N E W S F E AT U R E
Blood feud: The debate over how long blood lasts
npg
Illustrations by Matt Hansen
© 2014 Nature America, Inc. All rights reserved.
By Jeanne Erdmann
Each year, one out of every 70 people in the US receives a red blood cell transfusion. It can happen during heart surgery, organ transplants, trauma treatment and a multitude of other scenarios. Thankfully, there is a steady supply of donated blood for this purpose. And, with the help of preservatives developed in recent decades, the shelf life of red blood cells can last more than a month. Increasingly, though, some are wondering whether fresher blood is a better choice for certain patients. “There’s no question that old blood is really abnormal,” says Mark Gladwin, a vascular medicine specialist at the University of Pittsburgh, Pennsylvania. What’s debatable, he says, is whether red blood cells expire sooner than we think. As a rule of thumb, hospital blood banks in the US hang on to red blood cells for up to 42 days, and by practice, they conserve inventory by dispensing on a first-in, firstout basis. The underlying assumption is that bags of older red blood cells are as effective as fresh ones. But although blood donations are screened for infectious diseases such as HIV and hepatitis, it is impractical to assess each bag of blood to see how many red cells have survived or broken apart in a process called hemolysis. “Every unit of blood is
its own lot, so to speak, and you can’t test every unit because you would destroy it in the process,” says Richard Weiskopf, an anesthesiologist and emeritus professor at the University of California, San Francisco. Until recently, most trials of how long stored red blood cells last have been retrospective, including one conducted by Colleen Koch, a cardiac anesthesiologist at the Cleveland Clinic in Ohio. She and her team examined patient records, comparing individuals who had received blood transfusion near, during or just after coronary artery bypass surgery, a heart valve replacement or both from 1998 through 2006. Of the 2,872 patients who received blood stored for two weeks or less, 1.7% died of complications while still hospitalized for their procedure. Among the 3,130 patients who received blood that was stored longer than two weeks, 2.8% died of complications—a small but statistically significant difference1. Another retrospective trial that looked at more than 400,000 patient records in Denmark and Sweden found a 5% increased risk of death among patients who had received blood older than 30 days, but it concluded that this mostly reflected confounding factors2. Richard Benjamin,
NATURE MEDICINE VOLUME 20 | NUMBER 9 | SEPTEMBER 2014
chief medical officer of the American Red Cross in Washington, DC, explains that sick patients are more likely to get transfused more often, and they do poorly because they’re so sick. “The association between bad outcomes and the age of blood is therefore not necessarily causal,” he says. This, perhaps, is why not all studies of patient records have shown that older blood is harmful. To answer some of the questions the retrospective studies have left hanging, Koch and other researchers have embarked on prospective clinical trials. Two such trials, the Red Cell Storage Duration Study (also known as ‘RECESS’) and the Age of Blood Evaluation (or ‘ABLE’) trial have already concluded, and those in the field anticipate results by this fall. The RECESS trial followed patients undergoing cardiac surgery, and the ABLE trial studied patients in the ICU. The outcomes of studies such as these could change medical practice. If, for example, the trials show that only cardiac surgery patients fare better with fresher red cells, then perhaps those groups would get transfusions from red cells stored for shorter times. “If it turns out that older blood is bad, that basically means more blood will be outdated earlier,” Benjamin says. “We will have to be more efficient, but we will have 979
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Accumulating concern Although blood processing differs worldwide, whole blood is always spun after collection to separate red cells from the plasma and platelets; care is also taken to filter out white cells. The blood is tested for pathogens and tested for blood type and then shipped to hospital blood banks. Preservatives such as sodium citrate and dextrose have progressively extended the shelf life of red cells (see ‘What’s in the Bag?’, p. 981). But red blood cells (and the white blood cells that escape filtration) remain metabolically active in the bag, and as they rupture they release microvesicles, tiny packets of proteins that can scavenge nitric oxide. That’s potentially bad news as blood lacking nitric oxide might tighten blood vessels. During storage, as the pH drops, so do levels of 2,3-diphosphoglycerate, a molecule red cells need for oxygen delivery. And the million or so white cells that remain behind churn out inflammatory immune proteins in the bag. “This is not a natural place for human tissue to hang out,” explains James Zimring, a transfusion medicine specialist at the University of Washington School of Medicine and at the Puget Sound Blood Center, a Seattle-based nonprofit
Transfusable Blood Components Whole Blood
Red Blood Cells
Platelets
Plasma
Cryoprecipitated AHF
Colorless
Yellowish
White
5 Days
1 Year
1 Year
Room temperature Frozen with constant agitation to prevent clumping
Frozen
Color of this blood component Red
Red
Blood component shelf life 21 / 35 Days*
Up to 42 Days*
Storage conditions Refrigerated
Refrigerated
Key uses of this blood type Trauma
Trauma
Cancer treatments Burn patients
Hemophilia
Surgery
Surgery
Organ transplants Shock
Anemia
Surgery
Von Willebrand disease (most common hereditary coagulation abnormality)
Any blood loss
Bleeding disorders
Rich source of Fibrinogen
Blood disorders, such as sickle cell Source: American Red Cross * Shelf life of whole blood and red cells varies based on the type anticoagulant used.
organization that facilitates blood donation and transfusion medicine. But whether the physical and biochemical changes that accumulate during the first 42 days of storage can affect patients receiving red cell transfusions remains unclear—and that’s where the controversy lies in transfusion medicine. In the US, the Food and Drug Administration (FDA) considers donated blood for transfusions to be a biologic
product, and when new filtration and anticoagulation technologies for red blood cell units come along, the agency requires that developers demonstrate that, on average, 75% of the cells from each unit survive at least 24 hours in the body (as determined using radiolabeled cells and healthy volunteers during the testing stage). The FDA also requires information from makers of blood preservatives about how many cells survive in their preparations.
npg
© 2014 Nature America, Inc. All rights reserved.
more wastage,” and his team already works very hard not to waste any donated blood.
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N E W S F E AT U R E
npg
© 2014 Nature America, Inc. All rights reserved.
However, some researchers would like to see the current FDA regulations beefed up. “Think of the attention that we place on the development of stem cells and all of the validation of cellular therapeutics,” Gladwin says. “But because red cells are grandfathered in, we assume that every red cell is the same as another red cell.” Getting personal Gladwin notes that there are more than 1,000 known mutations in red-cell enzymes, membrane proteins and hemoglobins, and he is investigating how various mutations could affect the storage quality of blood. He and his colleagues plan to analyze the DNA of blood samples taken from 14,000 volunteers to find variations in the genome that affect various blood attributes. The number of days blood has been sitting on a shelf may be too blunt a measure of what the quality of a unit actually is, says
Zimring, because there’s also so much variability among donors. One person’s red cells may be pristine at 42 days, while another’s could be effectively unusable at seven days, Zimring asserts. Researchers are studying what contributes to those differences. In one study published this year, researchers collected red blood cells from 13 men with the same blood type and tested the cells from 5 to 42 days. The team put mechanical stresses on the cells to see how easily they burst and found that the blood from one man with a metabolic disorder called hypertriglyceridemia showed dramatically escalating fragility over time3. As some scientists tease apart the individual differences between blood donors, others continue to examine the effect of red blood cell transfusions. Koch has had a long interest in understanding how postoperative complications relate to the transfusion of red blood cells, including
lung damage, heart attack and infections and reduced long-term survival4–6. She and her team wondered whether the length of storage of the red cell units could somehow contribute to the complications they had already observed, which led up to their 2008 retrospective study. Today, Koch is leading a randomized clinical trial involving 3,200 individuals undergoing procedures including heart bypass and valve repair and replacement, comparing those receiving blood stored less than 14 days to those receiving blood stored more than 20 days. Another new trial is being co-led by Philip Spinella, a pediatric critical care specialist at St. Louis Children’s Hospital in Missouri, and Marisa Tucci, of Sainte-Justine Hospital in Montreal. The trial, called ABC PICU, is just underway and will include more than 1,500 critically ill children ranging in age from three days to 16 years to figure out whether fresher red blood cells can reduce the risk of
What’s in the Bag? The preservatives within the bags, or ‘units’, of red blood cells have made a tremendous difference when it comes to extending shelf life—and new research suggests that one new mixture called SOLX could perhaps expand this to as long as 56 days. Red cells in plastic bags, called blood units, are stored on refrigerated shelves until they’re needed for transfusion or until they’ve reached their approved shelf life (42 days in the US and 35 days in many European countries). Additives such as sodium citrate, which binds calcium, keep red cells from clumping together. The sugar dextrose gives the red cells energy. Phosphate, meanwhile, preserves levels of ATP, the red cell’s energy molecule. Adenine and mannitol help stop red cells from rupturing. According to Haemonetics, the Massachusetts-based blood management company that’s currently developing the preservative, SOLX (also known as AS-7) buffers pH levels, thus maintaining red cell metabolism. Two studies of SOLX are slated to be published online in the journal Transfusion this fall. One trial demonstrated that the percentage of transfused red cells recovered at 24 hours after the red cells were stored at 42 and 56 days and then transfused into healthy volunteers met FDA criteria. Red cells stored for 42 days in SOLX had less hemolysis and higher levels of ATP than blood stored in a standard storage solution. The second study tested whether SOLX could extend the hold time of whole blood to 24 hours at room temperature before processing. (In the US, red cells have to be stored in the refrigerator within eight hours of collection.) The cell recovery after transfusion at 42 days showed low amounts of hemolysis and met FDA requirements. Although the recovery and hemolysis rates did not meet FDA requirements at 56 days for the cells that were held 18–24 hours before processing, a lower percentage of red cells stored in SOLX during that hold period ruptured compared with those that had been held in a standard solution. The current US hold time of eight hours creates logistical problems for some blood centers because donated blood may often be collected hundreds of miles away from the handling labs. “People don’t donate blood at midnight, so collection centers need second and third shifts to process the blood,” Dumont says. Haemonetics is seeking approval from the FDA so that SOLX can be used to increase the hold time of collected blood to 24 hours. “A 24-hour hold could smooth out work flow,” Dumont notes, “and reduce cost and waste in some places.”
Jeanne Erdmann
NATURE MEDICINE VOLUME 20 | NUMBER 9 | SEPTEMBER 2014
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Time will tell In the meantime, the results of the prospective trials RECESS and ABLE are expected by the end of 2014. The RECESS trial has studied organ failure in more than 1,600 cardiac surgery patients at multiple centers who received red cell transfusions from blood stored less than ten days or more than 21 days. Researchers in the ABLE trial have looked at 90-day mortality in more than 2,500 adults in the intensive care unit. Patients received either red cells stored for seven days or cells stored on average from 15 to 20 days. Although the results of these trials are not yet in, the Clinical Center at the US National Institutes of Health (NIH) in Bethesda, Maryland, already set a lower cutoff date for red cell shelf life: starting February 2014, it began using blood no older than 35 days for all transfusions there unless there’s a shortage. They’re also evaluating the effectiveness of the blood and whether supply will become an issue. “We see no advantage to giving blood that’s in the final week of storage,” says Harvey Klein, chief of the department of transfusion medicine at the NIH’s Clinical Center. “While people are not dropping dead immediately from older red cells, I suspect we’re reducing their ability to
npg
© 2014 Nature America, Inc. All rights reserved.
organ failure. “While I highly suspect that fresher red cells are better, we need to do the research to determine this,” Spinella says.
recuperate. We can have better outcomes if we are giving them a higher-quality product.” Large blood collection agencies won’t make that kind of change until the results of the RECESS and ABLE trials are in. Even
though blood ages on hospital shelves, if those trials show, even in a small way, that fresher units of red cells are better for patients, “We would be compelled to develop and manage inventory practices in a more sophisticated manner than by what is on the shelf the longest,” says Graham Sher, head of the AABB, (formerly the American Association of Blood Banks), an accreditation organization in transfusion medicine with headquarters in Bethesda. Because so many units are transfused with red cells every year—more than 14 million at the last official count in 2011 in the US alone—even the smallest of findings in these clinical trials will be significant. “I’m studying a therapy that one out of 70 Americans gets every year,” Zimring says. “I think that any small differences will have a huge effect on a lot of lives.” Corrected after print 22 September 2014. Jeanne Erdmann is a health and science writer in Wentzville, Missouri. 1. Koch, C. et al. New Engl. J. Med., 358. 1229–1239 (2008). 2. Edgren, G. et al. Transfusion 50, 1185–1195 (2010) 3. Tarasev, M. et al. Transfusion 54, 933–941, (2014). 4. Koch, C.G. et al. Ann. Thorac. Surg. 82, 13–20 (2006). 5. Koch, C.G. et al. Ann. Thorac. Surg. 81 , 1650–1657 (2006). 6. Koch, C.G. et al. Crit. Care. Med. 34, 1608–1616 (2006).
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© 2014 Nature America, Inc. All rights reserved.
Correction In the September 2014 issue, the piece “Blood feud: The debate over how long blood lasts” (Nat. Med. 20, 979–982, 2014) stated that proteins in stored blood “can scavenge nitrous oxide” and that “nitrous oxide might tighten blood vessels.” However, the story should have referred to nitric oxide, not nitrous oxide. The error has been corrected in the HTML and PDF versions of this article.
Blood feud: The debate over how long blood lasts
npg
Illustrations by Matt Hansen
© 2014 Nature America, Inc. All rights reserved.
By Jeanne Erdmann
Each year, one out of every 70 people in the US receives a red blood cell transfusion. It can happen during heart surgery, organ transplants, trauma treatment and a multitude of other scenarios. Thankfully, there is a steady supply of donated blood for this purpose. And, with the help of preservatives developed in recent decades, the shelf life of red blood cells can last more than a month. Increasingly, though, some are wondering whether fresher blood is a better choice for certain patients. “There’s no question that old blood is really abnormal,” says Mark Gladwin, a vascular medicine specialist at the University of Pittsburgh, Pennsylvania. What’s debatable, he says, is whether red blood cells expire sooner than we think. As a rule of thumb, hospital blood banks in the US hang on to red blood cells for up to 42 days, and by practice, they conserve inventory by dispensing on a first-in, firstout basis. The underlying assumption is that bags of older red blood cells are as effective as fresh ones. But although blood donations are screened for infectious diseases such as HIV and hepatitis, it is impractical to assess each bag of blood to see how many red cells have survived or broken apart in a process called hemolysis. “Every unit of blood is
its own lot, so to speak, and you can’t test every unit because you would destroy it in the process,” says Richard Weiskopf, an anesthesiologist and emeritus professor at the University of California, San Francisco. Until recently, most trials of how long stored red blood cells last have been retrospective, including one conducted by Colleen Koch, a cardiac anesthesiologist at the Cleveland Clinic in Ohio. She and her team examined patient records, comparing individuals who had received blood transfusion near, during or just after coronary artery bypass surgery, a heart valve replacement or both from 1998 through 2006. Of the 2,872 patients who received blood stored for two weeks or less, 1.7% died of complications while still hospitalized for their procedure. Among the 3,130 patients who received blood that was stored longer than two weeks, 2.8% died of complications—a small but statistically significant difference1. Another retrospective trial that looked at more than 400,000 patient records in Denmark and Sweden found a 5% increased risk of death among patients who had received blood older than 30 days, but it concluded that this mostly reflected confounding factors2. Richard Benjamin,
NATURE MEDICINE VOLUME 20 | NUMBER 9 | SEPTEMBER 2014
chief medical officer of the American Red Cross in Washington, DC, explains that sick patients are more likely to get transfused more often, and they do poorly because they’re so sick. “The association between bad outcomes and the age of blood is therefore not necessarily causal,” he says. This, perhaps, is why not all studies of patient records have shown that older blood is harmful. To answer some of the questions the retrospective studies have left hanging, Koch and other researchers have embarked on prospective clinical trials. Two such trials, the Red Cell Storage Duration Study (also known as ‘RECESS’) and the Age of Blood Evaluation (or ‘ABLE’) trial have already concluded, and those in the field anticipate results by this fall. The RECESS trial followed patients undergoing cardiac surgery, and the ABLE trial studied patients in the ICU. The outcomes of studies such as these could change medical practice. If, for example, the trials show that only cardiac surgery patients fare better with fresher red cells, then perhaps those groups would get transfusions from red cells stored for shorter times. “If it turns out that older blood is bad, that basically means more blood will be outdated earlier,” Benjamin says. “We will have to be more efficient, but we will have 979
N E W S F E AT U R E
Accumulating concern Although blood processing differs worldwide, whole blood is always spun after collection to separate red cells from the plasma and platelets; care is also taken to filter out white cells. The blood is tested for pathogens and tested for blood type and then shipped to hospital blood banks. Preservatives such as sodium citrate and dextrose have progressively extended the shelf life of red cells (see ‘What’s in the Bag?’, p. 981). But red blood cells (and the white blood cells that escape filtration) remain metabolically active in the bag, and as they rupture they release microvesicles, tiny packets of proteins that can scavenge nitric oxide. That’s potentially bad news as blood lacking nitric oxide might tighten blood vessels. During storage, as the pH drops, so do levels of 2,3-diphosphoglycerate, a molecule red cells need for oxygen delivery. And the million or so white cells that remain behind churn out inflammatory immune proteins in the bag. “This is not a natural place for human tissue to hang out,” explains James Zimring, a transfusion medicine specialist at the University of Washington School of Medicine and at the Puget Sound Blood Center, a Seattle-based nonprofit
Transfusable Blood Components Whole Blood
Red Blood Cells
Platelets
Plasma
Cryoprecipitated AHF
Colorless
Yellowish
White
5 Days
1 Year
1 Year
Room temperature Frozen with constant agitation to prevent clumping
Frozen
Color of this blood component Red
Red
Blood component shelf life 21 / 35 Days*
Up to 42 Days*
Storage conditions Refrigerated
Refrigerated
Key uses of this blood type Trauma
Trauma
Cancer treatments Burn patients
Hemophilia
Surgery
Surgery
Organ transplants Shock
Anemia
Surgery
Von Willebrand disease (most common hereditary coagulation abnormality)
Any blood loss
Bleeding disorders
Rich source of Fibrinogen
Blood disorders, such as sickle cell Source: American Red Cross * Shelf life of whole blood and red cells varies based on the type anticoagulant used.
organization that facilitates blood donation and transfusion medicine. But whether the physical and biochemical changes that accumulate during the first 42 days of storage can affect patients receiving red cell transfusions remains unclear—and that’s where the controversy lies in transfusion medicine. In the US, the Food and Drug Administration (FDA) considers donated blood for transfusions to be a biologic
product, and when new filtration and anticoagulation technologies for red blood cell units come along, the agency requires that developers demonstrate that, on average, 75% of the cells from each unit survive at least 24 hours in the body (as determined using radiolabeled cells and healthy volunteers during the testing stage). The FDA also requires information from makers of blood preservatives about how many cells survive in their preparations.
npg
© 2014 Nature America, Inc. All rights reserved.
more wastage,” and his team already works very hard not to waste any donated blood.
980
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N E W S F E AT U R E
npg
© 2014 Nature America, Inc. All rights reserved.
However, some researchers would like to see the current FDA regulations beefed up. “Think of the attention that we place on the development of stem cells and all of the validation of cellular therapeutics,” Gladwin says. “But because red cells are grandfathered in, we assume that every red cell is the same as another red cell.” Getting personal Gladwin notes that there are more than 1,000 known mutations in red-cell enzymes, membrane proteins and hemoglobins, and he is investigating how various mutations could affect the storage quality of blood. He and his colleagues plan to analyze the DNA of blood samples taken from 14,000 volunteers to find variations in the genome that affect various blood attributes. The number of days blood has been sitting on a shelf may be too blunt a measure of what the quality of a unit actually is, says
Zimring, because there’s also so much variability among donors. One person’s red cells may be pristine at 42 days, while another’s could be effectively unusable at seven days, Zimring asserts. Researchers are studying what contributes to those differences. In one study published this year, researchers collected red blood cells from 13 men with the same blood type and tested the cells from 5 to 42 days. The team put mechanical stresses on the cells to see how easily they burst and found that the blood from one man with a metabolic disorder called hypertriglyceridemia showed dramatically escalating fragility over time3. As some scientists tease apart the individual differences between blood donors, others continue to examine the effect of red blood cell transfusions. Koch has had a long interest in understanding how postoperative complications relate to the transfusion of red blood cells, including
lung damage, heart attack and infections and reduced long-term survival4–6. She and her team wondered whether the length of storage of the red cell units could somehow contribute to the complications they had already observed, which led up to their 2008 retrospective study. Today, Koch is leading a randomized clinical trial involving 3,200 individuals undergoing procedures including heart bypass and valve repair and replacement, comparing those receiving blood stored less than 14 days to those receiving blood stored more than 20 days. Another new trial is being co-led by Philip Spinella, a pediatric critical care specialist at St. Louis Children’s Hospital in Missouri, and Marisa Tucci, of Sainte-Justine Hospital in Montreal. The trial, called ABC PICU, is just underway and will include more than 1,500 critically ill children ranging in age from three days to 16 years to figure out whether fresher red blood cells can reduce the risk of
What’s in the Bag? The preservatives within the bags, or ‘units’, of red blood cells have made a tremendous difference when it comes to extending shelf life—and new research suggests that one new mixture called SOLX could perhaps expand this to as long as 56 days. Red cells in plastic bags, called blood units, are stored on refrigerated shelves until they’re needed for transfusion or until they’ve reached their approved shelf life (42 days in the US and 35 days in many European countries). Additives such as sodium citrate, which binds calcium, keep red cells from clumping together. The sugar dextrose gives the red cells energy. Phosphate, meanwhile, preserves levels of ATP, the red cell’s energy molecule. Adenine and mannitol help stop red cells from rupturing. According to Haemonetics, the Massachusetts-based blood management company that’s currently developing the preservative, SOLX (also known as AS-7) buffers pH levels, thus maintaining red cell metabolism. Two studies of SOLX are slated to be published online in the journal Transfusion this fall. One trial demonstrated that the percentage of transfused red cells recovered at 24 hours after the red cells were stored at 42 and 56 days and then transfused into healthy volunteers met FDA criteria. Red cells stored for 42 days in SOLX had less hemolysis and higher levels of ATP than blood stored in a standard storage solution. The second study tested whether SOLX could extend the hold time of whole blood to 24 hours at room temperature before processing. (In the US, red cells have to be stored in the refrigerator within eight hours of collection.) The cell recovery after transfusion at 42 days showed low amounts of hemolysis and met FDA requirements. Although the recovery and hemolysis rates did not meet FDA requirements at 56 days for the cells that were held 18–24 hours before processing, a lower percentage of red cells stored in SOLX during that hold period ruptured compared with those that had been held in a standard solution. The current US hold time of eight hours creates logistical problems for some blood centers because donated blood may often be collected hundreds of miles away from the handling labs. “People don’t donate blood at midnight, so collection centers need second and third shifts to process the blood,” Dumont says. Haemonetics is seeking approval from the FDA so that SOLX can be used to increase the hold time of collected blood to 24 hours. “A 24-hour hold could smooth out work flow,” Dumont notes, “and reduce cost and waste in some places.”
Jeanne Erdmann
NATURE MEDICINE VOLUME 20 | NUMBER 9 | SEPTEMBER 2014
981
N E W S F E AT U R E
Time will tell In the meantime, the results of the prospective trials RECESS and ABLE are expected by the end of 2014. The RECESS trial has studied organ failure in more than 1,600 cardiac surgery patients at multiple centers who received red cell transfusions from blood stored less than ten days or more than 21 days. Researchers in the ABLE trial have looked at 90-day mortality in more than 2,500 adults in the intensive care unit. Patients received either red cells stored for seven days or cells stored on average from 15 to 20 days. Although the results of these trials are not yet in, the Clinical Center at the US National Institutes of Health (NIH) in Bethesda, Maryland, already set a lower cutoff date for red cell shelf life: starting February 2014, it began using blood no older than 35 days for all transfusions there unless there’s a shortage. They’re also evaluating the effectiveness of the blood and whether supply will become an issue. “We see no advantage to giving blood that’s in the final week of storage,” says Harvey Klein, chief of the department of transfusion medicine at the NIH’s Clinical Center. “While people are not dropping dead immediately from older red cells, I suspect we’re reducing their ability to
npg
© 2014 Nature America, Inc. All rights reserved.
organ failure. “While I highly suspect that fresher red cells are better, we need to do the research to determine this,” Spinella says.
recuperate. We can have better outcomes if we are giving them a higher-quality product.” Large blood collection agencies won’t make that kind of change until the results of the RECESS and ABLE trials are in. Even
though blood ages on hospital shelves, if those trials show, even in a small way, that fresher units of red cells are better for patients, “We would be compelled to develop and manage inventory practices in a more sophisticated manner than by what is on the shelf the longest,” says Graham Sher, head of the AABB, (formerly the American Association of Blood Banks), an accreditation organization in transfusion medicine with headquarters in Bethesda. Because so many units are transfused with red cells every year—more than 14 million at the last official count in 2011 in the US alone—even the smallest of findings in these clinical trials will be significant. “I’m studying a therapy that one out of 70 Americans gets every year,” Zimring says. “I think that any small differences will have a huge effect on a lot of lives.” Corrected after print 22 September 2014. Jeanne Erdmann is a health and science writer in Wentzville, Missouri. 1. Koch, C. et al. New Engl. J. Med., 358. 1229–1239 (2008). 2. Edgren, G. et al. Transfusion 50, 1185–1195 (2010) 3. Tarasev, M. et al. Transfusion 54, 933–941, (2014). 4. Koch, C.G. et al. Ann. Thorac. Surg. 82, 13–20 (2006). 5. Koch, C.G. et al. Ann. Thorac. Surg. 81 , 1650–1657 (2006). 6. Koch, C.G. et al. Crit. Care. Med. 34, 1608–1616 (2006).
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VOLUME 20 | NUMBER 9 | SEPTEMBER 2014 NATURE MEDICINE
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© 2014 Nature America, Inc. All rights reserved.
Correction In the September 2014 issue, the piece “Blood feud: The debate over how long blood lasts” (Nat. Med. 20, 979–982, 2014) stated that proteins in stored blood “can scavenge nitrous oxide” and that “nitrous oxide might tighten blood vessels.” However, the story should have referred to nitric oxide, not nitrous oxide. The error has been corrected in the HTML and PDF versions of this article.
