Retrovirus Epidemiology Donor Study-II (Reds-II) Leukocyte Antibodies Prevalence Study (LAPS)
Clinical Trials URL:
Study Type: Epidemiology Study
Prepared on March 26, 2010
Study Dates: 2006-2009
Consent: Restricted Consent
Consent Restrictions: Restrictions are related to genetic/non-genetic specimen use by research topic.
Commercial Use Restrictions: No
NHLBI Division: DBDR
Collection Type: Open BioLINCC Study - See bottom of this webpage for request information
The Leukocyte Antibody Prevalence Study (LAPS-I) was designed to measure the prevalence of HLA and neutrophil antibodies in blood donors with or without a history of pregnancy or blood transfusion and to develop a repository of blood samples from well characterized blood donors whose detailed pregnancy and transfusion histories are known.
The Leukocyte Antibody Prevalence Study II (LAPS-II) was designed to evaluate a primary endpoint of combined incidence of TRALI and possible TRALI in study recipients of at least one HLA antibody -positive high-plasma-volume component received from a LAPS-I donor versus control recipients of at least one HLA antibody-negative high-plasma-volume component.
Donor based risk reduction interventions for transfusion-related acute lung injury (TRALI) have been widely adopted in the United States and elsewhere in the past several years due to data indicating that TRALI has continued to be the leading cause of blood transfusion-related deaths in the US. By the year 2009, most blood centers in the US were transfusing plasma supplied primarily by male or never pregnant female donors, and some centers were selectively screening multiparous female platelet and plasma apheresis donors for HLA antibody. Most transfused components containing HLA antibodies do not result in recipients developing TRALI. Although several prior studies assessed outcomes in recipients of previously donated components from HLA antibody positive donors who were implicated as causing TRALI in an index recipient, they had significant limitations. These limitations included the use of different methods for HLA antibody screening and for reviewing recipient outcome data and diagnosing TRALI. Also they had small sample sizes considering the low incidence of TRALI and most did not evaluate TRALI occurrence in recipients of control components using a blinded study design.
LAPS-I was a cross-sectional multicenter study conducted at six REDS-II blood centers: American Red Cross New England Region, Dedham, MA; the American Red Cross Southern Region, Atlanta, Georgia; the Blood Center of Wisconsin, Milwaukee, Wisconsin; the Hoxworth Blood Center/University of Cincinnati Medical Center, Cincinnati, Ohio; the Institute for Transfusion Medicine, Pittsburgh, Pennsylvania; and the Blood Centers of the Pacific, San Francisco, California. Over a six month period (December 2006- May 2007), 7,900 adult whole-blood and apheresis donors were enrolled in the study. All blood donors age 18 and older at the selected sites were eligible for the study. Both male and female donors who were able to donate whole blood or apheresis products were enrolled in the study. Donors who tested reactive or positive in any of the infectious diseases donor screening tests were not eligible. The recruitment goals for enrollment of minority donor were consistent with the overall proportion of minority donors at each participating center.
LAPS-II consisted of five of the LAPS-I centers (the American Red Cross New England Region, Dedham, MA did not participate). Each blood center recruited participating hospitals in its region. In total, 42 hospitals participated; these hospitals received approximately 50% of the high-plasma-volume components issued by the five blood centers (51% of transfusable plasma and 48% of plateletpheresis). The donor HLA antibody status was obtained from the LAPS-I study. For blood donors, the inclusion criteria included those with HLA antibodies and some of the donors who did not have antibodies. Among donors without HLA antibodies, the selection was based on gender and parity frequency-matching at each REDS-II Center with the antibody positive donors. For transfusion recipients, recipients who received the study blood components at participating hospitals were included. Further record review was conducted on those recipients who were documented to have had a chest x-ray within 24 hours after the study transfusion.
In LAPS-I, donors were asked to complete a questionnaire related to pregnancy and transfusion history. Women with a history of pregnancy were asked additional questions about the number, outcome, and date of last pregnancy. All participating donors were asked if they had ever had a transfusion and the dates of prior transfusion episodes. Blood samples from donors were screened for HLA Class I and Class II antibodies using flow cytometry techniques. Cutoff values for positive HLA antibody results on the multi-antigen Luminex HLA antibody screening assays were determined by calculating the mean plus three standard deviations of the natural log-transformed distribution of assay values (expressed as the normalized background ratio- NBG) in the enrolled cohort of 1138 non-transfused male blood donors; assay cutoffs were thereby set at NBG values of greater than 10.8 for Class I and greater than 6.9 for Class II. For purposes of selecting control donors for LAPS-II, HLA antibody– negative donors were defined as donors with NBG values of less than 2.2. Further testing to determine the specificity of HLA antibodies (Class A, B, C, DR, DQ, and DP) was performed using the One Lambda LS1A04 or LS2A01 single-antigen bead assays; the LAPS-I assay cutoffs for a positive result were set at a median fluorescence intensity of greater than 2500 for Class I and greater than 1500 for Class II. A subset of 1171 donors (388 non-transfused males, 390 HLA antibody negative females with three or more pregnancies, and 393 HLA antibody positive females with three or more pregnancies) were tested for IgG and IgM HNA antibody using a granulocyte immunofluorescence flow cytometry assay.
For LAPS II, each blood center performed a record search to trace all high-plasma-volume components donated at the time of enrollment or within 2 years before the index donation by LAPS-I HLA antibody-positive donors. Recipients received a total of 2,596 plasma-rich blood components (transfusable plasma and plateletpheresis) which were sent to participating hospitals. Half of the components were collected from anti-HLA-positive donors (study arm) and half from anti-HLA-negative donors (control arm) matched by sex, parity, and blood center. A staged medical record review process was used. Final recipient diagnosis was based on case review by a blinded expert panel of pulmonary and critical care physicians.
HLA antibodies were detected in 17.3% of all female donors and in 24.4% of those with a history of previous pregnancy. The prevalence of HLA antibodies increased in women with greater numbers of pregnancy: 1.7% (zero), 11.2% (one), 22.5% (two), 27.5% (three), and 32.2% (four or more pregnancies; p < 0.0001). The findings of increased prevalence with greater numbers of pregnancies were confirmed when data from single antigen bead testing (which was used to determine HLA antibody specificities) were analyzed. Transfused blood donors did not appear to have a significantly higher prevalence of HLA antibodies than their non-transfused counterparts; i.e., HLA antibodies were detectable at low prevalence (1.0 - 1.7%) in male donors regardless of transfusion history (p = 0.16). HNA antibody prevalence in a specially selected group of LAPS-I donors was 0.7% (95% CI, 0.3 - 1.3%) with antibodies detected in female donors as well as in non-transfused male donors. Four of five HNA antibodies in females showed a definable HNA specificity whereas the HNA antibodies detected in three male donors were non-specific. In LAPS-II it was determined that TRALI incidence was 0.59% (seven cases) in recipients of anti-HLA–positive components versus 0.16% (two cases) in control arm recipients for an odds ratio of 3.6 (95% confidence interval, 0.7-17.4; p = 0.10). Based on this trend of an increased incidence of TRALI in the study arm along with recent surveillance data from other sources, the data were consistent with the likelihood that TRALI risk is decreased by selecting high-volume plasma components for transfusion from donors at low risk of having HLA antibodies.
Kleinman, S. H., Triulzi, D. J., Murphy, E. L., Carey, P. M., Gottschall, J. L., Roback, J. D., Carrick, D., Mathew, S., Wright, D. J., Cable, R., Ness, P., Gajic, O., Hubmayr, R. D., Looney, M. R., Kakaiya, R. M. and for the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II) (2011), The Leukocyte Antibody Prevalence Study-II (LAPS-II): a retrospective cohort study of transfusion-related acute lung injury in recipients of high-plasma-volume human leukocyte antigen antibody–positive or –negative components. Transfusion. doi: 10.1111/j.1537-2995.2011.03120.x
Triulzi, D. J., Kakaiya, R. and Schreiber, G. (2007), Donor risk factors for white blood cell antibodies associated with transfusion-associated acute lung injury: REDS-II Leukocyte Antibody Prevalence Study (LAPS). Transfusion, 47: 563–564.
Triulzi, D. J., Kleinman, S., Kakaiya, R. M., Busch, M. P., Norris, P. J., Steele, W. R., Glynn, S. A., Hillyer, C. D., Carey, P., Gottschall, J. L., Murphy, E. L., Rios, J. A., Ness, P. M., Wright, D. J., Carrick, D. and Schreiber, G. B. (2009), The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy. Transfusion, 49: 1825–1835.
Gottschall JL, Triulzi DJ, Curtis B, Kakaiya RM, Busch MP, Norris P, Glynn SA, Carrick D, Wright DJ and Kleinman S for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) The frequency and specificity of Human Neutrophil Antigen Antibodies in a blood donor population. Transfusion 2011; 51(4): 820-827.
Endres RO, Kleinman S, Carrick DM, Steele WR, Sun Y, Wright DJ, Norris PJ and Busch MP for the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II) Specificities of HLA Antibodies in Blood Donors: Baseline Data for a TRALI Lookback Study. Transfusion 2010; 50(8): 1749-1760.
Kakaiya R, Triulzi D, Wright D, Steele W, Kleinman S, Busch M, Norris PJ, Hillyer C, Gottschall J, Rios J, Carey P and Glynn S for the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II) Prevalence of HLA antibodies in remotely transfused or alloexposed volunteer blood donors. Transfusion 2010; 50(6): 1328-1334.
Carrick DM, Johnson B, Kleinman SH, Vorhaben R, Chance SC, Lee J-H, Roback JD, Pandey S, Sun Y, Busch MP and Norris PJ for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) Agreement amongst HLA antibody detection assays is higher in ever pregnant donors and improved using a consensus cutoff. Transfusion 2011; 51(5): 1105-1116.
Carrick DM, Norris PJ, Endres RO, Pandey S, Kleinman SH, Wright DJ, Sun Y and Busch MP for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) Establishing Assay Cutoffs for HLA Antibody Screening of Apheresis Donors. Transfusion 2011 (Feb 18 ePub) (In Press)
Norris PJ, Lee J-H, Carrick D, Gottschall JL, Lebedeva M, De Castro R, Kleinman SH and Busch MP for the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II) Long-term in vitro reactivity for HLA antibodies and comparison of detection using serum vs. plasma. Transfusion 2009; 49(2): 243-251.