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Department of Pathology, 

University of Pittsburgh 

Does the RBC storage lesion 

matter clinically? 

Mark Yazer, MD FRCPC

History of RBC storage 

• RBCs were initially stored in citrate at room temperature 

• Lasted for only a few days 

• In the refrigerator they lasted a bit longer 

• In the 1940s glucose was added to the RBCs along with citrate 

• 21 day expiration 

• In North America RBCs are stored in an adenine rich solution for 

up to 42 days

The RBC storage lesion 

• As RBCs are stored ex vivo they undergo changes 

• These include metabolic and shape changes 

• Collectively they are known as the storage lesion

How has the RBC storage lesion been studied? 

• 3 types of studies evaluating the RBC storage lesion: 

• In vitro, biochemical studies 

• In vivo, physiological studies without patient 

outcomes 

• Retrospective studies of recipient morbidity and 

mortality




‣ Have elucidated the changes in RBC 

metabolism and shape during storage 



• Retrospective studies of morbidity and mortality

Decrease in 2,3-DPG 

• Hb is a tetramer of 4 proteins each containing a heme unit 

• 2,3-diphosphoglycerate is a small molecule that binds into the 

Hb tetramer 

• 2,3-DPG promotes oxygen offloading in hypoxic areas

Decrease in 2,3-DPG 

• 2,3-DPG is depleted during storage 

• Its decline is mirrored by an increase in Hb oxygen 

saturation 

• 2,3-DPG is restored 24-72 hours after transfusion 

Bennett-Guerrero et al. PNAS, 2007

k on , oxygen binding rate constant, increases after day 14 

Gelderman MP et al. Transfusion Medicine in press

k off , oxygen off loading rate constant, does not change 

Gelderman MP et al. Transfusion Medicine in press

RBC shape change 

• Stored RBCs undergo shape changes 

• Normal morphology is maintained until severe drops in 

intracellular ATP occur 

Red Cell Shape, Bessis M, Weed RI, Leblond PF, 1973

Other biochemical/membrane changes 

• Altered NO metabolism 

• Increased aggregability 

• Increased adhesion to endothelial cells 

• Increases in RBC membrane sublethal injury (MFI) 

• Membrane vesiculation 

• Paralysis of Na/K ATPase 

• Reduced membrane deformability 

• Altered membrane protein/lipid composition

Conclusions on in vitro, biochemical studies 

• These are essential studies to understand the basic 

changes in the RBCs during storage 

• They define the biological elements of the storage 

lesion 

• Major limitation: 

• Should be interpreted only as defining a biological 

constellation of changes to RBCs during storage 

• Not intended to predict recipient outcomes to 

transfusion






‣ Evaluate changes in recipient’s physiological 

parameters only 

• Retrospective studies of morbidity and mortality

Analysis of tissue oxygenation 

• Study evaluated changes in tissue oxygenation after transfusion 

• Used Near Infrared Spectroscopy with sensor mounted on 

thumb 

• Does receipt of RBCs ≥21 days affect oxygenation? 

Kiraly LN et al. J Trauma 2009


• Patient undergoing active resuscitation, sepsis, requiring 

vasopressor support excluded 

60 

minutes 

Transfusion 

Baseline 

Transfusion starts 

Transfusion 

4 hours posttransfusion 

Endtransfusion 

-60 

0 100 160 

60


•Small numbers of patients in this study 

• Limited demographics 

• How many units were transfused in the 2 groups? 

Ages of the transfused RBCs? 



• Significant decrease in StO 2 during transfusion period in Old 

group 

• “This drop trended toward significance after the end of 

transfusion (p=0.06)” 

Baseline 

Transfusion 

Patient 

status? 

4 hours post transfusion 



• Age of the single oldest unit of RBCs 

• R = 0.5 (p < 0.05) 

• A modest correlation, at best 


Conclusions 

• No clinical outcomes reported 

• Did the apparently transient decrease in StO 2 impact 

morbidity or mortality? 

• Does StO 2 in the thumb reflect that in other tissues? 

• Limited demographic/RBC data reported 

• Although this study involved patients, its findings are no 

more clinically relevant than in vitro studies

Conclusions on in vitro, physiological studies 

• Like in vitro biochemical studies, these define 

physiological parameters in actual recipients 

• Involve actual human/primate recipients 


• If they do not measure clinical outcomes, the data 

cannot be used to predict outcomes in actual recipients 

• Contribute towards the basic science knowledge base of 

the storage lesion, not its clinical effects (if any)

Schieẞ ein Tor…






• Retrospective studies of morbidity and mortality 

‣ Review recipient’s charts after transfusion for 

morbidity and mortality information

Retrospective studies - Pro 

• Retrospective studies are easier to get past IRB than RCT 

• Data already exists, it just needs to be mined 

• Can feature enormous numbers of patients as consent is 

not usually required 

• Good for generating hypotheses

Retrospective studies - Con 

• If comparing an intervention, must ensure 2 groups are 

identical 

• Otherwise results could be due to confounders 

• Very hard to account for confounding variables 

• Demographics of groups must be presented 

• Often require complicated statistics to show a result

Remember… 

• # RBCs transfused is highly correlated to age of RBCs 

• Sicker patients receive more RBC transfusions 

• Thus sicker patients tend to get older RBCs 

• Sicker patients have worse outcomes 

• So is an unfavorable outcome due to the patients’ natural 

history or receipt of older RBCs?

Koch et al. NEJM 2008 

Large, retrospective study on age of RBCs in cardiac surgery 

patients 

• A large study of CABG or valve surgery patients was performed 

• RBC age: ≤ 14 days vs. >14 days 

• Patients who received a mix of “fresher” and “older” blood were 

excluded 

• Composite endpoint:


Both groups of patients received median 2 RBC units 

• 2872 patients in Newer group, 3130 patients in Older group 

• Same median number of RBCs transfused: 2 

• Newer RBCs were median 11 days, Older RBCs were 20 days 

50%


Matching of cohorts was not perfect 

• NYHA grades differed significantly between the 2 groups 

• Significant differences in ABO groups of RBCs

Outcome measures were broad and not easily explicable by RBC 

transfusion 

Dichotomous variable 

Koch et al. NEJM 2008


Greater mortality amongst recipients of median 2 RBC units 

92.6% 

92.6% 

Increased LV dysfunction 

Increased MV regurgitation 

89.0% (p

Conclusions 

• Mortality end points are very broad 

• Actual causes of death not presented 

• Death caused by being run over by a bus after receiving RBCs 

would appear as related to the transfusion 

• Authors offer no specific mechanism linking “older” blood to 

negative outcomes 

• Authors do not propose changing the current RBC issuing practice 

• Large study, hypothesis generator

Another retrospective study of mortality and the storage lesion 

• The largest retrospective study to date 

• Analyzed database containing Swedish and Danish 

transfusion recipients from 1995-2002 

• Inclusion criteria: 

• Ages 15 – 90 

• No tx 2 years prior to index transfusion 

• Exclusion criteria: 

• Receipt of autologous RBCs 

• Receipt of ABO non-identical units 

• Receipt of RBCs of unknown ABO group/age 

Edgren G et al. Transfusion 2010


• Patients were generally surgery or trauma patients 

• Divided into 4 groups based on RBC age 

• 0-9 days old 




• Mixed 

• The reference group of recipients was the 10-19 day 

old RBC group 


Mortality assessed over 2 periods 

• Short term survival (404,959 tx, 387,130 patients): 

• Transfused on day 1 and followed for 7 days 

• Long term survival (380,549 tx, 364,037 patients): 

• Transfused between days 1-7 and followed from day 8 

through 2 years 

• Surveillance also terminated upon death, emigration 

and end of study period (31 Dec 2002) 


Koch et al. 

10 km

Scandinavian study 

Cleveland 

650 km

Patient demographics 

• The recipients were well matched between the 5 

groups 

• Matched for age, gender, ABO, LOS, number of RBCs, 

indications for transfusion 

• Median storage ages: 

• 0-9 days: 7 (5-8) 

• 10-19 days: 14 (12-16) 

• 20-29 days: 23 (21-26) 

• 30-42 days: 34 (31-37) 

• Mixed: 17 (11-22) 


Mortality outcomes 

• Mortality not increased amongst recipients of oldest RBCs who 

were ≥70 years, or CABG, or ECMO 

• Leukoreduction did not affect survival 


Causes of mortality 

• Compared recipients of 30-42 days old to 10-19 days old 

• No single cause of death predominated 

Day 1-7 Day 8-730 


Chicken and egg… 

• The number of 30-42 day old units received did not influence 

mortality 

? 

Edgren G et al. Transfusion 2010; Middelburg RA et al. Transfusion 2010


• The largest, by far, study to date 

• Well matched patient demographics 

• Was the 5% increase in mortality causally related to 

RBC transfusion? 

• 5% increase in mortality surprisingly stable over time 

• No single cause of death predominated 

• No dose response relationship 

• How to explain the result in the mixed group? 

• Seems related to underlying disease, not RBC 

• Would have been nice to have seen morbidity data

Conclusions on retrospective studies 

• Hypothesis generating 


• Lack of randomization 

• Various types of confounding 

• Inadequate matching of groups can bias results 

• NOT hypothesis proving

RECESS study 

2 prospective randomized trials are coming! 

• Cardiac surgery patients 

• ≤ 10 day RBC vs. ≥ 21 day old LR RBC 

• Primary outcome:Multiple organ dysfunction score on POD 7 

• ~1832 patients 

ABLE study 

• ICU patients 

• RBC storage length ≤ 7 days vs. standard issue LR RBCs 

• Primary outcome: 90-day all cause mortality 

• 2510 patients

• The storage lesion is real! 

Conclusions 

• The clinical data has by no means proven that its effects 

are detrimental to recipients 

• What should be done about how the BB currently issues 

RBCs? 

אין דבר 

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