What is the next step for a patient with elevated hemoglobin (Hb) and hematocrit (Hct) with an elevated mean corpuscular volume (MCV), but no symptoms such as dizziness, fatigue, or headache?

Next Steps for Elevated Hemoglobin, Hematocrit, and MCV Without Symptoms

Order a complete metabolic panel with serum ferritin, transferrin saturation, vitamin B12, folate, JAK2 mutation testing, and reticulocyte count immediately to differentiate between polycythemia vera, secondary causes, and nutritional deficiencies. 1

Initial Laboratory Workup

The asymptomatic presentation does not exclude significant underlying pathology—elevated MCV with erythrocytosis creates a distinctive pattern requiring systematic evaluation:

• Confirm true polycythemia by repeating hemoglobin and hematocrit measurements, as single values are unreliable for diagnosis 1
• Obtain complete blood count with differential to assess white blood cell and platelet counts, which may reveal myeloproliferative features 1
• Measure serum ferritin and transferrin saturation to exclude iron deficiency, which paradoxically can coexist with erythrocytosis and cause microcytosis rather than macrocytosis 2, 3
• Check vitamin B12 and folate levels since deficiency of either causes macrocytosis and was identified in 24.1% and additional cases of macrocytosis in one study 4
• Order reticulocyte count to evaluate bone marrow response 1
• Measure serum erythropoietin (EPO) level to distinguish primary from secondary erythrocytosis—low EPO suggests polycythemia vera with >90% specificity 1, 3

JAK2 Mutation Testing

• Test for JAK2 V617F mutation (exon 14) and JAK2 exon 12 mutations immediately, as up to 97% of polycythemia vera cases carry these mutations 1
• If JAK2 is positive, refer immediately to hematology for bone marrow biopsy to confirm diagnosis and assess for trilineage myeloproliferation 1

Evaluate Secondary Causes

The elevated MCV narrows the differential but does not exclude secondary erythrocytosis:

• Order thyroid function tests as hypothyroidism can cause macrocytosis 4
• Obtain liver function tests since liver disease accounts for a proportion of macrocytosis cases 4
• Review medication history for drugs causing macrocytosis (hydroxyurea, antiretrovirals, chemotherapy agents), which accounted for 12.9% of macrocytosis in one series 4
• Assess alcohol consumption, as alcoholism was the leading cause of macrocytosis in 36.5% of cases 4
• Consider sleep study if clinical features suggest obstructive sleep apnea, which causes nocturnal hypoxemia driving erythropoietin production 1
• Obtain pulse oximetry at rest for at least 5 minutes to assess for hypoxemia 2
• Review for smoking history as "smoker's polycythemia" results from chronic carbon monoxide exposure causing tissue hypoxia 1

Critical Diagnostic Considerations

The combination of elevated hemoglobin/hematocrit with elevated MCV is unusual and requires careful interpretation:

• Polycythemia vera typically presents with normal or low MCV due to iron depletion from increased red cell production 3
• Elevated MCV in the context of erythrocytosis suggests either coexisting B12/folate deficiency, alcohol use, liver disease, medication effect, or possibly hemochromatosis 4, 5
• Check peripheral blood smear for macro-ovalocytes and hypersegmented neutrophils (suggesting megaloblastic anemia) or other morphologic abnormalities 1, 4

Management Thresholds

Do not perform therapeutic phlebotomy at this stage:

• Phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with hyperviscosity symptoms (headache, dizziness, visual changes) after excluding dehydration 2, 1
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 2, 1
• The absence of symptoms does not eliminate thrombotic risk—asymptomatic patients with polycythemia vera still require treatment to maintain hematocrit <45% once diagnosed 1

Common Pitfalls to Avoid

• Do not assume the elevated MCV excludes polycythemia vera—patients can have coexisting nutritional deficiencies or other causes of macrocytosis 3, 4
• Do not give iron supplementation before establishing the diagnosis, as this can worsen hyperviscosity and thrombotic risk if polycythemia vera is present 3
• Do not dismiss the findings due to lack of symptoms—hyperviscosity symptoms are unlikely with hematocrit <65%, but thrombotic risk exists at lower levels in polycythemia vera 2, 1
• Do not use MCV alone to screen for iron deficiency in erythrocytosis, as it is unreliable in this context—serum ferritin and transferrin saturation are required 1

Referral Indications

• Refer immediately to hematology if JAK2 mutation is positive, hemoglobin exceeds 20 g/dL with hyperviscosity symptoms, or unexplained splenomegaly is present 1
• Consider hematology referral if diagnosis remains unclear after initial workup or if secondary causes have been excluded 1