The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

improved control of body iron burden, 6,7 compared with a transfusion schedule (termed ''supertransfusion'') in which HE LAST 3 decades have witnessed profound changes in the management of patients with thalassemia major. Regular red blood cell (RBC) transfusions eliminate the baseline hemoglobins are permitted to exceed 11 g/dL. 8 complications of anemia and compensatory bone marrow Type of RB C Concentrates (BM) expansion, permit normal development throughout childhood, and extend survival. 1 In parallel, transfusions re-Early studies of the use of neocytes, or young RBCs, sult in a ''second disease'' while treating the first, 2 that predicted that prolonged survival in vivo of these concenof the inexorable accumulation of tissue iron that, without trates should reduce the RBC mass required to maintain treatment, is fatal in the second decade of life. Further alterappropriate baseline hemoglobin concentrations. 8-11 Clinical ing the prognosis of thalassemia major over the last 20 years investigations confirmed that an extension of transfusion inhas been progress in the development of iron-chelating therterval of 13% to 25% in thalassemia could be achieved with apy for iron overload. Deferoxamine mesylate, first introthe use of neocytes. 12-16 A recent study found that a 15% duced in short-term studies in iron-loaded patients in the extension of transfusion interval during administration of early 1960s, gained acceptance as standard therapy over a neocyte concentrates, expected to minimally reduce the redecade later in countries able to support the high costs of quirement for iron chelation therapy, could be achieved but this therapy. Twenty years later, extended survival free of at the cost of an increased exposure to donated units and a iron-induced complications, and dramatically improved fivefold increment in preparation expenses over those of quality of life, are observed in well-chelated patients. Indeed, standard concentrates. 16 Hence, the use of neocytes should over this period, iron-chelating therapy for thalassemia major have a limited impact on the long-term management of most has resulted in one of the most dramatic alterations in morchronically transfused patients. In contrast, the use of autobidity and mortality associated with a genetic disease. In this mated RBC exchange transfusions in regularly transfused review the experience gained in the use of deferoxamine, patients with sickle cell disease has been reported to substanthe benefits of and problems associated with this agent in tially reduce transfusional iron accumulation, permitting rethe treatment and prevention of iron overload, and recent duction in the intensity of chelation therapy. 17 Pilot studies progress in the development of orally effective iron-chelating in thalassemia major 18 suggest that a similar approach may drugs will be reviewed. warrant careful evaluation in this disorder.

Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.

The hepatic iron concentration is a reliable indicator of total body iron stores in patients with thalassemia major. In patients with transfusion-related iron overload, repeated determinations of the hepatic iron concentration can provide a quantitative means of measuring the long-term iron balance.

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

Physicians and Surgeons, New York, NY Key Points• Iron supplements at doses of 60 mg Fe as FeSO 4 or higher increase hepcidin for up to 24 hours and are associated with lower iron absorption on the following day.• The soluble transferrin receptor/ferritin ratio and hepcidin are equivalent predictors of iron absorption from supplements.Iron supplements acutely increase hepcidin, but the duration and magnitude of the increase, its dose dependence, and its effects on subsequent iron absorption have not been characterized in humans. Better understanding of these phenomena might improve oral iron dosing schedules. We investigated whether the acute iron-induced increase in hepcidin influences iron absorption of successive daily iron doses and twice-daily iron doses. We recruited 54 nonanemic young women with plasma ferritin £20 mg/L and conducted: (1) (study 1, n 5 25; study 2, n 5 16); and (2) a study giving three 60-mg Fe doses (twice-daily dosing) within 24 hours (study 3, n 5 13). In studies 1 and 2, 24 hours after doses ‡60 mg, serum hepcidin was increased (P < .01) and fractional iron absorption was decreased by 35% to 45% (P < .01). With increasing dose, fractional absorption decreased (P < .001), whereas absolute absorption increased (P < .001). A sixfold increase in iron dose (40-240 mg) resulted in only a threefold increase in iron absorbed (6.7-18.1 mg). In study 3, total iron absorbed from 3 doses (2 mornings and an afternoon) was not significantly greater than that from 2 morning doses. Providing lower dosages (40-80 mg Fe) and avoiding twice-daily dosing maximize fractional absorption. The duration of the hepcidin response supports alternate day supplementation, but longer-term effects of these schedules require further investigation. These clinical trials were registered at www.ClinicalTrials.gov as #NCT01785407 and #NCT02050932. (Blood.

A 16-year-old boy with sickle cell anemia undergoes routine screening with transcranial Doppler ultrasonography to assess the risk of stroke. This examination shows an abnormally elevated blood-flow velocity in the middle cerebral artery. The hemoglobin level is 7.2 g per deciliter, the reticulocyte count is 12.5%, and the fetal hemoglobin level is 8.0%. Long-term treatment with red-cell transfusion is initiated to prevent stroke. A hematologist recommends prophylactic iron-chelating therapy.

Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leukoreduced, double RBC units. One unit was autologously transfused "fresh" (3-7 days of storage), and the other "older" unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. IntroductionThe safety of transfusing RBCs after longer durations of refrigerated storage was recently identified as "the most critical issue facing transfusion medicine." 1 page 667 Concern was heightened when a large observational study of cardiac surgery patients found an increased risk of postoperative complications and reduced survival in those who received RBCs stored for more than 14 days. 2 Although still controversial, adverse clinical consequences have since been reported in most, [3][4][5] although not all, 6,7 epidemiologic studies of transfusions of RBCs stored for longer durations, but still within Food and Drug Administration (FDA) guidelines. The association between the duration of RBC storage and increased rates of serious infections, sepsis, and mortality is particularly strong in trauma patients. [7][8][9][10][11] Definitive determination of the potential risks associated with transfusion of RBCs stored for longer durations has been elusive, in part because the mechanisms responsible have not yet been identified.More than 14 million RBC units are transfused in the United States each year, with a mean storage interval of 18 days before transfusion. 12 During storage, RBCs undergo cumulative biochemical and biomechanical changes (the "storage lesion") that reduce their survival in vivo after transfusion. 13,14 In mouse models, 15 transfusion of RBCs stored for longer durations was followed by brisk extravascular clearance of a subpopulation of these cells, which were damaged during storage and removed by macrophages in the spleen and liver of recipient mice. The iron liberated by phagocytic digestion of these RBCs rapidly entered the systemic circulation in amounts that exceeded the transport capacity of plasma transferrin, the physiologic iron-binding protein; in this way, circulating non-transferrin-bound iron appeared and promoted the proliferation of pathogenic bacteria both in vitro 15 and in vivo. 16 We hypothesized that the infectious complications observed in human patients after transfusion of RBCs stored for longer durations were, at least in part, the result of the production of circulating non-transferrin-bound iron. Therefore, we prospectively examined healthy human volunteers to determine (1) if transfusion of autologous RBCs stored for longer durations was followed by the appearance of circulating non-transferrin-bound iron in vivo, and (2) if this increased circulating non-transferrinbound iron was assoc...