Stored red blood cell transfusions: iron, inflammation, immunity, and infection

Abstract

Emily Cooley was a highly regarded medical technologist and morphologist. The "Emily Cooley Lectureship and Award" was established to honor her, in particular, and medical technologists, in general. This article reviews some basic concepts about the "life of a red blood cell" (RBC) and uses these to discuss the actual and potential consequences that occur in patients after clearance of transfused refrigerator storage-damaged RBCs by extravascular hemolysis.

Figure 1. Macrophage-RBC interactions between macrophage surface receptors and RBC ligands (“eat me” signals)

Cell-surface receptors on macrophages recognize various ligands expressed or newly-exposed on RBC surfaces, which signal macrophages to initiate erythrophagocytosis. All indicated RBC ligands function as “eat me” signals, except for CD47, which is both an “eat me” and a “don’t eat me” signal. Abbreviations: βGal: terminal β-Galactose residue; PS: phosphatidylserine; Gas6: growth-arrest 6 protein; MFG-E8: milk-fat globule protein-E8; SIRP-α: signal regulatory protein-α; ASGR: asialo-glycoprotein receptor; CR3: complement receptor 3; FcγR: Fc gamma receptor; PS-R; PS receptor; MER: c-mer proto-oncogene protein; α_Vβ₅: an integrin subtype. Red text: “don’t eat me” signal; black text: “eat me” signal

Figure 2. Schematic representation of the “Iron Hypothesis”

In pathological phagocytosis, metabolism of the hemoglobin in the large amount of ingested RBCs acutely increases the intracellular “free” iron levels (blue filled circles) in the labile intracellular pool (LIP), which, through a signal transduction pathway, enhances the production and secretion of pro-inflammatory cytokines (green filled circles); the latter can enhance the severity of the systemic inflammatory response syndrome (SIRS). In addition, excess “free” iron is exported from the cell through ferroportin (green cylinder), the physiological iron export channel. If the amount of exported iron exceeds the binding capacity of transferrin, then NTBI is produced, which can induce oxidative damage and enhance pathogen proliferation.