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RBC storage lesions:What they are, and how we can
minimize them
Tatsuro Yoshida PhD
New Health Sciences Inc. Bethesda MD
Biomedical Engineering, Boston University
Boston MA
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Storage lesions What are they?
How are they related?
What are the consequences?
What can we do about them? Prevention
Reversal Targets for ideal refrigerated RBC
storage.
Recent review literatures [1-3]
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Refrigerated RBC storage:
altered parameters
Biochemical
MetabolicBiomechanical Oxidative
SNO-Hb
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Refrigerated RBC storage:
altered parameters
Biochemical
MetabolicBiomechanical Oxidative
SNO-Hb
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Refrigerated RBC storage:
altered parameters
Biochemical
MetabolicBiomechanical Oxidative
SNO-Hb
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Storage lesions of metabolic origin
Biochemical
MetabolicBiomechanical Oxidative
SNO-Hb
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Storage lesions of metabolic origin
References [4,5]
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Consequences of ATP depletion
References [4,5]
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Consequences of ATP depletion (2)
References [4,5]
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Storage lesion: loss of
vasoregulation Hemolysis [gradual increase]
NO scavenger--vasoconstriction
ATP release [gradual decrease]
Loss of ATP mediated vasodilation
Loss of NO delivery by RBC [fast]
Impaired vasoregulation
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Regulation of microvascular perfusion
mediated by ATP
References [4,5] From: Ellsworth ML et al., Am J Physiol
1995;269(6 Pt 2):H2155-61.
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Consequence of 2,3-DPG depletion
References [4,5]
Release DPG from Hb
Reduced oxygen delivery capacity
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Consequences of depleted 2,3-DPG
²reduction in tissue oxygen delivery
From Bunn & Forget 1986 [7]
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2,3-DPG and hemoglobin
References [4,5]
Release DPG from Hb
Reduced oxygen delivery capacity
Modified figure from Perutz, Nature 228:734,1970
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Loss of NO-linked vasoregulation by RBC
Studies: Stored blood lacks nitric oxide: Associated Press
October 8, 2007 08:06:20 PM PST
Vasodiatory activity of RBC is lost 3 hrs
after blood collection
Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of adverse changes in stored RBCs. Proceedings of the National Academy of Sciences 2007;104(43):17063-68.
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RBC is a carrier of NO for vasoregulation
References [27,28]
Regulation of microvascular perfusion
mediated by Hemoglobin + NO
SNO---biologically active S-nirtrosothiol
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Hemoglobin and nitric oxide
(Hb)3Hb-NO
(HbO2
)4
-SNO
O2RSNO
O2
NO
(Hb)4 T-State
R-State
LUNG
(Hb)4-SNO
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Loss of NO-linked RBC
mediated vasoregulation Immediately after transfusion, RBCs
may not only fail to increase peripheral
blood flow, but may also function as NO
sink
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Loss of NO-linked RBC
mediated vasoregulation Immediately after transfusion, RBCs
may not only fail to increase peripheral
blood flow, but may also function as NO
sink
How serious is this effect in relation toother storage lesions?
Is it reversible in vivo---most likely
How fast can it recover invivo
??
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Storage lesions linked to oxidative
damage
Biochemical
MetabolicBiomechanical Oxidative
SNO-Hb
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Oxidative damage pathway
References [8-11]
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Storage lesions linked to oxidative damage
References [8-11]
SNO-Hb
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Consequences: oxidative damage
References [12,13]
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Damage pathwaysBiochemical
/ Metabolic
alterations
Bio-mechanical
changes
Hemolysis
Post-transfusion removal
TRALI
Oxidative
Damage
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Reduction or delaying
development of storage lesions
Metabolically linked
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RBC metabolic pathways
[26]
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Prevention of metabolic storage lesions:
Embden-Meyerhof pathway² ATP and 23DPG
Metabolic modulation [14-15]
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Prevention of metabolic storage lesions:
manipulations with additive solution
Review: Hess 2006 [16]
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Prevention of metabolic storage lesions:
storage under anaerobic condition
References [17-19]
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Reduction or delaying
development of storage lesions
Oxidative damages
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Reduction of oxidative damage:
RBC redox system
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Reduction of oxidative damage:
metabolic manipulations
�GSH precursors [20]
�L-carnitine (protection of RBC
membrane [21])
�Anti-oxidant / free radical
scavenger in storage solution
Mannitol, N-acetylcysteine
tirilazad mesylate, etc
[11,22,23]
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Reduction of oxidative damage:
storage under anaerobic condition
Store RBC without oxygen� Stop hydroxyl radical-
mediated peroxidation cycles
� Prevent hemoglobindenaturation
Reference [19]
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Reversal of storage lesions
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Reversibility of storage lesions
SNO-Hb
?
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Rejuvenation Post-storage metabolic manipulations
Mixture of pyruvate, inosine, Pi,
adenine, PEP etc
Rejuvesol (Cytosol Laboratory Inc)
37rC incubation followed by cell washing [24]
Experimental PEP [references in 25]
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RBC metabolic pathways
[26]
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Rejuvenation by PIPA (Rejuvesol)
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Rejuvenation by PIPARejuvenation by PIPA (Rejuvesol)
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Rejuvenation by PIPARejuvenation by PIPA (Rejuvesol)
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Rejuvenation with PEP
Reference [25]
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Result of rejuvenation Restored ATP
Elevated 2,3-DPG
Increased 24-hr recovery rate Rejuvesol is approved by FDA, but RBC must be
washed
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Result of rejuvenation Restored ATP
Elevated 2,3-DPG
Increased 24-hr recovery rate Rejuvesol is approved by FDA, but RBC must be
washed
Rejuvesol can be added during storage High levels of ATP and 2,3DPG throughout
extended storage period
Prevent PS accumulation on RBC surface
Increased 24-hr recovery rate
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Goals for improved RBC
storage
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Reduced toxicity Reduce hemolysis
Reduce dead-on-arrival RBC Iron toxicity
Vasoconstriction via NO scavenging
Maintain deformability / prevent aggregation Prevent capillary blockage
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Increase 24-hr recovery rate and / or
extend shelf-life
Maintenance of high ATP
Minimize oxidative damage
Maintain below threshold parameters causing
removal after transfusion [to provide sufficient
time for recovery in body after transfusion]
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Targets for ideal refrigerated RBC storage
Reduced toxicity Reduce hemolysis
Reduce dead-on-arrival RBC Iron toxicity
Vasoconstriction via NO scavenging
Maintain deformability / prevent aggregation Prevent capillary blockage
Prevent release, and/or remove bio-activesubstances Prevention of TRALI
Leukoreduction, irradiation, pathogen-reduction, etc.
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Higher functionality for efficient
tissue oxygenation
Maintain high levels of:
2,3-DPG[oxygen release]
SNO-Hb [regulation of vascular perfusion]
ATP [regulation of vascular
perfusion]
Deformability [capillary perfusion]
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6HOHFWHGUHFHQWUHYLHZVStorage lesion
Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage on efficacy of red cell transfusion: when is itnot safe? Crit Care Med 2003;31(12 Suppl):S687-97.
Chin-Yee I, Arya N, d'Almeida MS. The red cell storage lesion and its implication for transfusion. Transfus Sci 1997;18(3):447-58.
Clinical consequences of transfusion (not covered in this talk)
Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in thecritically ill. Transfusion 2006;46(11):2014-27.
Solheim BG, Flesland O, Seghatchian J, Brosstad F. Clinical implications of red blood cell andplatelet storage lesions: an overview. Transfus Apher Sci 2004;31(3):185-9.
Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients.Jama 2002;288(12):1499-507.
Spiess BD. Blood transfusion: the silent epidemic. Ann Thorac Surg 2001;72(5):S1832-7.
Additive solutions
Hess JR. An update on solutions for red cell storage. Vox Sang 2006;91(1):13-9.
Vasoregulatory function of stored RBC Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of adverse changes in stored.
RBCs. Proceedings of the National Academy of Sciences 2007;104(43):17063-68.
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5HIHUHQFHV
1. Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of red cell storage in the critically ill.Transfusion 2006;46(11):2014-27.
2. Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage on efficacy of red cell transfusion: when is it not safe?Crit Care Med 2003;31(12 Suppl):S687-97.
3. Chin-Yee I, Arya N, d'Almeida MS. The red cell storage lesion and its implication for transfusion. Transfus
Sci 1997;18(3):447-58.4. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J
Physiol 1995;269(6 Pt 2):H2155-61.
5. Sprague RS, Ellsworth ML, Stephenson AH, Lonigro AJ. ATP: the red blood cell link to NO and localcontrol of the pulmonary circulation. Am J Physiol 1996;271(6 Pt 2):H2717-22.
6. Burnstock G, Kennedy C. A dual function for adenosine 5'-triphosphate in the regulation of vascular tone.Excitatory cotransmitter with noradrenaline from perivascular nerves and locally released inhibitoryintravascular agent. Circ Res 1986;58(3):319-30.
7. Bunn H, Foget B. Hemoglobin: Molecular genetics and clinical aspects. Philadelphia, PA: WB Sanders,1986.
8. Wolfe LC, Byrne AM, Lux SE. Molecular defect in the membrane skeleton of blood bank-stored red cells.Abnormal spectrin-protein 4.1-actin complex formation. J Clin Invest 1986;78(6):1681-6.
9. Wolfe LC. Oxidative injuries to the red cell membrane during conventional blood preservation. SeminHematol 1989;26(4):307-12.
10.Beppu M, Mizukami A, Nagoya M, Kikugawa K. Binding of anti-band 3 autoantibody to oxidativelydamaged erythrocytes. Formation of senescent antigen on erythrocyte surface by an oxidative mechanism. J
Biol Chem 1990;265(6):3226-33.
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5HIHUHQFHV
11. Knight JA, Searles DA. The effects of various antioxidants on lipid peroxidation in storedwhole blood. Ann Clin Lab Sci 1994;24(4):294-301.
12. Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red bloodcells cause acute lung injury in an animal model. J Clin Invest 1998;101(7):1458-67.
13. Boas FE, Forman L, Beutler E. Phosphatidylserine exposure and red cell viability in red cell
aging and in hemolytic anemia. Proc Natl Acad Sci U S A 1998;95(6):3077-81.
14. Messana I, Ferroni L, Misiti F, et al. Blood bank conditions and RBCs: the progressive lossof metabolic modulation. Transfusion 2000;40(3):353-60.
15. Messana I, Orlando M, Cassiano L, et al. Human erythrocyte metabolism is modulated by theO2-linked transition of hemoglobin. FEBS Lett 1996;390(1):25-8.
16. Hess JR. An update on solutions for red cell storage. Vox Sang 2006;91(1):13-9.
17. Asakura T, Sato Y, Minakami S, Yoshikawa H. Effect of deoxygenation of intracellular hemoglobin on red cell glycolysis. J Biochem (Tokyo) 1966;59(5):524-6.
18. Hamasaki N, Rose ZB. The binding of phosphorylated red cell metabolites to humanhemoglobin A. J Biol Chem 1974;249(24):7896-901.
19. Yoshida T, Aubuchon JP, Tryzelaar L, et al. Extended storage of red blood cells under anaerobic conditions. Vox Sang 2007;92(1):22-31.
20. Dumaswala UJ, Zhuo L, Mahajan S, et al. Glutathione protects chemokine-scavenging andantioxidative defense functions in human RBCs. Am J Physiol Cell Physiol2001;280(4):C867-73.
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21. Arduini A, Holme S, Sweeney JD, et al. Addition of L-carnitine to additive solution-suspended red cells stored at 4 degrees C reduces in vitro hemolysis and improves in vivoviability. Transfusion 1997;37(2):166-74.
22. Epps DE, Knechtel TJ, Bacznskyj O, et al. Tirilazad mesylate protects stored erythrocytesagainst osmotic fragility. Chem Phys Lipids 1994;74(2):163-74.
23. Racek J, Herynkova R, Holecek V, et al. Influence of antioxidants on the quality of stored blood. Vox Sang 1997;72(1):16-9.
24. Valeri CR. Use of rejuvenation solutions in blood preservation. Crit Rev Clin Lab Sci1982;17(4):299-374.
25. Hamasaki N, Yamamoto M. Red blood cell function and blood storage. Vox Sang2000;79(4):191-7.
26. Tanaka KR, Zerez CR. Red cell enzymopathies of the glycolytic pathway. Semin Hematol
1990;27(2):165-85.
27. Reynolds JD, Ahearn GS, Angelo M, et al. S-nitrosohemoglobin deficiency: Amechanism for loss of physiological activity in banked blood. Proceedings of
the National Academy of Sciences 2007: ;104(43):17058-62.
28. Bennett-Guerrero E, Veldman TH, Doctor A, et al. Evolution of adverse changes in storedRBCs. Proceedings of the National Academy of Sciences 2007;104(43):17063-68.
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