UC San Diego

Chronic intravascular hemolysis releases cell-free hemoglobin (Hb) and heme, promoting oxidative stress, inflammation, and tissue injury that drive cardiovascular and renal complications in hemolytic disorders. Haptoglobin (Hp) and hemopexin (Hpx) mitigate Hb and heme toxicity. However, their levels during chronic hemolysis decrease, allowing for Hb and heme tissue partitioning and multi-organ injury. To address this, we evaluated the apohemoglobin–haptoglobin (ApoHb–Hp) complex, a dual-function scavenger that neutralizes acellular Hb and free heme, in a chronic Hb-infusion mouse model. Male and female mice received daily Hb or Hb + ApoHb–Hp injections for six weeks. Cardiac and renal function were assessed by echocardiography and transdermal glomerular filtration rate (GFR), along with inflammatory and injury biomarkers. Chronic Hb impaired cardiac and renal function and elevated renal and cardiac-associated injury biomarkers, such as troponin and KIM-1. ApoHb–Hp treatment preserved cardiac and renal function, lowered inflammatory and injury biomarkers, while also reduced circulating heme and urinary iron. Although females showed partial resilience to Hb-induced dysfunction, both sexes benefited from ApoHb–Hp therapy. These results demonstrate that ApoHb–Hp effectively mitigates Hb- and heme-driven organ injury, supporting its potential as a targeted therapeutic for chronic hemolytic pathologies.