Full text of DOI:10.1177/107602960100700305

Clinical and Applied Thrombosis/Hemostasis
http://cat.sagepub.com/
Individual Dosing of ASA Prophylaxis by Controlling Platelet Aggregation
Günter Syrbe, Helge Redlich, Bärbel Weidlich, Jochen Ludwig, Sibylle Kopitzsch, Anke Göckeritz and Karin Herzog
CLIN APPL THROMB HEMOST 2001 7: 209
DOI: 10.1177/107602960100700305
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Report
Original
of ASA
Individual
Controlling
by
Prophylaxis
Aggregation
Dosing
Platelet
*Jochen
*Bärbel
Weidlich,
M.D.,
*Günter
Redlich, M.D.,
Ludwig,
M.D.,
*Helge
Syrbe,
and
*Anke
M.D.,
†Karin
Göckeritz,
M.D.,
Herzog
Kopitzsch,
*Sibylle
District
and
Medicine
Germany
Hospital of Stadtroda/Thuringia,
†Clinical
Laboratory,
of Internal
*Department
com-
can
to 500
to inhibit
even
used in
acid is
nearly
aggregation
the
platelet
that
mg/day
primary
widely
Acetylsalicylic
Summary:
results
routine
acid treatment in
demonstrate
In
These
as a
of cardiovascular
platelet aggregation
the
diseases.
vivo
pletely.
be used
secondary prevention
and
method
with
doses of
to control ace-
in
ex
used
we
induced
laboratory
simple
platelet-
platelet aggregation
study,
current
dis-
acid
a
cardiovascular
method
routine
acid as
a
with
arachidonic
patients
rich
tylsalicylic
plasma
individual
eases and to determine
individual
the
acetylsalicylic
the determination
of
inhibit
dose of
for
acetylsalicylic
of
With
inhibition
108
for a
in
aggregation.
to
platelet
nearly complete
acid
patients
a
aggregation
platelet
necessary
were
of
100
of
10%
nonre-
standard
dose
the
In 40% of all
studied,
patients
diseases.
mg/day,
with cardiovascular
patients
Words:
Platelet
and
to blockthe
of 30
arachidonic
was sufficient.
Key
aggregation—Acetylsalicyclic
sponders.
dose
mg/day
of
In 50%
secondary prevention—Cardio-
acid—Slope—Primary
acid-induced
nearly completely.
platelet
aggregation
mellitus.
vascular diseases—Diabetes
In10%ofall
or
100
was
dose of
a
all
patients,
necessary.
mg/day
patients,
the
to
300
dose
had
to be
further increased
mg/day
’
effects. The lowest
toxic
yet
tract
of milder
used
anti-
as an
is
acid
gastrointestinal
(ASA)
and
widely
Acetylsalicylic
but
has not
been
identified,
dose
of
effective
the
in
aspirin
secondary prevention
primary
drug
platelet
The most
be lowerthan 50
could
transient ischemic
(14,
1253).
t
attacks,
diseases
p.
of
mg/day&dquo;
infarction, stroke,
arterial
myocardial
function
for the detection
used
method
in
described
vascular
other
and
inhibits the
platelet
disease,
widely
peripheral
The
inhibition
1962
is
PA, as
(15).
agonists
acquired
It
specific
characterizes heredi-
selectively
platelet prostaglandin
cyclooxygenase
thromboxane
’1(1-4).
different
of PA induced
ofthe
a loss
with
by
activity
A2 bio-
synthase
suppression
’:1 G/H
and
abnormalities,
of
a
the
dysfunctions,
j-nd
tary platelet
platelet
the
and
the
into
shows
ofdifferent
formation
in other
and
tissues
pathophysiology
physiology
The inhibition of
insight
synthesis,
PA
induced
of
inhibited
is
by
(16-18).
E2,
effects
platelets
~ eicc~~anc~id~
pr~st~cyc~~rt)
(prostaglandin
inhibition ofthe
shows the
arachidonic acid
associated
and the
ofASAare
The
(AA)
cyclo-
antithrombotic
’. (5-8).
we
in
Therefore,
with the
of
(19,20).
inhibition
ofthe
platelets
pathway
(PA)
atherosclerot-
oxygenase
aggregation
platelet
PA
AA-induced
108
on the
focused
at
plasma
in platelet-rich
deposition of platelets
prevention
ic lesions
in-
medical
with a
and
is
ofASA
The
individual
dose
(PRP
investigated
ASA
patients
~~-l I ~.
optimal
vivo PA
to show that the ex
in order
for
dication
meta-
In
of discussion
1999, a
(12-14).
dose-response
The conclusion
v still a matter
’’ ’regression
to control ASA
routine method
can be used as
a
of ASA
of
1 on wasreported.
effect
the
simple
analysis
the
to define
it is
follows:
every patient,
possible
that leads to
of ASA
effective dose
~.~rc~~~ ~ wide
a
minimal
of 15% is uniform
reduction
risk
a nearly
?*The
of PA..
inhibition
The absence of
of
to
doses
l ~:~C~
complete
(50
mg/day).
the
fangc
use oflow-dose
minimize the risk
relationship supports
dose-response
aspirin,
because low-dose
may
aspirin
AND
PATIENTS
METHODS
Subjects
of
district
of the
hundred
One
hospital
patients
eight
Dr. G.
to
and
PD
Address
Syrbe,
reprint requests
with amedical indication for ASA
correspondence
Stadtroda
(Germany)
(52
standard
für
Stadtroda-
Ger-
und
Landesfachkrankenhaus
Psychiatrie
Neurologie
46to
93years;
None had
tested
menand56
women;
were
aged
of the mean
07646
Stadtroda,
Thüringen,
la,
Innere
Bahnhofstraße
Abteilung,
error
I
73.5
[SEMI).
many; e-mail: helgeredlich@t-online.de.
209
Downloaded from cat.sagepub.com at Scientific library of Moscow State University on December 2, 2013

210
wasmea-
was more than
dose ofASA
or other nonsteroidal
taken ASA
mawerk,
Oranienburg, Germany). Aggregation
drugs
antiinflammatory
if the
and
weeks
AA-induccd PA
for at least 2
before the
sured again,
including Cox-2-inhibitors
ofless than
30%
a
All
had
normal
first
Mood
70%), a
(inhibition
higher
platelet
sampling.
patients
and
count between
~~G,d~~
1t7~~, B~yer&dquo;Vital t~mb~I~
150,000
(100 mg/day Aspirin Protect
~L ~227,t?(~fl ~-
was
to the
for a
or
had no
Leverkusen,
further week.
Germany)
PA
6,000
trointestinal
applied
patients
and
tract abnormalities
gas-
bleeding
ppL
problems
history.
was measured
those
in their
again, and
patients
did not
inhibition received 300
who
show sufficient
Protect
for another
500
week. In
one
and
Blood collection
300@)
mg/day (Aspirin
preparation
platelet
to
the dose was increased
for a week
an
stom-
from
was drawn from
with
Blood
ach
case,
mg/day
empty
cases,
patients
of PA.
control
after
in some
vein
and,
the antecubital
from
blood
other
the arms
the routine
collec-
veins of
tion for
during
Other
laboratory parameters
7:00
or
determinations between
other
laboratory
of the
the
the follow-
hospital ization
patients,
During
of blood was
and
AM. The first
5
mL
discarded
8:00
were
laboratory parameters
performed routinely
ing
determinations. The
used for other chemical
tourniquet
acti-
before
with the blood
for PA
ASA treatment:
sampling
to minimize
had been or reduced
loosened
platelet
red blood
and
he-
blood
white
cell,
counts;
cell,
platelet
protein;
was
4.5 mL of blood
vation. For
drawn into
whole
platelet aggregation,
available
C-reactive
hematocrit;
mo~l~bin;
hemoglobin;
glycosylated
tubes
(nine
parts
as an anti-
commercially
sodium citrate
total
li-
creatinine;
cholesterol;
low-density
one
blood,
(3.8%)
part
final concentration
and
fibrinogen;
body
triglycerides; glucose;
poprotein ;
Dick-
Becton
0. I I
mol/L,
coagulant ;
mass
index.
inson Vacutainer
UK, 21-gauge
System, Plymouth,
of PRP was
Statistical
a
within
The
analysis
were
needle).
maximum
performed
preparation
andall
afterthe bloodcollection
of
minutes
45
as mean
between
standarderrorofthe
Results
expressed
out
the
within
werecarried
studies
mean
Correlations
and
wereana-
following
aggregation
(SEM).
by
parameters
at
was
Citrated whole blood
hours.
3
Student’s
t-test and
l ~t~ ~J
centrifuged
paired
p =
unpaired
lysed
stored at
was then
for
10 minutes to
PRP, which
as
~.~5 ’ was considered
prepare
statistically significant.
The
37°C in a water bath.
was
(PPP)
was
the Ethics Committee of
of the federal state of
The
plasma
pellet
minutes).
platelet-poor
of the
by
study
approved
the
after
of
the Chamber
by centrifugation
prepared
Physicians
of
collection
PRP
(1,5~t~
g for 10
Thuringia/Germany.
RESULTS
Platelet
aggregation
aggregation
aggregometer
different doses of
ASA
treat-
before ASA
four-
in a
was
Platelet
Inhibition of PA by
(PA)
performed
of all
Platelets
108)
with
channel
Horsham,
Germany)
(N
500 >g/mL
(PAP4, Biodata
patients
to
Corp.,
(Hilden,
irreversible
an
ment
from
MOLAB
ag-
PA,
and
responded
The
USA)
measured
purchased
of the traces was 43.7
1.4
different
Bom
(mean
slope
gregation.
using
ago-
turbidimetfically by
ofthe
76.1
after
transmission
3,
and the
to the method described
nists
SEM)
(15).
in-
degree
minutes was
light
by
according
and
and 10
83.2 ~-
1.4%,
of PRP were
1.9%,
One hundred
5,
aliquots
eighty-microliter
One week after
treat-
ASA
86.3
were stimulated
and
at 37°C
1.3%,
respectively.
cubated
adding
by
platelets
with 30
PA in PRP was
all
transmission
ment of
in
20
of the
mg/day,
showed
patients
Changes
light
f.LL..
agonist.
a
were recorded
as
to
100%
0
nearly complete
Forty-three patients
repeated.
inhibition
during
10 minutes.
for
(given
aggregation)
defined as an
of AA-induced
PA,
at
the PRP
constant stirring of
1,000
aggregation
with smaller
rpm
10 minutes.
All
inhibition ofAA-induced PAwere treated
a
less than
at
30%
differen-
the grin~
are
electronic
The values of
the
patients
by
slope
given
with
of
on
in the PAP4. It is based
the
the
tiation of
traces
degree
a
further
week.
of ASA for
of
Arachidonic
decrease
100
linear
a
of
mg/day
using
regression,
largest
ciples
the
inhibited
was then
with an
In withless.
recommen-
adrenaline
were
acid-induced PA
in 54
aggregation
inhi-
(manufacturer’s
acid,
(%)/minutes
Arachidonic
aggregation
less than 30%
patients.
dations,
collagen,
[21]).
to 300
of
four
ASA
the dosewasincreased
adenosine
and
bition,
a further
mg/day
(ADP)
diphosphate
(epinephrine),
of AA-induced PA was
The inhibition
week.
in the test
adrena-
concentrations
fromMOLAB
(final
purchased
in 10
after this dose.
to be sufficient
to be
0.19
found
one
tubes:
500
Only
patients
treated with500
AA,
mg/mL;
collagen,
~Lmol/L).
Rg/mL;
ofASAfor
20
100
ADP,
mg/day
AA-induced
line,
patient had
~M;
in order to inhibit
PAnearly
a
further week
I
showstypical traces of AA-induced
administration
completely. Figure
Drug
ASAtreatment and
the ad-
treatment
PAin
a
before
after
before
collected from
was
Blood
patient
ministration of 30 and 100
patients
values. The
of ASAfor
1
week.
obtain
to
order
with ASA in
mg/day
pretreatment
of 30
Phar-
The data ofall
the
weredivided into
three
a
dose
with
started
in all
treatment
7
ASA
patients
groups
AA-induced PAas
patients
ofinhibition of
following
degree
Oranienburger
(Miniasal~,
days
mg/day for
Downloaded from cat.sagepub.com at Scientific library of Moscow State University on December 2, 2013

211
but to
of
less
ASA for
i~~rntic~n c~f
1 week,
30 mg/day
of ASA for a
l (~
after treatment with
than 20%
further week.
mg/day
the last
included in
were
Ten
patients
group, and their PA was
reduced to less than 30% after
100
followed
with 300
for
with
treatment
for
by
mg/day
30 m,~/day
and
another
week,
finally
mg/day
further
for
a
week.
the
the
of
In
2b,
aggre-
corresponding slopes
Figure
dra-
were reduced
The
traces are
slopes
given.
gation
‘
and
avalue of
tothe inhibition ofPA
used to describe
according
matically
less than 10 can be
nearly complete
ASA at home.
ofPA.
inhibition
continued
were
taking
hospitalized
2).
patients
Discharged
in the
them
Some of
(n = 23)
again
Platelet
2
to 35 months
13 ’
these
in
aggregation
following
from the
checked
and 15
was
(8
30-mg
no
patients
100-mg group),
again
from
the
and
differ-
traces
group
with
dif-
treated
traces of
a
patient
Arachidonic
their
of
Typical aggregation
in the
ences in PA and
slope
aggregation
~ ~~~. 1:
acid
before treat-
ferent dosesof
induced
(AA)-
(ASA).
a~~tt~lsalicylic-~.~id
first and the
occurred between the
found to have
were
in
plasma
platelet-rich
platelet
aggregation
second
of
ment with
ASA,
1 weekafter treatment with 30
mg/day
ASA,
hospitalization.
with
of ASA.
treatment
as
100
in
further week after
and a
Platelet
mg/day
with
in PRP was also induced
Platelet
aggregation
adrenaline,
the
transmission.
is
of AA
changes
pg/mL.
light
given
aggregation
and
and was
ADP,
investigated af-
collagen,
ter
was
500
Final concentration
in-
The
with ASA.
aggregation
patients
treating
inhibited as
was not
these
duced
completely
by
agonists
the
2: the
shown in
Figure
43),
(n =
&dquo;30-mg ~~:c~up&dquo;
The most sensitive
as
an inducer.
with AA
compared
parameter
andthe
(n =
was treated with
(n = 54),
The
one
&dquo;300-mg group&dquo;
’ &dquo;!00-mg group&dquo;
of
seemed to be the
the
slope
aggregation
who
10),
500
respectively.
mg/day
patient
PA induced
which were summarized for the
traces,
by
pa-
included in the
Plate-
not
ofASAwas
figure.
of the
and after treatment
before
different
agonists
‘
with
at
before treatment
letaggregation in the
group
2.3%,
30-mg
84.2
doses
in
of ASA
3.
tients with different
Figure
and 86.9
2.~’°~’n
ASAwas
76.2
3.1 ~jc~,
mellitus
with diabetes
Patients
after
and I ~ minutes
In al 43
3, 5,
respec-
inducing aggregation,
had non-
The be-
50
the 108
group, PAdropped
in the
investigated,
mellitus
patients
Among
30-mg
tively.
patients
diabetes
for
1
weekwith
treatment
30
the
downto less than 20%after
ofASA.
(NIDDM).
insulin-dependent
to that of
identical
their
was
havior of
were included in
patients
to
platelets
Fifty-four patients
mg/day
diabetic
Nineteen
without NIDDM.
and their PA was reduced from
belonged
and
patients
100-mg group,
nearly
!00-mg group,
4 the
to
the
26 to
the
the
with
values
identical
group,
30-mg
30-mg
compared
aggregation
pretreatment
with 500
the one
treated
after the
65 to 73%
admin-
about
mg/day
patient
300-mg group;
group to
FIG. 2.
in
transmission
Changes
and
light
(ag-
arachidonic
slope (b) of
(a)
gregation)
pa-
acid (AA)-induced plateiet aggregation in
of
tients treated with different doses
acetylsali-
and 300
0.01; ***
ASA
acid
100,
(30,
cylic
respectively). (* p <
0.001 versus control without
(ASA)
mg/day,
<
<
0.05;
p
**
p
treatment
=
A
B = 30
in
0
C = 100 mg; D =
a).
mg;
mg;
300 mg.
Downloaded from cat.sagepub.com at Scientific library of Moscow State University on December 2, 2013

212
and
The
statistical
predictive
100-mg,
show
(30-mg,
300-mg).
relevant
analysis
labora-
not
did
any clinically
the
inhibition ofPA.
Interest-
tory
parameter concerning
increased levels in
were
ingly,
glycosylated
hemoglobin
in
found
NIDDM
the three different
8.58
of
with
groups
-F ~.4~1~,
patients
and
8.9
in
1.6%
0.27%,
(7.44
the
There
and
30-mg, 100-mg,
300-mg
groups, respectively).
wasno correlation in the
of
differences
the
aggre-
as
data
the use of other
gation
heparin,
(such
concerning
drugs
calcium-channel
blockers,
beta-blockers,
angio-
or
nitric oxide
do-
inhibitors,
comedication.
enzyme
tensin-converting
‘
that were
nators)
as
given
DISCUSSION
acid is a
used
in
Acetylsalicylic
and
widely
drug
the pri-
of cardiovascular dis-
mary
secondary
prevention
eases. Studies have shown that low
are
doses of
ASA
to
(30
IOO
sufficient to
reduce the risk for cardio-
mg/day)
vascular events and do not
differ
from
significantly
‘~ 1~,~~-~5).
doses
to
I
It is :
(300
1,500
mg)
higher
applied
well
established that the use of ASA as an
antiplatelet ;
cyctoox- !
is based
on the
inhibition of
drug
onl y
specific
I
with a reduction or
of
ygenase activity,
suppression
(5,7,26,27).
the first time in
control ofthis
then
thromboxane
The
formation
by platelets
I
i
described for
t962 j
plate-
platelet aggregation
Born allows the
by
ex vivo
specific
i
let
function
acid
Arachidonic
the throm-
(I5).
triggers
baxahe formation in
platelets including cyclooxygenase-
I. The
inhibition of this
in
to an
leads
enzyme
platelets
inhibition of
AA-induced PA ex vivo.
it is
Therefore,
FIG. 3.
line
standard
error of the
of the
adrena-
adenosine
(
Slope
mean)
and
(a)
(1MuM~-, (b) collagen (0.19
mg/mL)-,
(c)
(20pM)-induced
diphosphate
platelet
aggregation inpatients
treated
300
with different
acid
~.~?1;
mg.
and
100,
acetylsalicylic
(30,
<
<
0.05;
mg/day, respectively). (*
0 mg; B =
p
~?,C~t7~ ~.
** p <
*** p
=
A
30
100
300
mg; C =
mg; D =
ofASA alsohad
NIDDM.There wasnodifference in the
of nondiab~ti~
and diabetic
in each
4.
percentage
of
subjects
The
data are summarized in
group
patients.
Figure
P~att~~et
and other
aggregation
,
!laboratoryparameters
Platelet counts in
in
whole blood did not differ
signifi-
FIG. 4.
donic
different doses of
inhibition
of
of 108
with
thearachi-
Percentage
patients
/
the
over
time oftreatment with
ASA,
cantly
patients
the
administration
acid-induced ptate)et
by
aggregation
acid
of
I
j
and
did not differ
also
between the three different
acetylsalicylic
(ASA).
groups
Downloaded from cat.sagepub.com at Scientific library of Moscow State University on December 2, 2013

213
‘
Ischemic
Stroke
Stroke
Council, American
ment of
Transient
Heart Association.
4.
Attacks,
to control the inhibition of
PA as a consequence
possible
1999;30:2502.
in
as an
of ASA
agonist.
every patient
al.
intensive
et
Effects of
patients
Hansson
A, Carruthers
SG,
L, Zanchetti
in-
a medical
with
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