What are the next steps for a patient with elevated hemoglobin (Hb) and hematocrit (Hct) levels, specifically hyperhemoglobinemia and elevated hematocrit?

Evaluation and Management of Elevated Hemoglobin and Hematocrit

For a patient with hemoglobin 17 g/dL and hematocrit 51.5%, you should first confirm these values with repeat testing, then initiate a systematic workup including complete blood count with red cell indices, reticulocyte count, serum ferritin, transferrin saturation, and JAK2 mutation testing to distinguish between primary polycythemia vera and secondary causes of erythrocytosis. 1

Initial Diagnostic Confirmation

• Repeat hemoglobin and hematocrit measurements are essential, as a single measurement is insufficient for establishing a diagnosis of erythrocytosis. 1 These values (Hb 17 g/dL, Hct 51.5%) are borderline elevated but do not yet meet the strict diagnostic thresholds for polycythemia vera in males (Hb >18.5 g/dL, Hct >55%) or females (Hb >16.5 g/dL, Hct >49.5%). 1

• Serial monitoring is appropriate for borderline values to determine if this represents a persistent elevation or transient variation. 1

Comprehensive Laboratory Workup

Order the following tests immediately to evaluate for true erythrocytosis versus relative polycythemia: 1

• Complete blood count with red cell indices (MCV, MCH, MCHC) to assess red blood cell characteristics 2, 1
• Reticulocyte count to evaluate bone marrow erythropoietic activity 1
• Peripheral blood smear review to identify abnormal red cell morphology 1
• Serum ferritin and transferrin saturation to detect coexisting iron deficiency 1
• C-reactive protein (CRP) to assess for inflammatory conditions 1

Hemoglobin is the preferred measurement over hematocrit for ongoing monitoring because it remains stable during sample storage, whereas hematocrit can falsely increase by 2-4% with prolonged storage and is affected by hyperglycemia. 2, 1

Testing for Primary Polycythemia Vera

If initial workup confirms persistent erythrocytosis, test for JAK2 mutations (both exon 14 and exon 12) to evaluate for polycythemia vera, which is present in up to 97% of PV cases. 1, 3

The 2016 WHO diagnostic criteria for polycythemia vera require either:

• Both major criteria (elevated Hb/Hct/RBC mass AND JAK2 mutation) plus one minor criterion, OR
• First major criterion plus two minor criteria 1

Minor criteria include bone marrow hypercellularity, low serum erythropoietin level, or endogenous erythroid colony formation. 1

Evaluation for Secondary Causes

If JAK2 mutation testing is negative, systematically evaluate for secondary causes of erythrocytosis: 1

Hypoxia-Driven Causes

• Smoking history and carbon monoxide exposure - "smoker's polycythemia" results from chronic tissue hypoxia stimulating erythropoietin production 1
• Sleep study if nocturnal hypoxemia is suspected - obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production 1
• Pulmonary function testing - chronic obstructive pulmonary disease and other chronic lung diseases cause compensatory erythrocytosis 1
• Cardiac evaluation - cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia and compensatory erythrocytosis 1

Non-Hypoxic Causes

• Testosterone use assessment - both prescribed and unprescribed testosterone can cause erythrocytosis and should be considered, especially in younger adults 1
• Erythropoietin-producing tumors - renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently 1
• Exogenous erythropoietin therapy - review medication history 1

Relative Polycythemia

• Assess hydration status - dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause plasma volume depletion with relative erythrocytosis 1

Management Approach

At these levels (Hb 17 g/dL, Hct 51.5%), therapeutic phlebotomy is NOT indicated. Phlebotomy should only be performed when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65%, with associated symptoms of hyperviscosity, and only after excluding dehydration. 1

For secondary erythrocytosis, treatment focuses on the underlying condition: 1

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Management of chronic lung disease
• Dose adjustment or discontinuation of testosterone if causative

If iron deficiency is identified alongside erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 1 Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk even in the presence of erythrocytosis. 1

Critical Pitfalls to Avoid

• Do not perform aggressive phlebotomy at these borderline levels - repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1

• Do not overlook coexisting iron deficiency - iron deficiency can coexist with erythrocytosis, particularly in polycythemia vera, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin. 1 Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin and transferrin saturation are required. 1

• Do not use standard diagnostic thresholds without considering altitude - if the patient resides at high altitude, physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 1

Referral Indications

Refer immediately to hematology if: 1

• JAK2 mutation is positive
• Hemoglobin exceeds 20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly is present
• Diagnosis remains unclear after initial workup