Among the elderly, anemia occurs with increasing frequency with each advancing decade. Unlike when anemia occurs in younger adults, the cause of anemia in the elderly is oftentimes not readily apparent or attributable to a single cause. However, this commonly observed form of anemia in the elderly (termed unexplained anemia [UA]) can generally be dissected to its root causes, which include renal insufficiency, inflammation, testosterone deficiency, and stem cell proliferative decline. Myelodysplasia (MDS) occurs commonly in this age group but can and should, for both diagnostic and therapeutic considerations, be distinguished from UA.

Aging is associated with increased incidence and prevalence of anemia, leading to a number of adverse health outcomes. These include death, functional dependence, increased risk of therapeutic complications, falls, and dementia. In approximately 30% of cases, anemia in older individuals is due to either relative or absolute erythropoietin (EPO) deficiency. Absolute EPO deficiency may be primary or secondary to declining renal function. Relative EPO deficiency is due to an age-related pro-inflammatory status that reduces the sensitivity of erythropoietic precursors to EPO. Despite this condition of EPO deficiency, the management of anemia of aging with erythropoiesis-stimulating agents (ESAs) is controversial, unless the anemia is due to renal insufficiency. The main concern related to this treatment arises from eight studies of ESAs in cancer, suggesting that ESAs may reduce patient survival in addition to increasing the risk of deep vein thrombosis. The results of these studies contrast with a host of other trials showing the safety of ESAs. The discrepancy may be explained in part by the fact that, in the trials suggesting a detrimental effect of ESAs, the goal was to obtain hemoglobin (Hb) levels higher than 12 g/dL. Because of this concern, correction of anemia in elderly individuals with relative EPO insufficiency should not be attempted outside clinical trials.

Nutritional anemias are important because they are easily reversed and because their underlying causes, most often unrelated to dietary intake, require individualized assessment. Iron-deficiency anemia (IDA) usually results from iron losses accompanying chronic bleeding, including loss to intestinal parasites, or from gastric disorders or malabsorption in the elderly. Cobalamin-deficiency anemia, the only nutritional anemia with predilection for the elderly, nearly always stems from failure of intrinsic factor (IF)-related absorption. Folate-deficiency anemia, the only nutritional anemia usually caused by poor intake, has nearly disappeared in countries that fortify food with folic acid. Copper-deficiency anemia, which usually results from malabsorptive disorders or from medical or nutritional interventions that provide inadequate copper or excess zinc, is uncommon but increasingly recognized. The prevalences of nutritional anemias, which are not always distinguished from non-anemic deficiency, are uncertain. The mean corpuscular volume (MCV) provides an essential diagnostic tool leading to judicious matching of relevant biochemical changes with relevant anemia. Nutritional anemias usually feature abnormal MCV, whereas the predominant anemias in the aged, especially the anemias of chronic disease/chronic inflammation (ACD/ACI), of renal failure, and of unknown causes, are typically normocytic.

Anemia is a common, multifactorial condition among older adults. The World Health Organization (WHO) definition of anemia (hemoglobin concentration <12 g/dL in women and <13 g/dL in men) is most often used in epidemiologic studies of older adults. More than 10% of community-dwelling adults age 65 years and older has WHO-defined anemia. After age 50 years, prevalence of anemia increases with advancing age and exceeds 20% in those 85 years and older. In nursing homes, anemia is present in 48% to 63% of residents. Incidence of anemia in older adults is not well characterized. Among older adults with anemia, approximately one third have evidence of iron, folate, and/or vitamin B(12) deficiency, another third have renal insufficiency and/or chronic inflammation, and the remaining third have anemia that is unexplained. Several studies demonstrate that anemia is associated with poorer survival in older adults. This review details the distribution and consequences of anemia in older adults and identifies future epidemiologic research needs.

A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold (hemoglobin [Hb] concentration, 7-8 g/dL), and well above the threshold for cerebral tissue hypoxia (Hb 3-4 g/dL). However, hypoxic and nonhypoxic mechanisms of anemia-induced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide (NO), may help to maintain cerebral oxygen delivery during anemia as all three NO synthase (NOS) isoforms (neuronal, endothelial, and inducible NOS) have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor (HIF)-1alpha, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations (Hb 6-7 g/dL). This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1alpha degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1alpha transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore, NOS-derived NO may also stabilize HIF-1alpha in the absence of tissue hypoxia. Thus, during anemia, HIF-1alpha has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1alpha may have either neuroprotective or neurotoxic capacity depending on the cell type in which it is up-regulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1alpha, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.

PURPOSE OF REVIEW: Literature since 2006 was reviewed to identify the harms and costs of red blood cell (RBC) transfusion. RECENT FINDINGS: Several studies, on people having various cardiac surgery operations, found strong associations of RBC transfusion with mortality and postoperative morbidity. The effect on mortality was strongest close to the time of operation but extended to 5 years. Morbidity outcomes included serious wound and systemic infections, renal failure, prolonged ventilation, low cardiac index, myocardial infarction, and stroke. RBC transfusion was also strongly associated with increased intensive care and ward postoperative stay, and hence increased cost of admission; available studies did not consider all resources used and the associated costs. SUMMARY: The harms of RBC transfusion have potentially serious and long-term consequences for patients and are costly for health services. This evidence should shift clinicians’ equipoise towards more restrictive transfusion practice. The immediate aim should be to avoid transfusing small numbers of RBC units for general malaise attributed to anaemia, a practice which appears to occur in about 50% of transfused patients. Randomized trials comparing restrictive and liberal transfusion triggers are urgently needed to compare directly the balance of benefits and harms from RBC transfusion