What is leukoreduction?

Leukoreduction is the process of removing > 99.9% of the white blood cells (WBC) from cellular blood components (red cells and platelets).   In order to label a component as leukoreduced the American Association of Blood Bank Standards (19^th ed) requires that the residual leukocyte content in the component is < 5x10⁶ WBC.

Methods for leukoreduction:

Historically, washing was used as a method for leukoreduction but was not very efficient resulting in only 90% WBC removal. There are only  two methods currently available that can meet the labeling requirements for leukoreduction (<5x106 WBC): filtration and apheresis processing.  Almost all red cells are leukoreduced using a special filter either in the laboratory or blood center or at the patient’s bedside at the time of transfusion. Filtration is also used for whole blood pooled platelets while apheresis processing is the primary method of leukoreduction for single donor platelets.  Approximately 10% of the red cell or platelet component is lost in the filtration process.

Accepted indications for leukoreduction:

There are three currently accepted indications for using leukoreduced blood components: 1. Prevent recurrent fever chill reactions 2. Prevent or delay alloimmunization to HLA antigens, 3. Reduce the risk of CMV transmission. 

1. Recurrent fever chill non-hemolytic reactions - Approximately 1-5% of patients may experience fever, chills,  dyspnea and nausea/vomiting during transfusion. For red cell transfusions these reactions are most frequently due to white cells in the blood component to which the patients has antibodies (usually anti-HLA).  Platelet transfusions are associated with a similar reaction due to release of pyrogenic cytokines (IL-1, IL-6, TNF) from white cells in the platelet component during storage.  When the platelet component is transfused, the cytokines can cause a fever chill reaction. Leukoreduction at or near the time of collection of the unit (prestorage leukoreduction) can virtually eliminate these reactions. Alternatively, whole blood platelets which have been stored for £ 3 days have significantly less cytokine accumulation and a lower incidence of associated fever chill reactions. (1) Bedside filtration is effective in eliminating most of the fever chill reactions to red cell transfusions, but is not very effective for platelet transfusions.  Bedside filtration is less effective for platelet transfusions due to the inability of the filters to remove cytokines which have already been released into the platelet supernatant. 
   
   

2. Prevent or delay alloimmunization to HLA antigens -  White cells strongly express HLA class I antigens and may stimulate HLA antibodies in some individuals. The most common causes of HLA alloimmunization are transfusion and pregnancy.For most patients HLA alloimmunization is not associated with clinical problems. However it can be associated with two major clinical complications: platelet transfusion refractoriness or organ transplant rejection.  Platelets express HLA Class I antigens. Thus patients who are HLA alloimmunized may rapidly clear transfused platelets resulting in an inadequate platelet response called, platelet refractoriness. Prospective randomized studies have shown that leukoreduction of components can reduce the incidence of alloimmunization and refractoriness.(2) Based on these data leukoreduced components are now recommended for any patient requiring long term transfusion support such as patients with leukemia, lymphoma, aplastic anemia, myelodysplasia, or those undergoing stem cell transplantation.  HLA alloantibodies have also been implicated in graft rejection of kidney, heart and lung transplants. These patients should receive leukoreduced blood components. HLA alloimmunization is not associated with shortened liver allograft survival.
   
   

3. Reduce the risk of CMV transmission - Approximately 50% of blood donors are CMV seropositive and have latent CMV integrated into the DNA of their white cells.  Since CMV is exclusively WBC associated, removing the WBC from the unit reduces the CMV infectivity (“CMV safe”). Clinical studies in neonates, cancer patients, stem cell transplant recipients and organ transplant recipients have shown that units rendered CMV safe by leukoreduction are equivalent to CMV seronegative units in their risk of CMV transmission (3).
    

Potential benefits of leukoreduction

Potential benefits of leukoreduction which remain unproven include: preventing the immunosuppressive effect of transfusion and reducing the risk of Cruetzfeldt-Jakob Disease (CJD) transmission. WBC in blood components have been implicated in causing immunosuppression of the recipient. Clinical studies have suggested that this may result in a higher incidence of postoperative bacterial infection in transfused surgical patients or higher risk of cancer recurrence in transfused cancer patients. (4,5)  Published clinical studies however are not conclusive. To date there is no evidence that CJD, a spongiform encephalopathy caused by prions, can be transmitted by blood.  Animal data and some human clinical data suggest that B cells are important in disease pathogenesis, however there is no data that leukoreduction has any effect on the theoretical risk of CJD transmission. (6)

Universal leukoreduction

The FDA has announced publicly that it will require that all cellular blood components transfused in the U.S. be leukoreduced by the year 2002. The FDA’s decision was based on both the known, as well as the potential benefits of leukoreduction.  To ensure quality control, the FDA has stated that only leukoreduction performed in the laboratory or blood center will be acceptable.  Currently approximately 25-30% of all cellular blood components transfused in the U.S. are leukoreduced, primarily at the bedside, for the accepted indications noted above.   It is estimated that the cost to leukoreduce 100% of the nation's blood supply will exceed $500 million annually.  To date, more than 6 countries worldwide have implemented universal leukoreduction including Canada, Britain, and France.  It is not know whether the benefits of leukoreduction will offset the costs of implementation.

REFERENCES:

1.  Kelley DL, et al. The utility of  £ 3 day-old whole blood platelets in reducing the incidence of febrile nonhemolytic transfusion reactions. Transfusion 2000;40:439-42.

2.  TRAP Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. NEJM 1997;337:1861-9.