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Title: RBC storage lesions: What they are, and how we can minimize them


1
RBC storage lesionsWhat they are, and how we
can minimize them
  • Tatsuro Yoshida PhD
  • New Health Sciences Inc. Bethesda MD
  • Biomedical Engineering, Boston University
  • Boston MA

2
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
3
Refrigerated RBC storage altered parameters
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
4
Refrigerated RBC storage altered parameters
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
5
Refrigerated RBC storage altered parameters
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
6
Refrigerated RBC storage altered parameters
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
7
Storage lesions of metabolic origin
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
8
Storage lesions of metabolic origin
References 4,5
9
Consequences of ATP depletion
References 4,5
10
Consequences of ATP depletion (2)
References 4,5
11
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

12
Regulation of microvascular perfusion mediated by
ATP
References 4,5
13
Consequence of 2,3-DPG depletion
Release DPG from Hb
References 4,5
Reduced oxygen delivery capacity
14
Consequences of depleted 2,3-DPGreduction in
tissue oxygen delivery
From Bunn Forget 1986 7
15
2,3-DPG and hemoglobin
Release DPG from Hb
Modified figure from Perutz, Nature 228734,1970
References 4,5
Reduced oxygen delivery capacity
16
Loss of NO-linked vasoregulation by RBC
  • Studies Stored blood lacks nitric oxide
    Associated Press October 8, 2007 080620 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
    2007104(43)17063-68.

17
RBC is a carrier of NO for vasoregulation
Regulation of microvascular perfusion mediated
by Hemoglobin NO
SNO
SNO---biologically active S-nirtrosothiol
References 27,28
18
Hemoglobin and nitric oxide
NO
(Hb)3Hb-NO
(Hb)4
T-State
O2
RSNO
(HbO2)4-SNO
(Hb)4-SNO
R-State
O2
LUNG
19
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

20
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 to other
    storage lesions?
  • Is it reversible in vivo---most likely
  • How fast can it recover in vivo??

21
Storage lesions linked to oxidative damage
Biochemical Metabolic
Biomechanical
Oxidative
SNO-Hb ?
22
Oxidative damage pathway
References 8-11
23
Storage lesions linked to oxidative damage
SNO-Hb ?
References 8-11
24
Consequences oxidative damage
References 12,13
25
Damage pathways
Biochemical / Metabolic alterations
Oxidative Damage
Bio-mechanical changes Hemolysis Post-transfusion
removal TRALI
26
Reduction or delaying development of storage
lesions
  • Metabolically linked

27
RBC metabolic pathways
26
28
Prevention of metabolic storage
lesionsEmbden-Meyerhof pathway ATP and 23DPG
Metabolic modulation 14-15
29
Prevention of metabolic storage lesions
manipulations with additive solution
Review Hess 2006 16
30
Prevention of metabolic storage lesions
storage under anaerobic condition
References 17-19
31
Reduction or delaying development of storage
lesions
  • Oxidative damages

32
Reduction of oxidative damageRBC redox system
33
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

34
Reduction of oxidative damage storage under
anaerobic condition
  • Store RBC without oxygen
  • Stop hydroxyl radical-mediated peroxidation
    cycles
  • Prevent hemoglobin denaturation

Reference 19
35
Reversal of storage lesions
36
Reversibility of storage lesions
?
SNO-Hb
37
Rejuvenation
  • Post-storage metabolic manipulations
  • Mixture of pyruvate, inosine, Pi, adenine, PEP
    etc
  • Rejuvesol (Cytosol Laboratory Inc)
  • 37C incubation followed by cell washing 24
  • Experimental
  • PEP references in 25

38
RBC metabolic pathways
26
39
Rejuvenation by PIPA (Rejuvesol)
40
Rejuvenation by PIPA
Rejuvenation by PIPA (Rejuvesol)
41
Rejuvenation by PIPA
Rejuvenation by PIPA (Rejuvesol)
42
Rejuvenation with PEP
Reference 25
43
Result of rejuvenation
  • Restored ATP
  • Elevated 2,3-DPG
  • Increased 24-hr recovery rate
  • Rejuvesol is approved by FDA, but RBC must be
    washed

44
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

45
Goals for improved RBC storage
46
Reduced toxicity
  • Reduce hemolysis
  • Reduce dead-on-arrival RBC
  • Iron toxicity
  • Vasoconstriction via NO scavenging
  • Maintain deformability / prevent aggregation
  • Prevent capillary blockage

47
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

48
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-active
    substances
  • Prevention of TRALI
  • Leukoreduction, irradiation, pathogen-reduction,
    etc.

49
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

50
Selected recent reviews
  • Storage lesion
  • Ho J, Sibbald WJ, Chin-Yee IH. Effects of storage
    on efficacy of red cell transfusion when is it
    not safe? Crit Care Med 200331(12
    Suppl)S687-97.
  • Chin-Yee I, Arya N, d'Almeida MS. The red cell
    storage lesion and its implication for
    transfusion. Transfus Sci 199718(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 the
    critically ill. Transfusion 200646(11)2014-27.
  • Solheim BG, Flesland O, Seghatchian J, Brosstad
    F. Clinical implications of red blood cell and
    platelet storage lesions an overview. Transfus
    Apher Sci 200431(3)185-9.
  • Vincent JL, Baron JF, Reinhart K, et al. Anemia
    and blood transfusion in critically ill patients.
    Jama 2002288(12)1499-507.
  • Spiess BD. Blood transfusion the silent
    epidemic. Ann Thorac Surg 200172(5)S1832-7.
  • Additive solutions
  • Hess JR. An update on solutions for red cell
    storage. Vox Sang 200691(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
    2007104(43)17063-68.

51
References (1)
  • 1. Tinmouth A, Fergusson D, Yee IC, Hebert PC.
    Clinical consequences of red cell storage in the
    critically ill. Transfusion 200646(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 200331(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 199718(3)447-58.
  • 4. Ellsworth ML, Forrester T, Ellis CG, Dietrich
    HH. The erythrocyte as a regulator of vascular
    tone. Am J Physiol 1995269(6 Pt 2)H2155-61.
  • 5. Sprague RS, Ellsworth ML, Stephenson AH,
    Lonigro AJ. ATP the red blood cell link to NO
    and local control of the pulmonary circulation.
    Am J Physiol 1996271(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 inhibitory intravascular agent.
    Circ Res 198658(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
    198678(6)1681-6.
  • 9. Wolfe LC. Oxidative injuries to the red cell
    membrane during conventional blood preservation.
    Semin Hematol 198926(4)307-12.
  • 10.Beppu M, Mizukami A, Nagoya M, Kikugawa K.
    Binding of anti-band 3 autoantibody to
    oxidatively damaged erythrocytes. Formation of
    senescent antigen on erythrocyte surface by an
    oxidative mechanism. J Biol Chem
    1990265(6)3226-33.

52
References (2)
  • 11. Knight JA, Searles DA. The effects of various
    antioxidants on lipid peroxidation in stored
    whole blood. Ann Clin Lab Sci 199424(4)294-301.
  • 12. Silliman CC, Voelkel NF, Allard JD, et al.
    Plasma and lipids from stored packed red blood
    cells cause acute lung injury in an animal model.
    J Clin Invest 1998101(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
    199895(6)3077-81.
  • 14. Messana I, Ferroni L, Misiti F, et al. Blood
    bank conditions and RBCs the progressive loss of
    metabolic modulation. Transfusion
    200040(3)353-60.
  • 15. Messana I, Orlando M, Cassiano L, et al.
    Human erythrocyte metabolism is modulated by the
    O2-linked transition of hemoglobin. FEBS Lett
    1996390(1)25-8.
  • 16. Hess JR. An update on solutions for red cell
    storage. Vox Sang 200691(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) 196659(5)524-6.
  • 18. Hamasaki N, Rose ZB. The binding of
    phosphorylated red cell metabolites to human
    hemoglobin A. J Biol Chem 1974249(24)7896-901.
  • 19. Yoshida T, Aubuchon JP, Tryzelaar L, et al.
    Extended storage of red blood cells under
    anaerobic conditions. Vox Sang 200792(1)22-31.
  • 20. Dumaswala UJ, Zhuo L, Mahajan S, et al.
    Glutathione protects chemokine-scavenging and
    antioxidative defense functions in human RBCs. Am
    J Physiol Cell Physiol 2001280(4)C867-73.

53
References (3)
  • 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 vivo
    viability. Transfusion 199737(2)166-74.
  • 22. Epps DE, Knechtel TJ, Bacznskyj O, et al.
    Tirilazad mesylate protects stored erythrocytes
    against osmotic fragility. Chem Phys Lipids
    199474(2)163-74.
  • 23. Racek J, Herynkova R, Holecek V, et al.
    Influence of antioxidants on the quality of
    stored blood. Vox Sang 199772(1)16-9.
  • 24. Valeri CR. Use of rejuvenation solutions in
    blood preservation. Crit Rev Clin Lab Sci
    198217(4)299-374.
  • 25. Hamasaki N, Yamamoto M. Red blood cell
    function and blood storage. Vox Sang
    200079(4)191-7.
  • 26. Tanaka KR, Zerez CR. Red cell
    enzymopathies of the glycolytic pathway. Semin
    Hematol 199027(2)165-85.
  • 27. Reynolds JD, Ahearn GS, Angelo M,
    et al. S-nitrosohemoglobin deficiency A
    mechanism 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
    stored RBCs. Proceedings of the
    National Academy of Sciences 2007104(43)17063-68
    .
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