Thrombosis Research (2005) 116, 465 — 470
Effect of increasing doses of aspirin on plateletfunction as measured by PFA-100 in patients withdiabetes
Adnan Abacia,T, Yucel Yilmazb, Mustafa Caliskanb, Fahri Bayramc,Mustafa Cetind, Ali Unald, Servet Cetinb
aDepartment of Cardiology, Gazi University School of Medicine, Ankara 06550, TurkeybDepartment of Cardiology, Erciyes University School of Medicine, Kayseri, TurkeycDepartment of Endocrinology, Erciyes University School of Medicine, Kayseri, TurkeydDepartment of Hematology, Erciyes University School of Medicine, Kayseri, Turkey
Received 18 October 2004; received in revised form 7 February 2005; accepted 7 February 2005Available online 11 March 2005
Introduction: Platelets of diabetic patients have been reported to be less sensitive
to aspirin. The aim of this study is to compare a medium (300 mg) and low (100 mg)
dose of aspirin on platelet function in diabetic patients.
Methods: We have included one hundred and two patients with type 2 diabetesmellitus. Platelet function was measured as closure time (CT) with the PlateletFunction Analyzer (PFA)-100k before the administration of aspirin. Initially thepatients were given 100 mg aspirin once daily for seven days, and then themeasurements were repeated. If the CT exceeded the upper limit of 300 s, the studywas terminated. If not, the patients continued the aspirin therapy with a dose of 300mg daily for another seven days, and the CTs were measured again.
Results: After taking 100 mg aspirin, the CT significantly increased from 126 F 29 s to256 F 66 s ( p b 0.001). In 68 of 102 (67%) patients, the CT increased to 300 s. In theremaining 34 patients, the baseline CT was 113 F 29, and increased to 170 F 45 safter 100 mg aspirin ( p b 0.001). In these patients, there was a further increase inthe CT from 170 F 45 to 229 F 75 s following 300 mg aspirin ( p b 0.001). On average,the CT was increased by 60% and 39% following ingestion of 100 and 300 mg aspirin,respectively. CT N 300 s were obtained in 15 (44%) of 34 patients after 300 mg aspirin.
T Corresponding author. Gazi Universitesi Tip Fakultesi, Kardiyoloji Anabilim Dali, BesSevler/Ankara 06550, Turkey. Tel.: +90 312 318
E-mail address: email@example.com (A. Abaci).
0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved.
Conclusions: Although, a daily dose of 100 mg aspirin effectively inhibited plateletfunction in a majority of diabetics, a considerable proportion of patients showed agreater platelet inhibition with the use of 300 mg aspirin. The PFA-100k closuretime may be used to separate those patients who require a higher dose of aspirin toachieve desired antiplatelet effect.
D 2005 Elsevier Ltd. All rights reserved.
Aspirin reduces the risk of cardiovascular events in
previous upper gastrointestinal hemorrhage, a
all patients with coronary artery disease .
platelet count less than 150 Â 109/L, hemoglobin
However, the optimal dosage of aspirin is subject
b 12 g/dL, or known intolerance to aspirin were not
to great debate. Meta-analysis of the randomized
included in the study. Diabetes was defined if the
trials failed to reveal greater benefit from doses
patients were taking insulin or oral hypoglycemic
z 350 mg compared with lower doses The ACC/
drugs on the basis of elevated (N7.0 mmol/L) levels
AHA guidelines for the treatment of acute myocar-
of fasting blood glucose on at least two separate
dial infarction recommend an initial dose of 162—
assessments. The study was approved by the local
325 mg to achieve full antiplatelet effect rapidly
ethics committee of our institution, and written
Although, comparison of the two lower doses of
informed consent was obtained in all patients
aspirin with one another has not been performed,
75—325 mg of aspirin daily is recommended inpatients with chronic stable angina for long-term
Diabetes is associated with an increased risk of
Blood samples for the determination of platelet
cardiovascular events, even in the absence of
function was obtained from the antecubital vein
diagnosed cardiovascular disease The American
using a 19-gauge needle and collected in Vacutainer
Diabetes Association recommended low-dose (75—
tubes (Becton Dickinson, Franklin Lakes, NJ) anti-
150 mg daily) aspirin as a primary prevention
coagulated with 3.8% sodium citrate. Throughout
strategy not only in high-risk diabetic patients but
the study, same type of Vacutainer tubes were
for anyone with diabetes who is N30 years of age
used. One additional tube of blood anticoagulated
and has no known contraindications Platelets of
with ethylenediaminetetraacetic acid was col-
patients with diabetes exist in a relatively acti-
lected for the hematocrit and platelet count
vated state, and synthesize significantly higher
analysis. The blood was drawn 2 h after the last
amounts of thromboxane than those from non-
dose of aspirin. Daily variation of platelet aggrega-
diabetic controls Consequently, diabetics
tion has been reported in healthy subjects
have increased platelet aggregation and thrombus
Therefore, platelet function studies were per-
formed at the same time of day in all patients in
platelet thromboxane synthesis is lower in diabetic
patients compared to nondiabetic individuals and a higher incidence of aspirin resistance in
diabetics has been reported . Therefore, low-dose aspirin might be inadequate for inhibition of
Platelet function was measured by the Platelet
platelet function, and relatively higher doses of
Function Analyzer (PFA)-100k assay which is a
aspirin may be needed in diabetic patients. The aim
simple and easy to use system that can provide a
of the study was to compare the medium (300 mg)
quantitative measure of platelet function in vitro
and low (100 mg) dose of aspirin on platelet
using anticoagulated whole blood The test
cartridge simulates an injured blood vessel andmeasures the time required to form a platelet plug(defined as CT) that occludes a microscopic aper-
ture cut into a collagen/epinephrine or collagen/ADP coated membrane under high shear flow
We included the patients with type 2 diabetes
mellitus who did not use aspirin or other drugs
tridge is the primary cartridge for detection of
known to modify platelet function for at least two
aspirin effect on platelet function. Previous studies
weeks prior to beginning of the study. Patients with
have shown that effect of aspirin treatment on
an active duodenal or gastric ulcer, a history of
platelet function can be measured with the PFA-100
Effect of increasing doses of aspirin on platelet function in patients with diabetes
The baseline characteristics of the study
repeated. If the CT exceeded the upper limit of
300 s, the study was terminated. If not, the
patients continued the aspirin therapy at a doseof 300 mg daily for seven days, and the CT was again
Continuous variables were given as mean val-
ues F SD, and categorical variables as percentages.
A chi-square test was used for comparison of
categorical variables. Comparison of continuous
variables were performed by means of Student’s t
test. The relations between the variables and the
baseline CT were evaluated using the Spearman’s
correlation coefficient or the Pearson’s correlation
coefficient. Statistical analysis was performed by
use of the SPSS statistical software package (ver-
sion 10.0). A p value of b0.05 was considered
Values are given as mean F SD (range) or number (%).
CT = closure time, ACEI = angiotensin converting enzymeinhibitor, ARB = angiotensin receptor blocker, CCB = calcium
canal blocker, NS = non-significant.
One hundred and two patients with type 2 diabetesmellitus were included in the study. The baseline
characteristics of the study subjects are given in
using collagen/epinephrine cartridges according to
Of the patients, 46 (45.1%) were insulin-
the manufacturer’s instruction not earlier than 30
treated and 56 (54.9%) were treated by oral agents.
min after and within 2 h of blood sampling. The
The duration of diabetes ranged from 1 month to 25
maximal CT for collagen/epinephrine cartridges is
years, averaging 6.4 F 6.1 years. The mean level of
300 s and values greater than 300 s are reported as
HbA1c was 8.1 F 2.4%. There were no hemorrhagic
non-closure. Platelet function was determined
before the administration of aspirin. Initially the
Before aspirin administration, the CT ranged 71—
patients were given 100 mg aspirin once daily for
182 s, (mean 126 F 29, median 129.5 s). Patients
receiving insulin had a similar baseline CT as
Closure times before (A), after 100 mg (B) and 300 mg (C) doses of aspirin in 34 patients in which the closure
times did not exceeded the upper limit of 300 s. *p b 0.05 (100 mg vs. before treatment and 300 mg vs. 100 mg).
compared to patients receiving oral hypoglycemic
doses of aspirin, there may be no bidealQ dose of
agents (124 F 27 vs 128 F 31 s, respectively). There
aspirin for all patients. If optimal dose of aspirin for
is no relation between the baseline CT and age,
a particular patient can be known, a greater
gender, hypertension, smoking, serum cholesterol
proportion of patients may benefit from aspirin
level, hematocrit, platelet count, and HbA1c.
because the sensitivity of platelets to aspirin
At the end of one week of 100 mg per day aspirin
differs between patients. However, there is no
administration, the CT significantly increased to
study to detect the difference between individu-
256 F 66 s (range 91—300) ( p b 0.001). The CT was
alized aspirin dosage and the fix low dose aspirin.
the same in both genders after the administration
Whether individualized aspirin dosage is superior
of aspirin. In 68 of 102 (67%) patients, the CT
remains an open question. Platelet function tests
increased to 300 s, which is the upper limit for the
may be used to differentiate those patients most
collagen/epinephrine cartridges. In these patients
likely to benefit from a higher aspirin dosage. The
PFA-100k appears to be a simple test for the
In the remaining 34 patients, the baseline CT was
assessment of antiplatelet effect of aspirin that
113 F 29 s (range 71—167), and increased to
could be easily employed as a routine test in the
170 F 45 s (range 91—232) after 100 mg aspirin
clinical practice. However, studies relating to fail-
daily ( p b 0.001) (With these patients, there
ure of prolonged CT with aspirin and the clinical
was a further increase in CT from 170 F 45 s to
229 F 75 s (range 95—300) following 300 mg aspirin
Bedside testing of aspirin by the PFA-100k may
daily ( p b 0.001). On average, the CT was increased
allow us to measure the antiplatelet effect of
by 60% and 39% following ingestion of 100, and 300
aspirin and the ideal dose of aspirin for a particular
mg aspirin, respectively. In fifteen (44%) of the 34
patient may be determined. In our study, although
patients, the CT increased to the upper limit of 300
100 mg aspirin was effective for the majority of
diabetic patients, some patients showed a greaterplatelet inhibition with the use of 300 mg aspirin. Inaccordance with the results of our study, Watala etal. have recently shown that the inhibitory effect
of 150 mg aspirin a day on platelet function is lessprofound in diabetic patients compared to non-
Our results showed that aspirin at 100 mg daily was
diabetic individuals and have suggested that at
effective in the inhibition of platelet function as
least some patients with diabetes might require
assessed by PFA-100 in majority of patients. How-
higher aspirin doses Indeed, the results of the
ever, there was a further increase in platelet
primary prevention project trial suggested
inhibition with higher aspirin doses in patients
that low-dose aspirin might be less effective in
who have not achieved the desired level of anti-
primary prevention of cardiovascular disease in
platelet effects from 100 mg aspirin daily. The
diabetic patients as compared to nondiabetics.
discussion on the correct dosage of aspirin in
There are small-sized studies investigating the
platelet inhibition seems to be never ending.
effect of different doses of aspirin on platelet
Meta-analysis of randomized trials of antiplatelet
function in various diseases or health subjects
therapy failed to reveal greater benefit from doses
27]. A majority of these studies showed that aspirin
z 350 mg compared with lower doses . There-
inhibited platelet function in a dose dependent
fore, it is now accepted that high doses of 500—
1500 mg aspirin daily are no more effective than
bleeding time has been demonstrated in healthy
medium doses of 160—325 mg/day or low doses of
75—150 mg/day However, there is no large
inhibition of platelet function is dose dependent in
scale, randomized clinical study comparing the
patients taking aspirin for stroke prevention and
medium (160—325) and low dose (75—150) aspirin
increase of aspirin dose resulted in complete
inhibition of platelet function in more patients.
Preference of a low dose of aspirin is due to
Tohgi et al. showed that with higher doses,
fewer gastrointestinal side effects and undesired
platelet aggregability and thromboxane A2 produc-
cyclooxygenase inhibition of the vascular wall
tion were inhibited more conspicuously and in a
greater proportion of stroke patients. Two recent
mended in the use of the lowest dose of aspirin
studies have also shown that aspirin inhibited
shown effective in the prevention of events.
platelet function in a dose dependent manner in
Although the results of the previous studies dem-
patients with stable coronary artery disease or
onstrated preventive effects of low or medium
stroke To our knowledge, there is no study
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