New frontiers in transfusion biology: identification and significance of mediators of morbidity and mortality in stored red blood cells

Abstract

Red blood cell (RBC) transfusions are associated with inflammation and thrombosis, both arterial and venous, the mechanisms of which are not understood. Although a necessary life-saving procedure in modern medicine, transfusions have rarely been subjected to modern assessments of efficacy and safety, including randomized trials. Storage of RBCs induces changes, including the release of free hemoglobin and the accumulation of biologically active soluble mediators and microparticles. These mediators likely play a direct role in the inflammatory and prothrombotic properties of RBC transfusions. Methods such as leukoreduction, washing of RBCs, and rejuvenation may improve the quality of RBC transfusions.

Figure 1. Free hemoglobin, isoprostanes and microparticles accumulate during storage of red blood cells

Stored red blood cell membranes become ruffled and more rigid as ATP levels decrease (1). Microparticles bud off from the red cell membrane and expose the negatively charged phosphatidylserine on their surface (2). Hemoglobin is released upon storage-induced hemolysis, increasing the concentration of free hemoglobin in the stored unit (3). Oxidative damage occurs as oxygen dissociates from free hemoglobin yielding superoxide and hydrogen peroxide through a series of reactions (4). Reactive oxygen species generate free radicals upon interaction with iron containing compounds (5), which interact with membrane lipids to form lipid radicals (6). Free radicals may also be formed independent of hemoglobin and contribute to the generation of lipid radicals (7). Isoprostanes are formed from the free radical induced peroxidation of membrane lipids (8). Microparticles, free hemoglobin and isoprostanes may adversely affect the transfused recipient by causing inflammation and thrombosis (9).

Figure 2. Proven (leukoreduction) and potential future methods for reducing morbidity and mortality following red blood cell transfusions

One or a combination of these methods may be employed to improve the quality of stored red blood cells.