Eliminating leukocyte reduction for whole blood: Is it premature to consider this paradigm‐changing practice?

We read with interest the recent commentary in which Yazer et al. suggested that leukocyte reduction (LR) of low titer type O whole blood (LTOWB) should be reconsidered as routine practice.1 The authors' premise is that LR is a supererogatory obstacle to timely administration of a potentially life-saving therapy that adds unnecessary inventory pressures and logistical challenges. We applaud the authors for a creative and thought-provoking evaluation of the benefits of removing LR to provide timely hemodynamic and coagulation support in massively hemorrhaging patients. While an intriguing hypothesis, we contend that a paradigm shift away from the standard-of-care in transfusion resuscitation warrants stronger evidence and deeper consideration to avoid inadvertent harm to patients. This discussion must focus on both the reasons for discontinuing LR as well as the disadvantages that removing this procedure could elicit. In the current context, the most important fact to consider in any discussion of LTOWB is, as the authors astutely highlight, that the use of LTOWB is not based on randomized controlled trial data. While indeed biologically plausible that LTOWB transfusion to replace whole blood losses could be superior to component therapy for certain populations, this claim awaits unbiased evidence from rigorously designed clinical trials. As such, it is premature to consider removing an evidence-based step in blood processing to potentially increase the supply of a product that has not unequivocally demonstrated superiority over current practice. Moreover, while there are multiple trials investigating the question of the efficacy and safety of LTOWB in both adults (NCT04684719, NCT05638581) and children (NCT06070350) with trauma-related hemorrhage, the primary endpoint of these studies is not to assess LR. When trial data become available, subgroup analysis should be performed to evaluate the impact of LR versus non-LR in these groups. We note that a number of authors of this manuscript are participating in these trials to support this important research. A key argument from the authors rests on the potential clinical benefits of non-LR over LR LTOWB. This is particularly crucial in trauma patients, who are a vulnerable population that often present in extremis, and thus unable to consent to therapy. Trauma patients typically receive care under emergency waivers for consent, which presume medical benefit and alignment with accepted standards of medical practice. Available trial evidence, notably a secondary analysis of a randomized controlled trial evaluating LR and non-LR RBC from the early 2000s, does not show a difference in clinical benefit with either LR or non-LR RBC in trauma patients.2 Further, a large prospective, observational study showed no difference in 24-h survival when comparing LR versus non-LR LTOWB.3 At the turn of the century, it was unclear whether LR blood would find universal implementation, but the evidence available suggests that it has become an almost universal practice in high-resource settings. Despite this, the 2012 United States Food & Drug Administration (FDA) guidance on LR still only lists it as a recommendation in the United States as opposed to a requirement, speaking to the controversy of LR requirements for all patients.4 The authors invoke logistical challenges, including the supply chain and financial costs, as reasons for removing LR of LTWOB units. The authors note that while there are multiple benefits to LR, the additional steps required to manufacture LR LTOWB units limit its availability and exclude patients from purported survival benefits. However, an alternative to simply removing LR (and its potential benefits) entirely might be to pursue research into how the LR process could be improved to support emergency transfusion. This may include validating platelet-sparing filters beyond the current 8-h window following collection, which has been shown to be feasible.5, 6 The authors assert, despite evidence for lack of clinical benefit, that absolute platelet counts are important and a surrogate for hemostasis, thereby arguing against extended LR and storage time. However, this may be a stretch for 3-plus week-old platelets, and there may be issues related to the RBC storage lesion in a 35-day old unit. Investigations should further characterize outcomes when using older versus fresher units in LTOWB. Ultimately, concerns about shelf life and inventory may lose relevance if LTOWB proves inferior to component therapy in ongoing trials, which still offer the best shelf life. Similarly, the authors highlight the serious issue of the delicate supply chain and reliance on sole suppliers of transfusion equipment such as LR filters—a vulnerability that has come under intense scrutiny due to the biological (e.g., COVID-19), environmental (e.g., natural disasters), and logistical disruptions (e.g., cyberattacks) to the blood supply.7, 8 Rather than workarounds, a more prudent means to address supply chain bottlenecks might be to diversify suppliers to create a more reliable and robust blood supply. Further, Yazer and colleagues cite financial resources as a barrier to LR; however, we believe that eliminating an evidence-based safety step in blood processing simply to ensure the profitability of blood collection centers ignores known financial costs of transfusion reactions and adverse events that may be prevented with LR, and directly conflicts with the tenets of ethical medical practice.9 Cost–benefit trade-offs have long been debated for the implementation of LR; yet, while acknowledging the challenges that may particularly impact smaller organizations, it is incumbent upon blood collectors to optimize processing and overcome challenges to provide safe blood products to patients independent of medical condition or logistical convenience.10 In addition to these points, we believe that there may be additional benefits inherit to the biology of LR that were omitted or understated in the authors' review. Although the authors do discuss the reduction of febrile nonhemolytic transfusion reactions, transfusion-transmitted leukotropic pathogens, and human leukocyte antigen (HLA) alloimmunization, the immunomodulatory effects of LR should be considered.11-15 Leukoreduction reduces the infusion of allogeneic white blood cells, extracellular DNA, neutrophil extracellular traps, and histones, which have been associated with organ injury and mortality in animal models.16 A recent cohort analysis of the America College of Surgeons Trauma Quality Improvement database found that the use of whole blood was associated with an increase in acute lung injury.17 If a true causal association is present in this observational study, plausible mechanisms include the use of non-LR whole blood and/or the presence of platelets in LR whole blood. Platelet-derived sCD40L has been associated with acute lung injury after transfusion. Platelets that do not provide life-saving hemostasis could contribute to pulmonary injury, up to and including mortality.18 Many patients with severe hemorrhage do not require the platelet content of unfiltered or platelet-sparing filtering of whole blood, and thus represent the likelihood of harm with no potential benefit. This possibility provides an additional rationale for transfusing LR LTOWB rather than non-LR. A number of studies have demonstrated the benefit of LR in various patient cohorts, suggesting that it may be associated with reduced infections, cardiopulmonary complications, hospital length of stay, and mortality.11-14, 19-25 However, the benefit of LR remains controversial given that some studies have demonstrated no benefit.26 Despite this, multiple authors have shown that these negative studies were suboptimally designed, and included patients who did not undergo transfusion, thereby “diluting the observed clinical benefit of leukoreduction.”19, 27 However, we acknowledge that the most definitive data for benefit are not in the trauma or massively-hemorrhaging population. Trial data are needed to address the use of universal LR of LTOWB in this setting. Ultimately, some sites, in an effort to operationalize LTOWB inventories by blood suppliers or hospital blood banks, are already transfusing non-LR LTOWB in the United States. It is essential that these sites disseminate their experiences and knowledge acquired from this practice. Similarly, LR is the exception in many low-resource regions where whole blood is the most frequently available product28; leveraging these experiences, expertise, and data could impart meaningful insight into this ongoing debate. The reality of trauma resuscitation in the modern era, including in the civilian population, is that the adequacy of the blood supply, and the timeliness of blood availability, will always be questioned. Thus, the argument for streamlining release of LTOWB by any means necessary is warranted.29-32 However, as advances in trauma resuscitation continue to improve survival, addressing the long-term effects of transfusion, including HLA-sensitization and infection with emerging leukotropic pathogens, increases in importance. For trauma patients who ultimately receive only a small number of transfusions, this is especially meaningful. The article by Yazer et al. forwards an intriguing hypothesis, but frames it, to some extent, as a recommendation. Overall, obviating LR has some applications such as in scenarios (e.g., battlefield, extreme remoteness, severe acute blood shortages) where disregarding LR might be an acceptable option (at present), and this type of creative, flexible thinking is quite valuable for the transfusion medicine and trauma resuscitation fields. For care at most centers in high-resource settings, under near-ideal scenarios, we believe that the onus should be on improving logistics rather than lowering our standards. The commentary from Yazer and colleagues conflicts with contemporary hemovigilance and blood safety standards to accommodate a sense of urgency around the implementation of LTOWB in routine civilian settings. In the absence of unequivocal evidence, just as there is biological rationale—but not RCT data—for the superiority of LTOWB compared with component therapy, the same currently exists for the use of LR in trauma resuscitation. Indeed, most evidence to date regarding LR in a wide variety of clinical settings supports the hypothesis that LR in LTOWB, with either a platelet sparing or nonplatelet sparing filter, reduces harm in many trauma patients with serious hemorrhage. The authors have disclosed no conflicts of interest.