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

Abstract

The potential adverse effects of transfusion of red blood cells after prolonged storage have been hotly debated. During refrigerated storage, red blood cells are damaged, a process known as the red blood cell "storage lesion." We hypothesized that the delivery of a bolus of iron derived from these rapidly cleared, damaged, red blood cells is responsible for some of the adverse effects of transfusion. Iron may play a role in producing a pro-inflammatory response to transfused red blood cells, potentially through the effects of reactive oxygen species on stress pathways and inflammasome activation. Furthermore, the excess iron may impair the host's ability to combat infection by its innate iron-withholding pathways. This symposium paper summarizes the background for the "iron hypothesis" as it relates to transfusion of red blood cells after prolonged refrigerated storage. It also includes a summary of the data from recent murine and human studies, and concludes with a discussion of several unresolved questions arising from these published studies.

Fig. 1.

Iron hypothesis. The clearance of transfused “fresh” red blood cells should not differ from the clearance of endogenous, naturally-senescent red blood cells, leading to the clearance of approximately 1 mg of iron per hour. In contrast, if 25% of one unit of older, stored red blood cells are cleared by extravascular hemolysis in one hour, then approximately 60 mg of iron are cleared in that time. The diagram shows two macrophages, the one on the left has ingested one red blood cell; the one on the right has ingested multiple red blood cells. The iron released from hemoglobin is represented by blue-filled circles, intracellularly synthesized and secreted cytokines are represented by green-filled circles, the turquoise cylinder in the macrophage on the right represents ferroportin, the iron export channel. NTBI: non-transferrin-bound iron.

Fig. 2.

Iron, inflammasomes, and inflammation. This hypothetical model suggests a mechanism by which macrophage ingestion of an excess of red blood cells could activate NFκB, and also provide both signal 1 and signal 2 for inflammasome activation, thereby producing a pro-inflammatory cytokine response. HO-1: heme oxygenase-1; CO: carbon monoxide; ROS: reactive oxygen species; NLRP: nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain containing proteins; IL: interleukin; MCP-1: monocyte chemoattractant protein-1.