Is longer better?

During the past 100 years, a greater understanding of the red blood cell (RBC) “storage lesion” and resultant improvements in anticoagulant-preservative solutions and storage containers incrementally improved the ex vivo quality and storage duration of stored blood and blood components. Citrate and glucose solutions followed by acidified citrate dextrose (ACD) solutions, less acidified ones incorporating citrate-phosphate-dextrose (CPD), and those with adenine (CPDA-1) that increase ATP levels extended the shelf life of whole blood and RBC components from 14 to 35 days. Subsequently, additive solutions (ASs) applied only to RBCs lengthened storage to 49 days, later reduced to 42 days because of concerns about inadequate RBC recoveries. Interestingly, Dumont and colleagues1 note in this issue of TRANSFUSION that there are no published studies of in vivo RBC recoveries in healthy subjects receiving RBCs stored for 6 weeks in AS-1. Moroff and others eventually reported a 76.0 ± 5.4% 24-hour recovery of 42-day-stored, nonleukoreduced RBCs and a 79.2 ± 4.3% recovery after 35 days of storage. Importantly, these RBCs were prepared from whole blood maintained for 7 hours on 20 to 24°C “temperature stabilizing packages,” butane-1,4-diol plates, before AS-1 addition, refrigeration, and storage. Presumably, the 49-day storage interval would not meet current Food and Drug Administration (FDA) standards of “mean 24-hour, post transfusion, in vivo red cell recovery at end of storage of at least 75% with a standard deviation of at most 9% and lower limit of a one sided 95% confidence interval for the population proportion of successes is 70% or greater.” Recent evaluations of the “storage lesion” cast additional doubt about prolonged ex vivo RBC storage. The growing database demonstrates losses of RBC ATP and 2,3-DPG levels, membrane-protectant sugars, RBC deformity and concave shape with resultant increases in hemolysis, microvesicle shedding, iron release and associated nitric oxide scavenging or infection risk, echinocyte formation, and release of cytokines and procoagulants. Concomitantly, new information and logistic and economic considerations sparked interest in increasing the interval and modifying the temperature requirements of whole blood between collection and component processing (manufacturing). Specifically, an overnight hold (ONH) with flexibility regarding temperature requirements could eliminate some pick-ups at distant blood drives needed currently for transporting whole blood to component laboratories for platelet (PLT) and frozen plasma preparation within the 8 hours required by FDA regulations. Component preparation during a single shift on the day after collection could replace costly two or three shift manufacturing operations now in place. Other potential advantages include greater male plasma inventories for transfusion-related acute lung injury mitigation and longer contact of white blood cells (WBCs) promoting autosterilization. ONH potentially increases PLT yields and eliminates the current practice of placing whole blood on ice at blood drives. “Buffy coat” PLTs, in widespread use in Europe and Canada, take advantage of ONH.3, 4 Plasma produced from whole blood stored for 24 hours at ambient temperature maintains coagulation factor content, except for Factor (F)VIII.5, 6 Protein S levels decline approximately 10%, not considered clinically significant. Drs Greenwalt and Hess invented an anticoagulant-preservative solution with additional phosphate and bicarbonate, AS-7, that increases the pH of currently licensed adenine, glucose, and mannitol containing ASs. Articles by Cancelas and colleagues7 and Dumont and colleagues,1, 8 in this issue of TRANSFUSION, demonstrate the biochemical and clinical characteristics of leukoreduced RBCs stored for 42 and 56 days and plasma prepared from whole blood stored under current conditions or subjected to ONH and nonrefrigerated conditions before component preparation. By recognizing the importance of coordinating pH and metabolic rates at reduced temperature, this process demonstrates improved biochemical status, lessened hemolysis, and greater RBC recovery in AS-7–stored, leukoreduced RBCs after 56-day storage compared to currently approved systems (AS-1) at 42 days. With AS-7, the extracellular pH is lower at the beginning of storage compared to RBCs stored in AS-1 despite AS-7's higher pH, but a higher intracellular pH occurs because of the chloride shift mechanism. Higher glucose consumption and lactate production ensue with AS-7 rather than AS-1 since glycolysis runs faster with AS-7. In addition, the decreased ATP decline during storage in AS-7 compared to AS-1 takes place because an acidic pH inhibits RBC ATP synthesis. Cancelas and coworkers7 show that RBCs separated from whole blood within 8 hours of collection and maintained at 1 to 6°C before AS-7 addition had 88 ± 5% 24-hour recovery at 42 days of storage (better than historic reports with AS-1) and 82 ± 3% 24-hour recovery at 56 days of storage. All RBCs stored for 56 days under these conditions met FDA criteria; all had greater than 75% recoveries and had less than 1% hemolysis. Microvesicle shedding decreased significantly in RBCs stored 6 or 8 weeks in AS-7 compared to those stored in AS-1. They did not report 2,3-DPG results. Studies by others show losses of half to two-thirds of RBC 2,3-DPG activity with ONH compared to refrigerating RBCs within 8 hours of collection.2, 4 No correlation occurred between RBC ATP levels and recovery and hemolysis results, apparently attributed to the highly favorable observations. As such, they did not document improved ATP levels as the mechanism for AS-7's benefits, the only FDA approved RBC anticoagulant-preservative solution in 25 years. AS-7 added to the RBCs after separation from whole blood does not affect red plasma or PLTs as prepared currently. However, the interval between blood collection and component preparation and the storage temperature during this interval does. Dumont and coworkers1 using the same data set as described above7 examined in vitro and in vivo properties of AS-7 RBCs subjected to an ONH, that is, 18-hour, room temperature storage on an open laboratory bench. AS-7 units held for 18 hours at room temperature stored for 42 days (n = 28) and those refrigerated within 8 hours of collection and stored 56 days (n = 27) met FDA criteria. Seven of 28 AS-7 units kept at room temperature overnight failed FDA criteria for 24-hour recovery at 56 days. When examined for hemolysis, 60 of 60 ONH units met criteria when stored for 42 days, but 2 units of 60 stored for 56 days had greater than 1% hemolysis. Hence, ONH units stored for 42 days met FDA criteria, “less than 1% with 95% confidence that 95% of the products meet this criteria, i.e., 60 consecutive units tested will need to have hemolysis of less than 1%.” Residual WBC counts increased as the time before refrigeration increased from 2 hours (n = 60), 8 hours(n = 60), and 18 hours (n = 60) attributed to a progressive activation state relaxation of both WBCs and PLTs and their interaction with leukoreduction filters. None had residual WBC counts greater than 2.4 × 106, although a few contained more than 1 × 106. Dumont and colleagues1 did not measure in vivo recoveries with RBCs stored in AS-1 or other ASs such as AS-3, AS-5, or PAGGSM and refrigerated within 6 to 8 hours of collection, preventing direct comparisons. Additionally, Dumont and coworkers8 report on plasma prepared from whole blood units subjected to ONH at room temperature that was frozen and stored for 1 year. In the absence of defined criteria for frozen plasma, other than FVIII levels, Dumont and colleagues8 sought to demonstrate bioequivalence (levels 80%-125% of control) of plasma obtained from whole blood and held at room temperature for 24 hours (PF24RT24WB) before leukoreduction by filtration with their findings of plasma frozen within 8 hours of collection (FFP). They used a non–FDA-approved filter for these experiments, which may have significance in light of a recent report that leukoreduction is more important than hold time for plasma coagulant properties.9 FVIII levels failed bioequivalence criteria while meeting FDA requirements and protein S levels approximated 10% lower levels than FFP. Discussion at the May 2012 Blood Products Advisory Committee focused on the clinical impact of the lower protein S levels in plasma held at room temperature overnight before freezing, but concluded that the reduced levels would have minimal clinical impact. Dumont and colleagues8 found reduced antithrombin, thrombin : antithrombin complexes, fibrinopeptide-A, and complement fragment C5a, levels of uncertain impact on clinical outcomes. ADAMTS 13 levels retained activity. They did not present data about procoagulant and other factors levels in thawed plasma, although they expected no difference from those seen currently with FFP. In sum, with blood component preparation, longer is better provided that quality is maintained or enhanced. Cancelas and coworkers7 and Dumont and coworkers1, 8 investigated two elements pertinent to safety and logistic issues affecting transfusion medicine. They provide robust data demonstrating that AS-7 exceeds standards for blood storage for 42 and 56 days under current practice conditions. FDA approved AS-7 for 42-day storage; CE mark grants a 56-day shelf life. Unfortunately, they provide no information about storage characteristics at time points before 42 days, something relevant to current practice and concerns about storage time–related adverse events. Notably, the observations show excellent results for whole blood held overnight at room temperature in a controlled environment (but, notably not on butane-1,4-diol plates) before separation into components and stored for 42, but not 56, days. They show bioequivalence with FFP of plasma prepared after an ONH at room temperature that drained through a new leukoreduction filter. Dr Hess and the late Dr Tibbi Greenwalt deserve kudos for developing a new preservative solution and retaining biochemistry relevancy for blood banking into the 21st century. Longer RBC shelf life provides advantages to the military and remote hospital locations, but has less significance in other venues. Recent reports cast doubt about the validity of higher morbidity and mortality associated with longer-stored RBCs in selected patient subsets.10, 11 However subtle differences, such as the report of lower mortality rates observed after implementation of buffy coat PLTs with ONH compared to the prior period with PLT separation from whole blood within 8 hours of collection raises questions about the effects of ONH, WBC content, and other variables on patient outcomes. Considering these factors, lengthening the storage interval is less important than achieving better quality of stored RBCs. Lengthening the hold period between collection and manufacturing provides significant logistic and potential quality advantages. Going forward, Cancelas' and Dumont's observations provide encouragement for further research, guidelines or regulations, and business development in achieving ONH implementation in the United States. Revised FDA regulations would enable buffy coat PLT preparation, deemed by some as an improved product compared to PLT-rich plasma–prepared PLTs and would facilitate pathogen reduction treatment of whole blood. ONH should improve logistic considerations related to component manufacturing and generate meaningful data about associated costs and potential savings. Most importantly, the interactive effect of subtle differences in filters, container plastics and plasticizers, anticoagulant-preservative solutions, centrifugation and elutriation processes, and environmental transport and storage conditions on RBC and component effectiveness requires clinical outcome data.10 Presumably, the AS-7 approval represents the beginning of further improvements in anticoagulant-preservative systems for RBCs, PLTs, and plasma especially as new information accumulates from ongoing storage lesion–related research. The author has disclosed no conflicts of interest.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.