In recent years, interest in leukocyte-reduced blood products has increased as accumulating evidence suggests that cancer recurrence, graft-versus-host disease (GVHD), and postoperative infections are mediated by leukocyte contamination of blood components (Table 1). Herzig et al. (1) in the mid-1970s stimulated interest in leukocyte depletion by showing that leukocyte reduction of platelet components improved posttransfusion platelet counts in patients with human-leukocyte-associated (HLA) antigen incompatibilities. Further studies by Eernisse and Brand (2) demonstrated that leukocyte contamination of platelet concentrates was responsible for HLA antibody formation. These findings led to growing use of leukocyte-reduced platelet transfusions. However, debate continues as to how low the leukocyte count must be to prevent leukocyte-mediated alloimmunization.
In the last decade, great strides have been made in developing more efficient leukocyte filters, and the administration of leukocyte-reduced blood products has become routine. This review focuses on evidence that leukocyte-reduced blood products may decrease adverse effects associated with blood transfusion.
Methods to Achieve Leukocyte Reduction
Leukocyte content of whole blood averages two billion (2 × 109) leukocytes per 500 mL of whole blood (3). During blood component preparation, the majority of leukocytes (90%) fractionate with the red blood cells (RBCs). Platelet concentrates retain approximately 8% of the initial leukocytes whereas the remaining 2% are present in the plasma before freezing (4). The American Association of Blood Banks defines leukocyte-reduced red blood cells as containing <5 × 106 leukocytes per unit. The critical immunogenic leukocyte load, defined as the concentration of leukocytes necessary to cause sensitization in a previously nonsensitized individual, is generally accepted as 106 leukocytes per unit (5). In contrast, European RBC components, which undergo buffy-coat depletion as opposed to filtration, have a leukocyte content <1.2 × 109 per unit. Buffy-coat depleted RBCs are commonly prepared by centrifugation of whole blood followed by removal of the plasma and buffy-coat.
Leukocyte reduction can be achieved by various techniques, including centrifugation, leukocyte filtration, sedimentation, washing, freeze-thawing, and apheresis. At present, filtration is the most widely used method for producing leukocyte-reduced blood components. Three types of filters are currently used in the transfusion of blood components (Table 2). “First generation filters,” or “screen filters,” with a pore size of 170 to 260 microns remove gross debris, but not leukocytes (6–9). “Second generation filters” with a pore size of 20 to 50 microns, remove 70% to 90% of leukocytes (6–9). The most widely used leukocyte reduction filters are the “third generation filters” (6–9). These high efficiency filters remove 99.9% of leukocytes and may be used at the patient’s bedside during transfusion or by the hospital transfusion service before distribution of the blood. In contrast to the first generation and second generation filters that rely on pore size to entrap leukocytes, third generation filters, also referred to as “adhesion filters,” remove leukocytes by adhesion to negatively charged surfaces in the filter (6–9). Most bedside leukocyte reduction filters substantially impair blood administration rates (one unit RBCs/20–30 min). However, specially designed high-flow, high-efficiency filters (one unit RBCs/5 min) are available (8,9). Standard blood filters and/or microaggregate filters are unnecessary with the use of leukocyte reduction filters.
Apheresis techniques exploit density differences between blood cellular components to separate contaminating leukocytes (10). In Europe, solvent-detergent treated blood components are used extensively. Filtration, one of the steps in production of solvent-detergent treated blood components, partially removes both leukocytes and bacteria. Studies demonstrate that the incidence of adverse effects (i.e., fever, chills, rash, and dyspnea) are reduced by substituting solvent-detergent treated plasma for fresh frozen plasma (11,12).
Leukocytes can be removed shortly after collection (prestorage filtration) or after storage but before transfusion (poststorage filtration). Studies in animals suggest that prestorage leukocyte reduction is more effective than poststorage leukocyte reduction in preventing platelet alloimmunization (13). Prestorage leukocyte filtration also minimizes the formation of “soluble” leukocyte components, particularly early oxidative radicals released by intact leukocytes (14). These oxygen free radicals (O2-, OH-, H2O2, and others) are highly toxic to cell membranes and represent a threat to survival of surrounding RBCs and platelets (14).
Clinical Benefits of Leukocyte Reduction
Febrile Nonhemolytic Transfusion Reactions
A febrile nonhemolytic transfusion reaction is defined as a temperature increase of 1°C after an allogeneic blood transfusion. Most febrile nonhemolytic transfusion reactions are caused by alloantibodies in the recipient’s plasma against antigens present on donor leukocytes and/or platelets (15,16). The incidence of febrile nonhemolytic transfusion reactions is reduced in patients receiving a first transfusion (0.5%) as compared with chronically transfused patients (60%), the reason being that chronically transfused patients are more likely alloimmunized (17,18). Febrile nonhemolytic transfusion reactions can be decreased by reducing leukocyte concentrations below 0.5 × 109 (19). Despite the use of leukocyte-reduced blood products, febrile reactions may still occur. In these rare cases, febrile reactions correlate with increased concentrations of tumor necrosis factor and interleukins (IL-1β, IL-6, IL-8) (20). Prestorage leukocyte reduction may decrease the incidence of such reactions by reducing cytokine generation. With the availability of increasingly efficient leukocyte reduction filters during the last decade, the incidence of febrile nonhemolytic transfusion reactions in patients receiving multiple transfusions has been reduced substantially—from nearly 61% to as low as 2.5% (18).
Platelet Refractoriness and Alloimmunization
Alloimmunization, in patients who have had multiple transfusions, can reduce the clinical effectiveness of platelet transfusions by nearly 50%. This problem is especially prevalent among those patients receiving pooled random donor platelet concentrates (21). Investigations correlating platelet refractoriness with the presence of HLA antibodies has found that, in patients who develop platelet refractoriness, the majority previously have been pregnant or have received transfusions with nonleukocyte depleted blood products (22). Contaminating leukocytes in both platelet and RBC transfusions are the primary, but not exclusive, source of alloimmunization to HLA antigens. The Trial to Reduce Alloimmunization to Platelets directly compared the effect of leukocyte reduction and ultraviolet B-irradiation on the incidence of HLA alloimmune-mediated refractoriness to platelet transfusion (23). This investigation demonstrated that patients who have received transfusions with leukocyte-reduced or ultraviolet B-irradiated platelets were not alloimunized and did not develop refractoriness to platelet transfusions. In contrast, patients with preexisting HLA-specific antibodies did not benefit from leukocyte reduction (23). Studies in patients with severe aplastic anemia have demonstrated a reduced incidence of platelet alloimmunization with prestorage leukocyte reduction (24).
Immunomodulation and Postoperative Infectious Complications
In the 1970s, clinical evidence of transfusion-associated immunomodulation was first provided when it was shown that allogeneic RBC transfusions were beneficial in preserving both renal and cardiac allografts (25,26). Later studies suggested that contaminating leukocytes in RBC transfusions might be responsible for down-regulation of natural-killer (NK) cell activity, T cell proliferation, T lymphocyte antitumor activity, CD-4 helper to CD-8 suppressor ratio, and lymphocyte blastogenesis (27,28).
Leukocyte lysis during storage releases immunomodulators, including histamine, eosinophilic cationic protein, eosinophil protein X, myeloperoxidase, and plasminogen activator inhibitor-1 (29). These bioactive mediators impair immunosuppresion, up-regulate the inflammatory response, and by way of oxygen-free radicals, damage tissue (29). A prospective, randomized trial involving patients who underwent colorectal surgery demonstrated that patients who received transfusions with allogeneic whole blood had significantly more postoperative infections than those who received allogeneic blood depleted of 99.9% of leukocytes (28). NK cell activity was impaired as long as 30 days in patients receiving nonleukocyte-depleted allogeneic blood transfusions (28).
In the largest randomized, controlled study to date, van de Watering et al. (30) assigned 914 patients undergoing cardiac surgery to one of three RBC transfusion groups: (A) buffy-coat depleted packed RBCs, (B) prestorage leukocyte-filtered RBCs, and (C) poststorage leukocyte filtered RBCs. The incidence of infection was similar among the three groups (30). However, when the prestorage and poststorage leukocyte-filtered RBC groups were combined and compared with the buffy-coat reduced RBC group, patients receiving buffy-coat depleted RBCs had a statistically higher infection rate (30). In patients receiving more than 4 U of RBCs, the infection rate in the buffy-coat depleted group was 31.4% compared with 23.8% and 21.3% (P < 0.05) in the prestorage and poststorage leukocyte-reduced groups, respectively. The infection rate was 8% in patients receiving no transfusions (30). The authors concluded that in cardiac surgical patients requiring more than 3 U of packed RBCs, leukocyte reduction by filtration significantly reduced postoperative infections and mortality. The results of eight prospective studies are summarized in Table 3.
Differences in investigational design, nature of blood components transfused, and patient populations make comparisons among published studies difficult. Most investigations have occurred in Europe where the buffy-coat method is used to prepare leukocyte-depleted blood components. In the United States and Canada, filtration is preferred, and the buffy-coat method is rarely used. In contrast to third generation leukocyte reduction filters that remove 99.9% of leukocytes, blood products generated by the buffy-coat method retain a greater concentration of leukocytes and, therefore, provide only partially leukocyte-reduced blood components. Major controversy continues as to whether associations between allogeneic blood transfusions, immunosuppression, and postoperative infectious complications are causal. The definition of “infection” may be partially responsible. Defining infectious complications by the presence of positive blood cultures likely underestimates the number of clinically significant adverse events. In contrast, defining infectious complications by the presence of a fever likely overestimates the same.
Prevention of Bacterial Growth
Transfusion of blood components containing bacteria may lead to potentially fatal sepsis. Estimates as to the frequency of these rare reactions have been as high as 1 in 700 random donor platelet transfusions, 1 in 4000 single donor platelet transfusions, and 1 in 31,000 RBC transfusions (37). Most bacterial contamination occurs at collection as a result of inadequate skin preparation before venipuncture. Other causes include asymptomatic bacteremia at the time of blood donation and bacterial contamination during component processing. Common pathogens include Gram-negative endotoxin producing organisms such as Yersinia enterocolitica, Pseudomonas, and Enterobacter (38).
The role of leukocyte reduction to remove bacteria from contaminated blood components has been studied (39). Y enterocolitica was inoculated into fresh blood. After several hours of storage, leukocyte filtration was performed while a control aliquot of blood was retained without undergoing filtration. The incidence of positive cultures for Y enterocolitica after 42 days of storage was 8% in the leukocyte-filtered group as compared with 67% in the nonfiltered group. Optimal storage time before filtration to allow for maximal leukocyte ingestion of bacteria appeared to be between 2 and 12 hours. However, in a separate study, Wenz et al. (40) demonstrated bacterial growth of four organisms in leukocyte-reduced platelet concentrates after one day of storage. The beneficial effect of leukocyte reduction may lie in removal of leukocytes containing ingested bacteria (41). Newer leukocyte reduction filters remove up to 75% to 100% of Yersinia bacteria. Similar results have been demonstrated with Staphylococcus xylosus (42).
Numerous studies have explored the relationship between transfusion and cancer recurrence. Results of these studies are mixed, with approximately half suggesting an adverse effect of allogeneic transfusion on cancer recurrence (43–50). In most observational studies, cancer recurrence rates were evaluated in surgical patients who received allogeneic blood transfusions as compared with patients who received no blood transfusions. Perioperative blood transfusions are associated with several confounding variables that by themselves predict an overall worse outcome. Some of these variables include the difficulty of the operative procedure, skill of the surgeon, extent of tumor invasion and resection, and the overall health of the patient. Despite multivariate statistical analyses, it is possible that unaccounted for confounding variables could have influenced subsequent outcomes (51,52).
The most recent, relevant, and prospective human studies involve patients undergoing colorectal surgery (4,53) Two recent meta-analyses have addressed this issue. Both identified an association between allogeneic blood transfusion and colorectal cancer recurrence after surgery (54,55). Duke’s classification and blood transfusion were the only clinical variables that independently predicted cancer recurrence (56). Blood transfusions in colorectal surgery patients have been reported to increase cancer recurrence by 37% (55). Blood transfusions also have been associated with increased recurrence of breast, lung, kidney, prostate, stomach, cervical, laryngeal, soft tissue, and bone malignancies (57). Studies of leukocyte reduction in animal models have demonstrated reduced tumor growth and fewer lung metastases (58). These beneficial effects occurred only if leukocyte reduction occurred before blood storage (56,59).
GVHD is a potentially lethal condition caused by donor T lymphocytes. Nearly all types of blood components (i.e., whole blood, platelet concentrates, and granulocyte concentrates) have been associated with this condition. In immunocompromised recipients, host defense mechanisms fail to suppress viable transfused donor lymphocytes, which engraft within the recipient’s marrow, ultimately resulting in death (60). GVHD may also occur in immunocompetent recipients. This most often occurs when the donor and recipient share an HLA haplotype. The use of directed-donor blood from first degree relatives increases the potential for GVHD. The number of donor lymphocytes necessary for initiation of GVHD is unclear; however, animal studies suggest 107 lymphocytes per kilogram of body weight are needed (61). Host injury, and eventual death, results from epithelial damage and hematopoietic stem cell destruction. Cytokines, namely tumor necrosis factor and interleukins released by donor cytotoxic T lymphocytes and NK cells, mediate GVHD pathophysiologic responses (60).
Several methods are available to reduce the number of viable T lymphocytes before transfusion. Gamma-irradiation has been the traditional approach and remains the most widely accepted method for prophylaxis against GVHD. The recommended minimal dose, 25 Gy (γ-irradiation), decreases lymphocyte mitogen response by 90% (62). Ultraviolet- irradiation has been shown in animals to reduce the incidence of GVHD. In vitro studies have suggested that third generation leukocyte reduction filters also may decrease the incidence of GVHD (63).
Cytomegalovirus (CMV) Infections
CMV antibody prevalence rates in North America range from 30% to 80% (61). Transfusion-associated CMV infections are recognized as a significant cause of morbidity and mortality in immunocompromised patients and especially in organ transplant recipients. After either kidney or liver transplants, more than 60% of patients develop antibodies against CMV (64). CMV has been isolated from peripheral blood leukocytes of many infected patients. Studies in neonates suggest that transfusion of washed RBCs (87% leukocyte removal) from CMV-positive donors is associated with a lower incidence of CMV seroconversion (1.3%) than that seen in recipients of unwashed RBCs (13% to 35%) (65).
Data from patients undergoing bone marrow transplantation indicate that the use of leukocyte-reduced blood products is equivalent to the use of CMV-seronegative blood products in preventing transfusion-associated CMV infection (66). In the heart transplant setting, leukocyte-reduced blood transfusion resulted in none of 17 (0%) patients receiving seropositive transfusions developing CMV infection, whereas 14 of 36 (39%) patients transfused with nonleukocyte-depleted seropositive blood became acutely infected (67).
The use of leukocyte-reduced blood products may also be associated with decreased transmission of human T lymphotrophic virus which has been linked with T cell leukemias and myopathies resembling multiple sclerosis (68). The exact role of leukocytes in transmission of new variant Creutzfeldt-Jakob disease remains hotly debated. Infectious prion particles have been isolated from lymphatic tissue, and their subsequent spread into the blood is a possibility (69). Many European countries have concluded that adoption of leukocyte-reduced blood products may decrease the potential for blood-borne transmission of this devastating neurological disease. To date, no cases of new variant Creutzfeldt-Jakob disease have been reported in association with a transfusion.
Storage of RBC Components
Storage of RBCs leads to membrane and metabolic changes. Reduction in erythrocyte adenosine triphosphate in excess of 30% substantially reduces RBC survival after transfusion (70). Other indicators of poor RBC survival include glucose consumption, increased lactate/potassium production, free hemoglobin, and lactate dehydrogenase in the plasma supernatant. The presence of leukocytes in blood components reduces glucose availability, and leukocyte lysis leads to release of cytokines that reduce RBC survival (70). Studies demonstrate that erythrocyte adenosine triphosphate is significantly better preserved in leukocyte-reduced RBC components (71).
Storage of Platelet Concentrates
Similar studies with platelet concentrates demonstrate that increased leukocyte concentrations are associated with decreases in pH and increases in glucose consumption, lactate production, and lactic dehydrogenase release (72). Along with leukocyte concentration, the procedure used to prepare platelet concentrates is also crucial for improving the storage condition of platelet concentrates. The morphology score of leukocyte-reduced platelets prepared by the buffy-coat method is higher than that of leukocyte-reduced platelets prepared by the classical platelet-rich plasma (PRP) method. The latter involves harvesting platelets from whole blood of “random donors” within eight hours of collection. Approximately 500 mL of whole blood undergoes centrifugation to allow for segregation of the PRP. The PRP then undergoes a second centrifugation to yield platelet concentrate and plasma. Fijnheer et al. (73) concluded that platelets prepared from PRP are more frequently activated than platelets prepared by the buffy-coat method.
Sloand and Klein (74), have demonstrated that leukocytes stored in platelet concentrates have adverse effects on platelet function. Platelets stored with leukocytes express decreased quantities of glycoprotein Ib (GPIb) receptor, decreased thrombospondin, and a diminished agglutination response to ristocetin. Platelet GPIb receptors normally adhere to damaged endothelium by binding to von Willebrand factor and collagen. Thus, the loss of platelet GPIb receptors can impair platelet adhesion and potentially result in a bleeding disorder.
Prevention of Reperfusion Injury
Reperfusion of ischemic myocardium, after revascularization, may result in muscle necrosis and permanent damage. Reperfusion injury is believed to be associated with endothelial dysfunction (75), enhanced endothelial/leukocyte adhesion (76), generation of oxygen-free radicals by adherent leukocytes (77), and complement activation (78). Studies have examined the role of leukocyte reduction in reperfusion injury after cardiopulmonary bypass (79,80). Schmidt et al. (81) studied the effects of leukocyte reduction in a canine model of regional myocardial ischemia and reperfusion. The results of this study showed that endothelial function, as assessed by microvascular response to calcium and acetylcholine, was better preserved in the group that underwent leukocyte reduction by filtration. Pearl et al. (82), in a randomized study of 32 heart transplant patients, found that leukocyte reduction prevented ultrastructural damage. The same investigators demonstrated that leukocyte reduction was associated with reduced levels of biochemical markers for myocardial injury, yet they were unable to find any difference in postoperative hemodynamics in the investigational cohort (82). In a separate study, incorporation of leukocyte filters in the cardiopulmonary bypass circuit removed neutrophils selectively (83). Clinical benefits were not assessed in these patients. It remains to be seen whether leukocyte reduction will be clinically useful in reducing reperfusion injury of ischemic myocardium.
Prevention of Transfusion-Related Acute Lung Injury
Stored blood contains microaggregates of degenerated leukocytes, platelets, and fibrin (84). These microaggregates have been associated with pulmonary insufficiency after large volume resuscitations. Current standard 40-μm transfusion filters remove these microaggregates; however, these filters have not been associated with a reduction in pulmonary injury in randomized, controlled trials (85).
Transfusion-related acute lung injury (TRALI) is a rarer presentation of pulmonary insufficiency associated with blood transfusions. Patients develop severe dyspnea and radiographic findings consistent with noncardiogenic pulmonary edema (86). This form of acute lung injury is caused by agglutination of donor leukocytes by recipient antibodies (87). Transfusion of leukocyte-reduced blood components may decrease the occurrence of this fatal complication (88).
Cost Analysis of Leukocyte Reduction
Leukocyte reduction increases the price of one unit of blood by approximately $35 (3). It has been estimated, for the state of RI, that universal adoption of leukocyte-reduced blood products would increase annual transfusion expenditures in that state by $400,000 to $800,000 (4). However, lower overall medical costs would be expected as a result of a reduced incidence of transfusion-related adverse events (i.e., postoperative infections, HLA-alloimmunization, refractoriness to platelet transfusions, and febrile nonhemolytic transfusion reactions). Also, because leukocyte reduction leads to reduced transmission of CMV, the need to manage double inventories of blood components would be obviated.
So far, few studies have addressed the cost of leukocyte-reduced blood components. Jensen et al. (89) investigated the impact of using leukocyte-reduced blood transfusions in colorectal surgery patients. Postoperative infections were increased in patients receiving nonfiltered blood. Total hospital costs per patient were $12,347 in patients receiving nonfiltered blood, $7,867 in patients receiving filtered blood, and $7,030 in those receiving no transfusions. Similar results have been reported by other investigators (90,91). In adult patients with hematological malignancies, savings attributed to the use of leukocyte-reduced blood products were estimated to be $850-$5,260 per patient per month based on estimated costs of $300-$1,000 per febrile transfusion reaction (92). The probable antiinflammatory effect of leukocyte reduction and its cost effectiveness in patients undergoing cardiopulmonary bypass, was recently studied in a prospective, randomized clinical trial (93). The results of this trial demonstrated that in low risk coronary artery bypass graft surgery, leukocyte reduction decreased hospital length-of-stay by one day and mean total charges by $2,000 to $6,000 (94).
Clinical Indications for Leukocyte Reduction
Based on previous research, indications for use of leukocyte-reduced blood products include the prevention of febrile nonhemolytic transfusion reactions, reduction of platelet alloimmunization, and prevention of CMV transmission (Table 4). Other indications currently under investigation include reduction of postoperative infections, cancer recurrence, optimization of RBC and platelet storage conditions, reduction of GVHD, reduction of TRALI, reduction of reperfusion injury, and the reduction of bacterial counts in contaminated RBC and platelet concentrates (Table 4).
Adverse Effects of Leukocyte Reduction
Relatively few adverse effects have been reported in association with leukocyte-reduced blood components. A potential side effect involves hypotension. Negatively charged surfaces of leukocyte reduction filters may cause contact activation with release of bradykinin-like vasoactive substances (94). However, bradykinin is likely not the only factor involved because the concentrations of bradykinin measured in vivo do not reach those expected to cause hypotension (95). Profound hypotension has been reported in patients taking angiotension-converting-enzyme (ACE) inhibitors and receiving pretransfusion leukocyte-reduced blood products—platelets in particular (96). Presumably, ACE inhibitors decrease bradykinin degradation thereby prolonging its intravascular half-life. Hypotension also may occur with positively charged leukocyte filters and in patients not taking ACE inhibitors. The United States Food and Drug Administration recently issued an alert highlighting the association between hypotension and leukocyte reduction filters (97).
An unusual syndrome, known as the “red-eye” syndrome, or allergic conjunctivitis, has been linked to recipients of prestorage leukocyte-reduced RBCs (98). This condition is characterized by erythema (100%), periorbital edema (16%), eye pain (15%), and itching (98). In most patients, symptoms resolve within 48 hours, but erythema may require up to three weeks for complete resolution.
It is conceded that leukocyte reduction may adversely affect some cellular components of blood. A 2%–8% decrease in the potency of cellular blood components, namely RBCs, has been reported after filtration. Recently, it has been demonstrated that prestorage leukocyte reduction is associated with complement activation and the formation of platelet aggregates (99). As compared with unfiltered platelets, filtered platelets exhibit increased concentrations of platelet activation markers, in particular CD62 and CD63 (99). Characteristics of the remaining platelets were not altered, and there was no evidence of thrombin generation (99). At present, the clinical significance of these platelet aggregates is unknown.
In summary, there is increasing evidence that leukocyte-reduction of blood products improves outcomes. Recent investigations suggest that leukocyte-reduced platelet concentrates decrease the incidence of platelet alloimmunization, CMV transmission, and febrile nonhemolytic transfusion reactions. Further clinical trials are needed to define the benefits of leukocyte-reduced blood products as related to cancer recurrence, infections, GVHD, RBC and platelet storage, TRALI, and reperfusion injury. Several European countries, including the United Kingdom and France have adopted a policy of leukocyte reduction for all blood components. At present, the American Red Cross is pursuing a goal of leukocyte reduction for all blood components within the next year.
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