Rejuvenation of RBCs: validation of a manufacturing method suitable for clinical use

Smethurst, Peter A.; Jolley, Jennifer; Braund, Rebecca; Proffitt, Susan; Lynes, T. E.; Hazell, Matthew; Mellor, P.H.; Ridgwell, K.; Procter, Simon; Griffiths, Alexandra; New, Helen; Murphy, Gavin J.; Edmondson, Dave; Cardigan, Rebecca; Investigators, Redjuvenate Trial

doi:10.1111/trf.15426

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…The evolution, during storage and after metabolic rejuvenation, of intracellular ATP concentration, [34][35][36][37] PS exposure, 38 and hemolysis 39 of RBCs were consistent with previous studies. Variation in the intracellular concentration of ATP influences RBC morphology.…”

Section: Discussionsupporting

confidence: 91%

Metabolic rejuvenation upgrades circulatory functions of red blood cells stored under blood bank conditions

et al. 2020

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Background: Red blood cells (RBC) change upon hypothermic conservation, and storage for 6 weeks is associated with the short-term clearance of 15% to 20% of transfused RBCs. Metabolic rejuvenation applied to RBCs before transfusion replenishes energetic sources and reverses most storage-related alterations, but how it impacts RBC circulatory functions has not been fully elucidated. Study Design and Methods: Six RBC units stored under blood bank conditions were analyzed weekly for 6 weeks and rejuvenated on Day 42 with an adenine-inosine-rich solution. Impact of storage and rejuvenation on adenosine triphosphate (ATP) levels, morphology, accumulation of storage-induced microerythrocytes (SMEs), elongation under an osmotic gradient (by LORRCA), hemolysis, and phosphatidylserine (PS) exposure was evaluated. The impact of rejuvenation on filterability and adhesive properties of stored RBCs was also assessed. Results: Rejuvenation of RBCs restored intracellular ATP to almost normal levels and decreased the PS exposure from 2.78% to 0.41%. Upon rejuvenation, the proportion of SME dropped from 28.2% to 9.5%, while the proportion of normal-shaped RBCs (discocytes and echinocytes 1) increased from 47.7% to Abbreviations: 42R, rejuvenation on Day 42 without automatic washes; 42RW, rejuvenation on Day 42 with automatic washes; CFSE, carboxyfluorescein diacetate succinyl ester; DIC, differential interference contrast; EI, elongation index; IFC, imaging flow cytometry; NT, untreated RBCs stored for 42 days in SAGM; PS, phosphatidylserine; SME(s), microerythrocyte(s). Pierre A. Buffet and Pascal Amireault contributed equally to this work.

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Section: Discussionsupporting

confidence: 91%

Metabolic rejuvenation upgrades circulatory functions of red blood cells stored under blood bank conditions

et al. 2020

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“…However, the U.S. FDA has not verified its clinical use to date. The FDA approved a pyruvate-based product (Rejuvesol) in the 1990s, which was the sole commercial pyruvate-compounded solution stored at 4°C for the rejuvenation of stored RBCs in vitro before infusion ( 100 ). Early data regarding its acute toxicology showed that oral pyruvate LD 50 was over 10.0 g/kg in rats, and IV pyruvate LD 50 was over 1.25 g/kg in mice; thus, pyruvate was considered non-toxic in humans ( 39 , 92 ).…”

Section: Safety and Feasibility Of Pyruvate Fluidsmentioning

confidence: 99%

Pyruvate as a Potential Beneficial Anion in Resuscitation Fluids

Zhou

2022

Front. Med.

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There have been ongoing debates about resuscitation fluids because each of the current fluids has its own disadvantages. The debates essentially reflect an embarrassing clinical status quo that all fluids are not quite ideal in most clinical settings. Therefore, a novel fluid that overcomes the limitations of most fluids is necessary for most patients, particularly diabetic and older patients. Pyruvate is a natural potent antioxidant/nitrosative and anti-inflammatory agent. Exogenous pyruvate as an alkalizer can increase cellular hypoxia and anoxia tolerance with the preservation of classic glycolytic pathways and the reactivation of pyruvate dehydrogenase activity to promote oxidative metabolism and reverse the Warburg effect, robustly preventing and treating hypoxic lactic acidosis, which is one of the fatal complications in critically ill patients. In animal studies and clinical reports, pyruvate has been shown to play a protective role in multi-organ functions, especially the heart, brain, kidney, and intestine, demonstrating a great potential to improve patient survival. Pyruvate-enriched fluids including crystalloids and colloids and oral rehydration solution (ORS) may be ideal due to the unique beneficial properties of pyruvate relative to anions in contemporary existing fluids, such as acetate, bicarbonate, chloride, citrate, lactate, and even malate. Preclinical studies have demonstrated that pyruvate-enriched saline is superior to 0.9% sodium chloride. Moreover, pyruvate-enriched Ringer’s solution is advantageous over lactated Ringer’s solution. Furthermore, pyruvate as a carrier in colloids, such as hydroxyethyl starch 130/0.4, is more beneficial than its commercial counterparts. Similarly, pyruvate-enriched ORS is more favorable than WHO-ORS in organ protection and shock resuscitation. It is critical that attention first be paid to improving abnormal saline with pyruvate for ICU patients. Many clinical trials with a high dose of intravenous or oral pyruvate were conducted over the past half century, and results indicated its effectiveness and safety in humans. The long-term instability of pyruvate aqueous solutions and para-pyruvate cytotoxicity is not a barrier to the pharmaceutical manufacturing of pyruvate-enriched fluids for ICU patients. Clinical trials with sodium pyruvate-enriched solutions are urgently warranted.

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“…To support and enhance PPP activity, we supplemented the standard SAGM storage solution with an RBC processing solution, containing 20.8 g/L sodium phosphate, 26.8 g/L inosine, 11 g/L sodium pyruvate, and 680 mg/L adenine (PIPA rejuvenation solution; Rejuvesol Red Blood Cell Processing Solution, Zimmer Biomet; refs. 28,29), that is available for clinical use in the United States. Freshly processed RBCs were treated with copper/ascorbate after addition of 15% (vol/vol) PIPA solution.…”

Section: Figure 1 Effects Of Incubation At 37°c On Physical Propertimentioning

confidence: 99%

“…The increased EMP activity allows for repletion of 2,3-DPG, which promotes hemoglobin-oxygen dissociation in peripheral tissues, and is depleted during RBC storage. Production of 2,3-DPG is further supported by the addition of pyruvate and consequently increased availability of NAD + by conversion of pyruvate to lactate (29,46,47). Supplementation of RBCs stored at 4°C with the PIPA solution partially preserved NADPH after raising the temperature of stored RBCs to 37°C, indicating enhanced activity of the PPP.…”

Section: Figure 5 Effects Of Pipa On Physical Properties Prx2 Dimermentioning

confidence: 99%

Transition to 37°C reveals importance of NADPH in mitigating oxidative stress in stored RBCs

et al. 2019

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Rejuvenation of RBCs: validation of a manufacturing method suitable for clinical use

Cited by 9 publications

References 23 publications

Metabolic rejuvenation upgrades circulatory functions of red blood cells stored under blood bank conditions

Metabolic rejuvenation upgrades circulatory functions of red blood cells stored under blood bank conditions

Pyruvate as a Potential Beneficial Anion in Resuscitation Fluids

Transition to 37°C reveals importance of NADPH in mitigating oxidative stress in stored RBCs

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