Dangerous Female Blood Donors?

An interesting article about a possible side effect of pregnancy:

[B]lood banks are beginning to separate out women's plasma — the liquid part of blood — in an effort to fight a mysterious lung injury that has become the nation's leading risk from transfusions.

Ask about blood safety and most people think of HIV or other diseases that, thanks to strict testing, actually are incredibly rare in U.S. transfusions. Today the top threat is TRALI, or "transfusion-related acute lung injury," in which transfusions trigger reactions that fill patients' lungs with fluid, leaving them gasping for air.

There are no good counts, although TRALI is thought to strike a few hundred people a year and kill roughly 10 percent of them. It's a condition doctors don't always recognize since patients who need transfusions are seriously sick to begin with, but it's starting to gain attention.

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No one knows exactly what causes TRALI. But certain immune cells carried by women who have been pregnant are emerging as a chief culprit, cells called antibodies that mothers-to-be produce in reaction to their fetus' foreign father cells.

The antibodies do no harm to mother, baby or the vast majority of people who encounter them in a transfusion. To get TRALI requires what Celso Bianco of America's Blood Centers calls "a horrible coincidence" in which the transfusion recipient has white blood cells that just happen to recognize and clash with the donor's antibodies.

More on transfusion-related acute lung injury (TRALI):

The perception or fear that, nowadays, infections represent the most frequent cause of serious complications associated with transfusions of blood or blood derivatives may be unfounded. As illustrated by the causes of the few fatalities occurring after a transfusion that were reported to the US Food and Drug Administration (FDA) before 1995, hemolytic reactions (mostly due to ABO incompatibilities) represented the leading cause of death (50% to 62%), while respiratory syndromes represented the second leading cause (15% of fatalities). Bacterial contamination followed in the third place with a 10% to 16% frequency over the past 25 years.

Since the introduction of nucleic acid testing in 1999, transfusion-related viral infections have become a rare event -- only 3 documented cases per year. The specific risks have been calculated as follows: 1/205,000 transfusions for hepatitis B, 1/1,935,000 for hepatitis C, 1/2,135,000 for HIV 1 and 2 infections, and 1/2,993,000 for HTLV infections.

TRALI is Underrecognized

The respiratory distress syndrome associated with transfusions, called TRALI (transfusion-related lung injury), on the other hand, constitutes a serious risk that may be presently underestimated, as it often goes unrecognized and undertreated. Currently, at least 6 deaths per year are being formally attributed to TRALI. The actual prevalence is, however, probably far higher with an estimate of about 200 patients per year being affected.

According to detailed studies, TRALI might occur in 1/5000 transfusions, or as frequently as 1/300 transfusions of red blood cell derivatives. Others reported a frequency of 1/1323 in a recent study. Approximately 12 million transfusions are given per year in the United States. Something is amiss when only 6 cases of TRALI are officially diagnosed and reported. Data obtained in the United Kingdom from the SKOT (a confidential voluntary reporting system) seem to be aligned with this trend. Eighteen cases of acute lung injuries have been reported in 2000, ranking TRALI as the second most frequent cause (6 deaths) of transfusion-related complications after hemolysis.

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Treatment and Prognosis of TRALI

Treatment of TRALI requires interruption of the transfusion and ventilation with hemodynamic support. Diuretics and corticosteroids should not be given. Blood products should not be withheld if there is clinical indication. The risk of recurrence for TRALI is unknown, but it is being estimated at approximately 10%. The vast majority of cases, more than 80%, resolve within 96 hours with ventilatory support. With appropriate treatment, resolution is generally complete and no residual damages are observed in patients.

Etiopathogenesis

Which blood products may induce TRALI in a patient? Most, if not all, blood products have been linked to TRALI: whole blood, red blood cells, platelets (whole blood- or apheresis-derived), and granulocytes. TRALI has been found to be only rarely associated with administration of cryoprecipitates and intravenous immunoglobulins. Plasma, on the other hand, seems to be the blood product most frequently associated with TRALI, particularly units that contain more than 100 mL of plasma.

Donor-Derived Antibodies

Two, nonmutually exclusive, theories are being investigated as the possible cause of this respiratory syndrome feeding a bit into a climate of controversy. According to some investigators, donor-derived antibodies present in the transfused products react with the recipients' own blood cells, inducing release of inflammatory mediators. Anti-HLA antibodies are the most frequently "indicted" inducers in this category.

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Multiparous women are very good long-term blood donors, but owing to the multiple pregnancies, they may develop higher than usual titers of HLA antibodies to the fetal HLA antigens of paternal origin. Generally, only approximately 8% of the general population has detectable antibody titers vs more than 20% of multiparous women with more than 2 pregnancies. Does this etiopathogenetic theory imply that this donor group may carry a higher risk of inducing TRALI in the recipients?

A retrospective study published by Kopko and colleagues seems to suggest that, at times, there may be a correlation. In this study, the clinical histories of 50 recipients of blood transfusions from a 54-year-old multiparous woman (3 pregnancies) were evaluated retrospectively. Fifteen of the 36 evaluable recipients had developed transfusion-related respiratory complications: 7 with mild to moderate symptoms and 8 with a severe reaction. TRALI was formally diagnosed and reported only in 2 of these patients. In another investigation, 102 recipients of more than 2 units of plasma (FFP) prepared from multiparous women were studied retrospectively for complications. A total of 5 transfusion-related reactions had been reported, and only 1 as TRALI. These data are, however, of limited usefulness as antibodies titers and specificities were not evaluated in these recipients/patient combinations.

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Donor-Derived Lipids

The second theory mainly advocated by a single research group for the pathogenesis of TRALI points to lipids as the inducers of this syndrome. The presence of such lipids would increase over time in the donors' units, leading to accumulation of biologic mediators able to induce TRALI upon transfusion. Cell-rich blood products rather than plasma would thus carry the highest risk of transfusion reactions. The presence of lipid mediators would also be associated with autologous transfusions (transfusions of the patients' own blood cells or plasma). According to this hypothesis, the longer the storage, the higher the risk of developing TRALI.

A clinical case that might be ascribed to a lipid-induced TRALI is, in fact, that of the "autologous" TRALI. In this case, a 62-year-old man undergoing radical prostatectomy received 2 units of autologous blood (18 and 25 days old, respectively). After transfusion of the second unit, the patient experienced marked hypotension and hypoxemia. Symptoms resolved after interruption of the transfusion. No cardiac dysfunction and no volume overload were observed. The presence of bioactive lipids was later documented in the stored red blood cell units.

Practical Implications

Thus, according to the experimental results reported so far, both explanations may account for the occurrence of lung injury during TRALI. The relative role of each mechanism in the induction process is, however, being hotly disputed. While researchers investigating the pathogenetic role of antibodies report that up to 50% of TRALI cases appear to be antibody-mediated, Silliman's group found antibodies only in approximately 4% of cases claiming that the lipid priming activity would be responsible for most of the TRALI cases observed.

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More data would also shed light on questions that are, at the moment, unanswered, but that could influence standards of practice in transfusion medicine. Should donors be screened for the presence of leukoagglutinins? Should each unit be tested before transfusion for the presence of antibodies or lipid mediators? Should reverse lymphocyte crossmatches be performed?

As pointed out by Dr. Eder, the lack of agreement on the cellular and molecular mechanisms underlying the development of TRALI renders the task of improving the safety of blood transfusion far more complex and potentially more expensive.

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Two types of transfusions that are frequently perceived as "safer" by the general public may carry, in fact, a higher risk of TRALI: autologous components and maternal transfusions. While autologous transfusions would not be advisable on the basis of the long-term storage theory, maternal transfusions are contraindicated in some cases, owing to the high chance of having matching anti-HLA antibodies directed to the child's antigens of paternal origin, particularly after the second pregnancy (if the 2 children have the same biological father).

While we wait for a resolution of this etiopathogenetic controversy, more accurate diagnoses, a closer monitoring of patients, and a timely delivery of appropriate treatment will certainly help in making TRALI less of a burden in the posttransfusional setting.