1. Art and Diseño

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A Controlled Comparison of the Efficacy of Hetastarch and Pentastarch in
Granulocyte Collections by Centrifugal Leukapheresis
By J.-H. Lee, SF. Leitman, and H.G. Klein
Compared with hetastarch (HS), the low molecular weight
analog pentastarch (PS) has been reported to be equally
effectivefor granulocyte collectionby centrifugal leukapheresis, to result in fewer adverse donor reactions (ADR), and
to have a more rapid elimination profile. We prospectively
comparedthe granulocytecollection efficiency (GCE), granulocyte yield, and ADR in 72 randomly paired granulocytapheresis proceduresfrom 36 volunteer donors using
the model
CS-3000 Plus Blood Cell Separator(CS) and either PS or HS
as the sedimenting agent. Paired collections from each donor allowed us to compare the two agents directly while
controlling for intrinsic donor differences. In 33 of 36 (92%)
donors, HS procedures were significantly more efficient than
PS procedures ( P < .001). As anaverage, HS collections
yielded 2.3 rt 0.67 x 10” granulocytes at 58% 2 8.8% GCE,
whereas PS proceduresresulted in 1.4 2 0.76 x 10” granulocytes at 33% 2 15% GCE. No starch-induced ADR were seen
with either agent. For granulocyte harvests using the CS,
(1) in most donors,using HS as the red blood cellsedimenting agent during centrifugal leukapheresisresults in
significantly higher(nearly twofold) GCE and larger granulocyte yields in comparison with using PS, (2) ADR were not
observed with either agent, and (3) the potential benefit
of more rapid PS elimination should be balancedagainst
significantly lower granulocyte yields.
This is a US government work. There are no restrictions on
its use.
M
aged most collectors to substitute PS for HS in procuring
granulocytes. However, equivalent efficacy for PS and HS
has not been shown in a controlled trial. The present controlled study examines the granulocyte collection efficiency
(GCE), granulocyte yield, and the ADR in randomly paired
PS-HS collection procedures from the same donor and directly compares the performance characteristics of the two
agents for use in centrifugal granulocytapheresis.
ACROMOLECULEShave beenroutinelyadministered to volunteer blood donors during granulocyte
collection to promote redbloodcell (RBC) sedimentation
and increase granulocyte yield.’ During the past decade, 6%
hydroxyethyl starch (hetastarch [HS]) has been the preferred
sedimenting agent because it greatly enhances granulocyte
yield, the transient plasma expansion is generally well tolerated, and it has few clinically significant side effects in conventional doseand administrationfrequency.’,’ However,
significant HS blood levels persist for weeks andtrace
amountscanbe
detected years afterits
Delayed HSclearanceandconsequent
long-term donor
safety concerns resulted in a search for alternative agents.
Ten percent pentastarch (PS), a more recently developed
low molecular weight HS analog, is cleared from thecirculation relatively rapidly and has been reported to be equally
effective in enhancing granulocyte collection. Theability of
PS to separate blood cells and induce
RBC sedimentation, as
assessed in vitroby the recovery of blood cellsin supernatant
plasma, has been reported to be similar to that of HS.‘ The
results of a subsequent multicenter clinical trialinvolving
75 volunteer donors who underwent 179 centrifugation leuPS as
kapheresis procedures stronglysuggestedthatusing
thesedimenting agentresultsinan
adequategranulocyte
yield comparableto that from using HS, and also documented almostno clinicallysignificant adversedonoreffects.’ Initial studies could not detect PS in the blood within
a fewdays of its administration,’and the adversedonor
reactions (ADR) profile has been inferred to be even more
favorable thanthat of HS.*These initial studies have encourFrom the Department of Transfusion Medicine, Warren G. Mugnuson Clinical Center, National Institutes of Health, Bethesdu, MD.
Submitted November 7, 1994; accepted July 31, 1995.
Addressreprintrequeststo
J.-H. Lee,MD, Bldg IO, Room IC71l . National Institutes of Health, Bethesda, MD 20892.
The publication costs of this article were defrayed in part by page
chargepayment. This article must thereforebehereby
murked
“advertisement” i n accordunce with 18 U.S.C. section 1734 solely to
indicute this fuct.
This is a US government work. There are no restrictions on its use.
0006-497//95/8612-0001$0.00/0
4662
MATERIALS AND METHODS
We prospectively studied 72 consecutive granulocyte collections
from 36 volunteer blood donors using the model CS3000 Plus Blood
Cell Separator (CS; Fenwal Laboratories, Deerfield, IL). Each donor
underwent paired collections separated by approximately 2 months
(range, 2 weeks to 7 months) and randomly received a standard 500
mL dose of either 10%PS (McGaw, Inc, Irvine, CA) or 6% HS
(NPBI, Emmer-Compascuum, The Netherlands) during the first procedure and the alternate agent during the subsequent collection. The
HS preparation used was chemically and pharmacologically identical
to the preparation more widely used in the United States (McGaw,
Irvine, CA). Thirty milliliters of 46.7% trisodium citrate added to 500
mL of either PS or HS was evenly distributed over approximately 7
L of processed whole blood (1 :13 ratio with blood). After obtaining
informed consent for the procedure for procuring granulocytes, all
donors were premedicated with 8 mgof oral dexamethasone 12
hours before each procedure. The two RBC sedimenting agents are
compared in Table I . The specific instrument settings used are summarized in Table 2.
GCE. The GCE of each procedure was calculated by dividing
the granulocyte yield by the total number of granulocytes processed.
The yield was calculated as the product of the component cell count
and volume. The number of granulocytes processed (GP) was calculated as follows: GP = (WBC)(%G)(L), where WBC represents the
donor peripheral white blood count per liter, %G represents the
granulocyte fraction (neutrophils including bands), and L represents
the total volume of processed whole blood in liters. We used the
average of the cell counts immediately before and after each procedure, for both WBC and %G. The accuracy of averaging the two
cell counts has been previously verified.’ All cell counts were performed on the Coulter Counter Model S-PLUS V (Coulter Electronics, Inc, Hialeah, FL).
PS versus HS. For each donor, we plotted the GCE (Fig 1) and
the granulocyte yield (Fig 2) from the procedure using HS asa
function of the donor’s corresponding values using PS. We also
Blood, Vol 86, No 12 (December 15), 1995: pp 4662-4666
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4663
HYDROXYETHYLSTARCH IN GRANULOCYTAPHERESIS
Table 1. A Comparison of the Biochemical and Pharmacokinetic
Characteristicsof 10% PS and 6% HS
Characteristics
PS
480,000
264,000
Average molecular weight (MW)
71,00063,000
No. average molecular weight (MN)*
6.0
10.0
Hydroxyethyl starch concentration (g/dL)
0.70
0.45
Hydroxyethyl groups per glucose residue
25.5 (h)*
2.5
Time to reach 50% peak blood level
7
24-h plasma distribution (% dose)'
33
70
24-h urinary excretion (% dose)
33
24-h extravascular distribution23(% dose)*
96 h
Overall survival in blood*
HS
3%
17-26
wk
* Mishler et al.' Characteristics not taken from Mishler et all have
been listed directly from thepackage insert of each agent.
compared the mean and the standard deviation of the GCE and the
granulocyte yield for all procedures using PS versus all procedures
using HS. The GCE distribution of the 36 procedures on each sedimenting agent is compared in Fig 3.
Thedonorswereverballyquestioned
to detectanyADRfrom
either starch preparation at completion of each procedure and were
instructed to reportbyphoneanyproblemsarisingsubsequentto
each procedure. All granulocyte donors in this study werealso regularplateletdonorsat
our collection center,andsubsequent donor
visits allowed the opportunity to confirm absence of ADR.
Statistical methods. The significance of the results on GCE and
granulocyte yield wasanalyzed using the sign test." In brief,the
datapoints above the line of identity were labeled plus and
those
below the line of identity were labeled minus in determining the x'
(with one degree of freedom)and P values. Theadequacy of the
sample size was inferred from the resulting degree of significance.
In Figs 1 and 2, we used linearregression analysis (sum of least
squares method) to generate trend lines.
substantially more granulocytes in 32 ofthe 36 donors (89%,
P < .001). The wide interdonor variability in the GCE and
the granulocyte yield using PS were minimized by using HS,
as indicated by the relatively horizontal slope values less
than 1 (0.24 and 0.52 for Figs 1 and 2, respectively). For all
72 procedures, using HS resulted in a significantly higher
mean GCE (58% ? 8.8% v 33% 2 15%, P < .001) and a
larger mean granulocyte yield (2.3 -+ 0.67 v 1.44 2 0.76 X
10'' granulocytes, P < .OO1) than using PS.
The greater variability in cell yield with PS than with HS
may be also appreciated from Fig 3, which shows a distribution plot of the granulocyte yield for the 36 procedures with
each agent. The less efficient and more variable PS collections included 9 procedures (25%) with unacceptably low
cell numbers (< 1 X 10" granulocytes) and were more likely
(12 procedures [33%]) to result in a yield between 1.0 and
1.5 X 10'' granulocytes. In contrast, only one HS collection
(3%) generated less than 1 X 10" granulocytes. HS collection commonly (13 procedures [36%]) generated components with a cell dose between 2.0 and 2.5 X 10" granulocytes. Using HS assured a minimum GCE of 40%, whereas
using PS resulted in a collection failure with a GCE less
than 10% in 3 of the 36 procedures (8.3%).Infrequent ADR
100
-
Hetastarch GCE (%)
..
80
A
RESULTS
A
Figure 1 compares the expected relationship between HS
and PS if the GCE for the two agents are equal (dashed line)
with the observed relationship (solid line). The increased yintercept of the observed line describes minimization, by
using HS instead of PS, of unacceptably poor GCE or collection failures. Thirty-three of the 36 donors (92%) showed a
higher GCE with HS than with PS ( P < .001). The actual
granulocyte yields are plotted in Fig 2, in which comparable
predonation leukocyte counts for the two collections from
each donor resulted in a line comparable to that in Fig 1.
The overall mean predonation leukocyte count of approximately 8 X 109/L with80% granulocytes showed substantial
interdonor but relatively little intradonor variability. In comparison with PS, using HS resulted in a component with
A
.
60
.................
0
c
A
A
40 .
20 -
,,
0
1,000
Whole flow
blood
rate
Centrifuge RPM
volume
Blood
processed
Interface detector setting
Program
Chamber type
50 mUmin
6.5-7.0 L
33
2
Granulo
,,
0
O L
Table 2. Apheresis Parameters for Granulocyte Collection onthe
Model CS3000 Plus Blood Cell Separator
,
/'A
A
5
I
I
10
15
I
20
I
25
I
30
I
35
I
40
I
45
I
50
I
55
Pentastarch GCE (8)
Fig 1. A comparison of the GCE for PS and HS. The GCE using HS
was roughly linearly correlatedwith the GCE using PS, and a given
donor with a relatively highGCE on PSwas ah0 more likelyto show
a high GCE on HS. In 33 of 36 donors
(92%). HS resulted in a superior
GCE in cornperiwnto PS. The 3 remaining donors showed
a cornparabla GCE with either PS or HS. The dashed line indicates
the hypothetical plot assuming that the two agents are equally effective.
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LEE, LEITMAN, AND KLEIN
4664
from dexamethasone premedication (sleep disturbance) and
the apheresis procedure (mild vasovagal reactions and citrate
toxicity) did not favor collections using either agent. None
of the 36 donors reported ADR directly attributable to either
agent.
Collections
14
. .-Pentastsrch
12
.............
*
- Hetastarch
....."""
...................
DISCUSSION
l
Advances in blood component therapy and the therapeutic
efficacy of RBC, platelet, and plasma components allow
effective transfusion support of patients with complicated
hematologic disorders. As a result, infectious complications
unresponsive to optimal antibiotic therapy have become an
increasing cause of morbidity and mortality in patients with
prolonged cytopenias. In contrast to RBCs and platelets,
granulocytes have developed slowly as a therapeutic blood
component, owing in part to the difficulty in collecting sufficient numbers of cells that permit well-controlled studies
to assess granulocyte transfusion efficacy. Thus, despite numerous studies that have attempted to assess the therapeutic
role of granulocyte transfusions (GTs)in neutropenic patients, definitive information is not available and GTs have
fallen out of favor. Seven controlled studies comparing antibiotic therapy alone versus GT in addition to antibiotic ther-
. . . . . . . . . . . . * . . . . . . . . . . . .., ...........................
;i
L!
l
..
'i
...... .;
ri
. ...... 4
-:l
_. . . . . . . . . . . . . . . . . . . . . .
.....
5.
.l#
.................................
I
I-!
-. -:
m
=
Fi
Ij
......................................................
l
0.5
HS Yield
$1
li3
1
1.5
2
2.5
3
3.5
4
Granulocyte Yield
A
A
I
I
AI
I'
A
I
. . . . . . . . . . . . . .~I" " ' . . . " " " " ' . . . . .
..
/
A
I
/
/
I
I
I
/
I
/
0
I
I
I
l
I
I
0.5
1
1.5
2
2.5
3
3.5
PS Yield
Fig2. A comparisonof the granulocyte yield for PS and HS. A
plot of the actual granulocyte yield rather than
the GCE generated a
line analogous to the line shown in Fig 1. In 32 of 36 donors (89%).
HS resulted in a superior granulocyte yield in comparison
to PS.The
4 remaining donors showed a comparable yield with either agent.
The dashed line indicates the hypothetical plot assuming that the
two agents are equally effective.
Fig 3. The granulocyte yield distributions for
the two sedimenting
agents. The number of procedures generating a particular granulocyte yield was
plotted as a function ofthat yield ( x 10" granulocytes,
0.5) for the 36 procedureswith each agent.
grouped in increments of
with a higher granuUsing HS resulted in more uniform components
locyte yield than usingPS.
apy in infected neutropenic patients have generated conflicting conclusions. Five of the seven studies report at least
partial success of GT; no benefit was seen in the remaining
two studies involving 47 and 22 subjects. However, the latter
two studies used extremely low cell doses, approximately
only 20% of currently achievable dose." Recent reports using granulocyte colony-stimulating factor to stimulate normalblood donors again raise the possibility of routinely
collecting greater numbers of granulocytes in the future.''
Advances that increase cell dose may significantly improve
the efficacy of GT, especially in the pediatric setting, in
which a higher dose of granulocytes per kilogram of body
weight is possible. It thus seems appropriate to reanalyze the
technique for collecting granulocytes in optimal numbers.
The granulocyte yield depends primarily on the efficiency
at which the cells are extracted during an apheresis collection
procedure. The similarity of RBC and granulocyte sedimentahas necessitated
the
use of
tion rates
during
macromoleculesto enhance RBC sedimentation and
to achieve
optimal separation of these cells for a successful granulocyte
colle~tion.'~.'~
The macromolecules most widely used include
hydroxyethyl starch preparations, dextrans, and modified fluid
gelatins; of these, HS gained initial favor because it effectively
enhancedgranulocyteyield with few ADR in conventional
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HYDROXYETHYL STARCH IN GRANULOCYTAPHERESIS
4665
The initial studies on PS, which included one multicenter
dose and administration frequency.' However, significant HS
blood levels persist for weeks, and trace amounts may be declinical trial, concluded thatPS is as effective as HSin
tected years after its administrati~n.~-~
Incidence estimates of
centrifugal granulo~ytapheresis.~.~
In view of the current litclinically apparent HS-induced adverse reactions range from
erature on the effects of macromolecules on the physics
0.09%to 0.7%.','6,'7In doses of less than 1,500mL,HS induces
of blood cell separationz3 and the biochemical differences
onlytransient,mild,clinicallyinsignificantlaboratoryalterbetween PS and HS,' it would be surprising ifin fact PS
ations,includingprolongedpartialthromboplastinand
prowere as effective as HS. One intrinsic donor variable that
thrombin times, decreased platelet counts and fibrinogen levels, predictably influences granulocyte harvest by centrifugal leuvon Willebrand-likesyndrome,and
hyperamyla~emia.'.'~.'~ kapheresis is the donor erythrocyte sedimentation rate
However, serious reactions, including severe pruritus, dissemi- (ESR).9 Results of studies from our laboratory have sugnatedintravascularcoagulopathy,andshock,havebeenregested that PS may be less effective than HS, based on an
ported.2s22Althoughthey are exceedingly rare, these serious
indirect comparison of the respective formulas that predict
reactions and concern about long-term toxicity as a result of
GCE from the donor ESR. The slope and the y-intercept of
delayed HS clearance have prompted
a search fora sedimenting
the linear relationship GCE (%) = 1.3 ESR (m&) + 45
agentwith a morefavorableeliminationprofile.Theinitial
when one uses HS as the cell sedimenting agent decreases
studies which suggested that PS is
as effective as HS while
to 0.8 and 20, respectively, when PS is substituted for HS
being eliminated much more rapidly encouragedmany collecin otherwise identical collection procedure^.'^ In this study,
tors to choosePS for use in granulocyte harvests
by centrifugal
we directly compare the two agents in a controlled clinical
leukapheresis.6-8
trial; our results confirm the indirect comparison study. The
The separation of granulocytes from erythrocytes, which
more consistent HS collections assured a 40% minimum
dictate GCE, depends on the relative sedimentation rates of
GCE, whereas a substantial fraction (8.3%) of the less prethe two cell types and the granulocyte sedimentation rate
dictable PS procedures resulted in collection failures at less
relative to the upward plasma flow resulting from downward
than 10% GCE. Routine PS use will more likely result in
cell displacement. Macromolecules that promote RBC roufewer granulocytes than the criteria established by the Amerleaux formation increase the effective cell mass to cell surican Association of Blood Banks Standards Committee, or
face area ratio and thereby increase both the cell sedimenta1.0 X 10" granulocytes per unitin75%of
tested units.z6
tion rate and the consequent upward plasma flow. RBCs,
Finally, the lack of ADR from either agent in our series of
with a highly negatively charged outer cell surface, are much
only 36 collections in each of the two arms from 72 donors
more susceptible to polar macromolecules than are neutral
is not unexpected in view of the previously reported incigranulocytes, and RBC sedimentation is selectively indence of less than
creased over granulocyte sedimentation through both direct
We conclude the following for centrifugal granulocytaphcell and indirect plasma effects.23Although the precise moeresis using the model CS3000 Plus blood cell separator and
lecular mechanism of RBC rouleaux formation is unknown,
either PS or HS as the RBC sedimenting agent. (1) In most
kinetic studies using nuclear magnetic resonance relaxation
donors, HS results in a significantly higher (nearly twofold)
methods have shown that HS rapidly induces over 20 secGCE and a larger granulocyte yield in comparison to PS.
onds the formation of aggregates containing 4 RBCson
(2) Sedimenting agent-induced ADR were notobserved with
average at equilibrium, which effectively doubles the mass
either HS or PS. (3) The potential benefit of more rapid PS
to surface area ratio in comparison to a single RBC."
elimination should be balanced against the significantly
Two properties of macromolecules independently influlower granulocyte yield. The relative efficacy of PS and HS
ence RBC sedimentation. There appears to be a critical mousing other blood cell separators and under other collection
lecular weight (CMW) as well as a critical concentration
conditions requires further study.
(CC) below which RBC sedimentation is not enhanced. Although rigorous numbers are difficult to establish, the CMW
ACKNOWLEDGMENT
and the CC for hydroxyethyl starch compounds have been
The
authors
sincerely
thank David W. Alling, MD, PhD of the
determined to be 300,000 and 0.3 g/dL, respectively.' HS,
Biometry
Branch,
National
Institute of Allergy and Infectious Diswith a weight-average molecular weight (MW) of 480,000
eases, for his expert comments and advice in statistically analyzing
and relatively slow elimination over several days, readily
the data. We also gratefully appreciate the assistance from our demeets these criteria under virtually all collection conditions
partmental staff (Karen Diggs, Cynthia Martin, Sandra Bangham,
used today. In contrast, the substantially lower PS MW of
Phyllis Byrne, Rolande Grammont, Jeanette Rothberg, Kathleen
264,000 (below the CMW) may explain in part the decreased
Swisher, and Margaret Weller) for their skilled hemapheresis operaefficacy relative to HS. Because the number-average molecution. We thank Gail Carter and Virginia Morgan for diligent donor
lar weights of the two agents are fairly comparable, the
recruitment, Herb Cullis and Charles Carter for insightful technical
relatively few but large molecules present to a greater extent
suggestions, and Tim Jacobson for his helpful technical assistance.
in HS than in PS may be an important element that contributes to the more uniform, increased HS efficacy. FurtherREFERENCES
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1995 86: 4662-4666
A controlled comparison of the efficacy of hetastarch and
pentastarch in granulocyte collections by centrifugal leukapheresis
JH Lee, SF Leitman and HG Klein
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