18% of PV cases at diagnosis, limiting their diagnostic value 1

Specialized Testing for Equivocal Cases (Rarely Needed)

• Bone marrow immunohistochemistry for c-mpl (thrombopoietin receptor): Markedly decreased megakaryocyte expression supports PV diagnosis 1
• Neutrophil PRV-1 expression assay: High expression suggests PV versus secondary polycythemia (not detectable), though limited availability 1
• Spontaneous erythroid colony assay: Can distinguish PV from secondary polycythemia but requires considerable expertise and is rarely used 1
• Note: These specialized tests constitute <10% of routine clinical practice and negative results do not exclude PV 1

Clinical Features That Trigger Immediate Workup

• Sustained hemoglobin increase ≥2 g/dL from baseline, even if within normal reference range 2
• PV-related features accompanying borderline-high hematocrit: Thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly (36% of PV cases), aquagenic pruritus (33%), unusual thrombosis including Budd-Chiari syndrome, erythromelalgia (5.3%) 1, 3, 7
• Unexplained thrombosis, particularly in unusual sites like splanchnic veins (7% venous thrombosis, 16% arterial thrombosis at or before PV diagnosis) 3

Critical Diagnostic Pitfalls to Avoid

• Do not dismiss borderline elevations: Persistent mild elevations lasting one year warrant immediate JAK2 testing, as early PV can present with values near the upper normal range 2
• Do not overlook iron deficiency: PV patients often have microcytic hypochromic RBCs from iron deficiency, which can mask the true degree of erythrocytosis 4, 5, 6
• Do not assume normal EPO excludes PV: EPO sensitivity for PV is only 64-70%; normal EPO with elevated hemoglobin still requires JAK2 testing 1, 4
• Do not perform unnecessary red cell mass studies: Modern JAK2 testing and EPO levels have largely replaced the need for these measurements except in truly equivocal cases 1
• Do not use standard PV thresholds at high altitude without adjustment: Physiologic adaptation can increase hemoglobin substantially based on elevation 4, 2
• Do not overlook smoking: This is the most frequent cause of elevated hematocrit and should be addressed before extensive workup 1, 7

When to Refer to Hematology

• Immediate referral indicated if: JAK2 mutation positive, hemoglobin >20 g/dL with hyperviscosity symptoms, unexplained splenomegaly, or diagnosis remains unclear after initial workup 2, 5