Original Article

The effect of Hetastarch (670/0.75) invivoon platelet

closure time in the dog
Lisa Smart, BVSc, DACVECC; Karl E. Jandrey, DVM, DACVECC; Philip H. Kass, DVM, PhD,
DACVPM; Janelle R. Wierenga, DVM, DACVECC and Fern Tablin, VMD, PhD
Abstract
Objective To evaluate the effect of 6% hydroxyethyl starch (HES) solution in vivo, with an average
molecular weight of 670 kDa and degree of substitution of 0.75, on canine platelet function.
Design Prospective, controlled-experimental study.
Setting University of California, Davis, Veterinary Medical Teaching Hospital.
Animals Seven healthy employee-owned dogs.
Interventions Seven dogs were included in the treatment group. Four of these dogs also served as the control
group. Platelet closure time (CT) was measured using a platelet function analyzer and collagen/ADP cartridges.
Dogs were given 20 mL/kg of either sodium chloride 0.9% (control group, n54) or HES (treatment group, n57)
IVover 1 hour. CT was measured before the infusion, and at 1, 3, 5, and 24 hours after the start of the infusion.
Measurements and Main Results There was a signicant change over time from 0 to 24 hours (Po0.001), a
signicant difference between groups across time (Po0.001), and a signicant group-by-time interaction
(P50.007). At 3 hours, mean CT for the treatment group was 122.3 18.1 seconds, which was signicantly
different (Po0.001) from the control group (71.0 3.5s). At 5 hours, mean CT for the treatment group was
142.7 33.9 seconds, which was signicantly different (P50.001) from the control group (75.0 8.6s). Mean CT
at 24 hours was within the reference interval for both the control and treatment group (66.0 2.9 and 81.8 11.9s,
respectively); however, CT in 3 individual dogs in the treatment group at this time point remained prolonged.
Conclusions Aclinically relevant dose of HES 670/0.75 prolongs CTin dogs for up to 24 hours. This may be due
to platelet dysfunction in addition to the effects of hemodilution, and therefore, may increase the risk of bleeding.
(J Vet Emerg Crit Care 2009; 19(5): 444449) doi: 10.1111/j.1476-4431.2009.00464.x
Keywords: articial colloid, canine, closure time, coagulopathy, hydroxyethyl starch
Introduction
Hydroxyethyl starch (HES) solutions are articial col-
loid solutions used in veterinary medicine for plasma
volume expansion and to increase colloid osmotic pres-
sure. They consist of large starch polymers suspended
in isotonic saline or a similar crystalloid solution.
1
Commercially available HES solutions are classied by
their manufactured mean molecular weight (MW) and
degree of substitution (DS).
1
The DS refers to the av-
erage number of hydroxyethyl groups per glucose unit
within the branched-chain glucose polymer.
2
The most
commonly used HES solution in veterinary medicine in
the United States has an average MW of 670 kDa and a
DS of 0.75 (HES 670/0.75).
HES solutions have been shown to compromise
human platelet function in vitro
35
and in vivo
610
as measured by ow cytometry,
3,4,6,7
thromboelasto-
graphy,
5,6,912
platelet aggregometry,
13,14
and platelet
function analysis (PFA).
69,15
Compared with other
methods, PFA assesses platelet function under condi-
tions of shear stress
16
and attempts to mimic the
conditions under which a platelet plug is formed
in vivo.
Studies have shown that HES solutions with a higher
MW (4200 kDa) or a higher DS (40.5), such as HES
Study funded by the University of California, Davis, Small Animal Emer-
gency and Critical Care Service.
Presented in abstract form at the American College of Veterinary Internal Med-
icine Forum, San Antonio, TX, 2008. The authors declare no conicts of interest.
Address correspondence and reprint requests to
Dr. Lisa Smart, School of Veterinary and Biomedical Science, Murdoch
University, South St, Murdoch, WA 6150, Australia.
Email: l.smart@murdoch.edu.au
From the William R. Pritchard Veterinary Medical Teaching Hospital
(Smart, Wierenga), the Departments of Veterinary Surgical and Radiological
Sciences (Jandrey), Population Health and Reproduction (Kass), and
Anatomy, Physiology and Cell Biology (Tablin), School of Veterinary
Medicine, University of California, Davis, Davis, CA 95616; and the School
of Veterinary and Biomedical Sciences, Murdoch University, Murdoch, WA
6150, Australia (Smart).
Journal of Veterinary Emergency and Critical Care 19(5) 2009, pp 444449
doi:10.1111/j.1476-4431.2009.00464.x
& Veterinary Emergency and Critical Care Society 2009 444
670/0.75, have a more pronounced effect on platelet
function compared with other types.
7,8,10,13
Clinically,
some patient populations in human medicine have
been shown to have higher rates of postoperative blood
loss after HES administration.
1113,1719
Trials compar-
ing different types of HES solutions have shown that
those with a higher MW, or higher DS, had the most
signicant effect on blood loss or transfusion require-
ments.
1113,18,20
In contrast, some trials in human sur-
gical populations have shown no difference in platelet
function or degree of blood loss.
14,15
There have been limited studies assessing the effect
of HES on canine platelet function. Wierenga et al
21
compared the effects of HES 670/0.75 and 0.9% sodium
chloride (NaCl) solution on in vitro canine platelet
function, as measured by PFA. The study demonstrated
that HES 670/0.75, at a dilution of 1:3 with whole
blood, signicantly affected platelet plug formation to a
greater degree than hemodilution alone. Results of in
vitro studies, however, cannot be directly extrapolated
to predict in vivo results, as the effect that a HES
solution may have on hemostasis is largely determined
by its in vivo pharmacokinetics.
1
There have been no in
vivo studies evaluating the effect of HES 675/0.75 on
canine platelet function.
The objective of this study was to evaluate the effect
of HES 670/0.75 in vivo on canine platelet function,
as compared with NaCl. Our hypothesis was that a
20 mL/kg dose of HES 670/0.75 would signicantly
prolong closure time (CT) as measured by PFA.
Materials and Methods
This prospective, controlled experimental study in-
volved 7 healthy dogs of both sexes (5 male, 2 female),
with a minimum weight of 10 kg that were between 1.5
and 8 years of age. The dogs were owned by employees
of the University of California, Davis, Veterinary Med-
ical Teaching Hospital. Owners were notied of proce-
dures and risks involved, and signed a consent form
before each experiment. Animal handling and proce-
dures were approved by the University of California,
Davis, Institutional Animal Care and Use Committee.
The dogs were classied as healthy by the following
criteria: no clinically relevant abnormalities on physical
examination; the absence of current illness or disease;
no exposure to drugs, such as aspirin, for 44 weeks
before the experiment; and no history of disease that
may impair platelet function or coagulation. The fol-
lowing clinicopathologic measurements were within
their respective reference intervals: HCT, PCV, total
serum protein, serum electrolytes, blood glucose, BUN,
serum creatinine, urine specic gravity (1.0301.060)
a
urine dipstick (no blood, glucose, or ketones, o21
bilirubin),
b
platelet count (4150 10
9
/L) and CT.
c
If
urine protein was detected by dipstick, a 5% sulfosal-
icylic acid test was performed and only a negative
result was accepted.
All 7 dogs were included in the treatment group.
Four of these dogs were also included in the control
group (2 male, 2 female). Experiments for the treatment
group were conducted rst. A minimum of 4 weeks
elapsed between experiments for those dogs in both the
control group and the treatment group. On the morning
of each experiment, food was withheld and all dogs
were weighed to the nearest 0.1 kg. Water was available
ad libitum throughout the experiment.
Immediately before the start of each experiment, a 20-
Ga over-the-needle catheter
d
was placed in the cephalic
vein using aseptic technique. Dogs were given 20mL/kg
of either NaCl (control group, n54) or HES 670/0.75
e
(treatment group, n57) IV over 1 hour by an infusion
pump. Blood was drawn for CT measurement before
the infusion, and at 1, 3, 5, and 24 hours after the start
of the infusion. Blood (1.8 mL) was collected via veni-
puncture of the jugular or lateral saphenous vein directly
into tubes containing 3.8% trisodium citrate, using a 20-
Ga vacutainer needle.
f
The blood was maintained at
room temperature (251C) and analyzed within 2 hours of
collection. CT was measured in duplicate by use of a
bench-top platelet function analyzer
c
and collagen/ADP-
coated cartridges.
g
Results were discarded and the anal-
ysis repeated if the analyzer indicated an error with the
sample or if the variation between duplicate measure-
ments was 415%. The reference interval used was 5286
seconds.
22
The dogs were under constant observation through-
out the experiment. Heart rate and respiratory rate
were recorded every 30 minutes, starting 30 minutes
before the start of the infusion, and continuing until 150
minutes after the start of the infusion. The dogs were
monitored by a single operator for signs of active
bleeding such as petechiae of skin or mucous mem-
branes, ecchymoses, epistaxis, or episcleral hemorrhage
throughout the experimental period.
Statistical analysis
Duplicate measurements for CT were averaged. Two-
way repeated measures ANOVA was used to assess
changes over time, and differences between treatment
and control groups; 1 approach utilized all dogs as-
suming independence, although 4 of 7 dogs received
both treatment and control with a washout period be-
tween them, and a second approach that was restricted
to the 4 dogs with both treatment and control. Time-
specic group differences were evaluated using a
Student t-test (2-group for all dogs; paired for the 4
dogs with both treatment and control) and a sequen-
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00464.x 445
Hetastarch and platelet function
tially rejective method of multiple comparison adjust-
ment to control Type-I error.
23
Data normality was
conrmed using the Shapiro-Wilk W-test; a variance
ratios test was used to conrm homoscedasticity.
Student 2-group t-test was used to compare baseline
PCVand platelet counts between the 2 groups. P-values
o0.05 were considered statistically signicant.
Results
The 7 dogs ranged in weight from 15.2 to 57.5 kg. No
clinical abnormalities, including petechiae or ecchymo-
ses, were observed during the experimental period. The
only adverse effect reported by owners in the days after
the experiment was mild skin irritation at catheter sites,
which resolved without treatment. For dogs that were
included in both the control and treatment group, the
time between experiments ranged from 55 to 143 days
(median 58 days). A duplicate CT measurement could
not be obtained for 1 dog in the control group at 24 hours,
therefore the single value was accepted. CT could not be
obtained from 1 dog in the treatment group at 24 hours
due to repeated ow obstruction of the analyzer, there-
fore this dog was removed from statistical analysis at the
24-hour time point.
There was a signicant change in CT over time from
0 to 24 hours (Po0.001) in both groups, a signicant
difference between groups across time (Po0.001), and
evidence of a signicant group-by-time interaction
(P50.007). Examining only the 4 dogs that received
both treatments, the corresponding hypothesis test re-
sults were P50.002 for change in CT over time from
0 to 24 hours, Po0.0001 for difference between groups
across time, and P50.02 for the group-by-time interac-
tion. At 3 hours, mean CT for the treatment group was
122.3 18.1 seconds, which was signicantly different
(Po0.001) from the control group (71.0 3.5 s) (see Fig-
ure 1); a paired analysis yielded a signicant difference as
well (Po0.001). At 5 hours, mean CT for the treatment
group was 142.7 33.9 seconds, which was signicantly
different (P50.001) from the control group (75.0 8.6 s);
a paired analysis did not achieve signicance after the
multiple comparison adjustment (P50.02). Mean CT at
24 hours was within the reference interval for both the
control and treatment group (66.0 2.9 and 81.8 11.9 s,
respectively); however, CT in 3 individual dogs in the
treatment group at this time point remained above the
reference interval.
The mean baseline PCV was 48.5 5.1%. PCV could
not be attained for 1 dog in the treatment group. The
mean baseline platelet count was 319 10
9
243 10
9
/L.
There was no statistically signicant difference in mean
baseline PCV or platelet counts between the control and
treatment group.
Discussion
This study has shown that 20 mL/kg of HES 670/0.75
prolongs canine CT, as measured by PFA, for up to 5
hours after injection. Platelet dysfunction in dogs due to
HES 670/0.75 has been demonstrated previously in an in
vitro study. Wierenga et al
21
had shown that a 1:3 dilution
of canine blood with HES 670/0.75 prolonged CTs above
the reference interval, as compared with a 1:9 dilution. A
mild increase in CT above baseline was seen with a 1:3
dilution with saline (85.8 15.7 s) but not to the same
degree as with HES 670/0.75 (100.6 18.6 s). The authors
originally stated that 6% Hetastarch in 0.9% NaCl, the
same HES solution used in this study, had an average
MWof 600 kDa and a DS of 0.7 (HES 600/0.7 as opposed
to HES 670/0.75). Verication was sought from the man-
ufacturer and the HES solution was conrmed to have an
average MWof 670kDa and a DS of 0.75. The 1:3 and 1:9
dilutions simulated a change in blood volume in the
dog that would result from a colloid dose of 30 and
10mL/kg, respectively. This information led to a choice
of 20 mL/kg for the present study, and this is the rst in
vivo study in normal healthy dogs to show that HES
670/0.75 prolongs canine CT.
Platelet dysfunction in humans due to HES has been
attributed to decreased platelet adhesion by several
mechanisms. Firstly, HES can decrease circulating lev-
els of von Willebrand factor (vWF) in humans
10,24,25
;
this effect is similar to Type 1 von Willebrands disease.
Factor VIII (FVIII), which is stabilized by vWF in cir-
culation,
26
is also decreased,
10,24,27
which accounts for
mildly prolonged coagulation times that have variably
been observed in humans
10
after HES administration.
Decreases in vWF and FVIII may occur due to binding
Figure1: Platelet function analyzer closure time (CT) at
baseline, and after 20 mL/kg of either NaCl 0.9% (control
group) or 6% Hetastarch (670/0.75) (treatment group). The in-
fusion was given over 1 hour (as indicated by the black bar) and
CT was measured at 1, 3, 5, and 24 hours after the start of the
infusion (
n
signicant (Po0.05) time-specic group differences
using a 2-group Student t-test). The gray area represents the
reference interval for canine CT.
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00464.x 446
L. Smart et al.
with HES molecules and accelerated elimination of the
complex.
18
Secondly, HES decreases agonist-induced
expression and activation of platelet integrin a
IIb
b
3
(for-
merly known as GPIIb/IIIa).
7
Integrin a
IIb
b
3
on the
surface of the platelet binds brinogen and plays a vital
role in platelet aggregation and formation of a platelet
plug.
16
It has also been shown that HES molecules coat
the surface of the platelet,
4
limiting binding of ligands
to cell surface receptors, which may decrease function
of platelets independent of integrin a
IIb
b
3
blockade.
These mechanisms of HES-induced platelet dysfunc-
tion may have accounted for the peak in CT seen at 5
hours in this study, either due to progressive coating of
ligands with HES molecules, or binding and elimina-
tion of vWF over time.
The degree to which an HES solution affects in vivo
platelet function is determined by its rate of degrada-
tion.
18
Three chemical properties of HES affect the
rate of degradation; MW, DS, and the C2:C6 ratio.
18
The manufactured mean MW of a HES solution can be
divided into high MW (4400 kDa), medium MW (200
400 kDa) or low MW (o200 kDa).
18
The eventual in
vivo MWof a solution is a large determinant of its ef-
cacy as a colloid.
1
The DS describes the degree of
hydroxyethylation of glucose units,
1
and HES solutions
can be divided into high DS (40.5) or low DS (0.40.5).
1
Solutions with a high DS have a slower rate of degra-
dation. Finally, the C2:C6 ratio is determined by the
pattern of hydroxyethylation at the carbon positions of
C2 and C6,
18
and a higher C2:C6 ratio (ie, a greater
number of glucose molecules hydroxyethylated at the
C2 position compared with the C6 position) slows
down the rate of degradation.
1
If all 3 chemical prop-
erties that affect the rate of degradation are taken into
consideration, HES solutions can be divided into slowly
degradable (MW4200, DS40.6, C2:C6 ratio 48) or
rapidly degradable (MWo200, DSo0.6, C2:C6 ratio
o8),
18
with some HES solutions having properties of
both categories. HES 670/0.75 used in this study is
classied as slowly degradable. Although slowly de-
gradable HES solutions have better colloidal efcacy,
they also have a greater adverse effect on human plate-
let function compared with rapidly degradable solu-
tions, some of which have decreased to no adverse
effect on platelet function in vivo.
7,8,11,13,28
Clinical studies in humans that have evaluated the
effect of HES on platelet function are mostly limited to
several specic populations, including cardiopulmo-
nary bypass patients
12,13
and elective surgical pa-
tients.
9,11,14
Surgical patients can have increased vWF
and FVIII levels, and these patients have variable re-
sults in platelet function testing; some studies showing
that slowly degradable HES solutions had no effect at
all.
14,15
One study
8
was conducted on humans receiving
peridural anesthesia, who were not undergoing general
anesthesia or surgery. The authors found that CTs
were prolonged after HES administration compared
with lactated Ringers solution, and was especially
pronounced after slowly degradable HES administra-
tion as opposed to rapidly degradable HES.
The clinical relevance of platelet dysfunction after HES
administration has been documented in human medicine
as increased postoperative blood loss or increased trans-
fusion requirements in some patient populations.
1113,17,19
One study
17
showed an increase in bleeding events in
humans treated for post-subarachnoid hemorrhage va-
sospasm with HES as opposed to plasma protein frac-
tion, although this study was not blinded nor strictly
randomized. Some studies in surgical patients have
shown no signicant increase in blood loss.
14,15
Trials in
postoperative patients that have used rapidly degradable
HES solutions found no difference in rates of blood loss
and transfusion requirements when compared with al-
bumin or gelatin.
18
A recent pooled analysis conducted
by Kozek-Langenecker et al
20
included studies in major
surgery comparing HES 130/0.4 and HES 200/0.5 and
found that estimated blood loss and transfusion require-
ments were signicantly reduced in the group receiving
HES 130/0.4. The clinical impact of platelet dysfunction
induced by HES solutions in veterinary medicine is yet to
be established, and prospective, randomized trials need
to be conducted.
A limitation of this study is that the treatment and
control groups were not randomized. The control group
had received HES as a part of the treatment group
protocol. A minimum of 4 weeks between experiments
was chosen due to the pharmacokinetics of HES in the
dog. The biological half-life of HES 450/0.7 in dogs is
7.45 days, which is considerably shorter compared with
humans (12.8 d).
29,30
For humans, this equates to 90% of
the dose given being excreted by 42 days.
30
In earlier
research publications, HES 670/0.75 was listed as hav-
ing an average MW of 450 kDa, as older methods for
MW determination underestimated the true MW.
31
Therefore it is likely that the pharmacokinetics of HES
450/0.7 as described is comparable to 670/0.75. The
dogs used in this study had the control study per-
formed a minimum of 55 days after HES administration
therefore most of the HES would have been excreted. A
cross-over randomized experimental design would
have improved the strength of the study, however,
given that baseline CTs were similar between control
and treatment groups, it is unlikely that lack of ran-
domization affected the results.
The degree of dilution created by the effect of blood
volume expansion by HES may have contributed to
prolongation of CTs in the treatment group. Human CT
will become prolonged when the platelet count is
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00464.x 447
Hetastarch and platelet function
o100 10
9
/L
16,32,33
and the HCT is o2535%.
16
Sim-
ilar values for minimum platelet count and HCT
needed for accurate CT measurement have been iden-
tied in dogs.
22,34,35
Platelet count and HCT were not
measured after uid administration in this study. Direct
comparison of the treatment group results to the control
group is complicated by the fact that a crystalloid was
used for the control, rather than a colloid, which would
have caused less volume expansion, and therefore less
hemodilution, than HES. However, given the expected
degree of hemodilution that would have been achieved
in the treatment group,
36,37
it is unlikely that either
platelet count or HCT decreased to a level that would
have affected the CT. Silverstein et al
37
found that
20 mL/kg of HES 670/0.75 caused a 36.8 6.5% peak
increase in blood volume 30 minutes after the dose was
given, decreasing to 26.6 8.6% at 240 minutes. This
would extrapolate to a maximum decrease in platelet
count from 150 10
9
/L to approximately 110 10
9
/L,
and a maximum decrease in PCV from 48% to 35% at 30
minutes. It is expected that platelet count and PCV
would steadily increase from this point. Alternatively,
using a human mathematical model
36
for hemodilution
of platelets, and using an estimated blood volume of
90 mL/kg, it would take 440% hemodilution to de-
crease the platelet count from 150 10
9
to 100 10
9
/L.
Given the dogs in our study had a minimum of
150 10
9
/L, and most dogs well above this minimum,
it is unlikely that the platelet count was diluted to
o100 10
9
/L. This is supported by the pattern of the
CT results after HES administration. If this effect had
been created by hemodilution, the peak effect would
have been seen at 1 hour, instead of at 5 hours (see
Figure 1).
The results of this study have shown that 20 mL/kg
of HES 670/0.75 prolongs CT in dogs within 24 hours of
administration. This may be a direct result of platelet
dysfunction, in addition to the effect of hemodilution.
The clinical relevance of this effect needs to be inves-
tigated further with prospective, randomized trials.
Footnotes
a
Hand-held refractometer, Misco Products Division, Cleveland, OH.
b
Chemstrip 10 UA, Roche Diagnostics, Indianapolis, IN.
c
Platelet Function Analyzer-100, Dade Behring Inc, Miami, FL.
d
2-Ga 1.88-in BD Insyte IV catheter, Becton Dickinson, Sandy, UT.
e
Hetastarch (675/0.75) in 0.9% NaCl, Hospira, Lake Forest, IL.
f
Vacutainer Blood Collection Set, Becton Dickinson and Co, Franklin
Lakes, NJ.
g
Collagen/Adenosine Disphosphate Cartridge, Dade Behring Inc.
References
1. Treib J, Baron JF, Grauer MT, et al. An international view of hy-
droxyethyl starches. Intensive Care Med 1999; 25:258268.
2. Treib J, Haass A, Pindur G. Coagulation disorders caused by hyd-
roxyethyl starch. Thromb Haemost 1997; 78:974983.
3. Deusch E, Thaler U, Kozek-Langenecker SA. The effects of high
molecular weight hydroxyethyl starch solutions on platelets. Anesth
Analg 2004; 99:665668.
4. Deusch E, Gamsjager T, Kress HG, et al. Binding of hydroxyethyl
starch molecules to the platelet surface. Anesth Analg 2003; 97:
680683.
5. Jamnicki M, Zollinger A, Seifert B, et al. Compromised blood co-
agulation: an in vitro comparison of hydroxyethyl starch 130/0.4
and hydroxyethyl starch 200/0.5 using thromboelastography.
Anesth Analg 1998; 87:989993.
6. Stogermu ller B, Stark J, Willschke H, et al. The effect of hydroxy-
ethyl starch 200 kD on platelet function. Anesth Analg 2000;
91:823827.
7. Franz A, Braunlich P, Gamsjager T, et al. The effects of hydroxy-
ethyl starches of varying molecular weights on platelet function.
Anesth Analg 2001; 92:14021407.
8. Scharbert G, Deusch E, Kress HG, et al. Inhibition of platelet
function by hydroxyethyl starch solutions in chronic pain patients
undergoing peridural anesthesia. Anesth Analg 2004; 99:823827.
9. Innerhofer P, Fries D, Margreiter J, et al. The effects of perioper-
atively administered colloids and crystalloids on primary platelet-
mediated hemostasis and clot formation. Anesth Analg 2002; 95:
858865.
10. Jamnicki M, Bombeli T, Seifert B, et al. Low- and medium-molec-
ular-weight hydroxyethyl starches comparison of their effect on
blood coagulation. Anesthesiology 2000; 93(5):12311237.
11. Boldt J, Haisch G, Suttner S, et al. Effects of a new modied, bal-
anced hydroxyethyl starch preparation (Hextend
s
) on measures of
coagulation. Br J Anaes 2002; 89(5):722728.
12. Kuitunen AH, Hynyen MJ, Vahtera E, et al. Hydroxyethyl starch
as a priming solution for cardiopulmonary bypass impairs hemo-
stasis after cardiac surgery. Anesth Analg 2004; 98:291297.
13. Boldt J, Knothe C, Zickman B, et al. Inuence of different intravas-
cular volume therapies on platelet function in patients undergoing
cardiopulmonary bypass. Anesth Analg 1993; 76(6):11851190.
14. Macintyre E, Mackie IJ, Ho D, et al. The haemostatic effects of
hydroxyethyl starch (HES) used as a volume expander. Intensive
Care Med 1985; 11:300303.
15. Hu ttner I, Boldt J, Haisch G, et al. Inuence of different colloids on
molecular markers of haemostasis and platelet function in patients
undergoing major abdominal surgery. Br J Anaes 2000; 85(3):
417423.
16. Francis JL. The platelet function analyzer (PFA) 100, In: Michel-
son AD. ed. Platelets, 2nd edn. St Louis: Elsevier Inc; 2007, pp.
519534.
17. Trumble ER, Muizelaar JP, Myseros JS, et al. Coagulopathy with
the use of hetastarch in the treatment of vasospasm. J Neurosurg
1995; 82:4447.
18. Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions
on hemostasis. Anesthesiology 2005; 103(3):654660.
19. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxy-
ethyl starch in cardiopulmonary bypass surgery: a meta-
analysis of postoperative bleeding. Ann Thorac Surg 2001; 72(2):
527533.
20. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, et al. The
effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use
of blood products in major surgery: a pooled analysis of random-
ized clinical trials. Anesth Analg 2008; 107(2):382390.
21. Wierenga JR, Jandrey KE, Haskins SC, et al. In vitro comparison of
the effects of two forms of hydroxyethyl starch solutions on plate-
let function in dogs. Am J Vet Res 2007; 68(6):605609.
22. Callan M, Giger U. Assessment of a point-of-care instrument for
identication of primary hemostatic disorders in dogs. Am J Vet
Res 2001; 62(5):652658.
23. Holm S. A simple sequentially rejective multiple test procedure.
Scand Stat Theory Appl 1979; 6:6570.
24. Gandhi S, Weiskopf R, Jungheinrich C, et al. Volume replacement
therapy during major orthopedic surgery using Voluven
s
(hyd-
roxyethyl starch 130/0.4) or hetastarch. Anesthesiology 2007;
106(6):11201127.
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00464.x 448
L. Smart et al.
25. Treib J, Haass A, Pindur G, et al. Highly substituted hydroxyethyl
starch (HES 200/0.62) leads to Type-1 von Willebrand syndrome
after repeated administration. Haemostasis 1996; 26(4):210213.
26. Nichols WC, Cooney KA, Ginsburg D, et al. von Willebrand disease,
In: Loscalzo J, Schafer AI. eds. Thrombosis and Hemorrhage, 3rd
edn. Philadelphia: Lippincott Williams and Wilkins; 2003, 539pp.
27. Conroy JM, Fishman RL, Reeves ST, et al. The effects of desmo-
pressin and 6% hydroxyethyl starch on factor VIII:C. Anesth
Analg 1996; 83:804807.
28. Stoll M, Treib J, Schenk JF, et al. No coagulation disorders under
high-dose volume therapy with low-molecular-weight hydroxy-
ethyl starch. Haemostasis 1997; 27(5):251258.
29. Yacobi A, Gibson TP, McEntegart CM, et al. Pharmacokinetics of
high molecular weight hydroxyethyl starch in dogs. Res Commun
Chem Pathol Pharmacol 1982; 36(2):199204.
30. Yacobi A, Stoll RG, Sum CY, et al. Pharmacokinetics of hydroxy-
ethyl starch in normal subjects. J Clin Pharmacol 1982; 22:206212.
31. Jungheinrich C, Neff TA. Pharmacokinetics of hydroxyethyl
starch. Clin Pharmacokinet 2005; 44(7):681699.
32. Harrison P, Robinson M, Mackie I, et al. Performance of the plate-
let function analyser PFA-100
(R)
in testing abnormalities of pri-
mary hemostasis. Blood Coagul Fibrinolysis 1999; 10(1):2532.
33. Kundu S, Heilmann EJ, Sio R, et al. Characterization of an in vitro
platelet function analyzer, PFA-100t. Clin Appl Thromb Hemost
1996; 2(4):241249.
34. Keidel A, Mischke R. Clinical evaluation of platelet function an-
alyzer PFA-100 in dogs (in German). Berl Munch Tierarztl
Wochenschr 1998; 111(1112):452456.
35. Mischke R, Keidel Inuence of platelet count, acetylsalicylic acid,
von Willebrands disease, coagulopathies, and haematocrit on re-
sults obtained using a platelet function analyser in dogs. Vet J
2003; 165:4352.
36. Singbartl K, Innerhofer P, Radvan J, et al. Hemostasis and hemo-
dilution: a quantitative mathematical guide for clinical practice.
Anesth Analg 2003; 96:929935.
37. Silverstein DC, Aldrich J, Haskins SC, et al. Assessment of changes
in blood volume in response to resuscitative uid administration
in dogs. J Vet Emerg Crit Care 2005; 15(3):185192.
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00464.x 449
Hetastarch and platelet function