Facilitating blood component preparation: the impact of overnight room temperature storage

The Canadian Blood Services recently changed its method of processing whole blood into its components from the platelet-rich plasma (PRP) method to the buffy coat (BC) preparation method,1 to facilitate the logistics of blood processing and to increase the production of whole blood–derived platelet concentrates (WB PCs). In the BC method, whole blood units are stored at room temperature (RT; 20-24°C) overnight before centrifugation into their component parts. In this issue of TRANSFUSION, Serrano and colleagues1 provide research and validation data on the quality of plasma and cryoprecipitate components manufactured using the BC method and demonstrate that they meet Canadian quality control standards. Comparison data are also provided for BC plasma, PRP plasma, and plasma products produced utilizing a whole blood leukoreduction method. The three arms of the study varied in a number of factors, including duration and temperature of storage, the methods of cooling (passive or active, using RT cooling plates, packaging on ice, or placement in a refrigerator), methods of separation (BC or PRP method), and timing of leukofiltration. Plasma generated under these conditions all met the minimum Canadian standards for product quality, including volume, sterility, and Factor (F)VIII levels, although differences were noted. A formal comparison of coagulation factor activity in BC versus PRP plasma frozen within 8 hours demonstrated that BC plasma was significantly lower in FII, FVII, FVIII (72%), F IX, FX, FXI, and von Willebrand factor and higher in levels of fibrinogen and antithrombin III. These changes are viewed as clinically acceptable, although there is a paucity of clinical studies addressing the issue. Stanworth and coworkers2 have noted in a systematic review of the literature that there were few adequately powered, randomized clinical trials supporting the indications for any plasma product, suggesting that it is premature to hold changes in the production methods of plasma to the higher standards of evidence-based medicine. Indeed, other than somewhat arbitrary regulatory standards, we are left to rely on the lowest level (laboratory studies) of evidence and few clinical criteria with which to judge the acceptability of these changes. In the United States, two types of plasma for transfusion are utilized. One type is prepared and placed in the freezer within 8 hours of phlebotomy, referred to as fresh-frozen plasma (FFP). If WB PCs are to be manufactured, the blood is cooled toward RT before separation. If WB PC manufacture is not planned, units are cooled toward 1 to 6°C. The other type of plasma is made from whole blood cooled toward 1 to 6°C and prepared and frozen within 24 hours of phlebotomy (PF24). PCs may not be manufactured from these units, because cooling at the lower temperature is known to cause platelets (PLTs) to have markedly reduced in vivo viability. It is well documented that PF24 has 16% to 33% lower levels of FVIII than FFP,3-8 while most other factors are conserved. Indeed, the 2009 Circular of Information recognizes that FFP and PF24 are indicated for the same clinical conditions, implying that they are interchangeable in practice. The manufacture of FFP and WB PCs poses a number of logistical problems for blood centers: 1) collection drives must be staffed to pack units of WB for pick-up and delivery to the blood center while simultaneously collecting additional units, 2) increased transport vehicles and drivers are necessary so that multiple delivery runs can be made during collection hours, and 3) the manufacturing site must be staffed to process small batches of units within 8 hours on both evening and day shifts. Even when production of both FFP and WB PCs is the goal, if the production schedule is not met due to logistical challenges, the center is faced with conversion of the plasma to PF24 and the loss of the WB PC product. These issues are one reason why the United States has moved away from the production of WB PCs and increasingly relies on more expensive apheresis PLTs, while discarding millions of potential units of WB PCs on an annual basis. This wastage is particularly egregious, given that all recruitment and collection costs have already been expended and hospitals are often faced with apheresis PLT shortages. A second development has been the recent shift to the use of PF24 rather than FFP with the introduction of AABB recommendations9 to mitigate the risk of transfusion-related acute lung injury by minimizing patient exposure to plasma from donors that may have been alloimmunized. In effect, most US blood centers now distribute plasma prepared predominantly from male donors while submitting that from female donors for fractionation and further manufacture. Rather than invest in increased production of male FFP, centers draw on the more readily available supplies of male PF24 that previously may have been submitted for fractionation, so that most hospitals now use PF24 for transfusion. Upon thawing, both FFP and PF24 may be converted to “thawed plasma” and held at 1 to 6°C for up to 5 days on the shelves in blood banks, a practice that creates a pool of rapidly available plasma for use in urgent or emergent situations. For US blood centers, the question now arises whether the data are sufficient to allow WB to be stored overnight at RT rather than 1 to 6°C before separation, allowing the simultaneous manufacture of WB PCs, red blood cells (RBCs), and PF24. There are a number of reasons to make this change. Besides dispensing with the logistical inefficiencies tied to maintaining and monitoring the cooling of WB toward 1 to 6°C with the current practice, blood centers would have immediate access to a vast pool of WB PCs. Furthermore, the recent US Food and Drug Administration approval of a prestorage method to pool WB PCs with bacterial culture testing provides a means by which centers could process and supply pooled PLTs to hospitals that are practically indistinguishable from apheresis PLTs. Evidence also suggests that overnight RT storage may increase the efficiency of separation of PC from WB rendering higher yields.10 Finally, leukoreduction after overnight RT storage may be an effective means to reduce bacterial sepsis, presumably by allowing the phagocytosis of bacteria in the WB product followed by removal through leukoreduction.11,12 Of note, preliminary data suggest that attention must be paid to the timing and nature of the filtration process, because standard filters validated for use after overnight 1 to 6°C storage may not be equally as effective after RT storage.13 The data from Serrano and colleagues and a number of other studies13,14 suggest that PF24 manufactured after overnight (24 hr) storage at RT would meet the current standards for plasma in the United States and Canada. A study presented at the 2009 AABB meeting showed that, with a few exceptions, the measured levels of a series of coagulation factors and coagulation activation markers were comparable between units prepared after 8 or 24 hours of storage at RT. The essential differences were a further loss of FVIII and a longer activated partial thromboplastin time in the units held for 24 hours.15 Decades of experience in Europe with the BC method that includes RT overnight storage suggests that the concomitantly manufactured PCs and RBCs are safe and efficacious, although RBCs held at RT or 1 to 6°C do show biochemical differences, including decreased levels of 2,3-diphosphoglycerate during storage.13 As a result, the FDA has noted that all three components, PF24, WB PCs, and RBCs, would be considered novel products and require licensure by each WB bag manufacturer. Licensure is an expensive endeavor especially if extensive in vitro analysis and in vivo RBC and PC recovery and survival studies are required. That expense is ultimately passed on to the hospital customers. These costs and efforts are considerable obstacles to future progress in the United States. Given the vast European clinical experience in the use of RBCs, PCs, and plasma manufactured using the BC method with overnight RT storage, and the absence of a documented correlation between laboratory indices and clinical outcome, it is hoped that the industry and the FDA can reach an accommodation that will expedite the licensure of components manufactured from WB after RT overnight storage and open the flood gates for WB PCs. May these components, currently headed for the sewer, flood the field of transfusion medicine and dispel the sporadic PLT droughts that have pervaded hospitals and threatened our patients. The authors claim no conflict of interest.

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