Transfusion-related acute lung injury (TRALI) is a type of noncardiogenic pulmonary edema characterized by acute respiratory distress that can occur as a complication after transfusion. Although the pathogenesis of TRALI is only partially resolved, an increasing number of studies have confirmed the role of antibodies against HLA and HNA antigens in the development of TRALI.[2-6] Recent case control studies have shown that HLA Class I antibodies are weak triggers of TRALI compared to HLA Class II and HNA antibodies,[7-9] and a smaller study even debated the involvement of HLA antibodies at all.
TRALI accounted for 47% of the transfusion-related fatalities reported to the US Food and Drug Administration from 2005 through 2010. Although all blood components have been implicated in TRALI, products containing large amounts of plasma impose a higher risk. The Serious Hazards of Transfusion hemovigilance program conducted from 1996 to 2002 observed that plasma from female blood donors with white blood cell antibodies was the component most often implicated in TRALI. A passive surveillance study of TRALI cases reported to the American Red Cross came to similar conclusions.
Since then, several donor management strategies, for example, exclusion of female donors from single-unit fresh-frozen plasma production, have been proposed and implemented worldwide.[13, 15-17] Even with modern TRALI risk reduction strategies, TRALI remains an important cause of transfusion-related morbidity and mortality and is estimated to occur in approximately one in 12,000 transfused blood components.
At our institution, methylene blue–inactivated plasma has been, since 2004, produced originating only from male donors without a history of transfusion. In platelet (PLT) concentrates—both buffy coat derived and from apheresis—plasma content is significantly reduced by using PLT additive solutions (ASs). Before implementing additional measures for plateletpheresis donors, a pilot study was undertaken in our blood service to analyze the HLA immunization status in female plateletpheresis donors and in male plateletpheresis donors with a history of transfusion. Based on the outcome of this study, an HLA alloimmunization screening strategy was developed.
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In 2008, our blood service started reducing the volume of residual plasma by AS supplementation for all PLT products. This was, given the known relationship between transfusion of plasma and TRALI risk, an important step in reducing the risk for TRALI induced by donor antibodies in PLT products. Whereas for virus-inactivated plasma, all female donors are deferred, a similar approach for plateletpheresis products would result in an unacceptable loss of volunteer donors as approximately 32.0% of the plateletpheresis donations are female in our blood service. The ultimate goal of this study was to develop a strategy that would further reduce the risk of TRALI without compromising the supply of PLT concentrates. We therefore evaluated the effect of a history of transfusion or pregnancy on HLA alloimmunization in our plateletpheresis donor population and studied the influence of time since last pregnancy, the number of pregnancies, and the involvement of different biologic fathers on the occurrence of HLA alloimmunization.
The obtained data confirm that the frequency of HLA alloimmunization is higher in women with a history of pregnancy. Although donors that screened positive for RBC alloantibodies were already excluded in this cohort, 31.0% of the parous female donors screened positive for HLA antibodies. This percentage is equal to or even higher than the 25.4% of all female donors described in Powers and colleagues and the 24.4% in parous female donors reported by Triulzi and colleagues. In our study, a Luminex platform was used to perform the HLA screening. The high sensitivity of this method may explain the high percentage of HLA-positive parous women, even when testing was conducted decades after the last pregnancy.
The observation that even more than 30 years after the last delivery a significant association between pregnancy history and HLA immunization is detected supports that a strategy in which all parous female donors are tested for HLA alloantibodies irrespective of the time span since the last pregnancy makes sense and is in line with Powers and colleagues.
The increasing frequency of HLA alloimmunization with increasing number of pregnancies indicates that each pregnancy may act as an additional immunizing event. Therefore, screening for HLA antibodies, comparably to RBC alloantibody screening should be repeated after each pregnancy. Although the observed frequency of HLA immunization appeared higher if multiple pregnancies were induced by more than one biologic father, study numbers were too low to demonstrate significant difference. Surprisingly, 4.2% of all female donors without previous pregnancies or transfusions were found positive in our study. These HLA alloimmunizations may be related to missed abortions or intentional nondisclosure of induced abortions or pregnancies.
Powers and colleagues demonstrated the presence of HLA antibodies in 12.0% of male donors with a prior history of transfusion. Our study could not confirm these findings. Indeed, in our donor population, only one of 77 screened male donors with a history of transfusion had a (weak) positive result for HLA antibodies. In addition, none of the nulliparous women with a history of transfusion had HLA antibodies. Our data suggest that, compared to pregnancy, transfusion does not appear to be as potent for HLA immunization. In our blood service, leukoreduction of cellular blood components was implemented nationwide in 2005. This measure possibly decreased the risk for primary HLA alloimmunization after transfusion. Furthermore, the deferral of donors that screen positive for RBC alloantibodies could have lowered the percentage of donors sensitized to HLA antigens in the remaining active donor population. In general, our observations suggest that screening for HLA alloimmunization based on a history of transfusion has limited additional value in the era of leukoreduction. Future studies should confirm this finding.
The overall transfusion rate in our parous female donor population (5.1%) is high compared to transfusion rates in the general obstetric population in Flanders (Belgium; 1.0%-1.2% during the period 2002 and 2007) and compared to transfusion rates reported in other countries.[24-26] In our donor population we observed a decreasing transfusion rate over time, namely, 6.7% from 1960 to 1969, 6.1% from 1970 to 1979, 5.5% from 1980 to 1989, 4.1% from 1990 to 1999, and 3.8% after 2000, suggesting the existence of a more liberal transfusion policy in national hospitals in previous decades. In addition, the high transfusion rate in our study population might also be explained in part by increased motivation of women who themselves once needed transfusion to become a blood donor. The current study design tested male donors with a history of transfusion not including a control group that was never transfused; therefore, a comparison of HLA alloimmunization incidence between these two groups was not possible.
It should be pointed out that testing donors for HLA antibodies will never completely eliminate the risk of TRALI, especially as antibodies directed to neutrophil-specific antigens may be involved. At present, additional testing for HNA antibodies is not performed as the tests are not available in our institute. When routine HNA testing on the Luminex becomes available, the study group of HLA antibody positive tested donors will be reanalyzed for this variable.
After completion of this study, donors who tested positive for HLA Class I and/or Class II antibodies were excluded from plateletpheresis donation. This resulted in a loss of approximately 21.0% of the female PLT donor population and approximately 10.0% of the entire PLT donor population.
Within our institution, screening for HLA antibodies is now routinely conducted for all new female plateletpheresis donors and for female plateletpheresis donors after each pregnancy. For male and female plateletpheresis donors, we currently continue to screen for HLA antibodies after each transfusion episode to obtain more data to confirm that transfusion of leukoreduced blood constitutes a minor risk factor.