What are the implications of elevated hemoglobin and red blood cell count in a 53-year-old female with previous leukocytosis and normal hematocrit?

Elevated Hemoglobin and RBC Count: Evaluation and Management

This 53-year-old female with hemoglobin 16.6 g/dL, RBC 5.91, normal hematocrit, and previous leukocytosis requires immediate workup for polycythemia vera with JAK2 mutation testing, while simultaneously evaluating for secondary causes of erythrocytosis. 1, 2

Initial Diagnostic Confirmation

Repeat hemoglobin and hematocrit measurements immediately to confirm true erythrocytosis, as a single measurement is insufficient for diagnosis. 1, 2 Diagnostic thresholds for erythrocytosis are hemoglobin >16.5 g/dL in women or hematocrit >49.5% in women. 1, 2 This patient's hemoglobin of 16.6 g/dL meets the threshold for further evaluation, despite the reported normal hematocrit.

Note that hemoglobin is more reliable than hematocrit for diagnosis, as hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1, 2 The discordance between elevated hemoglobin/RBC and normal hematocrit warrants careful interpretation and repeat testing.

Essential Laboratory Workup

Order the following tests immediately: 1, 2

• Complete blood count with differential and red cell indices to assess all three cell lines, particularly given the history of leukocytosis 2
• JAK2 mutation testing (both exon 14 and exon 12) as the cornerstone diagnostic test, present in up to 97% of polycythemia vera cases 3, 1, 2
• Serum ferritin, transferrin saturation, and iron levels to identify coexisting iron deficiency, which commonly causes microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin 1, 2
• Reticulocyte count to evaluate bone marrow response 1, 2
• C-reactive protein (CRP) as part of the minimum workup 1
• Erythropoietin level to differentiate primary from secondary causes 1
• Peripheral blood smear review by a qualified hematologist to evaluate cell morphology and rule out primary bone marrow disorders 2

Diagnostic Criteria for Polycythemia Vera

According to the 2018 WHO criteria, polycythemia vera diagnosis requires either: 3

• All three major criteria, OR
• First two major criteria plus one minor criterion

Major criteria: 3

1. Elevated hemoglobin (>16.5 g/dL in women) or hematocrit (>49% in women)
2. Presence of JAK2V617F or JAK2 exon 12 mutation
3. Bone marrow biopsy showing hypercellularity with trilineage growth

Minor criteria include: 3

• Subnormal serum erythropoietin level
• Endogenous erythroid colony formation

Systematic Evaluation for Secondary Causes

If JAK2 mutation is negative, systematically evaluate for secondary causes: 1, 2

• Smoking history and carbon monoxide exposure: "Smoker's polycythemia" results from chronic tissue hypoxia stimulating erythropoietin production and resolves with cessation 1, 2
• Sleep study if nocturnal hypoxemia suspected: Obstructive sleep apnea produces erythropoietin-driven erythrocytosis 1, 2
• Pulmonary function testing: Evaluate for COPD or other chronic hypoxemic conditions 1, 2
• Medication review: Assess for testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis 1, 2
• Imaging if indicated: Evaluate for erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma) 1

Management Based on Diagnosis

If Polycythemia Vera Confirmed:

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV study showing significant reduction in thrombotic events with this target. 1, 2 A lower target of 42% is reasonable for women due to physiological differences in baseline hematocrit. 1

Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1, 2

Refer immediately to hematology for ongoing management and risk stratification. 1, 2

If Secondary Erythrocytosis:

Treat the underlying condition: 1, 2

• 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

Therapeutic phlebotomy is indicated ONLY if hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, after excluding dehydration. 1, 2 Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1, 2

Special Consideration: Concurrent Leukocytosis

The history of leukocytosis requires urgent assessment, particularly if white blood cell count exceeds 100,000/μL, which necessitates aggressive intravenous hydration at 2.5-3 liters/m²/day to prevent tumor lysis syndrome and leukostasis complications. 2 Monitor closely for leukostasis symptoms (respiratory distress, altered mental status, visual changes), which constitutes a medical emergency. 2

Elevated white blood cell and platelet counts can independently affect whole blood viscosity, increasing thrombotic risk beyond that attributable to elevated hemoglobin alone. 4 This combination warrants particularly careful evaluation and monitoring.

Critical Pitfalls to Avoid

Do not perform aggressive phlebotomy without confirming diagnosis and excluding dehydration or relative polycythemia. 1, 2

Do not overlook coexisting iron deficiency, which is common in erythrocytosis and requires cautious oral iron supplementation with close hemoglobin monitoring if confirmed. 1, 2 Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1

Do not use standard diagnostic thresholds without considering physiological variations such as altitude of residence, which can increase hemoglobin by 0.2-4.5 g/dL depending on elevation. 1

Do not rely on hematocrit alone for ongoing monitoring; use hemoglobin as it is more reproducible and stable during sample storage. 1, 2