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Vaccines, Blood & Biologics

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Reducing Medical Complications Caused by Transfusion with Blood Stored for Long Periods: A Study in Guinea Pig Model

Food and Drug Administration (FDA) scientists demonstrated in an animal model one potential approach to reducing complications in humans following transfusion of large amounts of whole blood that has been stored for an extended period of time.

The scientists showed that the complications are in-part caused by release of the hemoglobin from transfused red blood cells undergoing hemolysis (disintegration) within the circulation. Hemolysis is known to occur in blood cells stored for prolonged periods when biochemical changes that cause red blood cell “storage lesions” that alter the membranes of donated red cells that are stored for prolonged periods.

The complications caused by free hemoglobin include high blood pressure and damage to blood vessels and kidneys. These physiologic changes may have important consequences in patients who are already severely ill and receive massive transfusions of blood stored for maximum durations.

The FDA study found that massive transfusions of donor guinea pig blood that had been stored for the equivalent of 28 days (“old blood”) into recipient guinea pigs caused severe hypertension and injured blood vessels and kidneys. However, transfusion with “new blood” (blood stored for <2 days) did not result in these complications.

Furthermore, administering the molecule haptoglobin during transfusion of old blood significantly reduced complications caused by the hemoglobin. Haptoglobin is a protein normally found in bloodstream; it binds to hemoglobin that has escaped from damaged red blood cells and helps the body dispose of it. FDA scientists previously showed that haptoglobin can prevent the hypertension and kidney injury caused by infusing hemoglobin into guinea pigs and other animal species (http://www.fda.gov/downloads/BiologicsBloodVaccines/ScienceResearch/UCM267281.pdf).

Haptoglobin did not prevent the destruction of red blood cells caused by biochemical reactions that occur during prolonged storage of donated blood. However, it was effective in preventing the damage caused by hemoglobin escaping red blood cells during hemolysis.

In summary, the findings of this study study in a guinea pig model suggest that hemoglobin released from maximum storage duration of red blood cells following massive transfusion is partly responsible for the damage to blood vessels and kidneys. These data confirm results previously reported by other researchers. In addition, the FDA findings suggest that co-administration of haptoglobin or potentially other hemoglobin binding molecules during transfusion with stored blood may be able to reduce the pathological complications caused by hemoglobin that escapes from disintegrated red blood cells.

Title

“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”

The Journal of Clinical Investigation

2012; 122(4): 1444-1458.

doi:10.1172/JCI59770

Authors

Jin Hyen Baek(1), Felice D’Agnillo,(1) Florence Vallelian,(2) Claudia P. Pereira,(1) Matthew C. Williams,(1) Yiping Jia,(1) Dominik J. Schaer,(2,3)and Paul W. Buehler(1)

(1)Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, Bethesda, Maryland, USA. (2)Division of Internal Medicine and Division of Clinical Immunology, University Hospital, Zurich, Switzerland. (3)Center of Evolutionary Medicine and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

Schematic summary of experimental observations and a proposed mechanistic pathway for hemoglobin-driven  pathophysiology

Schematic summary of experimental observations and a proposed mechanistic pathway for hemoglobin-driven pathophysiology

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 red blood cells coupled with large-volume transfusion. In the circulatory compartment, this leads to hemoglobin-associated vascular effects, such as hypertension and direct vascular injury. In high clearance extravascular compartments such as the kidney, injury is driven by hemoglobin exposure, oxidative stress, and acute/chronic renal failure. Haptoglobin supplementation via co-infusion with older blood transfusion can (a) prevent renal filtration and (b) redirect clearance to liver and spleen for removal by macrophages. In the circulation, haptoglobin may effectively limit hemoglobin interaction with the vascular wall.