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.

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.

Universal white blood cell reduction in Europe: has transmission of variant Creutzfeldt-Jakob disease been prevented?

Universal white blood cell (WBC) reduction was introduced in Europe to prevent transmission of variant Creutzfeldt-Jakob disease (vCJD) by transfusion. Findings from rodent models indicate that WBC reduction should not prevent vCJD transmission because the residual plasma infectivity suffices to infect transfusion recipients even under optimistic infectivity assumptions. Although infectivity in human blood may not partition in the manner in which it is distributed in rodents, prion-reduction filters remove the residual plasma infectivity in rodent models. Precautionary introduction of prion filtration in the UK--for patients without dietary exposure to bovine spongiform encephalopathy and in the absence of a reported case of vCJD transmission attributable to infectivity residing in plasma--is consistent with the (already in place for such subjects) precautionary importation to the UK of fresh frozen plasma from low-risk countries. Thus, implementation of prion filtration in the UK does not imply that universal WBC reduction--as currently practiced in Europe--does not abrogate transmission of vCJD. Because neither a human case of vCJD transmission through transfusion of WBC-reduced red blood cells nor a case of experimental bovine spongiform encephalopathy transmission by WBC-reduced transfusion to sheep has been reported, it cannot be concluded that ordinary WBC reduction is ineffective in preventing transfusion transmission in humans. Accordingly, universal WBC reduction for the prevention of vCJD in Europe should continue.

Relative risk of reducing the lifetime blood donation deferral for men who have had sex with men versus currently tolerated transfusion risks.

The risks of known and emerging transfusion-transmitted infections (TTIs) from reducing the current lifetime blood donation deferral for men who have had sex with men (MSM) to 1 or 5 years were compared to the risk from continuing to transfuse in the United States 12.5% of platelet doses as pooled whole-blood-derived (rather than single-donor) platelets. Assumptions made in mathematical models and blood donor/transfusion studies of the risks of TTIs since 2000 were evaluated. The number of HIV, hepatitis B virus, or hepatitis C virus TTIs from reducing the MSM deferral to 1 year is, respectively, 0.88, 2.94, or 66.9, many more than 10 times smaller than the risk from pooled platelets. If erroneous release of HIV-positive units (a risk independent of a donor's source of infection) is not considered, the MSM risk is 1 HIV-infectious donation per 17 to 56 million MSM donations. Any purportedly increased risk of human herpesvirus-8 transmission from MSM donors is far smaller than the risk of transfusion-associated sepsis from pooled platelets. Single-donor platelets from MSM after 5 years' abstinence are as safe or 5 times safer than our current pooled platelets--if the next TTI to emerge were transmitted, respectively, sexually or by another route. Thus, acceptance of MSM as blood donors after 1 or 5 years' abstinence may result in a postulated increase in risk that is so much smaller than the currently tolerated transfusion risk and so small in absolute terms that the ethical question of fairness to the MSM group justifies the change in policy.

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.

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.

Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality.

After reviewing the relative frequency of the causes of allogeneic blood transfusion-related mortality in the United States today, we present 6 possible strategies for further reducing such transfusion-related mortality. These are (1) avoidance of unnecessary transfusions through the use of evidence-based transfusion guidelines, to reduce potentially fatal (infectious as well as noninfectious) transfusion complications; (2) reduction in the risk of transfusion-related acute lung injury in recipients of platelet transfusions through the use of single-donor platelets collected from male donors, or female donors without a history of pregnancy or who have been shown not to have white blood cell (WBC) antibodies; (3) prevention of hemolytic transfusion reactions through the augmentation of patient identification procedures by the addition of information technologies, as well as through the prevention of additional red blood cell alloantibody formation in patients who are likely to need multiple transfusions in the future; (4) avoidance of pooled blood products (such as pooled whole blood-derived platelets) to reduce the risk of transmission of emerging transfusion-transmitted infections (TTIs) and the residual risk from known TTIs (especially transfusion-associated sepsis [TAS]); (5) WBC reduction of cellular blood components administered in cardiac surgery to prevent the poorly understood increased mortality seen in cardiac surgery patients in association with the receipt of non-WBC-reduced (compared with WBC-reduced) transfusion; and (6) pathogen reduction of platelet and plasma components to prevent the transfusion transmission of most emerging, potentially fatal TTIs and the residual risk of known TTIs (especially TAS).

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.

Is human herpesvirus-8 transmitted by transfusion?

Studies of human herpesvirus-8 (HHV-8) transmission through transfusion have produced contradictory results. In North America-a region with a low prevalence of HHV-8 infection-3 studies that tested specimens from linked positive-donor/negative-recipient pairs collected before the introduction of white blood cell (WBC) reduction and the extension of red blood cell (RBC) storage found no case of transmission of HHV-8 to 151 transfusion recipients who were HHV-8-seronegative before the transfusion and received components from HHV-8-seropositive donors. In Uganda, a prospective cohort study of pediatric transfusion recipients observed a small (

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.

Scientific background on the risk engendered by reducing the lifetime blood donation deferral period for men who have sex with men.

The lifetime deferral for men who have sex with men (MSM) has not been harmonized with the 12-month deferral for similar-risk activities through heterosexual contacts. This occurs primarily because of fears of increased transfusion transmission of known sexually and transfusion-transmitted viruses for which donor blood is (eg, HIV) or is not (eg, human herpesvirus 8 [HHV-8]) tested and also of fears of novel agents that may share the epidemiology and long asymptomatic phase of HIV. A 12-month MSM deferral could result in release of 1 HIV-infectious donation every 11 years in the United States. This risk is smaller than the risk from allowing the continued use of pooled whole blood-derived platelets (release of 1 infectious platelet dose every 1.67 years), a risk that is considered "tolerable." Provided that measures to reduce the number of allogeneic-donor exposures to novel pathogens (which may be vector- or food-borne rather than sexually transmitted) are implemented, and the deferral for similar-risk activities through heterosexual contacts is extended to 5 years, a 5-year MSM deferral could be justified because of the interval between emergence of a novel pathogen and introduction of measures to protect the blood supply. Also, provided that measures to protect the blood supply from HHV-8 are implemented, a lifetime MSM deferral could be justified because of the uncertainty about the clinical consequences of transfusion transmission of HHV-8. Because such alternate measures, which would have had a greater impact on safety than the MSM deferral, have not been implemented to demonstrate a consistent approach to safety, maintenance of the current MSM deferral appears to be selectively precautionary and cannot be justified.