AABB held a public workshop on July 8 in Bethesda, Md., that provided a comprehensive overview of the information known about — and current risk-reduction strategies for — transfusion-related acute lung injury, or TRALI. Experts presented on topics that included the evolution of AABB policy positions on TRALI; considerations for antibody testing; the role of platelet additive solutions, or PAS; and the impact of current and future risk-reduction strategies on inventory, particularly for Apheresis Platelets. The workshop concluded with a discussion of the proposed TRALI risk reduction requirements to be included in the 29th edition of Standards for Blood Banks and Transfusion Services.
AABB president Susan Stramer, PhD, provided a summary of AABB’s actions with respect to TRALI and an overview of different interventions available to reduce the risk of TRALI. She also reminded attendees that TRALI remains responsible for a higher percentage of transfusion-related fatalities than any other transfusion complication.
AABB Senior Medical Advisor Steven Kleinman, MD, summarized the current state of knowledge regarding the pathogenesis of TRALI and its relationship to the range of interventions available. Kleinman highlighted a number of different scientific/epidemiological studies on TRALI, with particular attention to the findings of the Transfusion Medicine Specialized Center of Clinically Oriented Research (SCCOR) TRALI study. The SCCOR study confirmed an overall reduction in TRALI incidence since AABB recommended implementation of TRALI risk reduction measures in 2007. This decrease also is reflected in the number of TRALI-related fatalities reported to FDA after 2007.
Kleinman reviewed international hemovigilance data from France, the United Kingdom, and Germany, with particular attention to antibody-mediated TRALI cases. These findings are consistent with the SCCOR results, where risk factors identified by multivariate analysis included the quantity of HLA Class II antibodies and the volume of HNA antibodies received by the patient. He noted that the aggregate data indicate that HLA Class II antibodies are more important than Class I, though the latter remain an area of concern. Higher antibody levels appear to be a stronger risk factor than lower antibody levels, and there appears to be no leukocyte antibody specificity (other than HNA-3a, which is prominent in German hemovigilance data) that is more strongly associated with TRALI.
AABB Past President Darrell Triulzi, MD, and Brian Curtis, PhD, MT(ASCP)SBB, provided a thorough overview of considerations related to leukocyte antibody testing. Relying on data from the REDS II study, published in “Transfusion” in 2009, Triulzi explained that the rate of HLA alloimmunization was not significantly different between men who have been transfused and those who have not. However, the number of a donor’s pregnancies was highly correlated with significant increases in the HLA alloimmunization rate. Lost pregnancies, on the other hand, had a much smaller effect than did pregnancies carried to term. Additionally, HLA antibodies (at least those that are high titer) persist for many years after they are detected, and likely would permanently affect an individual’s ability to donate high plasma volume components. Finally, Triulzi discussed the challenging task of establishing optimal cutoffs for HLA antibody detection, noting that the conventional way of setting an assay cutoff (mean of the negative population plus three standard deviations) would result in diverting approximately 16 percent of female donors toward other kinds of donation. Curtis discussed the role of HNA antibodies in TRALI, pointing to the fact that HNA antibodies were detected in donors in 42 percent of the TRALI cases reviewed in the NHLBI SCORR study. (In 12 percent of cases this was the only antibody and in 30 percent it was combined with HLA Class II antibody). Curtis emphasized that HNA-3a antibodies tend to be associated with more clinically severe TRALI and also reported on two illustrative case studies of HNA-mediated TRALI.
Platelet additive solutions also generated discussion. According to Triulzi, PAS replaces 60-70 percent of plasma on Apheresis Platelets, leaving 80-100 milliliters of residual plasma. Karen King, MD, described Johns Hopkins Hospital’s experience with PAS from June 2012 to December 2012. During that time, Hopkins transfused close to 4,000 non-PAS Apheresis Platelets and slightly more than 1,000 PAS products. Patients receiving PAS products had a significantly lower rate of allergic reactions from transfusions, though no conclusions could be drawn about the effect of PAS on TRALI due to the size of the study. Claudia Cohn, MD, PhD, provided the perspective from her hospital, the University of Minnesota, with PAS platelets, and similarly reported a significantly lower rate of allergic transfusion reactions.
Several presenters gave an overview of the impact of TRALI risk reduction strategies on their inventory and donor base. Anne Eder, MD, highlighted the American Red Cross’ (Red Cross) efforts to move to male-predominant plasma. Although more than 95 percent of plasma distributed by Red Cross comes from male donors, the increasing demand for AB plasma has not been met from male-only donors, with only 60 percent of the Red Cross’ AB plasma inventory supplied from male donors. Of the units collected from female donors, roughly 30 percent came from female donors with no history of pregnancy.
Peter Tomasulo, MD, began his presentation on behalf of Blood Systems Incorporated (BSI) by reflecting on the Red Cross experience (as described by Eder et al. in 2012 in “Transfusion”). That intervention, Tomasulo noted, produced a rate of TRALI cases for plasma that was in line with the rate of TRALI seen for red cells. To Tomasulo, this means that doing the same is possible for plasma and platelets of all groups. Operationally, BSI opted to use its computer system to prohibit the labeling of plasma for transfusion from donors with any history of pregnancy. Following the configuration of the computer system, BSI saw the percentage of plasma components from women drop from 54 percent to 28 percent of units transfused.
Sarah Shunkwiler, MD, noted that LifeServe Blood Center had similarly been unable to meet the demand for AB plasma using exclusively male donors, though the facility can fill occasional requests from hospitals needing male-only AB plasma. From June 1, 2012, to June 1, 2013, only 5.1 percent of plasma units distributed by LifeServe came from female donors – all of which were AB plasma. Shunkwiler concluded by discussing the reduction in the number of clinical reports of possible TRALI in cases in which the donor was positive for HLA and/or neutrophil antigens, with no cases reported for calendar years 2009 and 2010.
Robert Makar, MD, PhD, shared the results of Massachusetts General Hospital’s single-center study to determine whether donor history accurately predicts the risk of leukocyte alloimmunization by comparing responses to the donor history questionnaire to HLA antibody screening results. One of the key conclusions of the study was that a negative pregnancy history has a high negative predictive value (NPV) for HLA antibodies. The hospital’s scheme for preparing frozen plasma from whole blood donors uses the donor history questionnaire to capture information about pregnancy history. Makar also noted that targeted testing (based on pregnancy history) is the most cost-effective strategy to identify donors with HLA antibodies. He stated that reduced risk to patients clearly justified the additional screening measures and the decline in the number of Fresh Frozen Plasma units produced per unit donated.
Many centers reported similar experiences with apheresis platelets. Eder reported that Red Cross continues to increase its laboratory capacity to handle the increased need for HLA antibody testing. Red Cross has been testing females with a history of pregnancy who are first-time apheresis donors and uses the test results to qualify the donor for the next donation. Based on historical information, Red Cross anticipates that roughly 25 percent of previously pregnant donors selected for testing will be antibody positive, and that, when they begin testing their repeat apheresis donors who have not been previously tested, this will result in the need to find an alternate source for approximately 14,000 Apheresis Platelet collections annually.
BSI approached the implementation of TRALI risk reduction in platelets slightly differently from its approach to plasma. Realizing that it would not be possible to maintain an adequate supply of Apheresis Platelets using only males and never pregnant females, BSI implemented an HLA antibody detection program that eventually was extended to all female donors reporting any pregnancy. In addition, donors are retested following any subsequent possible alloimmunization events. As with plasma, BSI’s computer system was configured to prohibit labeling of Apheresis Platelets unless the products came from donors meeting BSI’s suitability requirements (i.e., HLA testing required and negative or HLA testing not required.) Between May 23, 2011, and January 15, 2012, 16.4 percent of donors tested were positive for HLA antibodies. Following implementation of TRALI risk reduction strategies, the percentage of female Apheresis Platelet donors has dropped from 41 percent to 32 percent of all donations.
In addition, implementation of TRALI risk reduction was designed to accomplish the following goal, defined by senior leadership: plasma, platelets, and other high plasma volume components are to be collected from men, never pregnant women, or women tested and found negative for HLA antibodies. Since 2007, the percentage of plasma units collected from male donors has increased while the percentage of units collected from female donors has decreased. BSI was able to meet the demand for plasma, including AB plasma, using only never pregnant females and male donors, but concluded that it would not be possible to do the same for Apheresis Platelets. Accordingly, BSI initiated HLA antibody detection in female donors with a history of pregnancy. Since implementing its HLA testing strategy, BSI has been able to maintain an adequate supply of platelets while ensuring that hospital customer satisfaction with the supply of platelets and plasma remains high.
Speaking on behalf of BloodSource, Christopher Gresens, MD, related the facility’s experience with platelet products. BloodSource implemented an HLA antibody testing program for all Apheresis Platelets donors who reported more than three pregnancies as well as all first time female donors. Roughly 15 percent of women tested were deferred as a result. Gresens also acknowledged that BloodSource was fortunate to have a large population of dedicated male platelet donors and that this had allowed BloodSource to absorb the loss of eligible female donors.
Brenda Grossman, MD, MPH, noted that Barnes-Jewish identified 1,155 Apheresis Platelet donations from 627 female donors. Of those, 67 percent had a history of one or more pregnancies, and 54 percent had a history of two or more. As a result, Barnes-Jewish moved forward with PAS implementation but did not see a statistically significant change in transfusion reaction rates. Grossman urged AABB to remain open to different methods of meeting standards designed to reduce the risk of TRALI.
Judy Levitt, MT(ASCP)SBB, presented on behalf of AABB’s Blood Bank/Transfusion Service Standards Program Unit (BBTS SPU). She provided an overview of AABB’s legal responsibilities as a standards-setting organization, as well as a summary of the different kinds of feedback sent to the BBTS SPU during the comment period. Levitt noted that these comments generally addressed concerns about the availability of platelets, questions regarding which donors are at increased risk for HLA alloimmunization, which products should be considered “high plasma volume components,” and whether TRALI risk reduction measures can be implemented for platelet products before the 29th edition of the Standards goes into effect.
The last portion of the day was reserved for prepared comments from the floor. Andrea Neisser-Svae, MSc, PhD, provided comments on behalf of Octapharma regarding Octaplas. Neisser-Svae discussed the manufacturing process for Octaplas and highlighted recent publications which concluded that HLA antibodies are not detectable in Octaplas.
Susan Rossmann, MD, delivered prepared remarks from America’s Blood Centers (ABC). Rossmann indicated that ABC would not suggest or advocate particular language for the standards, since ABC members have not reached a consensus on the issue. ABC does, however, support evidence-based interventions to enhance safety of transfused blood, provided that adequacy of the supply is preserved. The position of ABC is that plasma, platelets, and whole blood for transfusion “will be from males, females of defined parity, or from females who have been tested and found to be negative for antibodies to HLA antigens in a validated test.” In addition, Rossman indicated that ABC would not support a requirement for antibody screening, stating that a number of open questions remain: Whether recipient factors should be considered? Whether pooled solvent-detergent treated plasma and PAS should be considered acceptable risk reduction strategies?
Throughout the day, workshop attendees had the opportunity to ask questions of presenters. At the end of the workshop, a number of individuals provided feedback that echoed the themes of the day. Individuals expressed the need to approach TRALI risk reduction from a patient-centered point of view, as well as establishing clear and unambiguous goals for TRALI risk reduction. According to these individuals, these goals should preserve the adequacy of the blood supply while allowing facilities the opportunity to identify the best means of achieving gains in safety based on their individual operational needs and abilities.
Select Presentations from AABB’s Public Workshop on TRALI Risk Reduction (member content)