Effects of pathogen reduction systems on platelet microRNAs, mRNAs, activation, and function.

Pathogen reduction (PR) systems for platelets, based on chemically induced cross-linking and inactivation of nucleic acids, potentially prevent transfusion transmission of infectious agents, but can increase clinically significant bleeding in some clinical studies. Here, we documented the effects of PR systems on microRNA and mRNA levels of platelets stored in the blood bank, and assessed their impact on platelet activation and function. Unlike platelets subjected to gamma irradiation or stored in additive solution, platelets treated with Intercept (amotosalen+ ultraviolet-A [UVA] light) exhibited significantly reduced levels of 6 of the 11 microRNAs, and 2 of the 3 anti-apoptotic mRNAs (Bcl-xl and Clusterin) that we monitored, compared with platelets stored in plasma. Mirasol (riboflavin+ UVB light) treatment of platelets did not produce these effects. PR neither affected platelet microRNA synthesis or function nor induced cross-linking of microRNA-sized endogenous platelet RNA species. However, the reduction in the platelet microRNA levels induced by Intercept correlated with the platelet activation (p < 0.05) and an impaired platelet aggregation response to ADP (p < 0.05). These results suggest that Intercept treatment may induce platelet activation, resulting in the release of microRNAs and mRNAs from platelets. The clinical implications of this reduction in platelet nucleic acids secondary to Intercept remain to be established.

Reasons for moving toward a patient-centric paradigm of clinical transfusion medicine practice.

The combination of patient blood management (PBM) modalities and multicomponent apheresis permits us to administer even safer transfusions than those using the "safer-than-ever" blood components distributed in the beginning of the 21st century. PBM identifies a patient at risk of transfusion and formulates a multidisciplinary and multimodal-yet individualized-plan for reducing the need for allogeneic transfusion. Multicomponent apheresis can collect any combination of red blood cells, platelets, and plasma from the same donor during the same donation, and it should eventually reserve all components harvested from the same donation for transfusion to the same recipient. Together, PBM and multicomponent apheresis represent a new paradigm-the patient-centric paradigm-of transfusion medicine whose purpose is to reduce the transfusion risk for each individual patient to the level of the ALARA (as-low-as-reasonably-achievable) risk. PBM and multicomponent apheresis can meet a patient's transfusion needs with at least twofold fewer allogeneic donor exposures, thereby reducing the risk of infectious and immunologic complications of transfusion by at least twofold. The reduction in risk includes the leading cause of transfusion-related mortality (transfusion-related acute lung injury) and the cardinal threat to transfusion safety (the next "HIV-like" pathogen to emerge in the future). Once it is determined that PBM and multicomponent apheresis can replace the current blood-procurement system at a "reasonable" cost and without jeopardizing the supply of blood and components, the patient-centric paradigm should replace the current, component-centric paradigm of transfusion medicine to reduce the transfusion risk to the level of the ALARA risk.

Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention.

As the risks of allogeneic blood transfusion (ABT)-transmitted viruses were reduced to exceedingly low levels in the US, transfusion-related acute lung injury (TRALI), hemolytic transfusion reactions (HTRs), and transfusion-associated sepsis (TAS) emerged as the leading causes of ABT-related deaths. Since 2004, preventive measures for TRALI and TAS have been implemented, but their implementation remains incomplete. Infectious causes of ABT-related deaths currently account for less than 15% of all transfusion-related mortality, but the possibility remains that a new transfusion-transmitted agent causing a fatal infectious disease may emerge in the future. Aside from these established complications of ABT, randomized controlled trials comparing recipients of non-white blood cell (WBC)-reduced versus WBC-reduced blood components in cardiac surgery have documented increased mortality in association with the use of non-WBC-reduced ABT. ABT-related mortality can thus be further reduced by universally applying the policies of avoiding prospective donors alloimmunized to WBC antigens from donating plasma products, adopting strategies to prevent HTRs, WBC-reducing components transfused to patients undergoing cardiac surgery, reducing exposure to allogeneic donors through conservative transfusion guidelines and avoidance of product pooling, and implementing pathogen-reduction technologies to address the residual risk of TAS as well as the potential risk of the next transfusion-transmitted agent to emerge in the foreseeable future.

Meta-analysis of the randomized controlled trials of the hemostatic efficacy and capacity of pathogen-reduced platelets.

BACKGROUND: A recent independently funded randomized controlled trial (RCT; Br J Haematol 2010;150:209-17) questioned prevailing opinion concerning the hemostatic capacity of pathogen-reduced platelets (PLTs). Meta-analysis was used to calculate the effect of pathogen reduction (PR) of PLTs on hemostatic efficacy and capacity based on all available data and to investigate possible reasons for the variation in reported findings. STUDY DESIGN AND METHODS: RCTs allocating patients to receive routine PLT transfusions with pathogen-reduced or untreated PLTs and reporting on at least one of six hemostasis endpoints were eligible for analysis. Five RCTs of hemato-oncology patients met eligibility criteria. Endpoints determined by similar criteria in all RCTs were integrated by fixed-effects methods. Endpoints determined by different criteria were integrated by random-effects methods. RESULTS: Studies were statistically homogeneous in all analyses. Pathogen-reduced PLTs were associated with a significant (p < 0.05) reduction in 1- and 24-hour posttransfusion corrected count increments (summary mean difference, 3260; 95% confidence interval [CI], 2450-4791; and summary mean difference, 3315; 95% CI, 2027-4603) as well as a significant increase in all and in clinically significant bleeding complications (summary odds ratio [OR], 1.58; 95% CI, 1.11-2.26; and summary OR, 1.54; 95% CI, 1.11-2.13). The frequency of severe bleeding complications did not differ. CONCLUSION: The results of the recent RCT are not inconsistent with those of the earlier studies. Introduction of PR technologies in their current stage of development would result in an increase in mild and moderate (albeit not severe) bleeding complications, which the transfusion-medicine community must explicitly tolerate to reap the benefits from PR.

Postoperative complications associated with transfusion of platelets and plasma in cardiac surgery.

BACKGROUND: Studies in cardiac surgery have reported increased postoperative morbidity and mortality after allogeneic red blood cell (RBC) transfusions. Whether platelet (PLT) and/or plasma transfusions are a marker for more concomitant RBC transfusions or are independently associated with complications after cardiac surgery is unknown. STUDY DESIGN AND METHODS: Data from two randomized controlled studies were combined to analyze the effects of PLT and/or plasma transfusions on postoperative infections, length of stay in the intensive care unit (ICU), all-cause mortality, and mortality in the presence or absence of infections in the postoperative period. RESULTS: After adjusting for confounding factors, plasma units and not RBC transfusions were associated with all-cause mortality. White blood cell (WBC)-containing RBC transfusions and PLT transfusions were associated with mortality occurring in the presence of or after infections. The number of (WBC-containing) RBC transfusions was also significantly associated with postoperative infections and with ICU stay for 4 or more days. CONCLUSION: Although it is difficult to separate the effects of blood components, we found that in cardiac surgery, perioperative plasma transfusions are independently associated with all-cause mortality. WBC-containing RBC transfusions and PLT transfusions are independently associated with mortality in the presence of infections in the postoperative period. Future transfusion studies in cardiac surgery should concomitantly consider the possible adverse effects of all the various transfused blood components.

Risk-reduction strategies for platelet transfusion in the United States.

Despite bacterial culture of platelets, transfusion-associated bacteremia/sepsis (TABS) may occur with a frequency of approximately 1/60,000 platelet transfusions, while an emerging transfusion-transmitted infection (TTI) could reproduce the epidemic of transfusion-transmitted human immunodeficiency virus (HIV) in the future. As platelet pathogen-reduction (PR) systems licensed in Europe may eventually become licensed in the U.S., three alternative strategies for reducing the residual risks of TTIs and TABS may become available in the U.S. in the future: (1) transfusion of (already-available) non-pathogen-reduced single-donor (as opposed to pooled whole-blood-derived [PWBD]) platelets, (2) transfusion of pathogen-reduced single-donor platelets, or (3) transfusion of pathogen-reduced PWBD platelets (if trials of this component are conducted in the U.S. in the future). PR of platelets will increase the risk of mild and moderate (albeit perhaps not severe) bleeding complications and it cannot protect from all pathogens. Compared to PWBD platelets, single-donor platelets can reduce, by at least twofold, the risk of all known and emerging TTIs, as well as the risk of TABS, without incurring any risk. The fewer donor exposures secured by the use of single-donor platelets - especially if combined with collection of red blood cells and/or plasma from the same donation for transfusion to the same recipient through the use of multicomponent apheresis - may also reduce the risk of transfusion-related acute lung injury. To choose between pathogen-reduced and non-pathogen-reduced single-donor platelets, the increased risks of bleeding complications as well as other possible adverse events secondary to PR need to be quantified precisely and weighed against the competing risks of TABS and emerging TTIs.

Meta-analysis of clinical studies of the purported deleterious effects of "old" (versus "fresh") red blood cells: are we at equipoise?

BACKGROUND: A meta-analysis examined whether the available data support an adequate suspicion that transfusion of old red blood cells (RBCs) is associated with increased mortality, organ failure, infection, prolonged mechanical ventilation, and prolonged stay in the hospital or the intensive care unit. Such suspicion is required for intentionally exposing patients enrolled in randomized controlled trials (RCTs) to the known or probable--but rare--risks of old RBCs, to document (and prevent) purported common adverse effects of old RBCs. STUDY DESIGN AND METHODS: Observational studies presenting adjusted results were eligible for analysis if the adequacy of the adjustment for confounding factors could be assessed. Three RCTs and 24 observational studies were retrieved. Medically and statistically homogeneous studies were integrated by fixed-effects methods. Otherwise homogeneous studies conducted in different clinical settings were integrated by random-effects methods. RESULTS: Based on "as-treated" analysis, transfusion of old RBCs was associated with a significant reduction in mortality (summary odds ratio, 0.38; 95% confidence interval, 0.14-0.99; p < 0.05) across two small RCTs. Integration of adjusted findings on the same outcome, from observational studies conducted in the same setting, produced summary results that were either negative (in six analyses) or impossible to evaluate owing to uncontrolled confounding by the number of transfused RBCs (in two analyses). CONCLUSION: The available data do not support an adequate suspicion that old RBCs may be associated with common adverse morbidity and/or mortality outcomes, so as to justify exposing experimental subjects to the other known or probable--but rare--risks of old RBCs.

The relative safety of pooled whole-blood-derived platelets prepared by the buffy-coat method versus single-donor (apheresis) platelets.

Conversion to a single-donor (apheresis) platelet inventory in Western Europe and other countries that provide similar health care to the US but rely on buffy-coat pooled whole-blood-derived platelets will confer the benefit of a > or = 2-fold reduction in the risk of all emerging transfusion-transmitted infections (TTIs). In Europe, this benefit will include a > or = 2-fold reduction in the risk of acquiring variant Creutzfeldt-Jakob disease (vCJD) from platelet transfusion. In countries that use buffy coats from first-time donors to produce platelet pools, there will also be a > or = 2-fold reduction in the risk of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infections. Conversion to a single-donor inventory collected from male donors (or female donors without a history of pregnancy or shown not to have white-blood-cell antibodies) should also reduce the risk of transfusion-related acute lung injury, although this prediction is based on theory and may not materialize or prove hard to document. Because conversion to a single-donor inventory can effect a > or = 2-fold reduction in the risk of all TTIs without incurring any risk, it is a more advantageous risk-reduction strategy for emerging TTIs compared with the introduction of pathogen-reduction systems for platelets. The latter cannot protect from vCJD and potentially also from some other emerging TTIs; moreover, they have recently been associated with an increased risk of bleeding.

Relative safety of pooled whole blood-derived versus single-donor (apheresis) platelets in the United States: a systematic review of disparate risks.

BACKGROUND: Risks of transfusion-transmitted infections (TTIs), transfusion-associated sepsis (TAS), and transfusion-related acute lung injury (TRALI) were compared between pooled whole blood-derived (PWBD) and single-donor platelets (PLTs) transfused in the United States. STUDY DESIGN AND METHODS: The literature was searched for estimates of the risk of TTIs and TAS and of the effect on bacterial contamination of PLTs of process improvements, bacterial culture, and surrogate methods to detect bacteria. Seven studies published between January 2005 and December 2008 and comparing bacterial contamination frequency between PWBD and single-donor PLTs after implementing bacterial culture testing of both components were subjected to meta-analysis. The three retrieved studies diagnosing TRALI based on the 2004 consensus definition in settings transfusing both PWBD and single-donor PLTs were not amenable to meta-analysis and were assessed qualitatively. RESULTS: Under a best-case scenario, if 100% (from the current 12.5%) of PLT doses were provided as PWBD PLTs, the number of additional transmissions of human immunodeficiency virus, hepatitis C virus, hepatitis B virus, bacteria, or a novel pathogen annually could be 1.2, 1.3, 9.0, 105.3, or 69.2 to 252.6, respectively. Compared with single-donor PLTs, US PLT pools of five concentrates have a 5.6-fold higher risk of bacterial contamination (summary odds ratio, 5.58; 95% confidence interval, 2.60-11.98; p < 0.05). The three studies that diagnosed TRALI based on the consensus definition did not demonstrate a difference in risk between PWBD and single-donor PLTs. CONCLUSIONS: TTIs and TAS determine the relative safety of PWBD versus single-donor PLTs. The available limited data do not support a higher risk of TRALI from single-donor (compared with PWBD) PLTs.

Transfusion-related immunomodulation (TRIM): an update.

Allogeneic blood transfusion (ABT)-related immunomodulation (TRIM) encompasses the laboratory immune aberrations that occur after ABT and their established or purported clinical effects. TRIM is a real biologic phenomenon resulting in at least one established beneficial clinical effect in humans, but the existence of deleterious clinical TRIM effects has not yet been confirmed. Initially, TRIM encompassed effects attributable to ABT by immunomodulatory mechanisms (e.g., cancer recurrence, postoperative infection, or virus activation). More recently, TRIM has also included effects attributable to ABT by pro-inflammatory mechanisms (e.g., multiple-organ failure or mortality). TRIM effects may be mediated by: (1) allogeneic mononuclear cells; (2) white-blood-cell (WBC)-derived soluble mediators; and/or (3) soluble HLA peptides circulating in allogeneic plasma. This review categorizes the available randomized controlled trials based on the inference(s) that they permit about possible mediator(s) of TRIM, and examines the strength of the evidence available for relying on WBC reduction or autologous transfusion to prevent TRIM effects.

The Canadian blood donor health assessment questionnaire: lessons from history, application of cognitive science principles, and recommendations for change.

Over the last 20 years, the Canadian Blood Services' (CBS) Donor Health Assessment Questionnaire (DHAQ), used to screen prospective blood donors to determine their eligibility, has grown in complexity and length. Its growth is inextricably linked to the evolution of the environment within which CBS operates from unregulated collection and distribution of labile blood products to a fully regulated environment and to the need to satisfy both Health Canada and US Food and Drug Administration (FDA) requirements. Within this context, the development of the CBS DHAQ has been characterized by addition of questions and items without any periodic reevaluation of the need for retaining existing questions and/or items. In this review, we apply principles from cognitive science relating to how people think when answering questionnaires to the situation of blood donors completing the DHAQ. We show that some items that were added at different times in separate questions, for reasons that were historically relevant, could be now asked more simply with a single question. The historical development of the DHAQ, resulting in the condensing of many items into lists, the use of complex wording, and the sheer number of items included in the questionnaire make accurate retrieval of information from the donor's memory difficult. Thus, we believe that redesigning the DHAQ will improve the quality and accuracy of the donors' answers to screening questions.

The development of West Nile virus safety policies by Canadian blood services: guiding principles and a comparison between Canada and the United States.

To address the emerging threat of West Nile virus (WNV) to the blood supply, Canadian Blood Services (CBS) made a series of policy decisions that were either similar to those adopted in the United States or more stringent than policies formulated in the United States at the same time. More stringent Canadian policies included the development of an in-house WNV RNA assay, the stockpiling of frozen plasma components in the winter for transfusion in WNV-affected areas in the summer, a special recruitment campaign for red blood cell collections before the start of the 2003 WNV season, and an inventory exchange (ie, WNV-tested for untested red blood cells) initiated 2 weeks after the onset of WNV screening, as well as the implementation of targeted individual-donation WNV testing on August 2, 2004, in the absence of any positive donors or clinical cases of WNV infection in Canada. The general principles that guided CBS decision making with regard to WNV safety included application of the precautionary principle, harmonization with policies in the United States, a consideration of logistic issues, compliance with Health Canada requests, responsiveness to public expectations about transfusion safety, and transparency in decision making with timely communication to stakeholders. Before implementing WNV blood safety policies, CBS assessed their impact on blood availability. When policies were implemented, data were obtained quickly to ensure that the prior impact assessments were accurate. This review discusses the guiding principles affecting CBS policy development and compares CBS WNV safety policies to policies adopted in the United States.

Is white blood cell reduction equivalent to antibody screening in preventing transmission of cytomegalovirus by transfusion? A review of the literature and meta-analysis.

The question whether the use of cytomegalovirus (CMV)-seronegative versus white blood cell (WBC)-reduced blood components is equally efficacious in preventing transfusion-acquired CMV infection remains unresolved. A total of 829 recipients of CMV-seronegative components were followed in 11 studies, and a total of 878 recipients of WBC-reduced components were followed in 12 studies. Twelve (1.45%) of 829 recipients of CMV-seronegative components and 24 (2.73%) of 878 recipients of WBC-reduced components developed CMV infection in these studies. Among bone marrow transplant (BMT) recipients, the risk of CMV infection was, respectively, 1.63% (11/674) and 3.01% (21/697). Four of 7 controlled studies of CMV-seronegative components and 1 of 3 controlled studies of WBC-reduced components indicated benefit from these special components compared with CMV-unscreened/non-WBC-reduced components. One of 3 controlled studies indicated benefit from CMV-seronegative components, as compared with WBC-reduced components. Across a subset of studies whose results were integrated in a meta-analysis, CMV-seronegative or WBC-reduced components were virtually equivalent to each other when they were compared with CMV-unscreened/non-WBC-reduced components. CMV-seronegative components were associated with a 93.1% reduction in the risk of CMV infection; WBC-reduced components were associated with a 92.3% reduction in risk (summary odds ratio [OR] = 0.069; 95% confidence interval [CI], 0.037-0.128; P < .05; and summary OR = 0.077; 95% CI, 0.031-0.190; P < .05, respectively). However, across 3 studies that compared CMV-seronegative and WBC-reduced components to each other, CMV-seronegative components were associated with a 58% reduction in risk (summary OR = 0.42; 95% CI, 0.22-0.79; P < .05). Thus, a meta-analysis of the available controlled studies indicates that CMV-seronegative blood components are more efficacious than WBC-reduced blood components in preventing transfusion-acquired CMV infection.

Evidence-based practice of transfusion medicine: is it possible and what do the words mean?

Evidence-based medicine (EBM) optimizes clinical decision making by dictating that clinical decisions be based on the best available research evidence and by integrating best research evidence with clinical expertise and patient values. Several rankings of the strength of the evidence generated from different types of clinical research designs have been presented, and, in addressing a particular problem, clinicians can base their decision making on the types of clinical reports that have been published, along with an assessment of the strengths and weaknesses of each study. At a policy level, the concept of EBM would dictate that policy decisions also be made based on the best available research evidence. In transfusion medicine, however, decisions are based on a broader range of inputs, and the criteria for evaluating the efficacy and/or cost-effectiveness of proposed interventions differ from those used in other areas. Reasons why policy decisions are often based on considerations other than the best research evidence include public expectations about transfusion safety and proposals for applying the precautionary principle to transfusion medicine. Using the debate over the appropriateness of introducing universal white-cell reduction as an example, this review describes 2 perspectives for assessing evidence and/or making clinical or policy decisions: the evidence-based approach and the precautionary-principle approach; and also considers whether decisions in transfusion medicine can be truly evidence based.

Uses and sources of data on long-term survival after blood transfusion.

Several public policy decisions in transfusion medicine require information on the long-term (> or =10-year) survival of transfused patients. This information is needed (1) to estimate the number of surviving transfusion recipients who have contracted a particular infection through transfusion, (2) to assess the cost-effectiveness of measures introduced to further improve the safety of the allogeneic blood supply, (3) to estimate the total anticipated number of transfusion-transmitted cases of disease when a novel transfusion-transmitted infection with a long incubation period emerges, and (4) determine the scope of any proposed lookback investigation in terms of the length of time that should be covered retrospectively by the lookback effort. Although the probabilities of survival of Olmsted County, MN, residents transfused in 1981 were often used previously when input data on long-term posttransfusion survival were needed in the United States, these data most likely do not reflect the survival of patients transfused in the 1990s. Recent data from Sweden, Northern England, and New York City suggest that the short-term (up to 5 years posttransfusion) probabilities of survival reported from Olmsted County may have to be reduced by up to 20% before they can be used for making public policy decisions in the future, and that probabilities of survival of 66%, 60%, and 47%, respectively, at 1, 2, and 5 years posttransfusion may reflect the life expectancy of subjects transfused in the 1990s. No empirical data on the 10-year probability of survival of such patients are currently available from population-based studies, but some data suggest that the 10-year survival of an unselected population transfused in 1988 to 1990 may be 40%. A population-based study that includes several US counties has to be undertaken to generate the information needed for public policy decisions in the future.

Meta-analysis of randomized controlled trials investigating the risk of postoperative infection in association with white blood cell-containing allogeneic blood transfusion: the effects of the type of transfused red blood cell product and surgical setting.

Previous meta-analyses of the randomized controlled trials (RCTs) investigating the association of perioperative allogeneic blood transfusion (ABT) with postoperative bacterial infection included studies transfusing either autologous or white blood cell (WBC)-reduced allogeneic red blood cells (RBCs) or whole blood to the control arm, and they were unable to investigate the type of RBC product administered as an explanation for the disagreements among the studies. The availability of additional RCTs has permitted investigation of this hypothesis in a meta-analysis restricted to RCTs transfusing WBC-reduced allogeneic RBCs or whole blood to the control arm. In this analysis, across 5 RCTs comparing recipients of non-WBC-reduced versus WBC-reduced allogeneic RBCs, there was no difference (P > .25) in the risk of postoperative infection between recipients of buffy-coat-reduced versus WBC-reduced allogeneic RBCs filtered before storage (summary odds ratio [OR] = 1.19; 95% confidence interval [CI], 0.87-1.63). In contrast, across 3 RCTs, there was an increased (P < .05) risk of postoperative infection in recipients of non-buffy-coat-reduced allogeneic RBCs, or whole blood, as compared with recipients of WBC-reduced allogeneic RBCs, or whole blood, filtered before or after storage (summary OR = 1.77; 95% CI, 1.02-3.09). Moreover, across 3 RCTs that enrolled patients undergoing open-heart surgery, there was an increased (P < .05) risk of postoperative infection in recipients of buffy-coat-reduced (compared with WBC-reduced) allogeneic RBCs (summary OR = 1.39; 95% CI, 1.08-1.80), but the findings of 5 RCTs that enrolled patients having abdominal surgery could not be combined because of extreme variation in the results of the studies. RCTs conducted in the setting of open-heart surgery or transfusing non-buffy-coat-reduced RBCs or whole blood to the treatment arm had administered various RBC products to the control arm, however, and thus the medical heterogeneity of the studies precludes any conclusion about an immunomodulatory (TRIM) effect of ABT mediated by non-buffy-coat-reduced RBC products. To determine whether such a deleterious immunomodulatory effect of ABT exists, additional RCTs transfusing non-buffy-coat-reduced RBCs to the treatment arm should be conducted.