Mark J. Koury, MD
Dr. Koury indicated no relevant conflicts of interest.
Baek JH, D’Agnillo F, Vallelian F, et al. Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. J Clin Invest. 2012;122:1444-1458.
Red blood cells (RBCs) processed for transfusion can be stored for a maximum of six weeks before they officially expire. However, during refrigerated storage, important properties of the RBCs change. Both 2,3-DPG and ATP content decrease, reducing hemoglobin oxygen affinity and membrane transport functions, respectively. Microvesicle shedding is observed and oxidative damage affecting the red cell membrane and membrane skeleton accumulates, thereby decreasing cellular deformability. These in vitro changes that are cumulative and time-dependent are collectively termed the red cell storage lesion, and the intravascular hemolysis and subsequent vascular dysfunction that follows transfusion is attributed to this process. Numerous publications have reported increased morbidity and mortality following transfusion of RBCs stored for longer periods within the allowable six-week time frame. These reports have been mainly retrospective and uncontrolled, the patient populations have been heterogeneous, and the definition of a longer versus a shorter storage period was variable. However, a recent meta-analysis showed a 16 percent higher relative risk of mortality for patients transfused with RBCs stored for longer compared with shorter time periods.1
To study the pathophysiology of the red cell storage lesion in vivo, Baek et al. developed a guinea pig exchange-transfusion model. Guinea pig RBCs had similar deformabilities at two days of storage (new blood) as did human RBCs. However, guinea pig RBCs had accelerated loss of deformability such that at four weeks of storage (defined as old blood) they were as fragile as human RBCs stored for six weeks. Compared with animals transfused with new blood, those transfused with old blood were found to have significantly more intravascular hemolysis that was accompanied by an increase in mean arterial pressure and development of renal failure within one day. Infused purified hemoglobin did not induce the vascular and renal effects that old blood transfusion did, and washed, old blood RBCs retained their vascular and renal toxicities despite loss of the most fragile RBCs during the washing procedure. The fact that bolus infusion did not reproduce the adverse effects of transfused old blood suggests that brief exposure to isolated hemoglobin (as might occur during transfusion) is insufficient to account for the red cell storage lesion.
The pathologic effects of old blood transfusion included necrotic damage affecting the luminal and medial layers of the aortic root and the epithelium of renal tubules. The renal tubules also accumulated large amounts of stainable iron. A role for intravascular-free hemoglobin in the pathologic process was suggested when co-administration of haptoglobin, the physiological scavenger of free hemoglobin in the plasma, was found to ameliorate the adverse events associated with old blood transfusion. Proteomics of kidneys from guinea pigs transfused with old blood showed increased expression of proteins associated with hemoglobin catabolism and oxidative stress, suggesting that renal damage was an oxidative process induced by free hemoglobin and heme. Haptoglobin co-administration greatly reduced the pathologic changes affecting vessels and renal tubules through binding and sequestration of free hemoglobin with subsequent delivery to macrophages where hemoglobin is catabolized.2 Pathologic vascular and renal effects intermediate between guinea pigs transfused with new blood versus old blood were observed in animals transfused with three-week-old blood, indicating a time-dependent worsening of the toxic effects of blood storage.
The study from Baek and colleagues provides a plausible explanation for some of the adverse events observed in patients who undergo massive RBC transfusions. In patients with pre-existing vascular lesions and/or in those having undergone a recent surgical procedure, lesser volumes of transfused old blood may have similar adverse effects. Amelioration of the pathologic effects of chronic storagerelated intravascular hemolysis by co-administration of haptoglobin, the plasma protein that binds free hemoglobin but is present in limited quantities, provides a potential therapeutic approach to preventing the clinical disease induced by the red cell storage lesion.
1. Wang D, Sun J, Solomon SB, et al. Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion. 2012;52:1184-1195.
2. Boretti FS, Buehler PW, D’Agnillo F, et al. Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs. J Clin Invest. 2009;119:2271-2280.