Insufficient nitric oxide bioavailability: a hypothesis to explain adverse effects of red blood cell transfusion

Abstract

While transfusion of red blood cells (RBCs) is effective at preventing morbidity and mortality in anemic patients, studies have indicated that some RBC components have functional defects ("RBC storage lesions") that may actually cause adverse events when transfused. For example, in some studies patients transfused with RBCs stored more than 14 days have had statistically worse outcomes than those receiving "fresher" RBC units. 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 primarily 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 transfusion recipients. We propose a unifying hypothesis, centered on insufficient nitric oxide bioavailability (INOBA), to explain the increased morbidity and mortality observed in some patients after RBC transfusion. In this model, variables associated with RBC units (storage time; 2,3-diphosphoglycerate acid concentration) and transfusion recipients (endothelial dysfunction) collectively lead to changes in nitric oxide (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 O(2) delivery to end organs. Under these circumstances, the likelihood of morbidity and mortality escalates. If the key tenets of the INOBA hypothesis are confirmed, it may lead to improved transfusion methods including altered RBC storage and/or processing conditions, novel transfusion recipient screening methods, and improved RBC-recipient matching.

Figure 1

Schematic diagram showing known changes that occur with RBC storage as well as the significant “unknown” links that that may lead from RBC storage lesions to adverse outcomes in transfusion recipients.

Figure 2

The INOBA hypothesis. Insufficient NO Bio-Availability (INOBA) is the common pathophysiological underpinning that ties together a number of diverse variables and manifestations associated with post-transfusion morbidity and mortality: RBC storage time (age), 2,3-DPG content, endothelial function, and post-transfusion hematocrit targets.