What is the management for elevated Hemoglobin (Hb) and Hematocrit (Hct) without testosterone use?

Management of Elevated Hemoglobin and Hematocrit Without Testosterone Use

When hemoglobin and hematocrit are elevated in a patient not on testosterone therapy, you must first investigate the underlying etiology before considering any intervention, as this represents true polycythemia or secondary erythrocytosis from another cause rather than medication-induced erythrocytosis. 1

Initial Diagnostic Workup

The evaluation must distinguish between primary polycythemia (polycythemia vera) and secondary causes:

• Measure serum erythropoietin (EPO) levels to differentiate primary from secondary erythrocytosis—low or inappropriately normal EPO suggests polycythemia vera, while elevated EPO indicates secondary causes 2

• Assess for hypoxic conditions including chronic obstructive pulmonary disease, sleep apnea, high altitude residence, chronic heart disease, or smoking history, as these are common causes of appropriately elevated EPO 1, 3

• Evaluate for inappropriate EPO production by checking for renal pathology (renal cell carcinoma, polycystic kidney disease, renal artery stenosis), hepatocellular carcinoma, uterine fibroids, or cerebellar hemangioblastoma 2

• Screen for other medications that can cause erythrocytosis including SGLT-2 inhibitors (2.1-22% incidence), anti-angiogenic tyrosine kinase inhibitors (up to 43.5% incidence), erythropoiesis-stimulating agents, and certain MDR-TB treatment regimens 2

Hematocrit Thresholds and Risk Assessment

The critical threshold for intervention is hematocrit >54%, which warrants immediate action due to increased blood viscosity and potential cardiovascular complications 1, 3

• Hematocrit between 50-54% requires close monitoring and investigation of etiology, with measurement intervals every 1-2 months 1, 3

• Elevated hematocrit increases blood viscosity, which aggravates vascular disease in coronary, cerebrovascular, and peripheral circulation, particularly dangerous in elderly patients or those with pre-existing vascular disease 1, 3

• The risk of hemoconcentration is substantially greater if concurrent conditions exist that independently raise hematocrit, such as chronic obstructive pulmonary disease 1, 3

Management Algorithm Based on Severity

For Hematocrit 50-54% (Mild Elevation):

• Intensify monitoring frequency to every 1-2 months rather than routine intervals 3
• Aggressively address modifiable risk factors including smoking cessation, treatment of sleep apnea, optimization of pulmonary disease management 4
• Continue investigation of underlying etiology 1

For Hematocrit >54% (Requiring Intervention):

• Implement therapeutic phlebotomy as first-line intervention to remove excess red blood cells and reduce cardiovascular and thromboembolic risk 4, 3
• The goal is to reduce hematocrit below 54% to decrease blood viscosity and improve microcirculation 3
• Continue phlebotomy sessions (typically removing 500 mL per session) until hematocrit normalizes, with frequency determined by rate of rise 3

For Hematocrit >54% with Identified Secondary Cause:

• Treat the underlying condition (e.g., CPAP for sleep apnea, discontinue causative medication if possible) 4, 2
• If SGLT-2 inhibitor-induced, discontinuation demonstrates improvement or resolution of erythrocytosis 2
• Therapeutic phlebotomy remains indicated while addressing root cause 3

Specific Considerations for Non-Testosterone Causes

For SGLT-2 inhibitor-associated erythrocytosis, the mechanism involves hemoconcentration and altered renal oxygen sensing, with rates ranging from 2.1-22% and thromboembolic events reported in up to 10% of affected individuals 2

For anti-angiogenic TKI-associated erythrocytosis in cancer patients, up to 43.5% develop elevated counts, requiring careful balance between cancer treatment efficacy and erythrocytosis management 2

Monitoring Strategy

• Baseline hemoglobin and hematocrit should be measured before starting any medication known to cause erythrocytosis 1, 3
• Follow-up intervals: 1-2 months initially, then every 3-6 months during the first year, and annually thereafter if stable 3
• Hemoglobin is a more accurate measure than hematocrit for monitoring, as it remains stable with blood sample storage and has lower coefficient of variation across automated analyzers 1

Critical Pitfalls to Avoid

• Do not ignore hematocrit 50-54%—this requires investigation even if below the intervention threshold of 54% 1
• Do not assume benign etiology—polycythemia vera and renal cell carcinoma must be excluded 2
• Do not delay phlebotomy when hematocrit exceeds 54%—the cardiovascular risk from hyperviscosity is immediate 1, 3
• Patients with additional cardiovascular risk factors (older age, diabetes, hypertension, smoking) require more aggressive monitoring and earlier intervention 1, 4