Health Organization criteria; causes of anemia included iron, folate, and B 12 deficiencies, renal insufficiency, anemia of chronic inflammation (ACI), formerly termed anemia of chronic disease, and unexplained anemia (UA). ACI by definition required normal iron stores with low circulating iron (less than 60 g/dL). After age 50 years, anemia prevalence rates rose rapidly, to a rate greater than 20% at age 85 and older. Overall, 11.0% of men and 10.2% of women 65 years and older were anemic. Of older persons with anemia, evidence of nutrient deficiency was present in one third, ACI or chronic renal disease or both was present in one third, and UA was present in one third. Most occurrences of anemia were mild; 2.8% of women and 1.6% of men had hemoglobin levels lower than 110 g/L (11 g/dL). Therefore, anemia is common, albeit not severe, in the older population, and a substantial proportion of anemia is of indeterminate cause. The impact of anemia on quality of life, recovery from illness, and functional abilities must be further investigated in older persons.

In 1990, a clinical trial was started using retroviral-mediated transfer of the adenosine deaminase (ADA) gene into the T cells of two children with severe combined immunodeficiency (ADA- SCID). The number of blood T cells normalized as did many cellular and humoral immune responses. Gene treatment ended after 2 years, but integrated vector and ADA gene expression in T cells persisted. Although many components remain to be perfected, it is concluded here that gene therapy can be a safe and effective addition to treatment for some patients with this severe immunodeficiency disease.

BACKGROUND Blood for transfusion is stored for up to 42 days. Older blood develops lesions and accumulates potentially injurious substances. Some studies report increasing toxicity as blood ages. We assessed the safety of transfused older versus newer stored blood. STUDY DESIGN AND METHODS PubMed, Scopus and Embase were searched using terms new and old and red blood cell and storage through May 6, 2011 for observational and randomized controlled studies comparing outcomes using transfused blood having longer and shorter storage times. Death was the outcome of interest. RESULTS Twenty-one studies were identified, predominantly in cardiac surgery (n=6) and trauma (n=6) patients, including 409,966 patients. A test for heterogeneity of these studies’ results was not significant for mortality (I2=3.7%, p=0.41). Older blood was associated with a significantly increased risk of death [odds ratio (OR) 1.16; 95% confidence interval (CI) (1.07, 1.24)]. Using available mortality data, 97 (63, 199; 95% CI) patients need to be treated with only new blood to save one life. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular type of patient, size of trial, or amount of blood transfused. CONCLUSION Based on available data, use of older stored blood is associated with a significantly increased risk of death.

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Key Points• In canine S aureus pneumonia, first randomized blinded trial showing blood transfused at end of storage period increases mortality.• Increased in vivo hemolysis, cell-free hemoglobin, pulmonary hypertension, tissue damage, and gas exchange abnormalities each contributed.Two-year-old purpose-bred beagles (n ‫؍‬ 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7-or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P ‫؍‬ .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P < .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ϳ 10 hours afterward (all P < .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P ‫؍‬ .03) noted at the infection site postmortem. Plasma cell-free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P < .03). The low haptoglobin (r ‫؍‬ 0.61; P ‫؍‬ .003) and high NO consumption levels at 24 hours (r ‫؍‬ ؊0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P ‫؍‬ .03) and not associated with survival (P ‫؍‬ NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. (Blood. 2013;121(9):1663-1672) IntroductionTransfusion of red blood cells (RBCs) is one of the most commonly used, potentially lifesaving medical therapies. Each year, some 80.7 million units of blood are collected in 167 countries worldwide, and approximately 15 million units are collected and transfused in the United States alone. 1,2 RBCs can be stored for up to 42 days to meet inventory needs, and by standard practice the oldest blood is usually used first ("first in, first out"). Food and Drug Administration (FDA) regulations only stipulate that at the end of the storage period 75% of the cells remain in the circulation at 24 hours after transfusion and that hemolysis in the storage bag does not exceed 1%, 3 no other product specification of quality is required. Although 6-week-old stored blood meets current FDA standards, laboratory and clinical studies have raised concerns that "older" blood may not be as safe as blood stored for a shorter duration. [4][5][6][7][8] Refrigerated storage of blood results in a "storage lesion" characterized by rheologic changes, metabolic derangements, changes in oxygen affinity and delivery, oxidative injury to lipids and proteins, RBC shape change, loss of membrane carbohydrates, and reduced RBC lifespan. [8][9][10] The storage lesion resu...

The beginning of the modern era of blood transfusion coincided with World War II and the resultant need for massive blood replacement. Soon thereafter, the hazards of transfusion, particularly hepatitis and hemolytic transfusion reactions, became increasingly evident. The past half century has seen the near eradication of transfusion-associated hepatitis as well as the emergence of multiple new pathogens, most notably HIV. Specific donor screening assays and other interventions have minimized, but not eliminated, infectious disease transmission. Other transfusion hazards persist, including human error resulting in the inadvertent transfusion of incompatible blood, acute and delayed transfusion reactions, transfusion-related acute lung injury (TRALI), transfusion-associated graft-versus-host disease (TA-GVHD), and transfusion-induced immunomodulation. These infectious and noninfectious hazards are reviewed briefly in the context of their historical evolution.

In TRICC and ARMA, randomization to fixed treatment regimens disrupted preexisting relationships between illness severity and therapy level. This created noncomparable subgroups in both study arms that received care different and opposite from titrated care, that is, practice misalignments. These subgroups reduced the interpretability and safety of each trial. Characterizing current practice, incorporating current practice controls, and using alternative trial designs to minimize practice misalignments should improve trial safety and interpretability.

• Washing older blood before transfusion reduces plasma iron, improving outcomes from established infection in canines.• In contrast, washing fresh blood before transfusion increases in vivo plasma CFH release, worsening outcomes.In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n 5 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7-or 42-dayold washed or unwashed canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes. (Blood. 2014;123(9):1403-1411 IntroductionTransfusion of older stored canine universal donor blood in a canine model of experimental Staphylococcus aureus pneumonia results in markedly increased lung injury and mortality rates.1 Transfusion with older blood is also associated with increased levels of cell-free hemoglobin (CFH), transferrin bound iron (TBI), non-TBI (NTBI) and plasma labile iron (PLI). NTBI represents iron excess bound to proteins that do not normally handle circulating iron, and PLI is the toxic iron moiety in plasma. Whereas increased nitric oxide scavenging by CFH causing vasoconstriction and vascular injury and increased available iron promoting bacterial growth represent 2 candidate mechanisms of injury, multiple other biological changes have been documented with increasing blood storage interval.2,3 Some of these changes involve the release into the plasma of biologically active proteins, microvesicles, potassium, acid, and plasticizer, all of which can be reduced by means of standard red cell (RBC) washing procedures. [4][5][6][7][8][9][10] The clinical effect(s) of washing on the RBC storage lesion has not been studied.RBC washing has long been performed to reduce potassium levels in stored blood transfused to neonates, debris from RBCs recovered during surgery, cryoprotectant glycerol from cryopreserved RBCs, and plasma proteins from blood intended for patients who have been sensitized to those proteins.11-13 Automated cell washers cap...