What is the appropriate management for a patient with elevated red blood cell (RBC) count, hemoglobin, and hematocrit?

Management of Elevated RBC Count, Hemoglobin, and Hematocrit

The first priority is to distinguish true polycythemia from relative polycythemia by assessing hydration status and plasma volume, then systematically evaluate for secondary causes before considering primary polycythemia vera. 1

Initial Diagnostic Approach

Confirm the elevation with repeat measurements, as a single abnormal value is unreliable—hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women defines erythrocytosis. 2 Hemoglobin is the preferred measurement over hematocrit because it remains stable during sample storage, while hematocrit can falsely increase by 2-4% with prolonged storage and is affected by hyperglycemia. 2

Rule Out Relative Polycythemia First

• Assess hydration status immediately by examining vital signs, mucous membranes, skin turgor, and recent fluid losses (vomiting, diarrhea, diuretic use), as dehydration is the most common cause of spurious RBC elevation. 1
• For relative polycythemia, restore euvolemia with oral or intravenous isotonic crystalloid as the primary intervention—this alone will normalize values if plasma volume depletion is the cause. 1
• Review medications causing hemoconcentration including diuretics, testosterone therapy, and erythropoietin-stimulating agents. 1

Systematic Evaluation for True Polycythemia

Once relative polycythemia is excluded, proceed with the following algorithm:

Step 1: Assess for Hypoxia-Driven Secondary Causes

• Check oxygen saturation and arterial blood gas to identify chronic hypoxemia, as this triggers compensatory erythropoietin production. 1
• Obtain detailed smoking history—carbon monoxide exposure causes "smoker's polycythemia" through chronic tissue hypoxia and resolves with smoking cessation. 2
• Consider sleep study if nocturnal hypoxemia is suspected, as obstructive sleep apnea produces erythropoietin-driven erythrocytosis that responds to CPAP therapy. 2
• Evaluate for chronic lung disease (COPD, pulmonary fibrosis) and cyanotic congenital heart disease with right-to-left shunting. 2

Step 2: Laboratory Workup

Order the following tests immediately: 2

• Complete blood count with red cell indices and reticulocyte count
• Peripheral blood smear review to assess red cell morphology and identify coexisting iron deficiency (microcytic polycythemia with elevated RBC count but reduced hemoglobin)
• Serum erythropoietin level to distinguish primary (low/normal EPO) from secondary polycythemia (elevated EPO)
• Serum ferritin and transferrin saturation—iron deficiency commonly coexists with erythrocytosis, particularly in polycythemia vera
• JAK2 V617F mutation testing if primary polycythemia is suspected (found in up to 97% of polycythemia vera cases) 2

Step 3: Evaluate for Non-Hypoxic Secondary Causes

If EPO is elevated but hypoxia is absent, assess for: 2

• Renal pathology with renal ultrasound and creatinine—renal cell carcinoma, polycystic kidney disease, and renal artery stenosis cause inappropriate EPO production
• Hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma (rare EPO-producing tumors)
• Testosterone use (prescribed or unprescribed)—dose adjustment or discontinuation is necessary if causative

Management Based on Etiology

For Secondary Polycythemia

Treat the underlying condition as the primary intervention: 2

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Optimize management of chronic lung disease
• Reduce or discontinue testosterone if causative
• Address renal pathology or EPO-producing tumors

Therapeutic phlebotomy is indicated ONLY when hemoglobin exceeds 20 g/dL AND hematocrit exceeds 65% with symptoms of hyperviscosity (headache, dizziness, visual disturbances, paresthesias), and only after excluding dehydration. 1, 2 In secondary erythrocytosis, a target hematocrit of 55-60% may be appropriate, as the elevated hematocrit serves a compensatory physiological role. 2

For Primary Polycythemia Vera

Refer urgently to hematology if JAK2 mutation is positive or if diagnosis remains unclear after initial workup. 2 The diagnosis requires both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 2

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk—this is the strongest evidence-based threshold, as the CYTO-PV trial demonstrated significantly reduced thrombotic events (2.7% vs 9.8%, P=0.007) with this target. 2 Elevated hematocrit increases platelet accumulation at sites of vascular injury and accelerates thrombus formation. 3

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

Critical Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement—this increases hemoconcentration and stroke risk. 2
• Do not transfuse RBCs in patients with elevated RBC counts, as this worsens hyperviscosity and increases thrombotic risk. 1
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 2
• Do not assume all elevated RBC counts require phlebotomy—appropriate secondary erythrocytosis may be physiologically necessary for oxygen delivery. 1
• Avoid iron deficiency even in the presence of erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 2 If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 2
• Do not use standard polycythemia vera diagnostic thresholds at high altitude without adjustment—physiologic adaptation to altitude can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 2

Monitoring Parameters

• Recheck hemoglobin and hematocrit weekly during initial phlebotomy until target levels are achieved. 1
• Monitor for thrombotic complications including deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction, as hyperviscosity significantly increases risk. 1
• For patients on testosterone therapy, close monitoring of hematocrit levels with consideration for dose adjustment or temporary discontinuation if levels continue to rise. 2