Clinical Benefits and Risks of Haptoglobin Therapy in Hemolytic Disorders of Diverse Etiologies: A Systematic Review

Hemolytic disorders release cell-free hemoglobin (CFH), a potent nephrotoxin and oxidant. Haptoglobin, an endogenous plasma protein, binds CFH to facilitate its clearance. While haptoglobin therapy is a promising strategy to mitigate CFH-induced organ injury, its clinical efficacy and safety across different hemolytic conditions remain unclear. This systematic review aims to evaluate the clinical benefits and risks of haptoglobin therapy in patients with hemolytic disorders of diverse etiologies. A systematic literature search was conducted in PubMed, Scopus, Web of Science, and Embase from 2015 to 2025, following PRISMA guidelines. Studies reporting on haptoglobin therapy (administered or endogenous) and clinical outcomes in patients with hemolysis were eligible. The risk of bias was assessed using the ROBINS-I tool. A narrative synthesis was performed due to study heterogeneity. Five observational studies were included, involving cardiac surgery, severe burn, and acute respiratory distress syndrome (ARDS) patients. In cardiac surgery, haptoglobin administration was associated with a significant reduction in postoperative acute kidney injury (AKI) (adjusted OR = 0.54). In contrast, no clinical benefit was observed in severe burn patients. Consistently, low endogenous haptoglobin levels were a strong, independent predictor of AKI and major adverse kidney events (MAKE) across all clinical settings. No significant adverse events were directly attributed to haptoglobin administration. The benefit of haptoglobin therapy is context-dependent, demonstrating significant renal protection in cardiac surgery but not in severe burns. Low endogenous haptoglobin is a robust biomarker for AKI risk. These findings support a targeted, biomarker-guided approach to haptoglobin therapy, rather than universal application. Future randomized trials are needed to confirm efficacy in selected high-risk populations.