The permanent availability of RBC for transfusion depends on refrigerated storage, during which morphologically-altered RBC accumulate. Among those, a subpopulation of small RBC, comprising echinocytes III, sphero-echinocytes, and spherocytes, and defined as "storage-induced micro-erythrocytes" (SME) could be rapidly cleared from the circulation after transfusion. We quantified the proportion of SME in RBC concentrates from healthy human volunteers and assessed their correlation with transfusion recovery. We then investigated the fate of SME upon perfusion through human spleens ex vivo. Finally, we explored where and how SME are cleared in a mouse model of blood storage and transfusion. In healthy human volunteers, high proportions of SME in long-stored RBC concentrates correlated with poor transfusion recoveries. When perfused through human spleens, 15% and 61% of long-stored RBC and SME were cleared in 70 minutes, respectively. High initial proportions of SME also correlated with high retention of RBC by perfused human spleens. In the mouse model, SME accumulated during storage. Transfusion of long-stored RBC displayed reduced post-transfusion recovery, which was mostly due to clearance of SME. Following transfusions of mice, long-stored RBC accumulated predominantly in the spleen, and were ingested mainly by splenic and hepatic macrophages. In macrophage-depleted mice, splenic accumulation and the clearance of SME were delayed and transfusion recovery was improved. In healthy hosts, SME are cleared predominantly by macrophages in the spleen and liver. When this well-demarcated subpopulation of altered RBC is abundant in RBC concentrates, transfusion recovery is diminished. Quantifying SME has the potential to improve blood product quality assessment.

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