Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease

Abstract

Blood transfusion represents the first and most prescribed cell-based therapy; however, clinical safety and efficacy trials are lacking. Clinical cohort studies have suggested that massive transfusion and/or transfusion of aged stored blood may contribute to multiorgan dysfunction in susceptible patients. In this issue of the JCI, Baek and colleagues report that aged stored blood hemolyzes after massive transfusion in a guinea pig model. Hemolysis led to vascular and kidney injury that was mediated by cell-free plasma hemoglobin and prevented by coinfusion of the specific hemoglobin scavenger protein, haptoglobin. These studies support an expanding body of research indicating that intravascular hemolysis is a pathological mechanism in several human diseases, including multiorgan dysfunction after either massive red blood cell transfusion or hemoglobin-based blood substitute therapy, the hemoglobinopathies, malaria, and other acquired and genetic hemolytic conditions.

Figure 1. Mechanisms by which hemolysis and cell-free hemoglobin can mediate vascular injury.

Intravascular hemolysis releases cell-free hemoglobin (Hb) into the plasma. The hemoglobin is maintained in the ferrous redox state, which will react with NO in a near-diffusion limited reaction to inhibit NO signaling. Extravasation of hemoglobin in the subendothelial space and reductive recycling back to the ferrous state may enhance this pathological effect. Oxidation of hemoglobin, particularly in the kidney, from the ferric state to the ferryl state may further drive fenton and peroxidase oxidative cellular injury (involving the lipid peroxyl species, LOO^•), leading to acute kidney injury. Free heme and iron promote inflammatory injury via activation of innate immune responses in macrophages and monocytes. Compensatory pathways that normally control these NO dioxygenation and oxidation reactions include haptoglobin- and hemopexin-mediated sequestration of hemoglobin dimer and heme, respectively. Downstream Nrf-2, hemoxygenase, and biliverdin reductase signaling detoxify heme and iron and provide catalytic antioxidant, antiproliferative, and antiinflammatory protective signaling.