What is the recommended management for a patient with an elevated red‑cell mass (high hemoglobin/hematocrit)?

Management of Elevated Red Blood Cells

For patients with elevated hemoglobin/hematocrit, immediately order JAK2 mutation testing along with a complete blood count, serum ferritin, transferrin saturation, and reticulocyte count to distinguish polycythemia vera from secondary causes, as therapeutic phlebotomy to maintain hematocrit <45% is only indicated for confirmed polycythemia vera, while secondary erythrocytosis rarely requires phlebotomy and instead demands treatment of the underlying condition. 1, 2

Initial Diagnostic Approach

Confirm True Erythrocytosis

• Repeat measurements to confirm persistent elevation, as a single measurement is unreliable—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, 2
• Hemoglobin is more reliable than hematocrit for diagnosis because hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable 1
• Exclude relative polycythemia first by assessing hydration status, recent fluid losses, and diuretic use, as plasma volume depletion is the most common cause of elevated hematocrit 1, 2

Essential First-Line Laboratory Testing

• JAK2 mutation testing (both exon 14 V617F and exon 12) should be ordered immediately as the first diagnostic test, present in up to 97% of polycythemia vera cases 3, 1, 2
• Complete blood count with red cell indices and manual differential to assess for thrombocytosis (53% in PV) and leukocytosis (49% in PV) 1, 4
• Serum ferritin and transferrin saturation are essential because iron deficiency commonly coexists with erythrocytosis, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin 1, 2
• Peripheral blood smear review by a qualified hematologist to identify abnormal morphology 1, 2
• Reticulocyte count to evaluate bone marrow response 1

Diagnostic Criteria for Polycythemia Vera

WHO Diagnostic Criteria (Revised)

Diagnosis requires EITHER:

• Both major criteria (elevated hemoglobin/hematocrit/RBC mass AND JAK2 mutation) PLUS at least one minor criterion 3, 1
• OR the first major criterion PLUS at least two minor criteria 3, 1

Major Criteria:

1. Elevated hemoglobin (>16.5 g/dL in women, >18.5 g/dL in men) or elevated hematocrit (>49% in women, >52% in men) 3, 1
2. Presence of JAK2V617F or other functionally similar JAK2 mutation 3, 1

Minor Criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis with prominent erythroid and megakaryocytic proliferation) 3, 2
2. Subnormal serum erythropoietin level 3, 2
3. Endogenous erythroid colony formation in vitro 3, 2

When Bone Marrow Biopsy is Required

• Mandatory if JAK2 mutation is positive to confirm PV diagnosis and assess for trilineage myeloproliferation 1, 2
• Essential for establishing baseline histomorphology and distinguishing PV from other JAK2-positive myeloproliferative neoplasms 5
• Consider if diagnosis remains unclear after initial workup to exclude other myeloid neoplasms 1

Evaluation for Secondary Causes (If JAK2 Negative)

Hypoxic Causes

• Sleep study if obstructive sleep apnea suspected (nocturnal hypoxemia drives erythropoietin production) 1, 2
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease 1, 2
• Smoking history and carbon monoxide exposure assessment—"smoker's polycythemia" resolves with smoking cessation 1, 2
• Arterial oxygen saturation measurement (secondary polycythemia if <92%) 3
• High altitude residence—physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (e.g., +1.9 g/dL at 3,000 meters) 1, 2

Non-Hypoxic Secondary Causes

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease that produce erythropoietin 1, 2
• Medication review, particularly testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in young adults 1, 2
• Evaluate for other erythropoietin-producing tumors: hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 1
• Serum erythropoietin level (low/normal suggests PV; elevated suggests secondary cause, though sensitivity is <70%) 1

Rare Genetic Causes

• High-oxygen-affinity hemoglobin variants 1
• Erythropoietin receptor mutations 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) 1

Management Based on Etiology

Polycythemia Vera (JAK2 Positive)

Universal First-Line Therapy for ALL Patients

• Therapeutic phlebotomy to maintain hematocrit strictly <45%—the CYTO-PV trial demonstrated this threshold significantly reduces thrombotic events (2.7% vs 9.8%, P=0.007) 1, 6, 4
• Low-dose aspirin (81-100 mg daily) for all patients unless contraindicated, as it significantly reduces thrombotic events without substantially increasing bleeding risk 6, 4

Risk Stratification for Cytoreductive Therapy

High-risk patients requiring cytoreductive therapy include those with: 6, 4

• Age ≥60 years 6, 4
• History of prior thrombosis 6, 4
• Poor tolerance of phlebotomy 6
• Symptomatic or progressive splenomegaly 6
• Severe disease-related symptoms (pruritus, erythromelalgia) 6
• Platelet count >1,500 × 10⁹/L 6
• Progressive leukocytosis 6

Cytoreductive Therapy Options

• Hydroxyurea as first-line cytoreductive agent, but use with caution in younger patients (<40 years) due to potential leukemogenic risk 6, 4
• Interferon alfa or pegylated interferon as alternative first-line option, particularly effective for intractable pruritus and may offer improved survival outcomes 6, 5
• Ruxolitinib (JAK inhibitor) for patients intolerant of or resistant to hydroxyurea, particularly effective for pruritus and splenomegaly 6, 4

Monitoring and Treatment Goals

• Complete response criteria: hematocrit <45% without phlebotomy, platelet count <400 × 10⁹/L, WBC count <10 × 10⁹/L, and no disease-related symptoms 6
• Monitor for transformation to myelofibrosis (12.7% of patients) or acute myeloid leukemia (6.8% of patients) 4
• Median survival from diagnosis ranges from 14.1 to 27.6 years with appropriate treatment 4

Secondary Erythrocytosis Management

Critical Principle: Avoid Routine Phlebotomy

Repeated routine phlebotomies are explicitly contraindicated in secondary erythrocytosis because they cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk 1, 2

The elevated hematocrit in secondary erythrocytosis represents a physiological compensatory response to hypoxemia—the body naturally regulates red cell mass to optimize oxygen transport 1

When Phlebotomy is Indicated (Rare Exceptions)

Therapeutic phlebotomy is indicated ONLY when ALL of the following criteria are met: 1, 2

• Hemoglobin >20 g/dL AND hematocrit >65% 1, 2
• Associated symptoms of hyperviscosity (headache, visual disturbances, dizziness) 1, 2
• Dehydration has been excluded and patient adequately hydrated with oral or IV normal saline 1, 2
• Iron deficiency has been excluded (if transferrin saturation <20%, treat with iron supplementation rather than phlebotomy) 1

When phlebotomy is performed:

• Replace with equal volume of dextrose or normal saline to prevent further hemoconcentration 1
• Target hematocrit 55-60% (NOT <45% as in PV) since elevated hematocrit serves a compensatory physiological role 1

Treatment of Underlying Conditions

• Smoking cessation for smoker's polycythemia—erythrocytosis resolves with cessation 1, 2
• CPAP therapy for obstructive sleep apnea 1, 2
• Management of chronic lung disease (COPD, pulmonary fibrosis) 1, 2
• Testosterone dose adjustment or temporary discontinuation if causative, with close hematocrit monitoring 1, 2
• Treatment of underlying malignancy if erythropoietin-producing tumor identified 1

Special Populations

Cyanotic Congenital Heart Disease

• Erythrocytosis is a compensatory mechanism to optimize oxygen transport in patients with right-to-left shunting and arterial hypoxemia 1, 2
• Evaluate for intercurrent issues (dehydration, iron deficiency, infection) rather than performing phlebotomy 1
• Phlebotomy only if hematocrit >65% with documented hyperviscosity symptoms after confirming adequate hydration 1

Iron Deficiency Coexisting with Erythrocytosis

• Iron deficiency commonly coexists with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera 1, 2
• Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1, 2
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis—serum ferritin, transferrin saturation, and iron levels are required 1
• If iron deficiency confirmed (transferrin saturation <20%), cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur 1, 6, 2

High Altitude Residents

• Do not use standard PV diagnostic thresholds without adjustment for altitude of residence 1
• Physiologic adaptation to altitude increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1,000-4,500 meters) 1
• Low or normal erythropoietin levels suggest high altitude polycythemia as a physiologic response to chronic hypoxia 1

Immediate Referral Indications

Refer immediately to hematology if: 1, 2

• JAK2 mutation is positive 1, 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 1, 2
• Unexplained splenomegaly with elevated blood counts 1, 2
• Diagnosis remains unclear after initial workup 1

Critical Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement—this increases hemoconcentration and stroke risk 1
• Do not assume dehydration without clinical confirmation—a near-normal hemoglobin may actually suggest dehydration masking anemia 1, 2
• Do not overlook coexisting iron deficiency in patients with erythrocytosis, as this requires the opposite treatment (iron supplementation, not phlebotomy) 1, 2
• Do not apply the hematocrit <45% target to secondary erythrocytosis—this threshold is specific to polycythemia vera and evidence-based only for that condition 1
• Do not perform repeated routine phlebotomies in secondary erythrocytosis—this causes iron depletion and paradoxically increases stroke risk 1, 2
• Do not ignore elevated total band count (>1,500 cells/mm³)—this has the highest likelihood ratio (14.5) for detecting bacterial infection, even without fever 1