What is the appropriate management for a patient with elevated hemoglobin (Hb) and hematocrit (Hct) levels, potentially due to underlying conditions such as polycythemia vera, chronic lung disease, sleep apnea, or dehydration?

Management of Elevated Hemoglobin and Hematocrit

For any patient with elevated hemoglobin and hematocrit, immediately confirm the values with repeat testing and order JAK2 mutation testing, complete blood count with differential, serum ferritin, transferrin saturation, and erythropoietin level to distinguish polycythemia vera from secondary causes. 1

Diagnostic Thresholds and Initial Workup

True erythrocytosis is defined as hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women. 1 However, a single measurement is unreliable—repeat testing is mandatory before proceeding with extensive evaluation. 1

Essential Initial Laboratory Tests

• Complete blood count with red cell indices to assess for concurrent leukocytosis or thrombocytosis, which suggest myeloproliferative disease 1
• Serum ferritin and transferrin saturation to identify iron deficiency, which can coexist with erythrocytosis and create microcytic polycythemia 1, 2
• Erythropoietin level to differentiate primary (low/normal EPO) from secondary causes (elevated EPO) 1
• JAK2V617F mutation testing (present in 97-98% of polycythemia vera cases) 1, 3, 4
• Reticulocyte count and peripheral blood smear to assess bone marrow response and red cell morphology 1

Critical Diagnostic Pitfall

Do not assume normal hemoglobin/hematocrit excludes polycythemia vera—a subset of patients have "masked" or "inapparent" PV due to concurrent plasma volume expansion or blood loss, yet still harbor JAK2 mutations and face thrombotic risk. 5, 6 If the patient presents with unexplained thrombosis (especially splanchnic vein thrombosis), splenomegaly, or unexplained leukocytosis/thrombocytosis, proceed with JAK2 testing even if hemoglobin appears normal. 5, 6

Distinguishing Primary from Secondary Erythrocytosis

Polycythemia Vera Diagnosis

The World Health Organization criteria require BOTH major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 1 Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal erythropoietin level, and endogenous erythroid colony formation. 1

• If JAK2 is positive, bone marrow biopsy is required to confirm trilineage myeloproliferation and exclude other myeloid neoplasms 1
• Refer immediately to hematology if JAK2 is positive, hemoglobin >20 g/dL with hyperviscosity symptoms, or unexplained splenomegaly 1

Secondary Erythrocytosis Evaluation

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

• Hypoxic causes: Order sleep study for suspected obstructive sleep apnea, pulmonary function tests for COPD, echocardiogram for cyanotic congenital heart disease 1, 2
• Smoking history: "Smoker's polycythemia" from chronic carbon monoxide exposure resolves with cessation 1
• Medication review: Testosterone therapy (prescribed or unprescribed) is a common cause in younger adults 1
• Erythropoietin-producing tumors: Consider renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma if EPO is inappropriately elevated 1
• Altitude adjustment: Hemoglobin increases 0.2-4.5 g/dL at elevations of 1000-4500 meters—do not use standard PV thresholds without altitude correction 1

Management of Polycythemia Vera

Universal First-Line Therapy (All Risk Categories)

Maintain hematocrit strictly below 45% through therapeutic phlebotomy—the CYTO-PV trial demonstrated this reduces cardiovascular death and major thrombotic events from 9.8% to 2.7% (HR 3.91, P=0.007). 7, 1, 2

Phlebotomy protocol: 2

• Induction phase: Remove 300-450 mL weekly or twice weekly until hematocrit <45%
• Maintenance phase: Same volume per session with intervals determined by hematocrit monitoring
• Always replace volume with equal amounts of dextrose or saline to prevent hemoconcentration 1

Add low-dose aspirin 81-100 mg daily unless contraindicated—the ECLAP study showed significant reduction in cardiovascular death, myocardial infarction, stroke, and venous thromboembolism. 7, 1, 2

High-Risk Patients Requiring Cytoreductive Therapy

Cytoreductive therapy is mandatory if: 7, 2

• 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

First-line cytoreductive agents: 7, 2

• Hydroxyurea: Most commonly used, well-tolerated in majority of patients. The PVSG trial showed lower leukemogenic risk compared to pipobroman (24% vs 52% at 20 years, P=0.004). 7
• Pegylated interferon-α: Particularly effective for younger patients and those with intractable pruritus; induces high rates of molecular response (reduction in JAK2V617F allele burden). 7 Consider as first-line in young patients to avoid prolonged hydroxyurea exposure. 7

Second-line agents: 2

• Ruxolitinib: For patients who fail first-line therapy
• Busulfan: Alternative second-line option

Monitoring and Response Assessment

• During induction: CBC every 2-4 weeks 2
• Maintenance: CBC every 3 months 2
• Complete response (European LeukemiaNet criteria): Hematocrit <45% without phlebotomy, platelet count <400 × 10⁹/L, WBC <10 × 10⁹/L, no disease-related symptoms 2
• Monitor for iron deficiency in patients undergoing repeated phlebotomy 2

Management of Secondary Erythrocytosis

Critical Management Principle

Do NOT perform routine phlebotomy in secondary erythrocytosis—this causes iron deficiency, decreases oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 2 The elevated hematocrit serves a compensatory physiological role. 2

When Phlebotomy IS Indicated in Secondary Erythrocytosis

Phlebotomy is indicated ONLY when ALL of the following are met: 1, 2

• Hemoglobin >20 g/dL AND hematocrit >65%
• Symptoms of hyperviscosity present (headache, poor concentration, visual disturbances)
• Patient is adequately hydrated
• No iron deficiency present (transferrin saturation >20%)

If these criteria are met: 2

• Target hematocrit 55-60% (NOT <45% as in PV)
• Always replace volume with equal amounts of saline
• Monitor iron status closely

Treatment of Underlying Conditions

Address the root cause rather than the erythrocytosis itself: 1, 2

• Smoking cessation for smoker's polycythemia
• CPAP therapy for obstructive sleep apnea
• Optimize management of COPD or other chronic lung disease
• Dose adjustment or discontinuation of testosterone if causative
• Hydration as first-line therapy for suspected hyperviscosity symptoms—NOT phlebotomy 2

Iron Management in Secondary Erythrocytosis

Iron deficiency should be avoided even in the presence of erythrocytosis—iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1

• If transferrin saturation <20%: Treat with cautious oral iron supplementation until stores are replete, monitoring hemoglobin closely 1, 2
• Common pitfall: Iron deficiency can mimic hyperviscosity symptoms; always evaluate iron status before considering phlebotomy 2

Special Clinical Scenarios

Cyanotic Congenital Heart Disease

• Erythrocytosis is a compensatory response to right-to-left shunting and hypoxemia 1, 2
• Patient's homeostatic processes generally achieve optimal red cell mass—routine phlebotomy is not supported by data and may be harmful 2
• Evaluate for intercurrent issues (dehydration, iron deficiency, infection) before considering phlebotomy 1

Pregnancy

• Consult hematology immediately for risk-stratified management
• Low-dose aspirin and phlebotomy remain cornerstones
• Interferon-α is preferred cytoreductive agent if needed (hydroxyurea is teratogenic) 3

Perioperative Management

• Target hematocrit <45% before elective surgery in PV patients
• Continue aspirin unless bleeding risk is prohibitive
• Ensure adequate hydration perioperatively 3

Cardiovascular Risk Factor Management

Aggressively manage all modifiable cardiovascular risk factors regardless of diagnosis: 2

• Smoking cessation (mandatory)
• Hypertension control
• Diabetes management
• Lipid optimization

These interventions reduce thrombotic risk independent of hematocrit control. 2

Common Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement—this increases hemoconcentration and stroke risk 1
• Never perform routine phlebotomy in secondary erythrocytosis without meeting strict criteria (Hb >20, Hct >65%, symptoms, adequate hydration, no iron deficiency) 1, 2
• Never overlook iron deficiency in patients with erythrocytosis—it can coexist and worsen outcomes 1, 2
• Never use standard PV diagnostic thresholds at high altitude without adjustment for physiologic adaptation 1
• Never assume normal hemoglobin excludes PV in patients with unexplained thrombosis or splenomegaly—test JAK2 anyway 5, 6