Effects of Aged Stored Autologous Red Blood Cells on Human Endothelial Function

Abstract

Rationale: A major abnormality that characterizes the red cell "storage lesion" is increased hemolysis and reduced red cell lifespan after infusion. Low levels of intravascular hemolysis after transfusion of aged stored red cells disrupt nitric oxide (NO) bioavailabity, via accelerated NO scavenging reaction with cell-free plasma hemoglobin. The degree of intravascular hemolysis post-transfusion and effects on endothelial-dependent vasodilation responses to acetylcholine have not been fully characterized in humans.Objectives: To evaluate the effects of blood aged to the limits of Food and Drug Administration-approved storage time on the human microcirculation and endothelial function.Methods: Eighteen healthy individuals donated 1 U of leukopheresed red cells, divided and autologously transfused into the forearm brachial artery 5 and 42 days after blood donation. Blood samples were obtained from stored blood bag supernatants and the antecubital vein of the infusion arm. Forearm blood flow measurements were performed using strain-gauge plethysmography during transfusion, followed by testing of endotheliumdependent blood flow with increasing doses of intraarterial acetylcholine. Measurements and Main Results:We demonstrate that aged stored blood has higher levels of arginase-1 and cell-free plasma hemoglobin. Compared with 5-day blood, the transfusion of 42-day packed red cells decreases acetylcholine-dependent forearm blood flows. Intravascular venous levels of arginase-1 and cell-free plasma hemoglobin increase immediately after red cell transfusion, with more significant increases observed after infusion of 42-day-old blood.Conclusions: We demonstrate that the transfusion of blood at the limits of Food and Drug Administration-approved storage has a significant effect on the forearm circulation and impairs endothelial function. Clinical trial registered with www.clinicaltrials.gov (NCT 01137656)

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…The current translational studies suggest that CFH contributes to increased microvascular permeability in PGD. While other studies have reported associations between circulating CFH and alterations in endothelial function in models of atherosclerosis, malaria, and sickle cell disease (38)(39)(40), there have been few prior studies of the direct effects of CFH on microvascular endothelial permeability (41). Oxidized CFH, which is present in atherosclerotic plaques, results in intercellular gap formation and increased permeability in cultured endothelial cell monolayers (42,43).…”

Red blood cells stored 35 days or more are associated with adverse outcomes in high‐risk patients

“…52 It has been shown that cell-free Hb increases as a consequence of hemolysis with increasing the storage duration of stored RBCs. 14,15,53,54 Therefore, the RBC units stored for more than 28 days will have more cell-free Hb that might negatively affect the vascular NO homeostasis in these patients. To our knowledge, the increased endothelial adherence and increased aggregation of RBCs after storage have not been studied to show whether these changes are readily or fully reversible.…”

Intravascular hemolysis and the pathophysiology of sickle cell disease

“…Infusing aged stored blood into rodents (89,93,94) and humans (90,95) causes intravascular hemolysis, pulmonary and systemic hypertension, and vascular endothelial dysfunction (due to impaired NO signaling) that can be blocked by haptoglobin (96). These effects are not always observed in models or patient populations in which hemolysis is not as severe, the dose of transfused red cells is not large, and the existing compensatory reserves of haptoglobin, hemopexin, and catalytic antioxidants are not as chronically depleted as in SCD.…”