Transfusion of red blood cells (RBCs) is often effective at preventing morbidity and mortality in anemic patients. In contrast, recent studies indicate that some RBC components may have functional defects ("RBC storage lesions") that actually cause morbidity and mortality when transfused. For example, patients transfused with RBCs stored \>14 days have statistically worse outcomes than those receiving "fresher" RBC units. In addition to the age of stored RBCs, the volume transfused may be important. The Transfusion Requirements in Critical Care (TRICC) study showed that specific patients whose transfusions were limited by a restrictive trigger (RBCs transfusions only when hemoglobin \[Hb\] \< 7 g/dL) had significantly better outcomes than those transfused with a more liberal trigger (\[Hb\] \< 10 g/dL Hb). This finding has been particularly difficult to understand since conventional wisdom suggests that an elevated \[Hb\] should be beneficial because it supports increased oxygen (O2) delivery. Recipient-specific factors may also contribute to the occurrence of these adverse events. Unfortunately, these events have been difficult to investigate because up to now they have existed only as "statistical occurrences" of increased morbidity and mortality in large data sets. There are currently no clinical or laboratory methods to detect or study them in individual patients.

The microcirculation is composed of a continuum of small vessels including small arterioles, capillaries, and post-capillary venules. The microcirculation represents an actively-adjusting vascular circuit that matches blood flow (and O2 delivery) to local tissue oxygen demands. While the physiologic mechanisms that match O2 delivery to local requirements are incompletely understood, endothelium-derived nitric oxide (NO) clearly plays an important role. Interestingly, recent work has revealed that in addition to transporting O2 and carbon dioxide (CO2), the RBC also controls local NO concentrations and thus may also play a surprisingly important role in regulating blood flow in the microcirculation.

Herein, the investigators bring together previously unconnected data to propose a unifying hypothesis, centered on insufficient NO bioavailability (INOBA), to explain the increased morbidity and mortality observed in some patients following RBC transfusion. In this model, variables associated with RBC units (storage time; 2,3-diphosphoglycerate (2,3-DPG) concentration) and transfusion recipients (endothelial dysfunction; hematocrit \[Hct\]) collectively lead to changes in NO levels in vascular beds. Under certain circumstances, these variables are "aligned" such that NO concentrations are markedly reduced, leading to vasoconstriction, decreased local blood flow and insufficient O2 delivery to end organs. Under these circumstances, the likelihood of morbidity and mortality escalates. The INOBA hypothesis is attractive because of its explanatory power and because it leads to a number of readily testable predictions, which will be investigated t determine the effects of transfused RBCs in patients with endothelial dysfunction due to cardiovascular disease. A non-invasive ultrasound assay will be used to test whether patients with cardiovascular disease and endothelial dysfunction (who have intrinsic defects in NO synthesis) are more susceptible to adverse effects from stored/processed RBCs (impaired in NO bioavailability) than fresh RBC units. Vasodilation and tissue oxygenation in response to transfusion will be monitored, and Framingham risk scores and cardiovascular disease biomarkers will be tested as potential predictive factors to identify patients most at risk from adverse effects of RBC transfusions.