Blood Products Advisory Committee

  89th Meeting - April 27, 2007

Hilton Hotel, Washington, D.C. North/Gaithersburg

620 Perry Parkway, Gaithersburg, MD 20877




Topic II:   Transfusion Related Acute Lung Injury (TRALI)


Issue:  FDA seeks to be advised whether available scientific data support the development of FDA policies on methods to reduce the incidence of TRALI




Transfusion Related Acute Lung Injury (TRALI) is defined as an acute syndrome including dyspnea, hypoxemia, and interstitial pulmonary infiltrates presenting within six hours of transfusion in the absence of other detectable causes.  While TRALI is treatable with supportive care, delayed recognition of the clinical manifestations of TRALI can lead to death.


In part due to increased recognition of the syndrome by transfusing clinicians, TRALI deaths reported to FDA have risen over the past several years and now represent the leading cause of transfusion-associated mortality.  An average of 24 annual TRALI deaths was reported in the two year period between October, 2003 and September 2005.  Thirty-five TRALI deaths were reported to FDA in calendar year 2006, and accounted for 50.7% of all reported transfusion-related fatalities. TRALI-related morbidity is substantially higher with a per-transfusion incidence estimated at 1/2500 to 1/5000. Due to the difficulty in establishing a definitive diagnosis, it is not known how many deaths may occur each year in which TRALI is a contributing factor. All transfusable blood components (and rarely IGIV) have been implicated in TRALI, however plasma and single donor platelet products account for the majority of cases.


Lung injury in most cases of TRALI appears to be mediated by host leukocytes, or less commonly by host antibodies to donor leukocytes. Although the mechanisms of pathogenesis are not fully known, 45-60% of cases have been reported to be associated with neutrophil-specific antibodies (NSA) found in the donor. Less commonly, antibodies to human leukocyte Class I and Class II antigens (HLA) have been implicated. However, antibodies alone do not appear to be sufficient to cause TRALI in the absence of a co-factor, possibly an antecedent “priming” event such as pro-inflammatory lipid exposures which may activate leukocytes.  Pregnancy is known to result in the development of leukocyte antibodies in a significant proportion of women (it has been reported that women who have had 0, 1-2, and ≥3 pregnancies had a 7.8, 14.6, and 26.3% prevalence of HLA antibodies respectively) and donors implicated in TRALI are often found to be women with leukocyte antibodies.  For this reason, reduced use of female donors for production of blood components containing large plasma volumes has been considered as a potential strategy to reduce TRALI incidence.  




Strategies to Prevent TRALI


A policy eliminating the use of transfusable plasma from female donors was initiated in the UK in 2003 and is credited with a reduced incidence of TRALI fatalities from 23 cases in 2003, to 6 cases in 2005, and no plasma-associated TRALI deaths in 2005.  In the US, a retrospective review of 38 TRALI-associated fatalities in the American Red Cross system has shown that 24 (63%) followed plasma transfusion.  Female donors positive for allogeneic WBC antibodies were involved in 75% of these plasma cases and in 71% of all TRALI fatalities.  


Despite the association of prior pregnancy with HLA and other leukocyte antibodies, there are practical difficulties in screening female donors for prior pregnancy. This is due to the potential sensitivities of asking donors about previous miscarriage or abortion, and the wide range of possible responses, including uncertainty about a prior pregnancy. The AABB has recently recommended that to reduce the incidence of TRALI, member blood establishments should minimize the use of high plasma volume components from donors known to have anti-leukocyte antibodies, or known to be at risk of leukocyte allo-immunization. The target date for voluntary implementation of these recommendations is November 2007.


The preferential use of male plasma in the US has been regarded as generally feasible from a plasma supply perspective, although conversion to a 100% male plasma supply may be problematic in situations where a need exists for large volumes of AB plasma, or during periods of localized plasma shortage. Avoidance of plasma for transfusion collected from previously transfused persons (who may also be allo-immunized to leukocyte antibodies), or from persons found to have circulating anti-leukocyte antibodies through the use of screening tests might also be considered, although there are no clinical data to support these interventions.


Whole blood donation in the US is divided approximately evenly between male and female donors.  One possible mechanism to modulate supply concerns is through modified labeling of plasma for transfusion to indicate the gender of the donor. While this approach would facilitate the preferential use of plasma from male donors, there have been concerns expressed about unintended adverse consequences of such labeling (e.g. direct and indirect impacts on the overall national blood supply.) 


The AABB has also recommended that interventions be considered to reduce TRALI incidence among recipients of Platelets, Pheresis by November 2008. Specific interventions to be considered were not described. Reduction of  TRALI  associated with single donor platelet units  is challenging, both from a platelet supply perspective, and due to the fact that laboratory assays for the detection of leukocyte antibodies or other possible etiologic moieties in blood are not widely available for use in donor screening.

The overall supply of single donor platelets in the US is not sufficient to support conversion to all male donors; however targeted testing of female repeat apheresis donors for anti-WBC antibodies may be feasible as such assays continue to evolve toward use in a donor setting. 


Relevance of Assays for Anti-Neutrophil and Anti-HLA Antibodies


Evidence to date including both case reports and experimental animal studies indicate that NSA are found in less than 1% of donors, and may have a high degree of association with TRALI, as well as with other forms of transfusion reactions. Research assays for NSA exist, but have to date only been implemented in small academic donation settings to characterize female donors of AB plasma and Platelets, Pheresis.  Similarly, donors with anti-HLA antibodies have also been implicated in TRALI. While HLA Class I and Class II antibody tests are widely available, the background prevalence levels in donors are higher, and the implication of HLA antibodies in TRALI causation is weaker.


Use of Plasma Transfusion in the US


FDA has licensed Fresh Frozen Plasma (FFP) and several forms of plasma components containing reduced amounts of labile coagulation factors.  Only FFP is indicated for replacement of the labile factors V and VIII.  Otherwise, the indications for use are identical and include:

•      Correction of coagulation test results.  A major use of plasma in current practice is to correct abnormal PT, PTT, and INR test results prior to surgery. However the efficacy of this practice has been questioned in recent publications based upon the limited value of these coagulation test results to predict hemostasis in patients with no history of bleeding.

•      Correction of known coagulation factor deficiency levels based upon bleeding or in anticipation of an invasive procedure

•      Reversal of coumarin derivative induced anticoagulation

•      Severe liver disease with coagulopathy

•      Thrombotic thrombocytopenic purpura


Practice guidelines currently do not exist for some of the major uses of plasma transfusion therapy in the US. This situation may contribute to the extensive use of plasma for transfusion and may impede the goal of reaching predominantly male-donated or antibody-screened plasma for TRALI reduction. The BPAC will hear data regarding this issue. 




Questions for the Committee:


1.      Do current scientific data support the concept that the following interventions will reduce the incidence of TRALI?


a.       Use of predominantly male plasma for transfusion.

b.      Non-use of plasma for transfusion from donors with a history of prior transfusion

c.       Selective donor screening for anti-neutrophil or anti-HLA antibodies


2.   Based upon available data, please comment on the effect on the US plasma supply of the following interventions


a.       Use of predominantly male plasma for transfusion

b.      Non-use of plasma for transfusion from donors with a history of prior transfusion 

c.       Selective donor screening for anti-neutrophil or anti-HLA antibodies





1.       Densmore TL, Goodnough LT, Ali S, et al. Prevalence of HLA sensitization in female apheresis donors. Transfusion 1999;39:103-6.

2.      Kleinman S, Caulfield T, Chan P, et al. Toward an understanding of transfusion-related acute lung injury: Statement of a consensus panel. Transfusion 2004;44:1774-89.


3.      US Department of Health and Human Services. The 2005 nationwide blood collection and utilization survey report. Bethesda, MD: AABB, 2006.

4.      Chapman CE, Williamson LM, Cohen H, et al. The impact of using male donor plasma on hemovigilance reports of transfusion-related acute lung injury (TRALI) in the UK (abstract). Vox Sang 2006;91(Suppl 3):227.

5.      Transfusion-related acute lung injury. Association Bulletin #06-07 (November 6, 2006). Bethesda, MD: AABB, 2006.

6.      Eder A, Heron R, Strupp A et al. TRALI surveillance (2002-2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007 in press.