Preservation of Red Blood Cells for Transfusion
R. BEN DAWSON, MD*
Development of red blood cell preservative solutions began in the
early 1900s. During the 1930s, definition of the glycolytlc path-
way of red blood cell metabolism provided a rational basis for
these studies and contributed to the establishment o f standard
criteria for satisfactory red blood cell preservation. Recently,
the use o f adenine in the preservative solution has allowed a 14-
day increase in red blood cell storage time. Additional approaches
to red blood cell preservation are the use of optional additive
solutions and rejuvenation. One major controversial issue is the
clinical significance o f transfusion o f stored red blood cells that
are depleted of 2,3-diphosphoglycerate and have a high oxygen
affinity. Hum Pathol 14:213-217, 1983.
ACID-CITRATE-DEXTROSE
ANTICOAGULANT PRESERVATIVE: THE FIRST
30 YEARS
Preservation o f red blood cells for transfusion
began in 1914 when citrate anticoagulant was safely
infused into humans, t'z Soon after, dextrose was
added to the citrate ~and citrate-dextrose b[oodstored
up to 26 days was given successfully to British sol-
diers. 4 During the 1930s, definition of the major car-
bohydrate pathway of the red blood ceil, including
generation of ATP (adenosine triphosphate) by oxi-
dation of glucose to lactate, provided a rational bio-
chemical basis for studies in red cell preservation.
Although citrate-dextrose blood stored by refrigera-
tion was supplied to soldiers during the Spanish Civil
War, ~ no major advances occurred until the second
World War. The demonstration that acidification of
the citrate-dextrose solution prevented its carameli-
zation during autoclaving 8 led to the formulation
of acid-citrate-dextrose (ACD) anticoagulant, which
became the standard blood preservative for more
than 30 years. The "benchmark" publication for red
cell preservation for transfusion is the July 1947
issue of the Journal of Clinical Investigation. 7-1~ T h e
first paper, by Rapoport, described red cell changes
d u r i n g storage at 4~ Acid-citrate-dextrose anti-
coagulant preservative maintained ATP levels bet-
ter than did citrate-dextrose or sodium citrate. Main-
tenance of red cell shape, relative lack of hemolysis,
and maintenance o f p H correlated with the ATP
levels. Lactate acid production, indicating continued
cell function, was also better maintained by ACD
solution. A metabolic index, indicating glycolytic
activity, showed that ACD stored cells maintained
activity after 30 days o f storage, but citrate-glucose
red cells were inadequate after 20 days and citrate cells
after ten days.7The second paper showed that ATP was
better maintained in ACD than it/ Alsever solution
* Director, Blood Bank Transfusion Labs; Professor, Depart-
ment of Pathology; Associate Professor, Department of Medicine;
Director, Blood Research Lab, University of Maryland Hospital,
Redwood and Greene Sts, Baltimore, MD 21201.
Address correspondence and reprint requests to Dr. Dawson.
213
and that storage at 25~ greatly shortened red cell
viability compared with storage at 4~ s The third
paper showed that the amount of glucose could be
reduced by 50 per cent and the volume could be
reduced from the 25 ml ACD/100 ml of blood then
used to 15 ml ACD/100 ml o f blood, a ratio used for
the next 35 years, s T h e fourth report dealt with
differences in red cells stored as whole blood in con-
trast to packed red cells, ~~a problem still faced today.
Strumia et al. 11 developed a different ACD solu-
tion, which provided for red cell survival considerably
better than did the ACD saline of Alsever and the
ACD of Rapoport. For preservation of packed red
cells, Strumia et al., tz like Rapoport, used another
crystalloid besides physiologic salt solution--i.e., 10
pe r cent corn syrup. Ross et al. 13 proposed an arbi-
trary value of 70 per cent for post-transfusion sur-
vival as a minimal r e q u i r e m e n t for satisfactory
transfusion properties. Gibson etal. z4 compared sur-
vival of Fe-labeled red cells with the previously stan-
dard agglutination technique ts and confirmed the
ability of certain ACD solutions to provide 21-day
storage in the "zone of safe transfusion," within which
70 per cent or more of transfused cells were viable. .6
These studies also revealed that at or above 80 per
cent survival, nonviable cells were completely re-
moved in 24 hours, and at any survival level the
majority of nonviable cells are removed from the
bloodstream during the first two hours after transfu-
sion. Therefore, on theoretical and practical grounds,
70 per cent retention of all transfused cells was con-
sidered the lowest safe survival level? ~Thus, 35 years
ago, the data were published and the guidelines es-
tablished u n d e r which red blood cell preservation has
been carried out.
During d e v e l o p m e n t o f these a n t i c o a g u l a n t
preservative solutions, survival of transfused red cells
was studied quantitatively using the selective aggluti-
nation method of Ashby? 5"t8 Because of problems
and questions o f the reliability o f this method, ~9
chromium labeling evolved as the standard method
for studying red cell survival. 26
2,3-DIPHOSPHOGLYCERATE AND ITS ROLE
IN HEMOGLOBIN FUNCTION
In 1953, Vahis and Kennedyzz described an in-
creased affinity of hemoglobin for oxygen in red cells
stored in ACD. They calculated that a transfusion o f
three units of seven-day-old ACD blood, sufficient to
raise the hematocrit from 35 to 55 per cent, actually
decreased the oxygen delivered to the tissues for up
to 24 hours. The discovery that the position of the
oxyhemoglobin dissociation curve is controlled by the
red cell carbohydrate intermediate 2,3-diphospho-
glycerate (2,3-DPG; fig. 1) was made simultaneously
 HUMAN PATHOLOGY
100
JS~l~t d, "" "*"
75 / / - ~ ' ~ ,.
/
" Normal 0 2 curve
/ /
i /
50 I /~//~// "right shifted" (~2,3-DPG)
II / r
% sis. These goals were achieved by reducing the citrate
SAT. r/
40 100
PO2
FIGURE 1. Oxyhemoglobin dissociation curves in human blood.
The normal oxygen (O2} curve has one m o l e c u l e of 2,3-
diphosphoglycerate (2,3-DPG} per hemoglobin molecule (tet-
ramer]. The left-shifted oxyhemoglobin curve reflects what occurs
in stored red cells depleted of 2,3-DPG. The right-shifted curve can
b e produced by raising 2,3-DPG levels above normal. SAT =
percentage of hemoglobin that is oxygenated.
by the Beneschs 2s and by Chanutin and Curnish and
othersY ~-27 The presence of 2,3-DPG in red ceils had
been known since 1925. 2~ Its formation during gly-
colysis and its decomposition in acidified blood 2'j were
described, and its formation and degradation 3~
were subsequently shown to be a function of a single
enzynle.32-3~
T h e next i m p o r t a n t step in u n f o l d i n g the
biologic mechanisms o f oxygen transport was the
proposal that red cell 2,3-DPG levels are controlled in
vivo by glycolate/pyruvate competition? 5 Our hy-
pothesis is derived fi'om the following unrelated ob-
servations: 1)Phosphoglycolate changes the activity of
the R a p o p o r t - L u e b e r i n g enzyme fi'om the mutase
toward the phosphatase fimction, 3G2) phosphoglyco-
late is synthesized frorn glycolate by pyruvate kinaseY
and 3) high pyruvate concentrations raise 2,3-DPG
levels during blood storage? 8 A h h o u g h there are
three other ways by which pyruvate could theoreti-
call)' raise 2,3-DPG levels, we lmve proposed that if
pyruvate kinase is saturated with the substrate pyru-
rate, glycolate would not be phosphorylated to phos-
p h o g l y c o l a t e a n d the m u t a s e f u n c t i o n o f the
R a p o p o r t - L u e b e r i n g enzyme would predominate,
raising 2,3-DPG levels? '~
The 1977 report of tile director of the National
Heart, Lung and Blood Institute to the President
said, " . . . For optimal storage of red blood cells, their
level of 2,3-DPG must be maintained." Recent devel-
opments that have provided for increased storage
time of red blood cells make the issue of nmintaining
red cell 2,3-DPG levels to provide optimal oxygen
transport even more important. 4~ Before further de-
scribing the effects of 2,3-DPG levels on the response
to transfllsion, it will be necessary to discuss the use of
adenine to extend red blood cell storage. 4t
Volume t4. No. 3 (March '1983)
CITRATE-PHOSPHATE-DEXTROSE
AND ADENINE
The first step in prolonging red cell storage be-
yond 21 days in ACD solution was the development of
c i t r a t e - p h o s p h a t e - d e x t r o s e (CPD) a n t i c o a g u l a n t
preservative,.Gibson, who participated in the original
development of ACD, ten years later improved upon
this with CPD. 42 Citrate-phosphate-dextrose was de-
veloped t o . r e d u c e acidosis following e x c h a n g e
transfilsions with ACD and to improve ATP synthe-
by 25 per cent and adding 2 mM phosphate. This
increased the pH of the preservative and the final
blood preservative mixture and prolonged the stor-
age time of the red cells, since red cell survival was
greater than 75 per cerlt after 28 days of storage. 4a
One benefit of this longer red cell storage was a de-
creased in outdating. 44 The US Food and Drug Ad-
ministration approved CPD for use with whole blood
and packed cells in 1967; however, it was not widely
nmrketed until 1972, when the FDA approved its use
for plasma to be manufactured into 7 globulin. An-
other advantage o f CPD w a s that it provided in-
creased levels of 2,3-DPG, compared with those pro-
vided by ACD, 4~ probably owing to the higher pH
of CPD? 6
In 1960 it was sbown that adenine is incorpo-
rated into red cell nucleotides 4r and generates ATP, ~8
allowing satisfactory red cell viability for at least
five weeks of storage. 49 A clinical trial of ACD sup-
plemented with a d e n i n e was stopped very earl}'
because of fear of adenine toxicity due to the obser-
vation of crystals of adenine and related compounds
after some ingestion and infusion studies. Toxicity
studies carried ont at the Army's Medical Research
Laboratory at Fort Knox and the accumulated expe-
rience of safety, especially in Sweden, were reassur-
ing. Finally, US muhi-institutional clinical trials of
CPD-adenine resuhed in the licensing in 1978 and the
general adoption around 1980 of the preservative
CPDA-I, which permitted whole blood and red cells
to be stored for 35 days. 56
Concern about the toxicity of adenine resulted in
the use of a lower than optimal concentration for the
first US product, CPDA-1. During storage of packed
cells with a hematocrit greater than 80 per cent,
adenine and glucose are depleted in the fiftb week of
storage. This leads to low levels of ATP and pre-
sumably inadequate red cell survival upon prolonged
storage2 z-56 The second product, CPDA-2, has twice
as much adenine and 40 per cent more glucose than
CPDA-I. Clinical trials have indicated satisfactory
preservation of whole blood and red cells in CPDA-2
for at least 42, and possibly 49, days. 5~
The survival of red cells from whole blood or
packed cells stored for 42 days is comp~irable with
tbat of Cells stored in CPDA-1 for 35 days. The prob-
lena of poor survival in packed cell units with a he-
matocrit greater than 80 per cent was addressed in a
comparative study of CPDA-1 and A-2 by Morse et
al. 57 Ahhough red cell survivals were similar, units
214
 RED CELL PRESERVATION(Dawson)
preserved with CPDA-2 had an average hematocrit 5
per cent higher than units preserved with CPDA-1.
Contrary to those authors' conclusions, CPDA-2 does
seem to provide better red cell nreservation. Based on
the experience with CPDA-I~ 5s it is expected that
CPDA-2 will be licensed for 49 days, since the prop-
erties of cells in this new preservative are similar at 49
days to those of CPDA-1 cells at 35 days. 5~
One problem with adenine is that it appears to ac-
celerate slightly the loss of 2,3-DPG during red blood
cell storage3 ~ It was partly for this reason, although
mostly for the reason o f potential toxicity, that the
first US adenine supplement was 0.25 m,~! rather than
0.5 m.~l. In spite of the lower amount of adenine,
there is still a deleterious effect on 2,3-DPG, which
has caused the Boston community to decline to use
CPDA-1. In CPD-preserved red cells, 2,3-DPG levels
decrease below 50 per cent of normal by about day
14. With CPDA-1, that point is reached one or two
days earlier, and with CPDA-2 one day earlier than
that." Thus, the question of the clinical effect of
transfllsion of DPG-depleted blood is increasingly
important. It is becoming clear that 2,3-DPG affects
oxygen transport at any concentration. Low 2,3-DPG
levels are deleterious to oxygen function and viability
in animals, 4~ and high DPG levels cause improved
survival in animals and can increase oxygen extrac-
tion by the liver at several levels of anemia. 66"67
Diphosphoglycerate can be raised to twice normal or
above without lowering ATP, using the additives as-
corbate, a s c o r b a t e - p h o s p h a t e , a n d DHA (dilly-
droxyacetone)fiG'67Any of these will maintain red cell
2,3-DPG levels near normal concentrations for at least
two weeks beyond the time DPG levels are currently
maintained with CPD and C P D - a d e n i n e preserva-
tives, as reviewed by Sohmer and Dawson. 4~ Whether
these additives will be introduced into routine use de-
pends on clinical information defining the impor-
tance of maintaining a normal oxygen dissociation
and DPG levels.
OPTIONAL ADDITIVE SYSTEMS
AND REJUVENATION
Optional additive systems, designed to provide
red cells with adequate nutrients and lower viscosity
for transfusion while allowing maximal plasma har-
vest, are evolving in three areas. To packed cells with
a 90 per cent hematocrit, the Australians add all
adenine saline solution immediately after plasma re-
moval to achieve a 50 per cent hematocrit? 9 The
Swedish solution called SAG (saline adenine glu-
cose) 6~ is similar to the US solution ADSOL, except
that ADSOL contains mannitol. These solutions are
used to resuspend high-liematocrit packed cells to a
hematocrit around 60 per cent for 35-day storage.
There is very little difference in the ATP and plasma
hemoglobin content and the post-transfllsion surviv-
al 6a of red cells stored in these solutions compared
with those stored conventionally. These solutions offer
no advantages over regular stored blood for the pa-
215
tient but they allow increased plasma harvesting and
increased ease of transfusion because the viscosity of
the resulting mixture is similar to that of whole blood.
I m p r o v e d oxygen t r a n s p o r t in stored blood
began with the development of CPD. A recently in-
troduced product, FRES (frozen rejuvenation o f
erythrocytes for storage; Fennal Labs, Deerfield,
Illinois), allows stored, even outdated, erythrocytes
to be rejuvenated for frozen storage. Rejuvenation
raises 2,3-DPG and ATP levels to normal or above.
Recent studies o f red cells stored 37 days in CPDA-I
and then rejuvenated showed slightly higher-than-
normal ATP and DPG levels and a post-transfusion
survival of 78 per centfi4
EFFECT OF RED CELL STORAGE TIME ON
BLOOD UTILIZATION
Tile ability of adenine to prolong tile shelf life o f
red cells leads to the potential for reduction o f
shortages and outdating32 The predicted and actual
reductions in outdating that have been studied for
several extensions of shelf life beyond the standard 21
days are of interest with respect to expectations with
CPD-adenine. For a shelf life exiension o f 3.5 days,
Jennings 7a predicted a one-third-reduction in out-
dating; for an extension o f seven days, Pegels and
Seagle 7a predicted a two-thrids reduction in outdat-
ing; and when a seven-day extension of shelf life with
CPD was actually achieved, Kevy et al. reduced out-
dating approximately 50 per cent. 75 For a 14-day ex-
tension of shelf life, which has been realized with
CPDA-I, Pegels and Seagle 74 predicted an 80 per cent
or better reduction in outdating, and a 50 per cent
reduction occurred in Sweden. 7~The one experience
with a 21-day shelf life extension in East Germany
reportedly caused a 100 per cent reduction in out-
dating. In general, however, the predictions o f im-
proved utilization are greatly in excess of tile realiza-
tions.
The amount of blood that becomes outdated in
the United States varies with local circumstances and
is not known for the country as a whole. In the mid-
1970s, NIH-supported studies showed the US out-
dating averaging approximately 25 per cent. 72 In the
late 1970s, outdating decreased to less than 20 per
cent in most regions, and the American Red Cross
system reported 10 per cent outdating in 1977.
However, some cemers reported up to 30 per cent
outdating in 1977. These centers were usually ab-
sorbing the o u t d a t i n g units from hospitals the},
supplied. It is essential to know the basis of the out-
dating figures. For example, in 1978, the New York
Blood Center outdating was 3 per cent, whereas the
New York City area it served had an estimated 10 to
15 per cent outdating. In the same }'ear the Baltimore
Red Cross outdating was 4 per cent, and the area
hospitals served had an average outdating of.7 per
cent, with a range of 0 to 50 per cent. Thus, outdating
figures must be totaled for these two areas; these
outdating figures equal 11 to 18 per cent.
During the conversion to CPDA-1, with its 14-
 HUMAN PATHOLOGY
day increase in shelf life, one o f the two medical
school hospitals in Baltimore decreased outdating
more than 50 per cent (from 3.4 to 1.5 per cent). Just
prior to this, however, a rather extraordinary event
occurred, which is noted here as an example of an-
other kind of influence on blood availability. Delays in
surgery because of blood shortages were estimated to
occur at one of these hospitals approximately four
times a month in 1976 and 1978, and at the other
hospital 40 times a month in 1976 but not at all in
1978. This striking change at the second hospital was
the result of the introduction of double and triple
crossmatching. For the Baltimore Red Cross region,
the outdating reports compiled by the Maryland
Society o f Pathology for 35 hospitals showed out-
dating of 5 per cent before and after the increase in
shelf life. It is said, however, with fair confidence,
that shortages are somewhat less frequent. T h e Gulf
Coast of Texas Regional Blood Center reported an
outdate decrease from 3.95 per cent in 1980 with
CPD to 2.4 per cent with CPDA-1 in 1981. Outdating
at Walter Reed Army Hospital decreased from 8 per
cent to between 2 and 3 per cent by 1982, as a result
o f the use of adenine, with its two-week extension
of shelf life.
An NIH-funded study on the impact of adenine
will determine the effect o f shelf Iife on outdating.
However, until data from that study are published,
we will have to depend on anecdotal reporting.
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