Female Plasma May Not Increase Risk for Transfusion-Related Acute Lung Injury

Laurie Barclay, MD

October 23, 2007

October 23, 2007 — Fresh-frozen plasma (FFP) from female donors may not increase risk for transfusion-related acute lung injury (TRALI), according to the results of a study presented at the American Association of Blood Bankers 2007 Annual Meeting in Miami Beach, Florida. Although fresh frozen plasma derived from female donors did have higher levels of leukocyte antibodies compared with that derived from male donors, there was no increased association of female donor–derived plasma with mortality, delayed recovery, or respiratory complications or failure.

"As blood banks in the United States consider adjusting the way they use female donor FFP, changes already having occurred in the United Kingdom, our study raises interesting questions regarding the best way to evaluate the safety of female donor transfusion," senior author Mark Stafford-Smith, MD, CM, FRCPC, FASE, professor of anesthesiology at the Duke Heart Center in Durham, North Carolina, told Medscape Hematology. "Previous evidence regarding safety for female donor blood products has come in part from case series that characterize features of recipient and donor in cases where a serious transfusion-related complication has occurred [ie, TRALI]. The current study takes an alternate approach by comparing donor characteristics in large cohorts of transfused cardiac surgery patients that did or did not sustain serious complications."

TRALI is a rare, but serious, complication of transfusion that has been linked to use of FFP from female donors, in part because leukocyte antibodies are potential TRALI mediators and are more common in women. Less severe respiratory dysfunction has also been associated with FFP from female donors. Some blood collection agencies are therefore transfusing FFP from male donors only.

The objective of this study was to determine whether female-derived FFP was associated with adverse outcomes in cardiac surgery patients.

From September 1993 to June 2002 at the authors' institution, transfusion, donor, demographic, and outcome variables were obtained from prospectively gathered databases for consecutive nonemergent aortocoronary bypass procedures. Off-pump and redo surgery and patients not receiving FFP were excluded, and the percentage of total female-derived FFP was calculated for each patient.

The main endpoints were 30-day mortality, length of stay exceeding 10 days, and respiratory complications, including pneumonia, pulmonary edema, acute respiratory distress syndrome, and respiratory failure requiring postoperative reintubation and/or tracheostomy. Secondary endpoints were neurologic complications, including stroke, delirium, or coma; cardiac complications; and acute kidney injury and infection. The relative frequency of female donor FFP transfused in patient groups with and without each adverse event was calculated.

Of 8300 patients in the database, 2157 received a median of 2 units FFP, of which 44.6% were from female donors. High volume of FFP transfusion was linked to mortality (P < .001). In groups experiencing various adverse events, female-derived FFP did not represent a significantly higher percentage of mortality (n = 132; 41.7% vs 44.8%; P = .31), length of stay exceeding 10 days (n = 279; 40.7% vs 45.2%; P = .06), respiratory complications (n = 209; 39.1% vs 45.2%; P = .03), and respiratory failure (n = 155; 42.4% vs 44.8%; P = .37).

Unexpectedly, a combined analysis of mortality and length of stay exceeding 10 days suggested a trend toward a protective effect of female-derived FFP (n = 366; 40.9% vs 45.4%; P = .02). There were no significant associations detected with secondary outcomes.

"Although evidence from TRALI cases series implicates transfusion of female donor plasma as an important risk factor, using this alternate approach in our study, we did not identify female donor as a risk factor for sustaining respiratory complications with FFP transfusions — we even noted an overall trend toward increased risk of major postoperative complications in those receiving male donor FFP," Dr. Stafford-Smith said.

"While an investigational approach evaluating obvious transfusion-related complications is sound and has highlighted an association of female donor product transfusion with severe TRALI, case series by their design evaluate a limited set of complications and risk overlooking more common but subtle adverse effects of transfusion that may only be evident in larger patient groups, which summatively could be more important to outcome than an occasional extreme complication attributable to transfusion," Dr. Stafford-Smith explained.

On the basis of these findings, the authors questioned whether an overall policy aiming to minimize TRALI risk should completely exclude transfusion of female-derived plasma. Dr. Stafford-Smith recommends validating these findings in another data set, ideally in a prospective, randomized trial. Future research should also analyze risk factors for antibody formation, such as donor parity, and further evaluate whether female-derived FFP has a protective effect in cardiac surgery.

"Since TRALI is so uncommon, it can take a very large study to detect a difference between male and female plasma," Patricia Kopko, MD, executive vice president of medical affairs and director of the histocompatibility laboratory at BloodSource in Sacramento, California, told Medscape Hematology. Dr. Kopko was not involved in this study but was asked to provide independent commentary.

"Please note the authors state they cannot confirm a difference between the transfusion of male and female plasma," Dr. Kopko said, citing a study by Mark Popovsky and coauthors that was published in Transfusion in 1985, which showed that the incidence of TRALI was 1 in 5000 transfusions, or about 1 in 2000 patients transfused. "Since the current study involved 2157 patients who received a median of 2 units, the study may not have been large enough to detect a difference. When the entire United Kingdom switched to all male plasma, they detected a substantial decrease in the number of TRALI cases."

Dr. Kopko notes that it is difficult to study TRALI because it occurs relatively infrequently and because fatalities are even less common, with a mortality rate of about 5% to 15%. Approximately 30 fatal cases of TRALI were reported to the US Food and Drug Administration (FDA) in 2006, and TRALI has been the leading cause of transfusion-related mortality reported in the United States in the last several years.

"Based upon the data from the United Kingdom and based upon reports of an association of female plasma with TRALI in other studies, many blood centers in the United States have started providing plasma for transfusion exclusively from males," Dr. Kopko said. "If there is no difference between male and female plasma, we should know in a few years by looking at the data from fatality reports to the FDA. If data in the United States look like data from the United Kingdom, we will know that in a few years also."

Donated whole blood is typically separated into packed red blood cells and plasma. At BloodSource, FFP from female donors is used for further manufacture of pharmaceuticals such as albumin and intravenous immune globulin.

"Essentially, the move to male plasma for transfusion was mostly an inventory issue for most blood centers," Dr. Kopko concluded. "Since more plasma is collected from whole blood than is needed for transfusion, some of the plasma from men also is used for further manufacture. When looking at this as an inventory issue, it was an easy decision to make."

Dr. Stafford-Smith reports no financial disclosures. BloodSource is a not-for-profit blood center providing blood and blood services in Northern and Central California, with headquarters in Sacramento.

American Association of Blood Bankers 2007 Annual Meeting. October 21-24, 2007.

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