What is the best course of action for a 57-year-old post-menopausal female with elevated hemoglobin (Hb) and hematocrit (Hct), and increased red blood cell (RBC) count, with normal kidney and liver function?

Evaluation and Management of Elevated Hemoglobin, Hematocrit, and RBC Count in a 57-Year-Old Post-Menopausal Female

This patient requires immediate workup for erythrocytosis, starting with JAK2 mutation testing, serum erythropoietin level, and evaluation for secondary causes, as her hemoglobin of 16.3 g/dL and hematocrit of 47.6% exceed the threshold for initiating anemia workup in post-menopausal females (Hgb >12 g/dL, Hct >37%) and approach diagnostic criteria for polycythemia vera. 1

Initial Diagnostic Approach

Confirm True Erythrocytosis

• Repeat hemoglobin and hematocrit measurements to confirm persistent elevation, as a single measurement is insufficient for diagnosis. 1
• The patient's values (Hb 16.3 g/dL, Hct 47.6%, RBC 5.36) are elevated compared to normal post-menopausal female ranges (Hb 14.0 ± 2.0 g/dL, Hct 41 ± 5%). 2
• Hemoglobin is the preferred measurement over hematocrit because it remains stable during sample storage, whereas hematocrit can falsely increase by 2-4% with prolonged storage and is affected by hyperglycemia. 1

Essential Laboratory Workup

Order immediately: 1

• JAK2 mutation testing (both exon 14 V617F and exon 12 mutations) - present in up to 97% of polycythemia vera cases
• Serum erythropoietin level - low or inappropriately normal suggests polycythemia vera; elevated suggests secondary causes
• Complete blood count with differential - assess for leukocytosis and thrombocytosis (suggests myeloproliferative disorder)
• Serum ferritin and transferrin saturation - iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia
• Peripheral blood smear - evaluate red cell morphology and identify abnormalities
• Reticulocyte count - assess bone marrow response

Diagnostic Algorithm Based on Results

If JAK2 Mutation is Positive

Diagnosis of polycythemia vera requires: 1

• Both major criteria: (1) Elevated hemoglobin/hematocrit AND (2) JAK2 mutation present, PLUS one minor criterion
• OR: First major criterion PLUS two minor criteria
• Minor criteria include: bone marrow hypercellularity with trilineage growth, subnormal serum EPO level, endogenous erythroid colony formation

Immediate actions: 1

• Refer to hematology immediately for bone marrow biopsy to confirm diagnosis and assess for trilineage myeloproliferation
• Initiate therapeutic phlebotomy to maintain hematocrit strictly below 45% (target <42% for women is reasonable due to physiological differences)
• Start low-dose aspirin (81-100 mg daily) as second cornerstone of therapy for thrombosis prevention

If JAK2 Mutation is Negative

Systematically evaluate secondary causes: 1

Hypoxic Causes to Assess:

• Obstructive sleep apnea - obtain sleep study if nocturnal symptoms, snoring, or daytime somnolence present
• Chronic lung disease - pulmonary function tests and arterial blood gas if respiratory symptoms or smoking history
• Cyanotic congenital heart disease - echocardiography if cardiac history or murmur present
• Smoking history - "smoker's polycythemia" from chronic carbon monoxide exposure causing tissue hypoxia; resolves with cessation

Non-Hypoxic Causes to Consider:

• Medication review - specifically testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in women
• Renal imaging - ultrasound or CT to exclude renal cell carcinoma, hydronephrosis, or cystic disease (can produce erythropoietin)
• Hepatic imaging - if liver function tests abnormal, exclude hepatocellular carcinoma
• Other EPO-producing tumors - pheochromocytoma, uterine leiomyoma, meningioma (rare)

Relative Polycythemia (Plasma Volume Depletion):

• Assess hydration status - dehydration, diuretic use, or stress polycythemia (Gaisböck syndrome)
• If suspected, recheck after adequate hydration

Management Based on Etiology

For Confirmed Polycythemia Vera

Primary treatment goals: 1

• Maintain hematocrit strictly <45% through therapeutic phlebotomy (evidence from CYTO-PV trial: 2.7% vs 9.8% thrombotic event rate, P=0.007)
• Target hematocrit <42% for women is reasonable due to lower baseline values
• Add low-dose aspirin (81-100 mg daily) for thrombosis prevention
• Consider hydroxyurea if high thrombotic risk (age >60, prior thrombosis) or inadequate control with phlebotomy alone

For Secondary Erythrocytosis

Treat the underlying condition: 1

• Smoking cessation for smoker's polycythemia - erythrocytosis resolves with cessation
• CPAP therapy for obstructive sleep apnea - corrects nocturnal hypoxemia
• Oxygen therapy for chronic lung disease with hypoxemia
• Testosterone dose reduction or discontinuation if causative - monitor hematocrit closely
• Surgical management of EPO-producing tumors if identified

Phlebotomy indications in secondary erythrocytosis: 1

• Only if hematocrit >65% with symptoms of hyperviscosity (headache, dizziness, visual disturbances, paresthesias)
• Must exclude dehydration first
• Replace with equal volume of saline to prevent further hemoconcentration
• Target hematocrit 55-60% if phlebotomy necessary (elevated hematocrit serves compensatory physiological role)

Critical Management Principles

What NOT to Do

Avoid these common pitfalls: 1

• Never perform aggressive phlebotomy without volume replacement - increases hemoconcentration and stroke risk
• Never perform repeated routine phlebotomies in secondary erythrocytosis - causes iron depletion, decreased oxygen-carrying capacity, and increased stroke risk
• Do not ignore coexisting iron deficiency - iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk
• Do not use standard PV diagnostic thresholds at high altitude without adjustment for altitude of residence

Iron Management in Erythrocytosis

If iron deficiency is confirmed: 1

• Provide cautious oral iron supplementation with close hemoglobin monitoring
• Monitor for rapid increases in red cell mass - can occur quickly with iron repletion
• Serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis (MCV is unreliable in erythrocytosis)

Immediate Referral Indications

Refer to hematology immediately if: 1

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup
• Thrombocytosis or leukocytosis present (suggests myeloproliferative disorder)

Thrombotic Risk Considerations

This patient's current values warrant urgent attention because: 1, 3

• Elevated hemoglobin and hematocrit increase blood viscosity and thrombotic risk
• Thrombotic events are the most lethal complications of polycythemia vera and often the initial manifestation
• Secondary polycythemia from chronic hypoxia also carries significant thrombotic risk, including cerebral and myocardial infarction
• The 45% hematocrit threshold for polycythemia vera is absolute and evidence-based for reducing thrombotic complications