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
Jin Hyen Baek, Felice D’Agnillo, Florence Vallelian, Claudia P. Pereira, Matthew C. Williams, Yiping Jia, Dominik J. Schaer, Paul W. Buehler
Jin Hyen Baek, Felice D’Agnillo, Florence Vallelian, Claudia P. Pereira, Matthew C. Williams, Yiping Jia, Dominik J. Schaer, Paul W. Buehler
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Research Article

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

Abstract

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

Authors

Jin Hyen Baek, Felice D’Agnillo, Florence Vallelian, Claudia P. Pereira, Matthew C. Williams, Yiping Jia, Dominik J. Schaer, Paul W. Buehler

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Figure 9

Cardiorenal response to 28-day-old blood transfusion before and after washing.

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Cardiorenal response to 28-day-old blood transfusion before and after wa...
(A) Hb exposure over 24 hours (AUC0–24) demonstrated significantly greater Hb exposure after transfusion of 28-day-old blood (with washing) and 28-day-old blood (without [–] washing) compared with that after new blood. (B) The EI of rbc stored for 28 days and measured before and after washes with PBS as well as the EI of blood sampled from guinea pigs at 24 hours after transfusion (n = 4 guinea pigs). The image shows supernatant from 6 washes of 28-day-old rbc. (C) H&E staining of aortic root tissue showing coagulative necrosis in the (washed) 28-day-old blood and (unwashed) 28-day-old blood transfusion groups. Original magnification, ×400. (D) Percentage of normal, abnormal, and necrotic aortic root. Significantly increased abnormal and necrotic regions were observed with transfusion of washed 28-day-old blood and (unwashed) 28-day-old blood compared with new blood. (E) Gross morphology images of kidneys after transfusion of new blood and 28-day-old blood before and after washing. (F) H&E-stained renal cortex. Dilated proximal and distal tubules can be seen as tubules with irregular shape, orange-colored casts, and irregular distribution of nuclei. Perls iron staining is shown as brown granular structures in tubules. Original magnification, ×400. (G) Iron deposition as ng iron per 100 mg tissue. Significantly greater iron deposition versus new blood. Scale bars (1 cm) = 25 μm (C and F). *P < 0.05.