Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e93577. https://doi.org/10.1172/jci.insight.93577.
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Research Article Hematology Vascular biology

Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood

Abstract

Non–transferrin-bound iron (NTBI) and free hemoglobin (Hb) accumulate in circulation following stored RBC transfusions. This study investigated transfusion, vascular disease, and mortality in guinea pigs after stored RBC transfusion alone and following cotransfusion with apo-transferrin (apo-Tf) and haptoglobin (Hp). The effects of RBC exchange transfusion dose (1, 3, and 9 units), storage period (14 days), and mortality were evaluated in guinea pigs with a vascular disease phenotype. Seven-day mortality and the interaction between iron and Hb as cocontributors to adverse outcome were studied. Concentrations of iron and free Hb were greatest after transfusion with 9 units of stored RBCs compared with fresh RBCs or stored RBCs at 1- and 3-unit volumes. Nine units of stored RBCs led to mortality in vascular diseased animals, but not normal animals. One and 3 units of stored RBCs did not cause a mortality effect, suggesting the concomitant relevance of NTBI and Hb on outcome. Cotransfusion with apo-Tf or Hp restored survival to 100% following 9-unit RBC transfusions in vascular diseased animals. Our data suggest that increases in plasma NTBI and Hb contribute to vascular disease–associated mortality through iron-enhanced Hb oxidation and enhanced tissue injury.

Authors

Jin Hyen Baek, Ayla Yalamanoglu, Yamei Gao, Ricardo Guenster, Donat R. Spahn, Dominik J. Schaer, Paul W. Buehler

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Figure 3

Transfusion-related mortality in guinea pigs with preexisting vascular remodeling and endothelial dysfunction is reversed by apo-transferrin (apo-Tf) and haptoglobin (Hp).

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Transfusion-related mortality in guinea pigs with preexisting vascular r...
(A) Nine units S-RBCs significantly increased 7-day mortality in high-fat and high-sucrose diet (HFSD) but not in normal diet (ND) guinea pigs over a 7-day observation period (n = 10, P = 0.0143, by log-rank [Mantel-Cox]); data are presented as percentage survival. (B) Survival after a 7-day observation period of ND and HFSD guinea pigs after different transfusion regimens with increasing RBC transfusion dose as indicated. Administration of apo-Tf (300 mg/kg) and Hp (300 mg/kg) at the time of transfusion restores survival in the HFSD animals dosed with 9 units of S-RBCs at the highest RBC transfusion dose (apo-Tf; n = 10, *P = 0.0001, ANOVA with a multiple comparisons test) and (Hp; n = 10, †P = 0.0001, ANOVA with a multiple comparisons test). (C) Left panel: H&E staining of thoracic aorta showing large thrombi in a nonsurviving 9-unit S-RBC–transfused animal. Original magnification, ×400. Scale bar: 200 μm. Right panel: High magnification of dashed box region. Original magnification, ×200. Scale bar: 50 μm. (D) Left panel: Verhoeff-Van Geison staining of elastic fibers from the same animal in C. Original magnification, ×400. Scale bar: 200 μm. Right panel: High magnification of dashed box region showing extensive elastin fragmentation indicated by white arrows. Original magnification, ×100. Scale bar: 50 μm. (E) Left panel: Masson’s trichrome staining of collagen from the same animal in C. Original magnification, ×400. Scale bar: 200 μm. Right panel: High magnification of dashed box region showing collagen deposition indicated by solid arrows. Original magnification, ×100. Scale bar: 50 μm. (F) Left panel: H&E staining of renal cortical tissue from a separate nonsurviving animal showing acute proximal and distal tubule necrosis (solid arrow). Original magnification, ×200. Scale bar: 50 μm. Right panel: High magnification of dashed box region showing loss of renal cortical tubule nuclei (solid arrows) and thrombi occurring in the glomerular capillary structure (white arrow). Original magnification, ×600. Scale bar: 20 μm. All images were captured identically with default settings. Magnification = ocular lens (×10) × objective.