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 10

Schematic summary of experimental observations and a proposed mechanistic pathway.

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Schematic summary of experimental observations and a proposed mechanisti...
The hypothesis of hemolysis as a major contributor to storage lesion toxicity–associated older storage blood is outlined. This process is hypothesized to be driven by increased rigidity of older storage rbc coupled with large-volume transfusion. In the circulatory compartment, this leads to Hb-associated vascular effects, such as hypertension and direct vascular injury. In high clearance extravascular compartments such as the kidney, injury is driven by Hb exposure, oxidative stress, and acute/chronic renal failure. Hp supplementation via coinfusion with older blood transfusion can (a) prevent renal filtration and (b) redirect clearance to liver and spleen for removal by macrophages. In the circulation, Hp may effectively limit Hb interaction with the vascular wall.