Female, Young Blood Donors May Boost Recipients' Death Risk

Diana Swift

July 13, 2016

A large Canadian study has found a significant association between blood donors' sex or age and poorer survival in transfusion recipients.

The study, published online July 11 in JAMA Internal Medicine, is the first to tie these donor characteristics to adverse outcomes.

Patients who received red blood cells from a female donor had a statistically significant 8% increased risk for death from any cause per unit transfused vs receiving male red blood cells, for an age-, sex- and comorbidity-adjusted hazard ratio (HR) of 1.08 (95% confidence interval [CI], 1.06 - 1.09; P < .001), report Michaël Chassé, MD, PhD, from the Department of Anesthesiology and Critical Care, Université Laval, Quebec, Canada, and colleagues.

An unexpected risk elevation also emerged from younger donors, with red blood cells from those aged 17 to 20 years appearing to confer an 8% increased mortality risk per unit transfused vs cells from donors aged 40 to 49.9 years. Adjusted HRs were 1.08 (95% CI, 1.06 - 1.10; P < .001) for donors aged 17 to 19.9 years and 1.06 (95% CI, 1.04 - 1.09; P < .001) for donors aged 20 to 29.9 years.

With more than 100 million red blood cell units transfused globally each year, an 8% mortality risk increase for each additional transfusion could have a significant effect in absolute terms, the authors note. For example, the observed 1-year mortality rate of 36.4% in recipients of 6 female donor units would decrease to 27.1% in recipients of male-only transfusions, for an absolute risk reduction of 9.3% (95% CI, 8.3% - 10.4%).

To determine the effect of donor characteristics, Dr Chassé and colleagues linked 30,503 red blood cell recipients who underwent 187,960 transfusions at four facilities in the The Ottawa Hospital and the University of Ottawa Heart Institute between October 2006 and December 2013 with their 80,755 unique donors. The mean age of recipients was 66.2 years, and 52.1% were women. They were followed for a mean of 2.3 years to a maximum of 7.2 years. Their comorbidities ranged broadly from cardiac and cerebrovascular disease, congestive heart failure, and diabetes to dementia, cancer, and HIV.

Donors were 51.3% male and had a mean age of 40.4 years at first blood donation. Divided into seven age categories from age 17 to 75 years and older, they were also characterized by number of previous blood donations (mean, 12.7) and eight blood types, the most common being O positive (38.4%) and A positive (29.5%).

Donor female sex was associated with reduced survival in both male and female recipients (adjusted HRs, 1.08 [95% CI, 1.07 - 1.10 per additional unit; P < .001] and 1.03 [95% CI, 1.02 - 1.05 per additional unit; P < .001]).

Interestingly, young donor age appeared primarily to decrease the survival of males, with the greatest risk in male recipients receiving blood from the youngest donors (adjusted HR, 1.14 [95% CI, 1.11 - 1.17] for each additional unit; P < .001). Animal research has suggested a different effect of younger blood, reporting improved cognitive function in mice transfused with young blood.

"These results are intriguing and suggest that if you require a transfusion, your clinical outcome may be affected by the blood donor's age and sex," said senior author Dean Fergusson, PhD, MHA, director of the Clinical Epidemiology Program at The Ottawa Hospital, in a University of Ottawa news release. He cautioned, however, that the study's observations do not constitute definitive evidence.

Underscoring that, hematologist Harvey G. Klein, MD, chief of the Department of Transfusion Medicine at the National Institutes of Health Clinical Center in Bethesda, Maryland, writes in a related invited commentary, "The findings should be considered hypotheses, not evidence of causality." As with all observational studies, this one was susceptible to biases and confounding.

As for mechanisms, "The most plausible explanation is that there are components in female and younger blood, such as antibodies, that stress and tax the recipient's immune system response," Dr Fergusson told Medscape Medical News.

Blood transfusion is associated with immune system changes, which likely differ according to donor characteristics. "Immunomodulatory effects may be associated with an increased risk of infections and cancer recurrence over time, hence the lag in mortality," Dr Chassé and colleagues write. They hypothesize that "currently unknown biological or environmental factors affecting young donors may influence the [red blood cell] products transfused. The resulting association with mortality may not be due to young age but rather due to factors associated with young age."

As for the female factor, the authors note that immunological phenomena such as pregnancy-triggered antileukocyte antibodies that occur can adversely affect clinical outcomes, citing, for example, the sex effect on transfusion-related acute lung injury. However, not all research has found evidence of significant increased risk from transfused female plasma.

Although excluding donors with negative biological or environmental factors such as young age or female sex could likely improve survival, the authors note that blood donor screening does not currently assess potential associations between donor characteristics and recipient survival. They call for further epidemiological research to determine the mechanisms of these characteristics.

Even in the absence of clear mechanistic causality, however, Dr Fergusson and colleagues state the associations are unlikely to be only a result of chance or unmeasured confounders.

Dr Klein observed that the association between donor demographics and transfusion outcomes emerged more than half a century ago, when the risk for transfusion-transmitted hepatitis was linked to donors' sex, age, socioeconomic status, and ethnicity, which related to their previous infection risk.

More recently, a study of donor age and recipient mortality using the Danish and Swedish Scandinavian Donations and Transfusions (SCANDAT) 2 database found no association between donor age and recipient 30-day or 1-year mortality, although patient exposure to transfusion was less than in the Canadian analysis. And in a single-center US study, no association emerged between donor age and recipient outcome in a large database of coronary artery bypass grafting.

"However, the absence of an obvious mechanism or of confirmatory studies does not refute the findings by Chassé and colleagues but indicates that verification is necessary before such findings can be acted on," Dr Klein writes.

Calling the study results "tantalizing," he stressed the need to investigate demographic and genetic donor factors beyond blood groups that affect the safety of different blood components; research so far sidelined by the need to prevent pathogen transmission. "Perhaps the most significant message may be recognition, as the authors point out, that to perform such studies one has to be able to track blood from 'vein to vein,' " Dr Klein writes, and databases such as SCANDAT would be an obvious means.

In line with that, phase 3 of the National Heart, Lung, and Blood Institute's 2011-launched Recipient Epidemiology and Donor Evaluation Study has created a detailed multisite database linking information on donors, the components made from their donations, and extracts from the electronic medical records of recipients in participating hospitals.

"Combining clinical trials research with database analysis should provide a powerful tool for tackling fundamental questions regarding blood transfusion, providing rapid responses to emerging transfusion issues and informing blood policy decisions that affect patient care," Dr Klein writes.

This study was funded by Canadian Blood Services and the Canadian National Institute of Health, neither of which had role in any aspect of the study. The authors and Dr Klein have disclosed no relevant financial relationships.

JAMA Intern Med. Published online July 11, 2016. Article abstract, Commentary extract

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