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provided by Elsevier - Publisher Connector review Why implement universal leukoreduction? Wafaa Y. Bassuni,a Morris A. Blajchman,b May A. Al-Mosharya
From the aCentral Laboratory and Transfusion Services, King Fahad Medical City, Riyadh, Saudi Arabia, and bMcMaster Transfusion Medicine Research Program, McMaster University, Hamilton, Ontario
Correspondence and reprints: Wafaa Bassuni, MD · Consultant, Hematopathology Central Laboratory and Transfusion Services, King Fahad Medical City · PO Box 51988 Riyadh 11553, Saudi Arabia · T: +966-1-470-7119 M: +966-506247993 · [email protected] · Accepted for publication February 2008
Hematol Oncol Stem Cel Ther 2008; 1(2): 106-123
The improvement of transfusion medicine technology is an ongoing process primarily directed at increas-i ing the safety of allogeneic blood component transfusions for recipients. Over the years, relatively little attention had been paid to the leukocytes present in the various blood components. The availability of leukocyte removal (leukoreduction) techniques for blood components is associated with a considerable improvement in various clinical outcomes. These include a reduction in the frequency and severity of feb- brile transfusion reactions, reduced cytomegalovirus transfusion-transmission risk, the reduced incidence of alloimmune platelet refractoriness, a possible reduction in the risk of transfusion-associated variant Creutzfeldt-Jakob disease transmission, as well as reducing the overall risk of both recipient mortality and organ dysfunction, particularly in cardiac surgery patients and possibly in other categories of patients. Internationally, 19 countries have implemented universal leukocyte reduction (ULR) as part of their blood safety policy. The main reason for not implementing ULR in those countries that have not appears to be primarily concerns over costs. Nonetheless, the available international experience supports the concept that ULR is a process that results in improved safety of allogeneic blood components.
he term paradigm was introduced into science blood products in vitro (for example, RBCs).13 and philosophy by Thomas Kuhn in 1962 to Considerable progress has been made over the past refer to the set of concepts that define particutl two decades to reduce the risk of the adverse events T 1 lar scientific thinking during a given period of time. associated with the transfusion of blood components. The term refers to the predominant worldview in a partt However, significant transfusion-associated morbidity ticular realm of human thought. Kuhn hypothesized and mortality remain a problem.14-17 Recent data from that paradigm shifts occur when new and more accurate various hemovigilance systems worldwide showed that theories (which represent approximations of the underts the most common causes of transfusion-associated standing about a topic) replace earlier, less comprehenst mortality include transfusion-related acute lung injury sive theories. (TRALI), ABO hemolytic transfusion events, and bactt The medical intervention known as blood transft terial sepsis associated with the transfusion of bacteria fusion is associated with both beneficial effects and present in contaminated blood components (Tables adverse events in recipients. Over the past 100 years, 2, 3). The number of transfusion-associated mortalti transfusion medicine has experienced many challenging ity cases reported annually increased considerably over periods resulting in the introduction of improvements the past 30 years, which is probably mostly related to in technology to increase the safety of allogeneic blood increased recognition of such events as being transfuts transfusion. There have thus been six major paradigtm sion-associated. As can be seen in both Tables 2 and 3, matic shifts associated with transfusion medicine sciet TRALI has become the most commonly reported cause ence and technology (Table 1). Conceptual and technolt of transfusion-associated mortality. logical developments in transfusion medicine are thus The transfusion transmission risk of many pathotg ongoing processes and more paradigm shifts are to be gens has been greatly reduced by the development of inct expected in the future. These may include modification creasingly sensitive screening methods; however, transft of the red blood cell (RBC) surface to reduce antigenicit fusion-transmitted infections still occur. Transfusion- ity11,12 and the development of novel ways to produce related infections continue to be reported as tests for
106 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review
Table 1. Major paradigm shifts in transfusion medicine. Karl Landsteiner discovers the ABO blood groups and humoral immunity becomes the main paradigm explaining Early 1900 the effects of allogeneic transfusion.2 1940 Edwin Cohn develops cold ethanol fractionation, the process of breaking down plasma into protein components and products.3 Carl Walter and W.P. Murphy introduce the plastic bag for blood collection and component preparation, 1950 replacing breakable glass bottles with durable plastic bags and most importantly allowing sterile blood component preparation.4,5 Post transfusion viral infections became a major concern affecting the blood recipient, resulting in the 1960 to 1980 development and implementation of effective screening methods to reduce pathogen transmission.6,7 Leukocyte reduction of blood components are shown to be associated with improved clinical outcome, which 1990 lead to the implementation of ULR in many countries.8 Development of pathogen inactivation (reduction) technology to reduce the risk of pathogen transmission by 1995 to 2010 blood components. This will lead to the development of pathogen inactivation technologies to treat the various cellular blood components to further improve blood safety.9,10 ULR = universal leukoreduction
Table 2. Annual number of transfusion-associated cases reported to the US FDA over the three decades from 1976 to 2005.14
Period Total annual rate ABO/HTR TRALI Bacterial sepsis Others* 1976 - 1985 25.6 15.8 3.9 2.6 3.3 1986 - 1995 30.3 15.1 4.4 4.9 5.9 1996 - 2000 62.6 11.2 NA NA NA 2001 - 2003 88.3 12.6 14.4 12.5 48.8 2004 82.0 7.0 21.0 6.0 48.0 2005 105.0 5.0 30.0 9.0 61.0 *Includes graft-versus-host disease, delayed hemolytic transfusion reactions, transfusion transmitted infections other than bacterial sepsis, anaphylaxis, post-transfusion purpura, transfusion-associated circulatory overload, and others. ABO/HTR=ABO/ hemolytic transfusion reaction, TRALI=transfusion-related acute lung injury, NA = data not available.
Table 3. Transfusion-associated causes of mortality reported to UK Serious Hazards of Transfusion (SHOT) program (1996-2004).15
Attributed cause of mortality Definite Probable Possible Total Transfusion related acute lung injury 8 5 23 36 Incorrect blood component 6 3 11 20 transfused† Graft-versus-host disease 13 0 0 13 Acute transfusion reaction‡ 2 3 7 12 Transfusion-transmitted infection 9 0 0 9
Delayed transfusion reaction 6 1 1 8 Post-transfusion purpura 1 0 1 2
Total 45 12 43 100 †Patient transfused with component or product that did not meet the appropriate requirement, or was intended for another patient. ‡Acute transfusion reaction occurring within 24 hours following a transfusion, excluding that due to IBCT. many known pathogens are not yet available or not beti sion of blood components containing donor leukocytes ing used.18-22 In addition, the ongoing emergence of new and their soluble biological mediators, such as cytotk agents demonstrates that potential threats to the blood kines, are known to have a number of biologic effects supply will continue to emerge worldwide. associated with transfusion.23 Leukocytes with their Potential adverse effects associated with the transfuts specific allogenic structure (the HLA class I and class II
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 107 review universal leukoreduction
Table 4. Putative clinical benefits of leukocyte reduction, subdivided as to whether the reduction are cost and logistics.28 The report from the benefit has been proven by evidence-based guidelines to be relevant clinically, likely Canadian Coordinating Office for Health Technology 8 relevant clinically, or clinical relevance is unproven. Assessment (CCOHTA) published in 1998 concluded Proven relevant clinically: that ULR of both platelets and RBCs would add a signt − Reduced frequency and severity of NHFTRs; nificant expense to the Canadian health care system, − Reduced risk of CMV transmission; but that leukocyte reduction of all transfused platelets − Reduced risk of HLA-alloimmunization and platelet refractoriness. 24 − Reduced mortality and organ dysfunction in cardiovascular surgery patients. might be cost effective. As a result, leukocyte reductt tion of all platelets was introduced in Canada during Likely clinically relevant: the first quarter of 1998. Leukocyte reduction of RBCs − Reduced infectious risk associated with immunomodulation (TRIM); was only introduced subsequently and ULR for all − Reduced direct risk of transfusion-transmission bacteria. blood products was fully implemented in Canada in 29 Unproven clinically: July 1999. − Avoidance of vCJD transmission. There is some loss in product potency associated − Avoidance of HTLV I/II, EBV etc. − Reduced risk of GVHD. with leukoreduction technology, although, at the preste − Reduced risk of TRALI. ent time, for RBCs this is unlikely to cause an increased
NHFTRs, non-hemolytic febrile transfusion reactions; CMV, cytomegalovirus; vCJD, variant Creutzfeldt-Jacob disease; demand for RBC transfusions because of the concurtr GVHD, graft-versus-host disease; TRALI, transfusion-associated acute lung injury. rent increase in the volume of whole blood collections that offsets this loss in product potency. With regard to the loss in platelet potency, there is considerable unct antigens on their surface) appear to be the main targets certainty about the proper therapeutic dose of platelets, of a recipient’s immune system. In addition, some vitr such that a 10% to 15% quantitative reduction is untl ruses can be transmitted as they exist within leukocytes likely to be noticeable clinically. As in the case of RBCs, (i.e. CMV, HHV-8, and HTLV-I/II). Another, not so the increase in whole blood collections will also likely well characterized effect of transfused leukocytes, is the increase platelet potency of whole blood-derived platetl potential modulating influence on the recipient’s imtm lets by negating the 11% filtration effect.30 mune system.2 Leukocyte reduction is typically defined Adverse effects associated with the use of leukocyte as a blood processing step for reducing the leukocyte reduction filters have been reported.31-33 The reported content of whole blood, RBCs, or platelet units down severe hypotensive reactions to leukocyte reduced to 5×106 (1×106 in Europe) residual WBCs per unit blood components have been associated mainly with of component. Universal leukocyte reduction (ULR) is the transfusion of blood components filtered at the bedts the routine application of the blood-processing step to side.34 These reactions are attributed to the generation all units of whole blood, RBCs, and platelets prior to of bradykinin and possibly other vasodilators, as dotn storage in a country or in a blood transfusion service.25 nor plasma passes over the filter media.35,36 Bradykinin To attempt to prevent the adverse effects of the leukt generated during filtration has a short half-life and is kocytes contained in blood components, several methot therefore biologically active only on direct intravenous ods have been developed to remove leukocytes from the administration. Blood components that are leukocyte various blood components.25,26 Leukocyte reduction reduced by pre-storage filtration appear not to cause procedures can be performed either pre-storage at the hypotensive reactions and current knowledge indicates blood collection facility, or post-storage either at the that transfusion of these blood components is generally hospital transfusion service or at the patient’s bedside free from complications associated with the use of leutk just prior to transfusion.27 Pre-storage leukocyte retd kocyte reduction filters.29 However, recent reports show duction of cellular blood components removes donor that hypotensive reactions can occur even with the WBCs before they undergo apoptosis or necrosis and prestorage leukoreduction of blood products in which before they release breakdown products or cytokines. a defect in the metabolism of kinins may be a risk factt The removal of leukocytes from various blood comtp tor.37 ponents can be associated with several improved clinical The implementation of ULR has created some new outcomes (Table 4). These outcomes, subdivided as to requirements relating to the need to standardize and whether each benefit has been proven by evidence-based to quality control the whole process.38 In our opinion guidelines to be clinically relevant, likely to be clinically the associated clinical benefits of leukocyte reduction relevant, and of unproven benefit (i.e. those that can be nonetheless far overweigh the adverse features, and in considered only of theoretical relevance).8 the absence of considerations of cost, most transfusion The major disadvantages associated with leukocyte medicine professionals would readily endorse a policy
108 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review to implement ULR by pre-storage filtration. Others Many studies have been done to evaluate the efficacy of argue that in the absence of adequate data suggesting leukocyte reduction to prevent or reduce adverse effects universal benefit the technology should be applied setl caused by leukocytes present in blood components. The lectively only to those patients who will clearly benefit following sections review the evidence for various clinict from this intervention.39 cal outcomes. In the opinion of the authors, implementation of ULR will improve transfusion safety, which should extt Non-hemolytic febrile transfusion reactions tend to all patients receiving blood components at the (NHFTR) very least for the proven benefits of this intervention. Historically, NHFTRs were thought to be associated Although patients who have not had a febrile non-hetm with the presence in the recipient of antibodies to transft molytic transfusion reaction (FNHTRs), who are not fused allogeneic leukocytes. NHFTRs, the most commt receiving long-term platelet transfusions, and are not mon adverse effect of blood transfusions, are thought at risk of developing symptomatic CMV disease may to be clinical manifestations of allo-immunization.41 derive no immediate benefit from prestorage leukocyte The minimum number and type of WBCs needed to reduction, it is possible that they may accrue tangible generate a post-transfusion NHFTR in an alloimmunt benefits in the future. There are also cost savings in rets nized recipient of blood components remains unclear.42 sources, time and effort associated with improvements Over the past decade, however, it has been established in the efficiency of the transfusion service and nursing that most NHFTRs are due to cytokines present in the personnel, which will further reduce the net community transfused blood components, having been elaborated cost. during storage by the leukocytes.43 The current practice of transfusion in Saudi Arabia Many studies make the point that the timing of filtt and other countries around the world is selective leukotc tration is important for reducing the rate of NHFTRs. cyte reduction. This review will thus present an up-to- The age of the blood component is also an accepted risk date review of the clinical issues associated with leukort factor. The older the component is, the greater the liketl reduction and the level of evidence indicating the efficact lihood of an adverse reaction. This is particularly the cy, the current international status and the international case for platelet concentrates, which are stored at higher experience, that we hope will influence the decision to temperatures (22±2°C) than RBC units. Thus, a more implement ULR. obvious cause for a transfusion reaction than the numtb ber of remaining leukocytes was postulated.41,44,45 Evidence-based clinical efficacy of leukoreduc-t Since older blood components have greater amounts tion of cytokines, the accumulation of soluble cytokines retl Evidence-based medicine has been defined as the intetg leased from leukocytes during storage may be the explant gration of best research evidence with clinical expertise nation for the higher rate of NHFTRs.44,46-48 It seemed and patient values. Various classifications of the differte reasonable therefore that pre-storage of blood compont ent types of scientific evidence available, to establish nents would significantly reduce cytokine accumulatt the efficacy of a particular intervention, have been protp tion during storage. Some clinical trials (not prospectt posed. Table 5 provides such a scheme for assessing the tive, randomized controlled trials) have demonstrated levels of medical and/or scientific evidence and is based such effects of pre-storage filtration for RBCs49 even on the various publications of Sackett and colleagues.40 in previously alloimmunized patients.47 Many studies
Table 5. Levels of scientific evidence that can be used to evaluate the efficacy of various transfusion medicine interventions (modified from Sackett).40
Level Scientific Evidence Data from RCTs that are sufficiently large to give clear cut results, with only a small risk of an error. This level of 1 evidence includes meta-analysis from such RCTs. Data from small RCTs that give uncertain results and that may have a moderate to high risk of error. This level of 2 evidence includes meta-analysis from such RCTs. 3 Nonrandomized cohort observational studies that use concurrent cohort data. 4 Nonrandomized cohort observational studies that use historical cohort data. 5 Case series that use data from uncontrolled observations; or that represent unsubstantiated “expert” opinion.
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 109 review universal leukoreduction
Table 6. Incidence of non-hemolytic febrile transfusion reaction (per transfusion, excluding allergic and other reaction) (modified from CCOHTA).26
Pre-storage filtration Post-storage filtration No filtration Platelets RBC Platelets RBC Platelets RBC 1.7% 1.1% 2.2% Federowicz et al (1996)44 NA NA NA 59/3405 60/5412 139/6447 1.6% 2.2% Dzieczkowski et al (1995)49+ NA NA NA NA 82/5197 152/7080 28% 37.5% Heddle et al (1993)41++ NA NA NA NA 7/25 12/32 0.9% 5% 0.8% Muir et al (1994)47+++ NA NA NA 2/223 14/280 4/467 +=apheresis platelets, FNHTR only; ++=pooled platelets, all reactions; +++=sensitized hematological patients, apheresis platelets. NA=Not available
published after 1990 have addressed the incidence of vention technology, may be as high as 30% per patient, febrile reactions in the context of leukocyte filtration depending upon the frequency of allogeneic blood compt (Table 6).26 All studies achieved a level of leukoreductt ponent transfusion.62 CMV-seronegative cellular blood tion of <5×106 leukocytes in the transfused blood comtp components have been the standard approach provided ponent.26 to CMV-seronegative patient populations at high risk Until recently the role of leukoreduction in ameliotr for significant morbidity for primary CMV infections.63 rating the rate of NHFTRs had not been clearly establt However, the increasing number of immunosuppressed lished. Several recent publications show clearly that leutk patients who might benefit from receipt of such compotn koreduction is associated with a significant reduction nents, the high prevalence of CMV antibody in some in the NHFTR rate (level 1 evidence) (Table 7).8 The blood donor populations, and the logistics of maintainit NHFTR rate following RBC transfusion was shown ing multiple inventories of blood components have led to be reduced by approximately 50%, from 0.35% to to the exploration of pre-storage leukoreduction as an 0.18%.50-52 Similarly, the pre-storage leukoreduction of alternative strategy for the provision of “CMV-safe” platelets, which is generally associated with an approxitm blood components.57 The American Association of mate frequency of a 30% rate of NHFTRs, has been Blood Banks (AABB) has thus suggested that residual shown to be reduced significantly by transfusing pre- leukocyte levels less than 5×106 make a blood compotn storage leukocyte reduced platelets.50,51,53 nent “CMV-safe”.64 It has been shown that the use of CMV seronegative Pathogen transmission Viruses. Leukoreduction is a known effective strategy for reducing the risk of the transmission of cell-associta Table 7. Reports describing non-hemolytic febrile transfusion ated viruses. The most prominent among these are the reactions (NHFTR) rate reduction associated with the pre-stage herpes viruses, particularly CMV, also known as hutm leukoreduction (LR) of RBCs and platelets.8 man herpes virus (HHV) 5.54-60 CMV is transmitted NHFTR rate reduction associated For RBCs by the leukocytes present in transfused blood compotn with LR nents. To acquire CMV from a blood donor, a blood Paglino et al50 0.34% to 0.18% transfusion recipient must be exposed to donor WBCs Yazer et al51 0.33% to 0.19% that are latently infected with CMV. CMV then must 52 be reactivated and the cell must survive long enough in King et al 0.37% to 0.19% the host to release infectious virus particles.61 Several For Platelets patient populations are at risk for serious morbidity as Heddle et al53 21.3% to 12.3%a a result of transfusion-associated CMV infection (TA- b CMV), including low birth weight infants, some oncolto 4.1% to 1.6% ogy patients, allogeneic bone marrow transplant recipite Paglino et al50 2.18% to 0.11% ents, but most particularly immunosuppressed patients. Yazer et al51 0.45% to 0.11% Early studies of TA-CMV indicate that the prevalence *Comparing NHFTR rate reduction of platelets from which in supernatant plasma was of post-transfusion CMV, without employing any pretv removed with that seen with pre-storage LR platelets. aAll NHFTR, bSevere NHFTR.
110 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review allogenic transfusions in these patients will reduce this plication of allogeneic blood transfusion in recipients. post-transfusion CMV risk to approximately 1.3%.58 The risk of contaminated pooled platelet transfusion In comparison, a recent study has shown that the use has been estimated to be as high as 2% (asymptomatic of pre-storage leukoreduced RBCs or platelet transfuts cases) since platelet concentrates are stored at room sions can reduce the risk of post-transfusion CMV to temperature (a temperature that facilitates bacterial approximately 2.5%.65 Over the years there have been growth) to preserve their viability and function.71-73 a large number of studies examining strategies to pretv Asymptomatic bacteremias and/or infections in a dont vent TA-CMV. Interpretation of some of these studies nor and the ability of Yersinia enterocolitica to grow at is difficult as many were not randomized, failed to use low temperatures in an iron-rich environment such as a control group, used historical controls, or were retrots in stored RBC components makes Y entercolitica the spective.57 most commonly encountered serious bacterial contamitn Nonetheless, the balance of the evidence from the nant associated with RBC transfusion.74,75 Several studti available clinical studies suggests that acceptable CMV ies have demonstrated that the bacterial overgrowth of safety can be achieved by pre-storage leukoreduction. blood components by Y enterocolitica inoculated into Although it is likely that leukoreduced blood compotn blood components under experimental conditions is dimt nents are effective in reducing the risk of TA-CMV, minished or prevented by pre-storage leukoreduction, there is insufficient evidence at this time to firmly torec after a room temperature holding period.75,76 One way of ommend the discontinuation of CMV testing even in reducing the risk of bacterial contamination in platelet the face of ULR.66 Considerable debate thus exists as concentrates is to reduce the level of leukocytes present. to whether leukoreduction and the use of serologically Filtration to remove leukocytes does not prevent bactetr negative CMV allogenic transfusion can be considered rial growth, although it can reduce the level of bacterial equivalent. A recent (2001) Canadian consensus conft contamination for some organisms. This process is not ference that has examined this issue in detail recommt effective against some species of bacteria (for example,S mended that high-risk patients (i.e. allogenenic bone epidermidis). This method, therefore, does not provide marrow transplant patients) receive leukoreduced blood full protection against the risk of bacterial contaminatt products that are also seronegative for CMV.61 tion, but has been shown to significantly reduce the risk A recent study provides strong evidence (level 2 of transfusion-associated sepsis.77 evidence) that human herpes virus 8 (HHV-8) can be The mechanisms by which leukoreduction removes transmitted by allogeneic transfusion, particularly in bacteria are complex and several possibilities have been high prevalence geographic regions.67 Based on the extp proposed, based on experimental data. First, bacteria perience with CMV, it is likely that pre-storage leukoct are phagocyted during the proposed 8-hour storage of cyte reduction may prevent the transmission of HHV- blood at ambient temperatures and then removed with 8 due to its WBCs associated nature. HHV-8 can cause the leukocytes upon leukoreduction. Secondly, bacteria a lifelong infection, with periodic reactivations, during are adsorbed directly by the filter matrix or indirectly which virus may circulate in peripheral blood WBCs by binding to leukocytes and platelets or on activated and be transmissible through transfusion (level 5 evidt complement components, which are removed by negatt dence).68 tively charged filters.78 For other viruses such as Epstein-Barr virus (EBV), Recent data from the Hemovigilance Network in human T-cell lymphotrophic virus type I and II (HTLV France clearly indicates that the bacterial sepsis rate, as I and II), no conclusive studies exist that demonstrate a the percentage of all transfusion event rates, was signifitc similar efficacy of virus removal by leukoreduction as cantly reduced (1.7% versus 3.8%) following the implemt seen for CMV. Some experimental in vitro studies inditc mentation of ULR in France compared with before the cate a significant reduction of HTLV I virus from blood implementation of ULR (Table 8).79 Of particular relte components by pre-storage leukoreduction but the prevt evance is the fact that 1 in 3000 cellular blood compont vention of clinical HTLV I infections with leukoreductt nents have been shown to contain bacteria.77 tion in humans has not been proven. 69 Nonetheless, it The risk of the transmission of Trypanosoma cruzi, is reasonable to assume that leukoreduction adds more the causative agent of Chagas’ disease, which is common safety to transfusion of blood components, since not in South America, but rare in other parts of the world, all HTLV I infected donors express HTLV I antibodit was shown to be decreased by leukoreduction, in an expt ies.70 perimental study in susceptible mice.80 Bacterial/protozoal infections. Bacterial contaminatt Variant Crutzfeldt-Jacob Disease transmission (vCJD). tion of blood components can result in a severe comtp vCJD is a major concern of the transfusion medicine
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 111 review universal leukoreduction
Table 8. Occurrence of transfusion incident report (TIR) before and after implementation of universal leukocyte reduction in France.79 Before universal WBC After universal WBC reduction reduction Number % Number % Variation P value† RBCs transfused 3 124 649 3 053 807 Before/After (%) HLA antibodies and NHFTR 112 6 33 2.3 -71 <.001 Isolated NHFTR 615 32.9 363 25.8 -41 <.001 Bacterial contamination 71 3.8 24 1.7 -66 <.001 Anaphylactoid 266 14.2 224 15.9 -16 .10 Hemolytic reactions (excluding 26 1.4 23 1.6 -12 .73 ABO & D) D incompatibility 12 0.6 11 0.8 -8 .88 ABO incompatibility 30 1.6 33 2.3 10 .64 Analysis of RBCs transfusion 18 months before and after implementation of universal WBC reduction shows as expected no significant impact on anaphylactoid reactions, ABO and D incompatibility and hemolytic reactions duo to other RBC antibodies. Conversely, there is dramatic reduction of TIRs related to HLA immunization, non-hemolytic febrile transfusion reactions (NHFTR) and bacterial contamination. †Comparison of rates (i.e. 1408/3 053 087 vs. 1872/3 124 649) using the chi–square test.
community, because infectivity can be detected in the of this study showed that filtration leukoreduction was lymphoreticular system as well as in blood.81 Evidence associated with reduced TSE infectivity, but that this from an immunodeficient animal model of scrapie suggt intervention was not sufficient to remove all TSE inft gests that host lymphocytes and/or follicular dendritic fectivity.91 Specific prion reduction filters for RBCs offt cells play a role in peripheral neuroinvasions.82,83 The fer the possibility of a further substantial reduction in abnormal prion protein PrPSc of vCJD has been dett vCJD infectivity and in the overall risk of vCJD transmt tected in lymph nodes, tonsillar tissue, spleen and the mission. However, concerns persist about how best to appendix in clinical cases of vCJD.84 Animal studies assess the efficacy of these technologies, since current have shown that B lymphocytes might play a key role assays are not sufficiently sensitive to detect infectivity in disease transmission.85 In several countries, partt in the blood of patients with clinical vCJD.92 ticularly in western Europe, ULR was instituted over the past 6 years in an attempt to reduce the theoretict Alloimmunization and platelet refractoriness cal risk of vCJD transmission via transfusion of allogt Alloimmunization is defined as a recipient immune geneic blood and blood components.86,87 Four cases of response against antigens on tissue from a genetically probable transfusion transmission of vCJD infection dissimilar donor. The direct allo-recognition pathway have recently been diagnosed in patients in the United occurs when recipient T-helper cells directly interact Kingdom. All four cases had received transfusions of with class II molecules encoded by the major histocompt non-leukoreduced RBCs between 1996 and 1999 from patibility complex (MHC) on donor antigen-presentit donors who developed symptoms of vCJD after blood ing cells (APCs). This pathway is the strongest known donation. These four cases of vCJD infection associated stimulator of immunity and the one targeted for retm with blood transfusion increases the level of concern moval by leukoreduction strategies.93 The reduction in about the possible risk of vCJD transmission between alloimmunization is a well documented beneficial effect humans by blood transfusion, although much remains of using leukoreduced blood component transfusions, unknown. This concern reinforces the importance of and is especially important for repeatedly transfused the existing precautions that have been introduced to patients and transplant recipients.93-98 Table 9 provides reduce the risk of transmission of vCJD infection by a cumulative meta-analysis of seven randomized, contt blood and blood components.88 Blood screening assays trolled trials which clearly showed that the relative risk are currently under development but are not yet ready of HLA alloimmunization can be reduced considerably for application.89 A recent study by Gregory et al, in a through the use of leukoreduced blood components hamster model of blood-born transmissible spongiform (level 1 evidence). In the years 1983 to 1995 there were encephalopathy (TSE) transmission, showed that filtratt seven reports whose cumulative relative risk reduction tion leukoreduction was associated with a reduced risk with the use of leukoreduced allogenic blood compotn of TSE infection (from 48.1% to 31.5%).90 The authors nents was 0.32, with 95% confidence intervals of 0.18
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Table 9. Cumulative meta-analysis of randomized, controlled trials on the efficacy of leukoreduction in preventing LH A alloimmunization.99 Cumulative sample size Cumulative relative risk (RR) of HLA Study Publication Year (study n) alloimmunization (95% Confidence intervals) Schiffer et al100 1983 56 (56) 0.35 (0.10–0.16) Sniecinski et al95 1988 96 (40) 0.32 (0.17–0.60) Andreu et al96 1988 165 (69) 0.26 (0.16–0.49) Kooy et al101 1991 218 (53) 0.21 (0.12–0.35) Oksanen et al102 1991 249 (31) 0.23 (0.13–0.38) Williamson et al103 1994 372 (123) 0.27 (0.16–0.46) Sintnicolas et al104 1995 418 (46) 0.32 (0.18–0.56) TRAP105 1997 818 (400) 0.30 (0.20–0.46)
to 0.56. These seven studies involved a total of only 418 still remain to be defined, has been referred to in the patients.8 In 1997, the TRAP study which examined transfusion medicine literature as transfusion-related the relative risk of HLA alloimmunization and platelet immunomodulation (TRIM).115 refractoriness in 400 patients provided level 1 evidence TRIM and surgery. The value of leukoreduction for (a large randomized controlled trial) that the relative preventing postoperative complications in patients untd risk of HLA alloimmunization and platelet refractoritn dergoing surgery has been investigated in many observt ness with the use of leukoreduced blood components vational studies as well as in 12 randomized controlled was statistically significant.99 The cumulative relative trials, which were recently the subject of a meta-analysis risk reduction of HLA immunization for all the pubtl that looked at the association between allogenic blood lished studies, following the use of leukoreduced blood transfusion and postoperative infection.110-112,116-124,125 components, was recently estimated to be 0.30 (95% The hypothesis of homogeneity was rejected across the confidence intervals; 0.20 to 0.46).99 12 trials (P<.01 for the Q-test statistic). When the rets A recent retrospective analysis of 13 902 platelet sults were combined under conditions of heterogeneit transfusions in 617 Canadian patients undergoing chetm ity, the effect of the WBC-containing allogenic blood motherapy for acute leukemia or stem cell transplantatt transfusion on postoperative infection did not quite tion before (n=315) and after (n=302) the introduction attain statistical significance (summary OR=1.24; 95% of ULR showed a significant reduction in alloimmunizt CI, 0·98-1·56; P>.05). Four of these trials showed an zation (19% to 7%, P<.001) and in alloimmune platelet increased association between allogenic blood transfuts refractoriness (14% to 4%, P<.001). Alloimmunization sion and postoperative infection, but the others did not and alloimmune refractoriness in 318 patients who were (Figure 1).116,120,122,123 One possible explanation for the previously pregnant and/or transfused were also retd lack of consistency among the trials is that the TRIM duced after ULR (P=.23 and P=.005, respectively).106 effect may in fact be quite small (i.e. less than 10%).8 Vamvakas and Blajchman have postulated that to dett Transfusion-related immunomodulation (TRIM) tect a 5% to 10% reduction in the risk of postoperative Most animal studies using whole blood transfusion infection, a randomized trial enrolling 10 000 to 20 000 have found immunosuppressive-like responses in retc subjects would be required. Such a study has not been cipients, primarily due to the leukocyte content of done and is unlikely to be done in the foreseeable futt the donor blood.107 Moreover, evidence from a variety ture.126 of sources indicates that allogenic blood transfusion There is also evidence that the use of leukoreduced (ABT) enhances the survival of renal allografts,108 and blood components is associated with improvement in may increase the recurrence rate of resected malignanct morbidity and mortality in cardiac surgery.110,119,121-123- cies,109 increase the incidence of postoperative bacterial 125 A randomized trial involving a large series of patients infections,110-112 reduce the recurrence rate of Crohn’s in whom the mortality rate was 50% less in patients retc disease,113 and reduce the risk of recurrent spontaneous ceiving leukoreduced blood also reported a significantly abortion.114 This clinical syndrome, whose mechanisms lower postoperative infection rate.110 The findings of
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 113 review universal leukoreduction
Favors leukoreduction
Does not favor leukoreduction 0.1 1 10 100 0.1 1 10 118 111 117 119 120 112 121 116 110 123 124 122 allis et al ilgin et al B racey et al W Tartter et al Tartter athens et al atering et al oshkov et al Jensen et al Jensen et al B Titlestad et al Titlestad B N Houbiers et al W Van Hilten et al Van van de
Figure 1. Randomized controlled trials (RCTs) investigating the association of white blood cell (WBC)-containing allogeneic blood transfusion (ABT) with postoperative infection.125 For each RCT, the figure shows the odds ratio (OR) of postoperative infection in recipients of non-WBC-reduced vs. WBC-reduced allogeneic red blood cells (RBCs) or whole blood, as calculated from an intention- to-treat analysis. Each OR is surrounded by its 95% confidence interval (CI). If the 95% CI of the OR includes the null value of 1, the immunomodulatory (TRIM) effect is not statistically significant P( >·05). A deleterious effect of ABT is indicated by an OR >1, provided that the associated 95% CI does not include the null value of 1.
this large study suggest that leukoreduction should transfused leukoreduced RBCs might benefit from a be applied for all patients undergoing cardiac surgery decrease in postoperative infections. A decrease in mortt in order to improve patient outcome. Figure 2 shows tality may have been realized if more patients had been the summary odds ratio of short-term mortality in retc enrolled in the various randomized trials.132 cipients of non-leukocyte reduced versus leukocyte-redt The results of a retrospective before/after study follt duced allogeneic RBCs, from 5 randomized, controlled lowing the institution of ULR in Canada compared trials conducted in cardiac surgery. When the 5 trials cardiac surgery, hip fracture repair, and intensive care were studied in a meta-analysis, WBC-containing allotg unit patients and found decreased mortality, fewer fever geneic blood transfusion was associated with a 72% intc episodes, and subsequent use of antibiotics in high-risk crease in postoperative mortality (summary OR=0.99; patients (Table 10).133 Subsequent reduced length of 95% CI, 0.73-1.33; P>.05) compared to patients receivti hospital stay and cost of hospital care may be an addt ing leukoreduced allogeneic blood.127 ditional financial benefit.134,135 A prospective randomized study by Alexiou et al TRIM and cancer. A higher rate of tumor growth reported that leukoreduction reduces the numbers and recurrence with allogenic transfusion and lower of circulating activated leukocytes and pulmonary inft rates with leukoreduced ones have been reported in a flammations during cardiopulmonary bypass (CPB).128 number of experimental animal model studies.136,137 Improved lung function and reduced mechanical ventilt Approximately 90 observational studies in man have lation requirements also have been reported following examined the effect of TRIM on tumor growth protm the use of leukoreduction in patients having abnortm motion.138 Of these, 33 (30 observational and 3 randt mal preoperative pulmonary function.129-131 Recently domized, controlled trials) have been in patients with two meta-analyses of 10 randomized, controlled trails a colorectal malignancy; 14 in patients with a head and evaluated the efficacy and effectiveness of RBC leukotr neck malignancy; 10 in patients with a breast maligtn reduction and demonstrated that patients who were nancy; 8 in patients with a gastric malignancy and 8 in
114 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review
Favors leukoreduction
Does not favor leukoreduction
121 119 122 123 110 0.1 1 10 100 0.1 1 10 Summary odds ratio allis et al ilgin et al racey et al W B oshkov et al atering et al B B W van de
Figure 2: Randomized controlled trials (RCTs) conducted in cardiac surgery investigating the association of WBC-containing allogeneic blood transfusion with short-term (up to 3 months post transfusion) mortality from all causes.127 The odds ratio (OR) of short- term mortality in recipients of non-WBC-reduced versus WBC-reduced allogeneic RBCs, is shown. These ORs are calculated from intention-to-treat analysis. The figure also shows the summary RO s of short-term mortality across the depicted RCTs, as calculated from a meta-analysis.110,119,121-123
Table 10. Before-after study evaluating the effect of the implementation of universal leukoreduction on various primary and secondary outcomes in 14 786 patients.79 Leukoreduction (%) Non-leukoreduction (%) Odds ratio (95% P Value (n=7804) (n=6983) confidence interval) Primary outcomes In-hospital mortality 6.19 7.03 0.87 (0.76-1.00) .04 Suspected infections 12.7 13.9 0.91 (0.83-1.00) .05 Confirmed infections 10.1 10.7 0.93 (0.84-1.04) .21
Secondary outcomes Respiratory failure 9.6 10.1 0.94 (0.84-1.05) .30
Hemodynamic failure 1.9 1.9 1.02 (0.80-1.13) .93 Renal failure 1.0 1.1 0.93 (0.67-1.30) .72 Fever 22.5 24.7 0.88 (0.82-0.95) <.01 Antibiotic use 14.8 16.4 0.89 (0.81-0.97) <.01 Transfusion reactions 0.46 0.64 0.71 (0.45-1.13) .16
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 115 review universal leukoreduction
patients with a lung malignancy. Approximately 50% components as well. Both measures simultaneously aptp of the available observational studies (level 3 evidence) plied in order to prevent TA-GVHD will result in the indicate that patients having allogeneic transfusions increased safety of allogeneic transfusions. Another appt (compared with those not having such transfusions) proach might be the use of pathogen inactivation.151This had a higher incidence of cancer recurrence or death as report also describes a reduction in cases of post-transtf a result of cancer recurrence as well as a shorter overall fusion purpura (PTP) following the introduction of survival after the cancer resection operation.138-141 ULR (mean number of reports/year before ULR 10.3; The three randomized, controlled trials in colorectal post ULR 2.3).149 cancer patients that compared the incidence of cancer recurrence in recipients of buffy coat-reduced allogeneic Transfusion-related acute lung injury (TRALI) RBCs with that of recipients of control blood, showed TRALI is a severe, often fatal, and complex complication no statistical difference in the incidence of cancer retc of transfusion. TRALI has become the most common currence.106,109,116 The randomized, controlled trials cause of transfusion-associated mortality reported to in human are thus still inconclusive. This may be due both the United States Food and Drug Administration to the lack of homogeneity among the studies, the difft (US FDA) and UK SHOT.14,15,151 Although the pathopt ference in blood component preparation used (buffy physiology of TRALI is not well understood,152 sevte coat method versus leukofiltration), multicenter versus eral mechanisms for TRALI have been postulated: single center trials and the type of data analysis by intv Popovsky’s immune-mediated model,153 in which donor vestigators (multivariate versus univariate). Studies in a antibodies and less frequently recipient antibodies causit rabbit allogenic transfusion tumor growth model clearly ing an immune reaction targeting leukocyte antigens indicated that buffy coat reduction was associated with and Silliman’s two-hit model.154 In the latter model, the a significant reduction in pulmonary tumor nodule fortm first hit is a physiological insult that activates pulmotn mation.142,143 nary endothelium and promotes priming, resulting in the adhesion of neutrophils, (sepsis and trauma). The Transfusion-associated graft-versus-host-disease second hit is an event that activates the neutrophils, (TA-GVHD) causing the release of biological active mediators present TA-GVHD is an infrequent, although almost uniformtl in the blood components.155 If Silliman’s model is valid, ly fatal complication of blood transfusion, caused by a pre-storage leukocyte filtration and the use of younger proliferation of T-cell lymphocytes derived from the dont blood components in at-risk patients should reduce the nor. Patients with cell-mediated immunodeficiency are incidence of TRALI. Leukoreduction reduces biologitc at particular risk for TA-GVHD. Another risk group cally active mediators associated with prolonged storat includes patients who have an HLA genotype that is age,154-158 but whether leukoreduction can reduce the haploidentical with that of the donor.144 No studies exit incidence of TRALI is not currently known. ist investigating the efficacy of leukoreduction for the prevention of TA-GVHD. There are only single case Current international status of ULR reports and animal studies.145 These reports conclude Internationally, 19 countries (Table 11) have impletm that the minimum threshold of transfused lymphotc mented ULR as part of their blood safety policy. Several cytes which prevents the development of TA-GVHD other countries are also currently moving toward imtp cannot currently be defined.146-148 A very recent report plementing ULR, including Sweden, Denmark, Italy, describes a reduction in reports of TA-GVHD to the Belgium, Cyprus and Japan.159 The motivation to implemt United Kingdom Serious Hazards Of Transfusion ment ULR varies from one country to another. Some Program (UK SHOT) since the introduction of ULR countries, including the United Kingdom and Portugal, in the UK (11 reports of GVHD associated with non- decided to adapt ULR in an effort to comply with the leukoreduced blood components, and only two with the precautionary principle concerning the theoretical risk use of leukoreduced blood components). This low rate of TA-vCJD.160 This decision was taken because of has occurred with the use of a combination of ULR and evidence that indicated that the pathogenic prion, the the provision of gamma-irradiated blood components causative agent of vCJD, was associated with B-lymtp for patients at risk.149 The gamma-irradiation of blood phocytes. The precautionary principle calls for reducing components has been demonstrated as the best current potential serious risks to public health even if cause and technology to reduce the risk of TA-GVHD.150 In any effect relationships are not fully established scientifitc event, most patients who need gamma-irradiated blood cally. Other countries, such as Germany and Canada, components also should receive leukoreduced blood have relied on the evidence of clinical benefit in other
116 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review
Table 11. Countries that have mandated universal leukocyte the basis for the controversy in the United States over reduction as a matter of public blood safety policy. ULR. Both the FDA blood product advisory committt Country Date tee (BPAC) in 1998 and the blood safety and availabilit ity (BSAC) in 2001 recommended ULR for the United France April 1998 States blood supply.162,163 Canada July 1998 (platelets only) Both the additional cost of ULR and the controversy Luxembourg December 1998 over the available clinical evidence to support the use of leukoreduction for all patients has delayed implementatt Austria January 1999 tion of ULR in the United States, despite the BPAC Eire (Southern Ireland) January 1999 and BSAC recommendations. In fact, the ULR debate Canada July 1999, ULR has become so politicized that it has become one of the most divisive issues in the history of US transfusion Wales August 1999 medicine. In 2005, approximately 65% to 70% of the Scotland August 1999 blood supply was leukocyte reduced in the US.161 It is Switzerland September 1999 important to note in this context that many centers and hospitals in the US provide ULR blood components. England October 1999 At present ULR is practiced in only approximately Northern Ireland October 1999 20 countries. The main reason for not implementing Malta January 2001 ULR universally appears to be financial. Other reasons include the opinion that there is not yet sufficient evitd Spain (Portugal) May 2001 dence to justify adopting the policy of ULR.164,165 New Zealand June 2001 United Arab Emirates July 2001 International experience Hebert et al133 evaluated clinical outcomes after the Germany October 2001 adoption of ULR in Canada by conducting a retrost Qatar January 2002 spective before and after cohort study in 23 academic Holland January 2002 and community hospitals (n=14 786). Although an increased risk of nosocomial infections was not demonts Norway January 2002 strated in this trial, in-hospital mortality was found to Finland November 2002 be significantly lower P( =.04) following the introductt ULR=Universal leukocyte reduction, platelets and RBCs. tion of ULR in Canada.133 The authors of this study indicate that assuming a 7% mortality rate in the contt clinical areas to justify the adoption of ULR for all trol period, the decreased odds of death based on these transfused patients. In some countries, such as Canada, results would translate to one life saved for every 120 blood safety is considered paramount, and the use of patients who received leukocyte reduced blood as optp safer blood components, such as those that are leukotc posed to non-leukoreduced blood. This observation, cyte reduced cannot be restricted and must be applied according to the authors, was consistent among all subgt to all patients.161 groups and throughout the range of blood exposures. In The adoption of ULR in the United States has been addition, this study also found that ULR was associated delayed primarily because of economic issues, leading to with a decreased frequency of febrile episodes and subts the approach of selective leukocyte reduction protocols sequent use of antibiotics.133 for patients thought to be at greatest risk for adverse Fergusson et al166 evaluated the clinical outcome follt effects associated with the presence of leukocytes in lowing implementation of a ULR program in prematt blood components. The selective patient populations ture infants admitted to neonatal intensive care units include those who are immunocompromised or chronitc (NICUs) by conducting a retrospective before and aftt cally transfused. The well-established leukocyte mediat ter study in three Canadian tertiary care NICUs from ated reactions include febrile reactions (fever), alloimmt January 1998 to December 2000. Thus study demonts munization and its clinically significant consequence strated no significant reduction in NICU mortality or known as platelet refractoriness, and transfusion transmt bacteremia, but reported an improvement in several mitted leukocyte associated viruses such as CMV. The clinical outcomes in premature infants requiring RBC differences in practice, belief, and opinion on how best transfusions (Table 12).166 The authors therefore recot to spend money for blood components has formed ommended the adoption of ULR in the care of all low
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 117 review universal leukoreduction
Table 12. Outcomes and odds ratios among 515 premature infants who underwent transfusion before and after implementation of ULR in Canada.166
Odds Ration (95% confidence interval)† Outcomes* Non-leukoreduction period Post-leukoreduction period Adjusted‡ Primary outcomes Bacteremia 79 (29.6) 63 (25.6) 0.59 (0.34-1.01) Mortality 45 (16.8) 44 (17.8) 1.22 (0.59-2.50)
Major NICU morbidities Retinopathy of prematurity 130 (59.1) 96 (41.7) 0.56 (0.33-0.93) Bronchopulmonary dysplasia 141 (52.6) 86 (34.8) 0.42 (0.25-0.70) Necrotizing enterocolitis 32 (12.5) 16 (6.7) 0.39 (0.17-0.90) Grade 3 or 4 IVH 45 (17.4) 33 (13.7) 0.65 (0.35-1.19) Any major NICU morbidity§ 207 (83.5) 157 (66.5) 0.31 90.17-0.56) Abbreviations: IVH, Intraventricular hemorrhage; NICU, neonatal intensive care unit; ULR, universal leukoreduction. * All outcomes data are expressed as No. (%). Denominators vary from 268 and 247 because of missing data. †Odds ratios of less than 1.00 indicate a beneficial effect of leukoreduction. ‡All multivariate models included site, admission status (outborn/inborn), gestational age, sex, birth weight, mode of delivery, antenatal steroids, volume transfused, apgar score at 5 minutes, score for Neonatal Acute Physiology on day 1, any cardiovascular pressor on day 1, continuous positive airway pressure, (0, 1-10. 11-25, or >25 days), influenza season (December-March), mechanical ventilation on day 1, high-frequency ventilation on day 1, supplemental oxygen support on day 1, surfactant use on day 1, steroids on day 1, umbilical catheter, and percutaneous catheter, § Including retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and grade 3 or 4 IVH.
birth weight infants requiring RBC transfusions. experts believe that the clinical benefit for ULR has Another before and after study (n=2095), conductet been shown for many potential recipients who suggest ed in the United Kingdom by Llewelyn et al167 examit therefore that this technology be applied universally, as ined 11 hospitals with patients undergoing cardiac bypt the only downside is cost.168 Others argue that in the pass surgery or total hip and/or knee replacement and absence of data suggesting universal benefit, the techtn found no impact of ULR on postoperative infections, nology should be applied only selectively to patients as reported in the Canadian study, but this study was who will clearly benefit.165 considerably smaller than the Canadian study (n=2095 All the data presented in this review clearly indicate versus n=14 786). that leukoreduction is associated with a reduced risk to Yazer et al,51 Paglino et al50 and King et al52 demot patients for some clinical indications, but not for others. onstrated that hospitals moving from a selective prott In some instances the available evidence is quite strong, tocol to ULR had a significantly reduced rate of fevers but in others the evidence for instituting ULR is not associated with RBC and platelet transfusions. These as strong. It is nonetheless clear that ULR does reduce fevers occurred in patients who would have been unlt the risk and severity of NHFTRs (level 1 evidence), the likely to receive leukocyte reduced blood with a selectt risk of CMV transmission (level 1 evidence), and is asst tive protocol. The difficulty in conducting such studies sociated with a reduced risk of HLA alloimmunization will increase over time because there are few European and platelet refractoriness (level 1 evidence). A causal countries that do not currently use ULR and because relationship between allogeneic blood transfusions and approximately 70% of the blood in the United States cancer recurrence seems to be indicated by the obsertv is already leukocyte reduced. Finding study sites which vational studies (level 3 evidence) reported between will also have a parallel and appropriate control arm to 1985 and 2000 but not by the available randomized, receive non-leukocyte reduced blood is becoming inct controlled trials in colorectal cancer patients (level 1 creasingly difficult. evidence). Specifically, the three available randomized, controlled trials provide no indication that perioperatt Conclusions tive allogeneic blood transfusion causes an increase in The ongoing development of safer transfusion options cancer recurrence or death as a result of cancer recurtr for use in the care of patients has created many contt rence. Relevant experimental animal studies nonethelt troversies for the field of transfusion medicine. In the less indicate that allogenic blood transfusions enhance debate concerning the implementation of ULR, some tumor growth promotion in animal models. Concerning
118 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review whether leukoreduction is associated with a decreased sence of considerations of cost, there is both scientific incidence of preoperative mortality and postoperative and medical consensus that leukocyte reduction is aptp infections, there is evidence, particularly in patients propriate medical practice. The WBCs are not a comtp undergoing cardiac surgery,125 that the use of leukoretd ponent of blood generally intended to be transfused duced blood components is associated with a decreased and they can be viewed as undesirable. Furthermore, risk for bacterial infection (level 1 evidence); reduces the leukoreduction is almost entirely risk free at least in risk of multi-organ dysfunction (level 3 evidence); and most situations”.170 most importantly leukoreduction significantly reduces Blajchman ended his 1999 editorial by quoting Sir the risk of mortality (level 1 evidence in cardiac surgery Anthony Bradford Hill,168 the father of randomized patients).125,127 controlled trials: “All scientific work is incomplete, Some have noted that there are significant problems whether it is observational or experimental. All scientt with the use of selective transfusion protocols. One tific work is liable to be upset or modified by advancing problem involves the selection of a patient who might knowledge. This does not confer on us a freedom to ignt meet the criteria for the selective use of leukoreduction, nore the knowledge we already have, or to postpone the but who is not being recognized. Such patients thus do action that it appears to demand at a given time”.171 not get the best blood component and thus will not bente If zero risk is the goal of transfusion medicine, the efit from this intervention. This could result from physt legacy from the HIV/HCV experience over the last two sician ignorance, incomplete hospital databases, or patt decades dictates that all risks should be considered and tients undergoing allogeneic transfusions at sites where the resources allocated for each according to priority leukoreduced blood components are not provided.169 goals. As important as the direct financial cost is the posts What about female patients with multiple pregnantc sibility of re-direction of resources away from risks that cies? Transfusion with non-leukocyte reduced blood have already been documented. In this regard it is impt will likely further alloimmunize them. Does this then portant to note that most early manufacturing interventt represent the mortgaging of their medical future? For tions or changes in practice in transfusion medicine were example, if certain treatments might be required by not introduced based on quality of evidence! Moreover such patients, such as kidney allograft transplantation, ULR should also be seen as an important processing or the need for chemotherapy to manage a malignancy step that will contribute to improving the safety and for which transfusion therapy support might be retq purity of blood components. In addition, it can also be quired?161 seen as an important but necessary preliminary processti It seems illogical to support laboratory-based progt ing step both resulting in safer products for transfusion grams of quality management to reduce the errors and recipients, but also one that will be required in anticipatt accidents affecting blood transfusion recipients without tion of the next new paradigm in transfusion medicine: recognizing that selective transfusion programs are a pathogen inactivation (see Table 1).172 major source of error. Thus, the implementation of good manufacturing practices and quality initiatives in blood Acknowledgement centers and transfusion services will be inherently intc Dr. Bassuni and Dr. Al-Moshary would like to thank complete until they can assure that transfusion requiremt McMaster transfusion medicine research program staff ments can be met without error.170 for their cooperation. Special thanks to Professor Morris In discussing public policy considerations, Vamvakis, Blajchman for sharing his extensive knowledge and experire Dzik and Blajchman stated the following: “In the abts ence.
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 119 review universal leukoreduction References 1. Kuhn TS. The Structure of Scientific Revolutions. RNA - screened blood donation. Vox Sang. 2004 learned. Transfusion and Aphaeresis Science. 2nd Enlarged Edition. The University of Chicago Apr;86(3):171-7. 2003;29(2):105-117. Press, Chicago, IL. 1970. 21. Phelps R, Robbins K, Liberti T, Machuca A, Lep-a 39. Vamvakas EC. The case against universal 2. Blumberg N, Heal JM. Transfusion and the arc G, Chamberland M, et al: Window-period hum- white blood cell reduction. ISBT Science Series. Immune System: A paradigm shift in progress? man immunodeficiency virus transmission to two 2006 Sept;1(1):64-72. Transfusion. 1995 Oct;35(10):879-83. recipients by an adolescent blood donor. Transfu-s 40. Sackett DL. Rules of evidence and clinical 3. Cohn EJ. The history of plasma fractionation. sion. 2004 Jun;44(6):929-33. recommendations on the use of antithrombotic Adv. Mil. Med. 1948;1: 364-443. 22. Schutter CG, Caspari G, Jursch CA, Willems agents. Chest. 1989 Feb;95(2 Suppl):S2-S4. 4. Hogman CF. Additive system approach in blood WR, Gerlich WH, Schaefer S, et al: A blood dona-t 41. Heddle NM, Klama LN, Griffith L, Roberts R, transfusion: Birth of the Sag and Sagman systems. tion negative in nucleic acid amplification tests for Shukla G, Kelton JG. A prospective study to identi-f Vox Sang. 1986;51:339-340. viral RNA. Lancet. 2000;355:41-42. fy the risk factors associated with acute reactions 5. Mollison PL. The introduction of citrate as an 23. Bordin JO, Heddle N, Blajchman M. Biological to platelet and red cell transfusions. Transfusion. anticoagulant for transfusion and of glucose effects of leukocytes present in transfused cellu-l 1993 Oct;33(10):794-7. as a red cell preservative. Br J Haematol. 2000 lar blood products. Blood. 1994;84(6):1703-1721. 42. Dzik S. Prestorage leukocyte reduction of Jan;108(1):13-18. 24. Lee JH, Klein HG. From leukocyte reduction to cellular blood components. Transfusion Sci. 1994 6. Busch MP, Dodd RY. NAT and blood safety: what leukocyte transfusion: the immunological effects Jun;15(2):131-9. is the paradigm? Transfusion. 2000;40(10):1157- of transfused leukocytes. Baillieres Best Pract Res 43. Muylle L. The role of cytokines in blood transfus- 1160. Clin Haematol. 2000 Dec;13(4):585-600. sion reactions. Blood Rev. 1995 Jun;9(2):77-83. 7. Stramer SL, Cagliotis S, Strong DM. NAT of the 25. Wortham ST, Ortolano GA, Wenz B. A brief his-t 44. Federowicz I, Barrett BB, Andersen JW, United States and Canadian blood supply. Transfu-s tory of blood filtration: clot screens, microaggreg- Urashima M, Popovsky MA, Andersen KC. Char-a sion. 2000 Oct;40(10):1165-8. gate removal, and leukocyte reduction. Transfus acterization of reactions after transfusion of cellul- 8. Blajchman MA. The clinical benefits of the Med Rev. 2003 Jul;17(3):216-22. lar blood components that are white cell reduced leukoreduction of blood products. J Trauma. 2006 26. Canadian Coordinating Office for Health Techn- before storage. Transfusion. 1996 Jan;36(1):21-8. Jun;60(6 Suppl):S83:S90. nology Assessment (CCOHTA): Leukoreduction: 45. Muylle l, wouters e, de bock r, peetermans me. 9. Allain PJ, Bianco C, Blajchman MA, Brecher The techniques used their effectiveness and Reactions to platelet transfusion: the effect of stor-a ME, Bush M, Leiby D, et al. Protecting the blood costs. Ottawa, ON, Canadian Coordinating Office age time of the concentrate. Transfusion medicine supply from emerging pathogens: the role of for Health Technology Assessment (CCOHTA). 1992; 2:289-93. pathogen inactivation. Transfus Med Rev. 2005 1998. 46. Heddle NM, Klama LN, Singer J, Richards C, Apr;19(2):110-26. 27. Vamvakas EC, Blajchman MA. Prestorage Fedak P, Walker I, et al. The role of plasma from 10. Pelletier JP, Transue S, Snyder EL. Pathogen versus poststorage white cell reduction for the platelet concentrates in transfusion reactions. N inactivation techniques. Best Pract Res Clin Haem- prevention of the deleterious immunomodulatory Engl J Med. 1994;331:625-628. matol. 2006;19(1):205-42. effects of allogeneic blood transfusion. Transfus 47. Muir JC, Jacobson S, Herschel L, Aubuchon 11. Scott MD, Bradley AJ, Murad KL. Camouflaged Med Rev. 2000;14:23-33. JP. Does prestorage leukocyte reduction of blood blood cells: low-technology bioengineering for 28. Shapiro MJ. To filter blood at universal leuko-r components reduce the risk of febrile reactions transfusion medicine? Transfus Med Rev. 2000 reduction: what is the answer? Crit Care. 2004;8(2 in sensitized patients? Blood. 1994;84(10 Suppl Jan;14(1):53-63. Suppl):S27-30. 1):464a. 12. Doucet J, Gao ZH, MacLaren LA, McAlister 29. Vamvakas EC, Blajchman MA. Universal WBC 48. Huh YO, Lichtiger B. Nonhemolytic transfusion VC. Modification of xenoantigens on porcine reduction: the case for and against. Transfusion. reaction to platelet concentrates: induction by cy-t erythrocytes for xenotransfusion. Surgery. 2004 2001 May;41(5):691-712. tokines released during storage. Current Issues in Feb;135(2):178-86. 30. Sweeney JD, Kouttab NM, Penn CL, Mettugh Transfusion Medicine. 1995 Jan-Apr;4. 13. Douay l, Andreu G. Ex vivo production of human KE, Nelson EJ, Oblon DJ. A comparison of prestora- 49. Dzieczkowski, JS, Barrett BB, Nester D, Camp-b red blood cells from hematopoietic stem cells: age WBC-reduced whole-blood-derived platel- bell M, Cook J, Surgrue M, et al. Characterization what is the future in transfusion? Transfus Med lets with bedside-filtered whole-blood-derived of reactions after exclusive transfusion of white Rev. 2007 Apr;21(2):91-100. platelets in autologous progenitor cell transplant. cell-reduced cellular blood components. Transfu-s 14. Blajchman MA. Allogenic transfusion associ-a Transfusion. 2000 Jul;40(7):794-800. sion. 1995 Jan;35(1):20-5. ated mortality. In global perspectives in transfus- 31. Adverse ocular reactions following transfu-s 50. Paglino JC, Pomper GJ, Fisch GS, Champion sion medicine. Lozano M, Contras M, Blajchman sions-United States, 1997-98. JAMA. 1998;279:576- MH, Snyder EL. Reduction of febrile but not aller-g MA(eds). Bethesda, Md: AABB Press. 2006:67-81. 578. genic reactions to RBCs and platelets after conv- 15. Stainby D, Jones H, Asher D, Atterbury C, Bon-c 32. Mair B, Leparc GF. Hypotensive reactions version to universal prestorage leukoreduction. cinelli A, Brant L, et al. On behalf of the shot seeing associated with platelet transfusions and angio-t Transfusion. 2004;44(1):16-24. group. Serous hazards of transfusion: a decade of tensin-converting enzyme inhibitors. Vox Sang. 51. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. hemovigilance in the UK. Transfus Med Rev. 2006 1998;74(1):27-30. The effect of prestorage WBC reduction on the Oct;20(4):273-82. 33. Pittman DL. Rationale for universal WBC re-d rates of febrile nonhemolytic transfusion reactions 16. Robillard P, Nawej KI, Jochem K. The Quebec duction of blood components? Transfusion. 2000 to platelet concentrates and RBC. Transfusion. hemovigilance system: description and results Mar;40(3):389 2004 Jan;44(1):10-5. from the first two years. Transfus Apher Sci. 2004 34. Sweeney JD, Dupuis M, Mega AT. Hypotensive 52. King KE, Shirley RS, Thomas SK, Bensen-Ken-n Oct;31(2):111-22. reactions to red cells filtered at the bedside, but nedy D, Tanz WS, Ness PM. Universal leukoreduc-t 17. Andreu G, Morel P, Forestier F, Debir J, Re-b not those filtered before storage, in patients taking tion decreases the incidence of febrile nonhemol- bibo D, Janvier G, et al. Hemovigilance network ACE inhibitors. Transfusion. 1998 April;38(4):410- lytic transfusion reactions to RBCs. Transfusion. in France: organization and analysis of immedi-a 411. 2004 Jan;44(1):25-9. ate transfusion incident reports from 1994 to 1998. 35. Takahashi TA, Abe H, Hosoda M, Nakai K, Seki-g 53. Heddle NM, Blajchman MA, Meyer RM, Lip-t Transfusion. 2002 Oct;42(10):1356-64. guchi S. Bradykinin generation during filtration of ton J, Walker JR, Sher GD, et al. A randomized 18. Ling AE, Robbins KE, Brown TM, Funmire V, platelet concentrates with a white cell-reduction controlled trail comparing the frequency of acute Thoe SYS, Wong SY, et al: Failure of routine HIV-1 filter (letter). Transfusion. 1995:35:967. reactions to plasma-removed platelets and pre- tests in case involving transmission with presero-c 36. Hild M, Soderstrom T, Egberg N, Lundahl J. Kin- storage WBC-reduced platelets. Transfusion. 2002 conversion blood components during the infect- netics of bradykinin levels during and after leukoc- May;42(5):556-66. tious window period. JAMA. 2000;284:210-214. cyte filtration of platelet concentrates. Vox Sang. 54. Roback JD. CMV and blood transfusions. Rev 19. Glynn SA, Kleiman SH, Schreiber GB, Busch 1998;75(1):18-25. Med Virol. 2002 Jul-Aug;12(4):211-219. MP, Wright DJ, Smith JW, et al: Trends in incidence 37. Arnold D, Molinaro G, Warkentin TE, DiTomasso 55. Dumont LJ, Luka J, Vander BJ, Whitley P, and prevalence of major transfusion-transmissible J, Webert KE, Davis I, et al. Hypotensive transfu-s Ambruso DR, Elfath MD. The effect of leukocyte- viral infections in US blood donors, 1991 to 1996. sion reactions can occur with blood products that reduction method on the amount of human cytom- Retrovirus Epidemiology Donor Study (REDS). are leukoreduced before storage. Transfusion. megalovirus in blood products: a comparison of JAMA. 2000;284:229-235. 2004 Sep;44(9):1361-6. aphaeresis and filtration methods. Blood. 2001 20. Delwart EL, Kalmin ND, Jones TS, Ladd DJ, 38. Seghatchian J. International forum: UK-Part Jun;97(11):3640-3647. Foley B, Tobler LH, et al: First report of human 2. Universal leucodepletion: an overview of some 56. Roback JD, Bray RA, Hillyer CD. Longitudinal immunodeficiency virus transmission via an unresolved issues and the highlights of lessons monitoring of WBC subset in packed RBC units aft-
120 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review ter filtration: implications for transfusion transmis-s AABB Technical/Scientific Workshop, Bethesda, brugge GJj, Eernisse JG. Alloimmunization against sion of infections. Transfusion. 2000 May;40(5):500- Md. American Association of Blood Banks. 1996. the MHC antigens after platelet transfusion is due 506. 75. Dzik W. Use of leukodepletion filters for the re-m to contaminating leukocytes in the platelet sus-p 57. Preiksaitis JK. The cytomegalovirus-”safe” moval of bacteria. Immunol Invest. 1995;24:95-115. pension. Exp Hematol. 1981 Jan;9(1):84-9. blood product: Is leukoreduction equivalent 76. Siblini L, Lafeuillade B, Ros A, Garraud O, 95. Sniecinski I, O’Donnell MR, Nowicki B, Hill LR. to antibody screening? Transfus Med Rev. Pozzetto B. Influence of blood prestorage condit- Prevention of refractoriness and HLA-alloimmuniz- 2000;14(2):112-136. tions and white blood cell filtration on the bacterial zation using filtered blood products. Blood. 1988 58. Leukocyte reduction for the prevention of transf- load of blood deliberately inoculated with Gram- May:71(5):1402-7. fusion transmitted-cytomegalovirus (TT-CMV): Ass- positive and Gram-negative pathogens. Vox Sang. 96. Andreu G, Dewailly J, Leberre C, Quarre MC, sociation bulletin 97-2. Bethesda, Md: American 2004 Nov;87(4):241-249(9). Bidet ML, Tardivel R, et al: Prevention of HLA im-m Association of Blood Banks. 1997;19:10-12. 77. Blajchman MA, Goldman M, Baeza F. Improv-i munization with leukocyte-poor packed red cells 59. Narvios AB, Przepiorka D, Tarrand J, Chan ing the bacteriological safety of platelet transfus- and platelets concentrates obtained by filtration. KW, Champlin R, Lichtinger B, et al. Transfusion sions. Transfus Med Rev. 2004 Jan;18(1):11-24. Blood. 1988;72(3):964-969. support using filtered unscreened blood products 78. Vasconcelos E, Seghatchian J. Bacterial con-t 97. Novotny VM, van Doorn R, Witvliet MD, Claas for cytomegalovirus-negative allogeneic marrow tamination in blood components and preventive FH, Brand A. Occurrence of allogeneic HLA and transplant recipients. Bone Marrow Transplant. strategies: an overview. Transfusion and Aphaere-s non-HLA antibodies after transfusion of prestora- 1998 Sep;22(6):575-7. sis Science. 2004;31(2):155-163. age filtered platelets and red blood cells: a pros- 60. Bowden RA, Slichter SJ, Sayers M, Wesidorf D, 79. Andreu G, Morel P, Forestier F, Debier J, Re-b spective study. Blood. 1995 Apr 1;85(7):1736-41. Cay SM, Schoch G, et al. A comparison of filtered bibo D, Janvier G, et al. Hemovigilance network 98. Kao KJ, Mickel M, Braine HG, Davis K, Enright leukocyte-reduced and cytomegalovirus (CMV) in France: organization and analysis of immediate H, Gernsheimer T, et al. White cell reduction in seronegative blood products for the prevention of transfusion incident reports from 1994-1998. Trans-f platelet concentrates and packed red cells by filt- transfusion-associated CMV infection after mar-r fusion. 2002 Oct;42(10):1356-1364. tration: a multicenter clinical trail. The Trap Study row transplant. Blood. 1995 Nov;86(9):3598-603. 80. Moraes-Souza H, Bordin JO, Bardossy L, Group. Transfusion. 1995 Jan;35(1):13-9. 61. Blajchman MA, Goldman M, Freedman JJ, MacPherson DW, Blajchman MA. Prevention of 99. Vamvakas EC. Meta-analysis of randomized Sher GD. Proceedings of a consensus conference: transfusion-associated Chagas’ disease: efficacy controlled trails of the efficacy of white cell re-d prevention of post transfusion CMV in the era of of white cell-reduction filters in removing Trypano-s duction in preventing HLA-alloimmunization and universal leukoreduction. Transfus Med Rev. 2001 soma cruzi from infected blood. Transfusion 1995 refractoriness to random-donor platelet transfus- Jan;15(1):1-20. Sep;35(9):723-6. sions. Transfus Med Rev. 1998;12(4):258-270. 62. Tegtmeier GE. Posttransfusion cytomegal- 81. Ironside JW. Pathology of variant Creutzfeldt- 100. Schiffer CA, Dutcher JP, Aisner J, Hogge lovirus infections. Arch Pathol Lab Med. 1989 Jakob disease. Arch Virol. 2000;16 Suppl:143-151. D, Wiernik PH, Reilly JP. A randomized trail of Mar;113(3):236-45. 82. Klein MA, Frigg R, Flechsig E, Raber AJ, Kalinke leukocyte-depleted transfusions to modify all- 63. Preiksaitis JK. Indications for the use of cytom- U, Bluethmann H, et al. A crucial role for B cells loimmunization in patients with leukemia. Blood. megalovirus-seronegative blood products. Transf- in neuroinvasive scrapie. Nature. 1997 Dec 18- 1983;62(4):815-820. fus Med Rev. 1991 Jan;5(1):1-17. 25;390(6661):687-690. 101. van Marwijk Kooy M, van Prooijen HC, Moes 64. Smith DM Jr. Leukocyte reduction for the 83. Klein MA, Frigg R, Raber AJ, Flechsig E, Hegyi I, M, Bosma-Stants I, Akkerman JW. Use of leukoc- prevention of transfusion-transmitted cytomega-l Zinkernagel RM, et al. PrP expression in B lympho-c cyte-depleted platelet concentrates for the prev- lovirus (TT-CMV). American Association of Blood cytes is not required for prion neuroinvasion. Nat vention of refractoriness and primary HLA alloimm- Banks. 1997;97:10-1. Med. 1998 Dec;4(12):1429-33. munization: a prospective, randomized trial. Blood. 65. Boeckh M, Nichols WG. The impact of cyto-m 84. Hill AF, Butletworth RJ, Joiner S, Jackson G, 1991;77(1):201-205. megalovirus serostatus of donor and recipient Rossor MN, Thomas DJ, Frosh A, et al. Investigat- 102. Oksanen K, Kekomaki R, Ruutu T, Koskimies before hematopoietic stem cell transplantation tion of variant Creutzfeldt-Jakob disease and other S, Myllyla G. Prevention of alloimmunization in in the era of antiviral prophylaxis and preemptive human prion diseases with tonsil biopsy samples. patients with acute leukemia by use of white cell- therapy. Blood. 2004 March 15;103(6):2003-2008. Lancet. 1999 Jan 16;353(9148):183-9. reduced blood components - a randomized trail. 66. Joint United Kingdom Blood Transfusion Serv- 85. Aguzzi A. Prion diseases, blood and immune Transfusion. 1991 Sep;31(7):588-94. vices and National Institute for Biological Stan-d system: concerns and reality. Haematologica. 2000 103. Williamson LM, Wimperis JZ, Williamson dards and Control Professional Advisory Comm- Jan;85(1):3-10. P, Copplestone JA, Gooi HC, Morgenstern GR, et mittee: Position Statement: CMV seronegative 86. St Romaine C, Hazlehurst G, Jewel AP. Leuk- al. Bedside filtration of blood products in the pre-v vs. Leukodepleted blood components for at risk kodepletion for transmissible spongiform encepha- vention of HLA alloimmunization - a prospective recipients. 2003 Nov 07. alopathies. Br J Biomed Sci. 2004;61:48-54 randomized study. Alloimmunisation Study Group. 67. Hladik W, Dollard SC, Mermin J, Fowlkes AL, 87. Llewelyn CA, Hewitt PE, Knight RS, Amar K, Blood. 1994 May 15;83(10):3028-35. Dowing R, Amin MM, et al. Transmission of human Cousens S, Mackenzie J, et al. Possible transmis-s 104. Sintnicolaas K, van Marwijk M, van Prooij- herpesvirus 8 by blood transfusion. N Engl J Med. sion of variant Creutzfeldt-Jakob disease by blood jen HC, van Dijk BA, van Putten WL, Claas FH, et 2006 Sep 28;355(13):1331-8. transfusion. Lancet. 2004 Feb 7;363(9407):417-21. al. Leukocyte depletion of random single-donor 68. Blajchman MA, Vamvakas EC. The continuing 88. Editorial team. Fourth case of transfusion-as-s platelet transfusions does not prevent secondary risk of transfusion-transmitted infections. N Engl J sociated vCJD infection in the United Kingdom. human leukocyte antigen-alloimmunization and Med. 2006 Sep 28;355:1303-5. Euro Surveill. 2007 Jan 18;12(1):E070118.4. refractoriness: a randomized prospective study. 69. Cesaire R, Kerob-Bauchet B, Bourdonne O, 89. MacGregor IR, Prowse CV. Impact and con-c Blood. 1995;85(3):824-828. Amar KO, Halbout P, Dehee A, et al. Evaluation of cerns for vCJD in blood transfusion: current stat- 105. The Trial to Reduce Alloimmunization to Plate-l HTLV-1 removal by filtration of blood cell compo-n tus. Curr Mol Med. 2004 Jun;4(4):361-73. lets Study Group. Leukocyte reduction and ultravio- nents in a routine setting. Transfusion. 2004;44:42- 90. Gregori L, McCombie N, Palmer D, Birch P, olet B irradiation of platelet to prevent alloimmuniz- 8. Spermino-Coker SO, giulivi A, et al. Effectiveness zation and refractoriness to platelet transfusions. 70. Zucker-Franklin D, Gorman JG. HTLV-I provirus of leukoreduction for removal of infectivity of N Engl J Med. 1997 Dec 25;337:1861-1870. in seronegative healthy blood donors (letter). Lan-c transmissible spongiform encephalopathies from 106. Seftel MD, Growe GH, Petraszco T, Benny cet. 1997 Apr 5;349(9057):999. blood. Lancet. 2004; 364(9433):529-31. WB, Le A, Lee Chao-Yong, et al. Universal prestora- 71. Yomtovian R. Bacterial contamination of blood: 91. Joint ukbts/nibsc professional advisory com-m age leukoreduction in Canada decreases platelet lesson from the past and road map for the future. mittee: position statement: creutzfeldt-jakob dise- alloimmunization and refractoriness. Blood. 2004 Transfusion. 2004 Mar;44(3):450-60. ease: will universal leukodepletion reduce the risk January 1;103(1):333-339. 72. Kuehnert MJ, Roth VR, Haley NR, Gregory KR, of transmission of variant cjd?. 2006 june 5. 107. Bordin JO, Blajchman MA. Blood transfu-s Elder, KV, Schreiber GB, et al. Bacterial contami-n 92. Gregori l, gurgel p v, lathrop j t, son edward p, sion and tumor growth in animal models. In Imm- nation and blood transfusion safety: experience in lambert bc, carbonell rg, et al: reduction in infec-t munomodulatory Effects of Blood Transfusion. the United States, 1998 through 2000. Transfusion tivity of endogenous transmissible spongiform enc- Vamvakas EC, Blajchman MA, Eds. AABB press. 2001; 41: 1493-1499. cephalopathies present in blood by adsorption to 1999:29-42. 73. United States General Accounting Office. selective affinity resins. Lancet 2006; 368: 2226-30. 108. Opelz G, Sengar DPS, Mickey MR, Terasaki PI. Blood supply: FDA oversight and remaining issues 93. Semple JW. Leucodepletion and immune Effect of blood transfusions on subsequent kidney of safety. GAO/PEMD-97-1 (Washington, DC: Feb. response mechanisms. Vox Sanq. 2004 Jul;87(2 transplants. Transplant Proc. 1973;5:253-9. 25, 1997). Suppl):136-8. 109. Heiss MN, Menpel W, Delanoff C, Jauch 74. Transfusion reactions: Refresher and update. 94. Claas FH, Smeenk RJ, Schmidt R, van Steenb- KW, Gabka C, Mempel M, et al. Blood transfu-s
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 121 review universal leukoreduction
sion-modulated tumor recurrence: first results of 124. Nathens AB, Nester TA, Rubenfeld GD, Nirula 139. Francis DM. Relationship between blood randomized study of autologous versus allogeneic R, Gernsheimer TB. The effects of leukoreduced transfusion and tumor behavior. Br J Surg. blood transfusion in colorectal cancer surgery. J blood transfusion on infection risk following inj- 1991;78:1420-8. Clin Oncol. 1994;12:1859-67. jury: a randomized controlled trial. Shock. 2006 140. Blumberg N, Hal JM. Effects of transfusion on 110. van de Watering LM, Hermans J, Houbiers Oct;26(4):342-347. immune-function. Cancer recurrence and infec-t JG, van den Broek PJ, Bouter H, Boer F, et al. Bene- 125. Vamvakas EC. White-blood-cell-containing tion. Arch Pathol Lab Med. 1994 Apr; 118(4):371-9. eficial effect of leukocyte depletion of transfused allogeneic blood transfusion and postoperative 141. Vamvakas EC. Perioperative blood transfus- blood on postoperative complications in patients infection or mortality: an updated meta-analysis. sion and cancer recurrence: meta-analysis for undergoing cardiac surgery: a randomized clinical Vox Sang. 2007;92(3):224-232. explanation. Transfusion. 1995 Sep;35(9):760-8. trail. Circulation. 1998;97:562-568. 126. Vamvakas EC, Blajchman MA. Deleterious 142. Blajchman MA. Immunomodulatory effects of 111. Jensen LS, Andersen AJ, Christiansen PM, clinical effects of transfusion-associated immuno-m allogeneic blood transfusions: clinical manifesta-t Hokland P, Juhl CO, Madsen G, et al. Postoperative modulation: fact or fiction? Blood. 2001 March 1; tions and mechanisms. Vox Sang. 1998; 74 Suppl infection and natural killer cell function following 97(5):1180-1195. 2:315-9. blood transfusion in patients undergoing elective 127. Vamvakas EC, Blajchman MA. Transfusion- 143. Blajchman MA. Immunomodulation and blood colorectal surgery. Br J Surg. 1992 Jun;79(6):513- related immunomodulation (TRIM): An update. transfusion. Am J Ther. 2002;9:389-395. 6. Blood Rev. In press. 2007 Sep 3. 144. Linden JV, Pisciotto PT. Transfusion associ-a 112. Tartter PI, Mohandas K, Azar P, Endres J, 128. Alexiou C, Tang AA, Sheppard SB, Smith DC, ated graft-versus-host disease. N Engl J Med. Kaplan J, Spivack M. Randomized trial comparing Livesey SA, Manro JL, et al. The effect of leu-c 1990;323:315-21. packed red cell blood transfusion with and without codepletion on leucocyte activation, pulmonary 145. Karger R, Kretschmer V. In line filtration. leukocyte depletion for gastrointestinal surgery. inflammation and respiratory index in surgery Transfusion and Apheresis Sci. 2002;27:137-152. Am J Surg. 1998 Nov;176(5):462-6. for coronary revascularisation: a prospective 146. Akahoshi M, Takanashi M, Masuda M, 113. Peters WR, Fry RD, Fleshman JW, Kodner IJ. randomised study. Eur J Cardiothorac Surg. 2004 Yamashita H, Hidano A, Hasgaua K, et al. A case of Multiple blood transfusions reduce the recurrence Aug;26(2):294-300. transfusion-associated graft-versus-host disease rate of Crohn’s disease. Diseases of the Colon & 129. Sheppard SV. Leucocyte filtration in cardiac is not prevented by white cell reduction filters. Rectum. 1989 Sep;32(9):749-753. surgery [Phd Thesis]. Porstmouth, UK, University Transfusion. 1992;32:169-72. 114. Worldwide collaborative observational study of Portsmouth. 1999. 147. Hayashi H, Nishiuchi T, Tamura H, Takeda K. and meta-analysis on allogenic leukocyte immu-n 130. Karaiskos TE, Astras GM, Panagoitou MS, Transfusion-associated graft-versus-host disease notherapy for recurrent spontaneous abortion. Vassili MI, Palatianos GM. Effectiveness of leukoc- caused by leukocyte-filtered stored blood. Anes-t Recurrent Miscarriage Immunotherapy Trialists cyte filtration during cardiopulmonary bypass in thesiology. 1993 Dec;79:1419-21. Group. Am J Reprod Immunol. 1994 Sep;32(2):55- patients with chronic obstructive pulmonary dis-e 148. Anderson KC. Current trends: evolving conc- 72. ease (abstract). Annual Meeting of the American cepts in transfusion medicine. Leukodepleted cell- 115. Blajchman MA. Allogeneic blood transfu-s College of Chest Physicians, Philadelphia, USA. lular blood components for prevention of transfus- sions, immunomodulation, and postoperative 2001 November. sion-associated graft-versus-host disease. Transf- bacterial infection: do we have the answers yet? 131. Fabri A, Manfredi J, Piccin C. Use of leuko-c fus Sci. 1995 Sep;16(3):265-268. Transfusion. 1997 Feb;37(2):121-5. cyte depletion arterial line filter during deep hyp- 149. Williamson LM, Stainsby D, Jones H, Love 116. Houbiers JG, Brand A, van de Watering LM, pothermic cardiopulmonary bypass and circulat- E, Chapman CE, Navarrete C, et al. The impact of Hermans J, Verwey PJ, Bijnen AB, et al. Ran-d tory arrest (abstract). 12th Annual Meeting of the universal leukodepletion of the blood supply on domized controlled trail comparing transfusion European Association for Cardiothoracic Surgery, hemovigilance reports of posttransfusion purpura of leukocyte-depleted or buffy-coat-depleted Brussels, Belgium. 1998 September. and transfusion-associated graft-versus-host dis-e blood in surgery for colorectal cancer. Lancet. 132. Fergusson D, Khanna MP, Tinmouth A, Hebert ease. Transfusion. 2007;47:1455-67. 1994;344:573-578. PC. Transfusion of leukoreduced red blood cells 150. Przepiorka D, Leparc GF, Stovall MA, Werch 117. Jensen LS, Kissmeyer-Nielsen P, Wolff B, may decrease postoperative infections: two meta- J, Lichtinger B. Use of irradiated blood compo-n Ovist N. Randomized comparison of leukocyte- analyses of randomized controlled trails. Can J nents: practice parameter. Am J Clin Pathol. 1996 depleted versus buffy-coat-poor blood transfusion Anaesth. 2004 May; 51(5):417-424. Jul;106(1):6-11. and complications after colorectal surgery. Lan-c 133. Hebert PC, Fergusson D, Blajchman MA, Wells 151. Klein HG. Pathogen inactivation technol-o cet. 1996 Sep 28;348:841-845. GA, Kmetic A, Coyle D, et al. Clinical outcomes fol-l ogy: cleansing blood supply. J Intern Med. 2005 118. Titlestad IL, Ebbesen LS, Ainsworth AP, Lill- lowing institution of the Canadian universal leukor- Mar;257(3):224-237. levang ST, Quist N, Georgsen J. Leukocyte-deplet- reduction program for red blood cell transfusions. 152. Bux J, Sachs UJ. The pathogenesis of trans-f tion of blood components does not significantly JAMA. 2003 Apr 16;289(15):1941-9. fusion-related acute lung injury (TRALI). 2007 reduce the risk of infectious complications: Re-s 134. Volkova N, Klapper E, Pepkowitz SH, Denton Mar;136(6):788-99. sults of a double-blinded, randomized study. Int J T, Gillaspie G, Goldfinger D. A case-control study 153. Popovsky M, Abel MD, Moore SB. Transfusion- Colorectal dis. 2001;16(3):147-153. of the impact of WBC reduction on the cost of related acute lung injury. Blood. 2005;105:2266-73. 119. Wallis JP, Chapman CE, Orr KE, Clark SC, Forty hospital care for patients undergoing coronary 154. Silliman CC, Thurman GW, Ambruso DR. JR. Effect of WBC reduction of transfused RBCs on artery bypass graft surgery. Transfusion 2002 Sep Stored blood products contain agents that prime postoperative infection rates in cardiac surgery. ;42(9):1123-1126. the neutrophill NADPH oxidase through the Transfusion. 2002 Sep;42(9):1127-34. 135. Blumberg N, Heal JM, Cowles JW, Hicks platelet-activating-factor receptor. Vox Sang. 120. Van Hilten JA, van de Watering LM, van GL, Risher WH, Samuel PK, et al. Leukocyte-re-d 1992;63(2):133-136. Bockel JH, van de Velde CJ, Kievit J, Brand R, et duced transfusions in cardiac surgery results of 155. Swanson K, Dwyre DM, Krochmal J, Raife TJ. al. Effects of transfusion with red cells filtered to an implementation trial. Am J Clin Pathol. 2002 Transfusion related acute lung injury (TRALI): cur-r remove leucocytes: randomised controlled trial Sep;118(3):376-81. rent clinical and pathophysiologic considerations. in patients undergoing major surgery. BMJ. 2004 136. Blajchman MA, Bardossy L, Carmen R, Sas-t Lung. 2006 May-Jun;184(4):177-85. May 29;328(7451):1281-1284. try A, Singal DP. Allogeneic blood transfusion-ind- 156. Hudson L, Milberg J, Anardi D, Maunder R. 121. Bilgin YM, van de Watering LM, Eijsman L, duced enhancement of tumor growth: two animal Clinical risks for the development of the acute Versteegh MI, Brand R, van Oers MH, Brand A. models showing amelioration by leukodepletion respiratory distress syndrome. American Jour-n Double-blind, randomized controlled trial on the and passive transfer using spleen cells. Blood. nal of Respiratory and Clinical Care Medicine. effect of leukocyte-depleted erythrocyte transfu-s 1993 Apr;81(7):1880-2. 1995;151(1):293-301. sions in cardiac valve surgery. Circulation. 2004 137. Bordin JO, Bardossy L, Blajchman MA. 157. Silliman CC, Voelkel NF, Allard JD, Elzi DJ, Jun 8;109(22):2755-60. Growth enhancement of established tumors by Tuder RM, Johnson JL, et al. Plasma and lipids 122. Bracey AW, Radovancevic R, Nussmeier NA, allogeneic blood transfusion in experimental ani-m from stored packed red blood cells cause lung Larocco M, Vaughn WK, Cooper JR. Leukocyte- mals and its amelioration by leukodepletion: the injury in an animal model. J Clin Invest. 1998 reduced blood in open-heart surgery patients: eff- importance of the timing of the leukodepletion. Apr;101(7):1458-67. fects on outcome. Transfusion. 2002;42(Suppl):5s. Blood. 1994;84:344-8. 158. Silliman CC, Ambruso DR, Boshkov LK. 123. Boshkov LK, Furnary A, Morris C, Chien G, van 138. Brand A, Hobiers JGA. Clinical studies of Transfusion-related acute lung injury. Blood. 2005 Winkle D, Reik R. Prestorage leukoreduction of red blood transfusion and cancer. In immunomodula-t Mar;105(6):2266-73. cells in elective cardiac surgery: results of a dou-b tory effects of blood transfusions. Vamvakas EC, 159. Wortham ST, Ortalano GA, Wenz B. A brief ble-blind randomized controlled trial (abstract). Blajchman MA (Eds). Bethesda, Md; AABB Press. history of blood filtration: clot screens, microagg- Blood. 2004; 104:112a. 1999:145-190. gregate removal, and leukocyte reduction. Transf-
122 Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com universal leukoreduction review fus Med Rev. 2003 Jul;17(3):216-22. leukocyte depletion of blood components: cell (editorial). Transfusion. 1999;39:665-70. 160. Wilson K, Wilson M, Hebert PC, Graham I. concentrates and plasma. Vox Sang. 2001;81:56- 169. Ness PM, Lipton KS. Selective transfusion The application of the precautionary principle to 77. protocols: errors and accidents waiting to happen. the blood system: The Canadian blood system’s 165. Thurer RL, Luban NL, AuBuchon JP, Silver H, Transfusion. 2001 May;41(5):713-715. vCJD donor deferral policy. Transfus Med Rev. McCarthy LJ, Dzik S, et al. Universal WBC reduct- 170. Vamvakas EC, Dzik W, Blajchman MA. Dele- 2003 Apr;17(2): 89-94. tion (letters). Transfusion. 2000 Jun;40(6):751-2. eterious effects of transfusion-associated imm- 161. Angelbeck JH, Ortalano GA. Universal leuko-c 166. Fergusson D, Hebert PC, Lee SK, Walker R, munomodulation: appraisal of the evidence and cyte reduction: Is it appropriate medical practice Barrington KJ, Joseph L, et al. Clinical outcomes recommendations for prevention. In: Vamvakas or not? J Infus Nurs. 2005 Jul-Aug;28(4):273-281. following institution of universal leukoreduction of EC, Blajchman MA (Eds). Immunomodulatory ef-f 162. Advisory committee on blood safety and blood transfusions for premature infants. JAMA. fects of blood transfusion. Bethesda, Md; AABB availability. Blood safety resolution. January 2001. 2003 Apr 16;289(15):1950-6. Press. 1999:253-285. Available from: http://www.hhs.gov/bloodsafety/ 167. Llewelyn CA, Taylor RS, Todd AA, Steven 171. Hill AB. The environment and disease: as-s resolutions/resjanol.html. Accessed 2001 Janu-a SW, Murphy MF, Williamson LM, et al. The ef-f sociation or causation? Pro R Soc Med. 1965 ary 29. fect of universal leukoreduction on postoperative May;58:295-300. 163. Advisory committee on blood safety and infections and length of hospital stay in elective 172. Bryant BJ, Klein HG. Pathogen inactivation: availability. Blood safety summary. January 2001. orthopedic and cardiac surgery. Transfusion. 2004 the definitive safeguard of blood supply. Arch Available from: http://www.hhs.gov/bloodsafety/ Apr;44(4):489-500. Pathol Lab Med. 2007 May;131(5):719-33. summaries/sumjano1.html. Accessed 2001 Febru-a 168. Blajchman MA. Transfusion-associated im-m 173. Sweeney JD. Leukoreduction of the blood ary 1. munomodulation and universal white cell reduct- supply in Rhode Island. Med Health R I. 1998 164. Engelfriet CP. International forum. Universal tion: are we putting the cars before the horse? Dec;81(12):386-91.
Hematol Oncol Stem Cell Ther 1(2) April 2008 hemoncstem.edmgr.com 123