What is the workup and management for elevated hemoglobin (Hb) and hematocrit (Hct) levels?

Workup and Management of Elevated Hemoglobin and Hematocrit

The first critical step is to differentiate between true polycythemia (increased red cell mass) and relative erythrocytosis (hemoconcentration from dehydration or plasma loss), as this fundamentally determines whether treatment involves phlebotomy and cytoreduction versus fluid resuscitation. 1

Initial Diagnostic Approach

Confirm the Elevation and Assess Clinical Context

• Verify that hemoglobin/hematocrit exceeds the 95th percentile for sex and race, or document an increase above the patient's individual baseline regardless of absolute values 2
• Evaluate for dehydration immediately: assess for dry mucous membranes, decreased skin turgor, orthostatic hypotension, review fluid intake/losses, and consider fasting status 3
• Ensure adequate hydration and repeat CBC within 1-2 weeks to determine if values normalize, as a single measurement may mask the true clinical picture 2, 3
• Obtain serial measurements every 4 hours if acute illness is present, since initial normal values can mask evolving pathology 2, 4

Identify Associated Features Suggesting Polycythemia Vera

Look specifically for 2:

• Thrombocytosis (platelet count >400 × 10⁹/L)
• Leukocytosis (WBC >10 × 10⁹/L)
• Microcytosis from iron deficiency
• Splenomegaly on examination
• Aquagenic pruritus (itching after water exposure)
• Unusual thrombosis including Budd-Chiari syndrome
• Erythromelalgia (burning pain in extremities)

Diagnostic Algorithm After Confirming Persistent Elevation

Step 1: Measure Serum Erythropoietin (EPO) Level

• Low serum EPO (specificity >90%) is highly suggestive of polycythemia vera but not diagnostic, as it can occur in other myeloproliferative disorders 2
• Normal serum EPO does not exclude PV (sensitivity <70%), so PV remains a consideration 2
• Elevated serum EPO strongly suggests secondary erythrocytosis from hypoxemia (chronic lung disease, congenital heart disease, sleep apnea, high altitude) or other causes 2, 1

Step 2: Test for JAK2, CALR, and MPL Mutations

• JAK2 V617F mutation testing is essential to confirm polycythemia vera diagnosis and differentiate from secondary causes 1
• If JAK2 is negative, test for CALR and MPL mutations to identify other myeloproliferative neoplasms 1

Step 3: Bone Marrow Examination (When Indicated)

Perform bone marrow biopsy with cytogenetics when 2:

• Serum EPO is low or normal AND
• Mutation testing is negative or equivocal AND
• Clinical suspicion for PV remains high

Look for characteristic PV features: hypercellularity, increased megakaryocytes with clustering, giant megakaryocytes, pleomorphism, mild reticulin fibrosis (12% of cases), and decreased iron stores 2

Step 4: Evaluate for Secondary Causes

If EPO is elevated or mutations are negative, investigate 1:

• Hypoxemia: pulse oximetry, arterial blood gas, pulmonary function tests, echocardiogram for right-to-left shunt
• Sleep apnea: polysomnography if clinically indicated
• Renal pathology: renal ultrasound, creatinine
• Testosterone or erythropoietin use: medication history
• Smoking history: carboxyhemoglobin level

Management Based on Diagnosis

Polycythemia Vera Management

Risk Stratification

High-risk patients (requiring cytoreductive therapy) include those with 1:

• Age ≥60 years
• History of prior thrombosis
• Poor phlebotomy tolerance
• Symptomatic or progressive splenomegaly
• Platelet count >1,500 × 10⁹/L
• Leukocyte count >15 × 10⁹/L

Therapeutic Phlebotomy (All PV Patients)

• Maintain hematocrit strictly below 45% to reduce cardiovascular death and major thrombotic events from 9.8% to 2.7% (hazard ratio 3.91) 1
• Induction phase: Remove 300-450 mL weekly or twice weekly until hematocrit <45% 1
• Maintenance phase: Same volume per session with intervals determined by hematocrit monitoring 1

Antiplatelet Therapy

• Prescribe low-dose aspirin 100 mg daily for all PV patients unless contraindicated to significantly reduce thrombotic events 1

Cytoreductive Therapy (High-Risk Patients Only)

First-line agents 1:

• Hydroxyurea: Most commonly used first-line agent
• Interferon alfa or pegylated interferon: Particularly effective for younger patients and those with intractable pruritus
• Ruxolitinib: Consider for patients who fail first-line therapy

Monitoring

• CBC every 2-4 weeks during induction, then every 3 months once stable 1
• Assess iron status regularly as repeated phlebotomy causes iron deficiency 1
• Monitor for disease transformation to myelofibrosis or acute leukemia 1

Secondary Erythrocytosis Management

Critical Principle: Avoid Routine Phlebotomy

• Do NOT perform routine phlebotomy in secondary erythrocytosis, as it causes iron deficiency, decreases oxygen-carrying capacity, and paradoxically increases stroke risk 1, 5
• The patient's homeostatic processes generally achieve optimal red cell mass without intervention 1

Indications for Phlebotomy (All Must Be Present)

Phlebotomy is indicated ONLY when 1:

1. Hematocrit >65% (hemoglobin >20 g/dL) AND
2. Symptoms of hyperviscosity present (headache, poor concentration, visual disturbances) AND
3. Patient is adequately hydrated AND
4. No iron deficiency is present (transferrin saturation >20%)

Perform phlebotomy with equal volume fluid replacement to avoid worsening hypovolemia 1

Iron Management

• Evaluate iron status using serum iron, ferritin, and transferrin saturation 1
• If transferrin saturation <20%, treat with iron supplementation until stores are replete, monitoring hemoglobin closely 1
• Iron deficiency can mimic hyperviscosity symptoms and increase thrombotic risk 1

Address Underlying Cause

• Optimize treatment of chronic lung disease: bronchodilators, oxygen therapy if indicated
• Treat sleep apnea: CPAP therapy
• Smoking cessation: mandatory intervention
• Optimize congenital heart disease management: cardiology consultation

Special Clinical Scenarios

Suspected Hyperviscosity Symptoms

• Hydration is first-line therapy—NOT phlebotomy: administer oral fluids or IV normal saline before any other intervention 1, 4
• If symptoms persist despite adequate hydration and hematocrit remains significantly above baseline, consider phlebotomy only after confirming no iron deficiency 1

Plasma Leakage Syndromes (Dengue, Capillary Leak)

• Do NOT transfuse or phlebotomize based on elevated hematocrit during active plasma leakage, as this represents hemoconcentration, not true polycythemia 4
• Begin aggressive crystalloid resuscitation through large-bore IV access 4
• Monitor hematocrit every 4 hours: rising values indicate worsening plasma leak requiring more aggressive fluid therapy 4
• Hematocrit should normalize spontaneously as plasma volume restores during recovery phase 4

Iron Deficiency with Elevated Hematocrit

• Low MCHC with normal MCV suggests early iron deficiency before microcytosis develops 3
• Treat iron deficiency first before considering any phlebotomy, as iron deficiency paradoxically increases thrombotic risk 1

Common Pitfalls to Avoid

• Performing routine phlebotomy in secondary erythrocytosis without clear indications leads to iron deficiency and compromises oxygen transport, potentially increasing stroke risk 1, 5
• Overlooking dehydration as a cause of relative erythrocytosis results in unnecessary workup and potential harm from phlebotomy 3
• Treating plasma leakage with phlebotomy would be catastrophic, worsening hypovolemia 4
• Using a single hematocrit measurement to guide major decisions, as values fluctuate with hydration status and may mask evolving pathology 2
• Ignoring iron deficiency, which mimics hyperviscosity symptoms and independently increases thrombotic risk 1
• Failing to recognize that thrombotic risk in erythrocytosis is not solely determined by hematocrit level but involves multiple cellular and molecular factors 5

Cardiovascular Risk Factor Management

Aggressively manage all cardiovascular risk factors regardless of diagnosis 1:

• Smoking cessation (mandatory)
• Hypertension control
• Diabetes management
• Lipid optimization
• Antiplatelet therapy as indicated