What is the treatment approach for pure red cell aplasia (PRCA)?

Pure Red Cell Aplasia: Presentation and Workup

Clinical Presentation

PRCA should be suspected in any patient receiving ESA therapy for more than 4-8 weeks who develops sudden, severe anemia with specific hematologic features. 1

Diagnostic Criteria

The hallmark presentation includes all of the following:

• Rapid hemoglobin decline of ≥0.5-1.0 g/dL per week (or 5-10 g/L per week) 1, 2
• Transfusion dependence requiring approximately 1-2 units of red cells per week 1, 2
• Absolute reticulocyte count <10,000/μL (or <10 × 10⁹/L) 1, 2
• Normal white blood cell and platelet counts (distinguishes from other bone marrow failure syndromes) 1, 2

Risk Factors

• Subcutaneous ESA administration carries significantly higher risk (0.5 cases per 10,000 patient-years) compared to intravenous route, which has not been associated with PRCA cases 1, 2
• Most cases occur in patients with chronic kidney disease receiving ESAs 1
• Peak incidence occurred in 2002, associated with Eprex formulation changes; incidence has since declined 1, 3

Diagnostic Workup

Initial Laboratory Evaluation

When ESA hyporesponsiveness develops, perform systematic evaluation before pursuing PRCA-specific testing:

• Complete blood count with differential to confirm isolated red cell aplasia with normal white cells and platelets 1
• Absolute reticulocyte count (must be <10,000/μL for PRCA diagnosis) 1, 2
• Serum iron studies, B12, and folate to exclude other causes of ESA resistance 3
• Inflammatory markers (CRP, ferritin) to identify infection or inflammation 3

Confirmatory Testing

If initial screening suggests PRCA:

• Bone marrow examination showing absent or markedly reduced erythroblasts with normal myeloid and megakaryocytic lineages 4, 3, 5
• Anti-erythropoietin antibody testing using both binding and neutralizing antibody assays 1, 3, 5

Important caveat: Anti-EPO antibody assays may be falsely negative in some confirmed PRCA cases, so clinical diagnosis based on presentation and bone marrow findings remains valid even with negative antibody testing. 4, 3

Differential Diagnosis to Exclude

Evaluate for other causes of ESA hyporesponsiveness before confirming PRCA:

• Iron deficiency (absolute or functional) 3
• Active infection or inflammation 3
• Occult blood loss 3
• Hemolysis 3
• Bone marrow infiltration or myelodysplasia 3
• Aluminum toxicity (in dialysis patients) 3
• Hyperparathyroidism 3

Management Algorithm

Immediate Actions Upon PRCA Diagnosis

Permanently discontinue all ESA therapy immediately—this is non-negotiable. 1, 2 Do not switch to alternative ESA products (epoetin alfa, darbepoetin alfa, or other erythropoietin formulations) as neutralizing antibodies cross-react with all erythropoietin molecules. 1, 2

Immunosuppressive Therapy

Initiate cyclosporine as first-line immunosuppressive treatment to eliminate anti-erythropoietin antibodies. 6, 3, 5

• Cyclosporine achieves complete hematological response in approximately 80% of refractory PRCA cases 6
• Response typically occurs within 3-6 months of therapy initiation 6
• Dose-dependent efficacy; maintain therapeutic levels while monitoring for nephrotoxicity 6

Alternative for patients intolerant to cyclosporine: Prednisolone 0.5-1.0 mg/kg daily, though lower doses (0.2 mg/kg) may be effective in elderly patients or those with comorbidities who cannot tolerate standard immunosuppression. 7

Anemia Management During Treatment

• Provide red blood cell transfusions as needed to maintain hemoglobin and prevent symptomatic anemia 1, 2
• Irradiate and filter all blood products to prevent transfusion-associated complications 2
• Avoid arbitrary hemoglobin thresholds; transfuse based on symptoms 1

Novel Therapies

Consider HIF-prolyl hydroxylase inhibitors (e.g., Roxadustat) for maintenance therapy after immunosuppression achieves remission, as these agents do not stimulate anti-EPO antibody production. 4, 5

Common Pitfalls to Avoid

• Never continue ESA therapy after PRCA diagnosis, even at reduced doses 1, 2
• Never switch between ESA products thinking this will avoid cross-reactivity—it will not 1, 2
• Do not rely solely on antibody testing for diagnosis; negative results do not exclude PRCA if clinical features are present 4, 3
• Do not delay bone marrow examination in patients with severe ESA hyporesponsiveness meeting clinical criteria 3, 5
• Avoid subcutaneous ESA administration in future patients when intravenous route is feasible, as this significantly reduces PRCA risk 1, 2

Monitoring After Treatment

• Serial reticulocyte counts to assess response to immunosuppression 6, 5
• Anti-erythropoietin antibody titers (when initially positive) to confirm antibody elimination before considering any future erythropoiesis-stimulating therapy 1
• Renal function monitoring if using cyclosporine 6