Red blood cells stored for increasing periods produce progressive impairments in nitric oxide–mediated vasodilation

Alexander, Jason; El-Ali, Alexander; Newman, James L.; Karatela, Sulaiman; Predmore, Benjamin L.; Lefer, David J.; Sutliff, Roy L.; Roback, John D.

doi:10.1111/trf.12111

Cited by 47 publications

(50 citation statements)

References 49 publications

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“…Most notably, Hb levels were elevated in the Cysβ93 mutant mice, indicative of tissue hypoxia and thus affirming an essential role for Cysβ93. Thus, the most parsimonious explanation for restoration of vessel relaxations by RBCs that are depleted of SNOHb [but not nitrite (34)] through storage and then repleted with S-nitrosylating agents, involves a SNO-based mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…We and others previously reported that storage of blood leads to marked losses in SNO-Hb within 1 d (32,33), which are paralleled by losses in the ability of RBCs to effect hypoxic vasodilation (32). Blood is >80% depleted in SNO-Hb by 7 d and remains low thereafter [whereas, nitrite levels do not decline during storage (34)]. We further showed that the defect in RBCmediated vasodilation could be corrected by selectively repleting SNO-Hb (32,35), but this has only been demonstrated with very small amounts of blood (1 mL).…”

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confidence: 99%

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S-nitrosylation therapy to improve oxygen delivery of banked blood

Reynolds¹,

Bennett²,

Cina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO 2 , but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO 2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O 2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.ethyl nitrite | hemoglobin cysbeta93 | nitric oxide | storage lesion

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

S-nitrosylation therapy to improve oxygen delivery of banked blood

Reynolds¹,

Bennett²,

Cina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The current paradigms now include a role of RBCs as not only a vehicle of oxygen delivery, but also as both an agent of CO 2 removal, a sensor of tissue oxygenation, and a regulator of biological processes extrinsic to the RBC (eg, vascular tone through NO biology). 55 Thus, additional metrics of RBC storage have been added to the above-mentioned details, including distinguishing hemoglobin outside of intact RBCs (eg, either free or in the form of microparticles that may scavenge NO), the amount of S-nitrosylation of hemoglobin itself (SNO-Hg), 55 adhesion of RBCs to endothelial beds, 56 effects of stored RBCs on models of vascular tone (eg, isolated aortic rings), 57 and in vivo measures of how stored RBCs affect vascular tone, both in animals and directly in humans. 58 However, as with the long list of more traditional measures, the clinical meaning of these indications remains largely undetermined (and in some cases controversial) and the ability to predict RBC function is unclear.…”

Section: Biological Properties Of Rbcs Other Than Carrying Oxygen: Momentioning

confidence: 99%

Established and theoretical factors to consider in assessing the red cell storage lesion

Zimring

2015

Blood

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The collection and storage of red blood cells (RBCs) is a logistical necessity to provide sufficient blood products. However, RBC storage is an unnatural state, resulting in complicated biological changes, referred to collectively as the "storage lesion." Specifics of the storage lesion have been studied for decades, including alterations to cellular properties, morphology, molecular biology of carbohydrates, proteins and lipids, and basic metabolism. Recently, mass spectrometry-based "omics" technology has been applied to the RBC storage lesion, resulting in many new observations, the initial effects of which are more information than understanding. Meanwhile, clinical research on RBC transfusion is considering both the efficacy and also the potential untoward effects of transfusing stored RBCs of different ages and storage conditions. The myriad biological changes that have now been observed during the storage lesion have been extensively reviewed elsewhere. This article focuses rather on an analysis of our current understanding of the biological effects of different elements of the storage lesion, in the context of evolving new clinical understanding. A synopsis is presented of both established and theoretical considerations of the RBC storage lesion and ongoing efforts to create a safer and more efficacious product. (Blood. 2015;125(14):2185-2190 Biology of RBC storage: effect upon the red cell and effects upon the patientThe practice of storing red blood cells (RBCs) prior to transfusion has been in place for close to a century.

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“…Previous work has shown that chemical or mechanical alteration of the red cell cytoskeleton results in increased red cell NO scavenging attributed to increased permeability to NO [52]. A recent publication argues that the changes in intrinsic RBC NO scavenging ability that occur during blood storage are more important in reducing NO bioavailability upon transfusion than effects from cell-free hemoglobin and microparticles [44]. Based on our previous work [34,53,57], we think it is more likely that cell-free Hb and microparticles play a larger role.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent studies show that the effects of storage will lead to an increased intrinsic NO scavenging by older stored RBCs, as measured by nitric oxide competition experiments and inhibition of aortic vasodilation [20,43,44]. However, the extent of the increase in NO scavenging by older red blood cells compared to fresh ones was not fully explored and the mechanism for this phenomenon was not satisfactorily provided.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Faster NO Scavenging by Older Stored Red Blood Cells

Liu

Janes

et al. 2013

Free Radical Biology and Medicine

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a b s t r a c tThe blood storage lesion involves morphological and biochemical changes of red blood cells (RBCs) that occur during storage. These include conversion of the biconcave disc morphology to a spherical one, decreased mean corpuscular hemoglobin concentration, varied mean corpuscular volume, reduced integrity of the erythrocyte membrane with formation of microparticles, and increased cell-free hemoglobin. We studied the extent that older stored red blood cells scavenge nitric oxide (NO) faster than fresher stored red blood cells. Using electron paramagnetic resonance spectroscopy and stoppedflow absorption spectroscopy to measure the rate of NO uptake and reaction with hemoglobin in red cells, we found that older stored red blood cells scavenge NO about 1.8 times faster than fresher ones. Based on these experimental data, we simulated NO scavenging by fresher or older stored red blood cells with a biconcave or spherical geometry, respectively, in order to explore the mechanism of NO scavenging related to changes that occur during blood storage. We found that red blood cells with a spherical geometry scavenges NO about 2 times slower than ones with a biconcave geometry, and a smaller RBC hemoglobin concentration or volume increases NO scavenging by red blood cells. Our simulations demonstrate that even the most extreme possible changes in mean corpuscular hemoglobin concentration and mean corpuscular volume that favor increased NO scavenging are insufficient to account for what is observed experimentally. Therefore, RBC membrane permeability must increase during storage and we find that the permeability is likely to increase between 5 and 70 fold. Simulations using a two-dimensional blood vessel show that even a 5-fold increase in membrane permeability to NO can reduce NO bioavailability at the smooth muscle. Background: Transfusion of older stored blood may be harmful. Results: Older stored red blood cells scavenge nitric oxide more than fresher cells. Conclusion: As stored red blood cells age, structural and biochemical changes occur that lead to faster scavenging. Significance: Increased nitric oxide scavenging by red blood cells as a function of storage age contributes to deleterious effects upon transfusion.

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Red blood cells stored for increasing periods produce progressive impairments in nitric oxide–mediated vasodilation

Cited by 47 publications

References 49 publications

S-nitrosylation therapy to improve oxygen delivery of banked blood

S-nitrosylation therapy to improve oxygen delivery of banked blood

Established and theoretical factors to consider in assessing the red cell storage lesion

Mechanism of Faster NO Scavenging by Older Stored Red Blood Cells

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