What are the side effects of Erythropoietin (Epo) stimulation?

Side Effects of Erythropoietin (EPO) Stimulation

EPO therapy carries significant risks including hypertension (occurring in approximately 23-35% of patients), thromboembolic events (67% increased relative risk), and rare but serious complications such as pure red cell aplasia and seizures, with these adverse effects being most pronounced when targeting higher hemoglobin levels or during rapid correction of anemia. 1, 2

Cardiovascular Side Effects

Hypertension (Most Common)

• Blood pressure elevation occurs in 23-35% of patients treated with EPO, representing the most frequently reported adverse effect 1, 3
• Hypertension typically develops within 2-16 weeks of initiating therapy, though some patients may experience delayed onset after several months 1
• Patients at highest risk include those with severe baseline anemia, rapid correction of anemia, and pre-existing hypertension 1
• The mechanism involves increased systemic vascular resistance due to elevated blood viscosity, reversal of hypoxic vasodilation, and inadequate reduction in cardiac output 3, 4
• Hypertensive encephalopathy with seizures can occur as an acute complication, even in previously normotensive patients, and is associated with rapid BP increases rather than the rate of hematocrit rise 1, 3

Thromboembolic Events

• The relative risk for thromboembolism increases by 67% (RR 1.67; 95% CI: 1.35-2.06) in ESA-treated patients compared to placebo 1
• Hemodialysis access thrombosis incidence increases as target hemoglobin levels are raised, with an average incidence of 7.5% in patients targeting hemoglobin of 36% 1
• High-risk patients include those with previous thrombosis history, recent surgery, prolonged immobilization, and multiple myeloma patients receiving thalidomide/lenalidomide combinations 1
• Deep vein thrombosis, coronary thrombosis, and cerebral thromboses have been reported, particularly with excessive erythrocytosis 5

Hematologic Complications

Pure Red Cell Aplasia (PRCA)

• PRCA represents a rare but severe adverse effect with an incidence of approximately 0.5 cases per 10,000 patient-years following subcutaneous exposure 1
• Caused by neutralizing anti-EPO antibodies that block both endogenous and exogenous erythropoietin 1
• Suspect PRCA in any patient receiving EPO for >4 weeks who develops sudden hemoglobin decline (≥5 g/L/week) or requires >1 unit red cell transfusion weekly, with normal white cell and platelet counts plus low reticulocyte count (<10 × 10⁹/L) 1
• Subcutaneous administration carries higher risk than intravenous route; cases peaked in 2002 related to specific formulation issues but have since returned to baseline 1
• If confirmed, all ESA therapy must be discontinued immediately and immunosuppressive therapy or transplantation considered 1

Neurologic Side Effects

Seizures

• Seizures occur in approximately 3% of EPO-treated patients (range 0-13% across studies) 1
• Most commonly reported within the first 90 days of therapy, particularly when higher doses were used and during periods of rising hemoglobin 1
• Often associated with hypertension and hypertensive encephalopathy 1
• Patients with chronic kidney disease have increased susceptibility to EPO-induced seizures 2

Common Mild-to-Moderate Side Effects

Injection Site and General Symptoms

• Pain at injection site, headache, and arthralgia are the most frequently reported mild adverse effects 1
• Peripheral edema occurs commonly 1
• Pyrexia, muscle spasm, dizziness reported in ≥5% of CKD patients 2

Other Documented Side Effects

• Rare allergic reactions including dyspnea, skin rash, and urticaria 1
• Nausea and vomiting (particularly in cancer and surgical patients) 2
• Myalgia and bone pain 2
• Pruritus and injection site irritation 2

Context-Specific Considerations

Cancer Patients

• Decreased survival times and poorer loco-regional control observed in trials targeting hemoglobin >12 g/dL in patients with baseline hemoglobin >10 g/dL 1
• Increased mortality and/or tumor progression risk documented 2

Chronic Kidney Disease Patients

• Aiming for higher hemoglobin targets associated with earlier need for renal replacement therapy in some studies 1
• Worsening hypertension requires particularly close monitoring as it accelerates progression to ESRD 1

Hepatitis C Triple Therapy

• EPO generally well tolerated in this population with severe adverse events being rare 1
• Isolated cases of convulsion and thrombotic phenomena described 1

Contraindications

EPO is absolutely contraindicated in: 2

• Uncontrolled hypertension
• Known hypersensitivity to EPO or excipients 1
• PRCA that developed after EPO treatment
• Use of benzyl alcohol-containing formulations in neonates, infants, pregnant women, and lactating women

Critical Monitoring Requirements

• Blood pressure monitoring is mandatory, particularly during the first 4 months of therapy 1, 3
• Iron status assessment before and during treatment with maintenance of iron repletion 2
• Hemoglobin levels should not exceed 11 g/dL as higher targets increase cardiovascular risks without additional benefit 2
• Seizure monitoring increased in CKD patients for changes in frequency or premonitory symptoms 2