What are the differential diagnoses (DDX) and management options for an increased hematocrit (Hct)?

Differential Diagnosis and Management of Elevated Hematocrit

Primary Differential Diagnoses

The two fundamental categories that must be distinguished are polycythemia vera (a myeloproliferative neoplasm) and secondary erythrocytosis (a physiological response to hypoxemia or other stimuli). 1

Polycythemia Vera (Primary)

• Myeloproliferative neoplasm with autonomous red blood cell production 2, 1
• Test for JAK2, CALR, or MPL mutations to confirm diagnosis 1
• Associated with increased thrombotic risk independent of the elevated hematocrit 2

Secondary Erythrocytosis

• Hypoxemia-driven causes: chronic lung disease, cyanotic congenital heart disease, high altitude, sleep apnea 1
• Tumor-related: renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma (erythropoietin-secreting tumors) 1
• Other causes: testosterone therapy, anabolic steroid use, post-renal transplant erythrocytosis 1

Relative Polycythemia (Pseudopolycythemia)

• Decreased plasma volume with normal red cell mass (dehydration, diuretic use, Gaisböck syndrome) 1

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Management Algorithm

Step 1: Determine the Underlying Cause

Order JAK2, CALR, or MPL mutation testing to differentiate polycythemia vera from secondary causes. 1 Simultaneously evaluate for:

• Oxygen saturation and arterial blood gas (identify hypoxemia) 1
• Erythropoietin level (low in PV, high in secondary causes) 1
• Imaging for occult tumors if secondary erythrocytosis suspected 1

Step 2: Management Based on Diagnosis

For Polycythemia Vera:

Maintain hematocrit strictly below 45% through therapeutic phlebotomy—this is mandatory and reduces cardiovascular death and major thrombotic events from 9.8% to 2.7%. 1, 3

Phlebotomy protocol: 1

• 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

Add low-dose aspirin 100 mg daily for all patients unless contraindicated to significantly reduce thrombotic events. 1, 3

Cytoreductive therapy is mandatory if: 1, 3

• 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: 1, 3

• Hydroxyurea: Most commonly used, but use cautiously in patients <40 years
• Interferon alfa or pegylated interferon: Particularly effective for younger patients and those with intractable pruritus
• Ruxolitinib: Reserved for patients who fail first-line therapy

For Secondary Erythrocytosis:

Do NOT perform routine phlebotomy—this is harmful and can cause iron deficiency, decrease oxygen-carrying capacity, and paradoxically increase stroke risk. 1

Phlebotomy in secondary erythrocytosis is ONLY indicated when ALL of the following are present: 1

• Hematocrit >65% (or hemoglobin >20 g/dL)
• Symptoms of hyperviscosity (headache, poor concentration, visual disturbances)
• Patient is adequately hydrated
• No iron deficiency is present

Before any phlebotomy consideration, hydration is first-line therapy: 1

• Administer oral fluids or intravenous normal saline
• Reassess symptoms after adequate hydration
• Many "hyperviscosity" symptoms resolve with hydration alone

If phlebotomy is performed: 1

• Replace with equal volume of fluid
• Remove 250-500 mL per session
• Monitor for iron deficiency development

Address the underlying cause: 1

• Optimize treatment of chronic lung disease
• Consider surgical correction of cyanotic heart disease if feasible
• Discontinue causative medications (testosterone, anabolic steroids)
• Treat sleep apnea with CPAP

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Critical Management Principles

Iron Status Assessment is Mandatory

Evaluate iron deficiency using serum iron, ferritin, and transferrin saturation before any intervention. 1, 4 Iron deficiency is frequently overlooked in patients with elevated hematocrit because hemoglobin appears "normal" or elevated. 4

If transferrin saturation <20%, treat with iron supplementation until stores are replete, monitoring hemoglobin closely. 1 Iron deficiency can:

• Mimic hyperviscosity symptoms 1
• Reduce oxygen-carrying capacity despite elevated hematocrit 1
• Increase stroke and myocardial ischemia risk 1

Thrombotic Risk Management

Elevated hematocrit is an independent risk factor for venous thromboembolism. 5 Men with hematocrit ≥46% have a 1.5-fold increased risk of total VTE and 2.4-fold increased risk of unprovoked VTE. 5

In polycythemia vera, increased hematocrit enhances thrombosis through multiple mechanisms: 2

• Increased whole blood viscosity at low shear rates
• Enhanced platelet-endothelial interaction
• Qualitative platelet defects with increased thromboxane A2 production
• Leukocyte and endothelial cell activation
• Reduced levels of anticoagulants (antithrombin III, proteins C and S)

Phlebotomy substantially reduces but does not abolish thrombotic risk, which is why aspirin is also required. 2

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Monitoring and Follow-Up

For polycythemia vera patients: 3

• Monitor complete blood count every 2-4 weeks during induction, then every 3 months
• Assess response using European LeukemiaNet criteria
• Complete response: hematocrit <45% without phlebotomy, platelet count <400 × 10⁹/L, WBC <10 × 10⁹/L, no disease-related symptoms

For secondary erythrocytosis patients: 1

• Monitor hematocrit every 3-6 months
• Assess iron status regularly (ferritin, transferrin saturation)
• Evaluate for progression of underlying disease

For all patients on cytoreductive therapy: 1

• Monitor for potential side effects (cytopenias, skin ulcers with hydroxyurea)
• Assess for disease transformation in PV patients

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Common Pitfalls to Avoid

Do not perform routine phlebotomy in secondary erythrocytosis without clear indications—this is the most common error and leads to iron deficiency, compromised oxygen transport, and increased cardiovascular risk. 1

Do not overlook iron deficiency in patients with elevated hematocrit—always check ferritin and transferrin saturation, as iron deficiency can coexist with erythrocytosis and worsen outcomes. 1, 4

Do not target supraphysiological hematocrit levels in fetal transfusions or other special populations—higher blood viscosity at hematocrit >50% increases complication risk. 2

Do not forget cardiovascular risk factor management—aggressively manage smoking cessation, hypertension control, and diabetes regardless of the underlying diagnosis. 1

Do not use hematocrit values from improperly collected specimens—in patients with hematocrit >55%, citrate anticoagulant concentration must be adjusted for accurate coagulation testing. 6