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.