As Vs Clo
As Vs Clo
As Vs Clo
ORIGINAL ARTICLE
To cite this article: Li C, Hirsh J, Xie C, Johnston MA, Eikelboom JW. Reversal of the anti-platelet effects of aspirin and clopidogrel. J Thromb
Haemost 2012; 10: 521–28.
Introduction
Summary. Background: Guidelines recommend stopping aspi-
rin and clopidogrel 7 to 10 days before surgery to allow time for Aspirin and clopidogrel are effective anti-platelet drugs for the
replacement of permanently inhibited platelets by newly prevention of cardiovascular events but are often stopped
released uninhibited platelets. Objectives: The purpose of the before surgery because they can cause bleeding [1,2]. The
present study was to determine the rate of offset of the anti- timing of stopping anti-platelet treatment before procedures is
platelet effects of aspirin and clopidogrel after stopping important because prolonged discontinuation can increase the
treatment and the proportion of untreated donor platelets that risk of ischemic events whereas delayed discontinuation can
are required to reverse their anti-platelet effects. Meth- increase the risk of bleeding [3]. The American College of Chest
ods: Cohort 1 consisted of 15 healthy subjects who received Physicians and the American College of Cardiology/American
aspirin 81 mg day)1 or clopidogrel 75 mg day)1 for 7 days and Heart Association guidelines recommend stopping aspirin and
underwent serial blood sampling until platelet function testing clopidogrel 7 to 10 days before surgery [4,5] based on their
results normalized. Cohort 2 consisted of 36 healthy subjects irreversible platelet-inhibitory effects and the premise that
who received aspirin 325 mg day)1, clopidogrel 75 mg day)1, recovery of hemostatic function after stopping treatment
aspirin 81 mg day)1 plus clopidogrel 75 mg day)1 or no requires the replacement of irreversibly inhibited platelets by
treatment for 7 days and underwent a single blood sam- newly synthesized uninhibited platelets released from the bone
pling. Results: In cohort 1, arachidonic acid (AA)-induced marrow. An alternative approach to stopping anti-platelet
light transmission aggregation (LTA) returned to baseline levels therapy before surgery might be to transfuse patients with
in all subjects within 4 days of stopping aspirin, coinciding with uninhibited donor platelets [6,7]. However, it is uncertain
the partial recovery of plasma thromboxane B2 concentrations. whether platelet transfusion can fully reverse the anti-platelet
ADP-induced LTA did not return to baseline levels until effects of aspirin and clopidogrel and, if so, the proportion of
10 days after stopping clopidogrel. In cohort 2, AA-induced non-treated platelets required to reverse their effects.
LTA in patient treated with aspirin reached control levels after The first objective of the present study was to compare the
mixing with 30% untreated donor platelets whereas ADP- time course of recovery of platelet function after stopping
induced LTA in patients treated with clopidogrel reached aspirin and clopidogrel treatment. The second objective was to
control levels only after the addition of 90% or more donor determine the proportion of untreated donor platelets required
platelets. Conclusions: Platelet aggregation recovers within to fully reverse the platelet inhibitory effects of aspirin and
4 days of stopping aspirin but clopidogrel must be stopped clopidogrel.
for 10 days to achieve a normal aggregatory response.
Study population
We designed two cohort studies, and enrolled 51 healthy
subjects aged at least 18 years who did not have a history of
Correspondence: Chunjian Li, Department of Cardiology, First
cardiovascular disease and were not taking anti-platelet
Affiliated Hospital of Nanjing Medical University, 300, Guangzhou
Road, Nanjing 210029, China.
therapy from January 2009 to July 2010 in Hamilton General
Tel.: +86 25 83718836 6018; fax: +86 25 83674380. Hospital, Hamilton, Canada. Exclusion criteria were (i) allergy
E-mail: [email protected] or intolerance to aspirin or clopidogrel; (ii) subjects at a high
risk of bleeding (e.g. thrombocytopenia [platelet count
Received 13 November 2011, accepted 14 January 2012 < 150 · 109 L)1]), known bleeding diathesis, active peptic
Bleeding time
Aspirin: 81mg qd×7days Withdrawal of aspirin Days 1,3,5,8
(n = 7)
Platelet function testing
RPFA
Cohort 1
Days 1,2,3,4,5
Withdrawal of clopidogrel
Clopidogrel: 75mg qd×7days LTA (PLAA, PLADP, PLCOLL)
(n = 8) Platelet function testing Days 1,2,3,4,5,6,8,10,12,14
Plasma TXB2
Days 1,2,3,4,5,6,8,10,12,14
Healthy
Volunteers 325mg qd×7days Mixing
Aspirin:
(n = 51) Serum TXB2
(n = 5) studies
Days 1,2,3,4,5,6,8,10,12,14
Platelet
Control: no anti-platelet drug ×7days
function
(n = 5) Urinary 11-dH-TXB2
testing
Days 1,2,3,4,5,6,8,10,12,14
ulcer disease; (iii) cigarette smoking; (iv) diabetes; (v) preg- into a sterile tube simultaneously with the blood sampling, then
nancy; and (vi) consumption of drugs within the preceding transferred into a 2-mL tube and frozen at )80 C until further
week that potentially could interfere with the anti-platelet analysis.
effects of aspirin (e.g. non-steroidal anti-inflammatory drugs)
or clopidogrel (e.g. proton pump inhibitors). The study design Bleeding time For subjects treated with aspirin, bleeding
is shown in Fig. 1. time was measured using the Surgicutt device (International
The present study complies with the Declaration of Helsinki, Technidyne Corporation, Edison, NJ, USA) by a single
and approved by the Research Ethics Board of Hamilton operator (C. Li) on days 1, 3, 5, and 8 after the last dose of
Health Science Corporation. All study subjects provided aspirin. Briefly, the volunteerÕs arm was placed on a table with
written informed consent. the volar surface exposed. A blood pressure cuff was placed
around the upper arm and inflated to 40 mmHg for the duration
of the test. An area on the volar surface of the forearm was
Cohort 1: recovery of platelet function after stopping aspirin
swabbed with alcohol and allowed to air dry. A single incision
and clopidogrel
was made parallel to and 5 cm below the antecubital crease
Study treatments Fifteen subjects were treated with either using the Surgicutt device and the blood was blotted with filter
aspirin (PharmaScience Inc., Montreal, QC, Canada) 81 mg paper every 30 s until bleeding stopped. Care was taken during
(n = 7) or clopidogrel (Sanofi-aventis, Paris, France) 75 mg the blotting not to touch the edge of the clot and wound. The
(n = 8) taken once daily at 08.00 hours for 7 days. time from the incision to the end of bleeding was measured.
Blood and urine collection Venous blood samples were Laboratory analyzes Light transmittance aggregation
collected by venipuncture into two 4.5-mL draw vacutainer (LTA) was performed in platelet-rich plasma using
tubes (Becton, Dickinson and Company, Mississauga, arachidonic acid (AA), ADP and collagen as agonists. All
Canada) containing 0.105 M buffered sodium citrate (3.2%), agonists were obtained from Chronolog (Havertown, PA,
one 2-mL draw Greiner Bio-One vacuette (Accumetrics, San USA). In aspirin-treated subjects, we also assessed platelet
Diego, CA, USA) containing 0.105 M buffered sodium citrate function using the rapid platelet function assay (RPFA) aspirin
(3.2%) and one 4-mL draw BD vacutainer tube without cartridge (Accumetrics, San Diego, CA, USA) and we
additive immediately before starting the study drug and on measured serum thromboxane B2 (TXB2), plasma TXB2 in
days 1 to 6, 8, 10, 12 and 14 after the last dose of the study drug. platelet-rich plasma after AA aggregation and urinary 11-
In patients treated with aspirin, 10 mL of urine was collected dehydro thromboxane B2 (11-dH-TXB2).
Statistical analyzes
Laboratory procedures
Results of categorical variables are presented as number and
Sample preparation PRP and platelet-poor plasma (PPP)
percentage and results of continuous variables as
were prepared shortly after blood collection by spinning the
means ± standard deviations or median (interquartile range
sample at 200 g for 8 min. The PRP was carefully removed and
[IQR]) where appropriate. The statistical significance of
the remaining blood centrifuged at 2465 g for 10 min to obtain
differences in means and medians was analyzed using two-
PPP. The centrifuge temperature was maintained at 22 C.
way analysis of variance or the Kruskal–Wallis rank test, and
Platelet counts were adjusted by the addition of PPP to the
DunnettÕs multiple comparison tests. The three-parameter
PRP to achieve a count of 250 · 109 L)1. Platelet aggregation
logistic function was adopted to explore the relation between
studies were completed within 3 h of preparation of PRP.
AA-induced platelet aggregation (PLAA) and plasma TXB2
Venous blood was allowed to clot in a warmed additive free
concentration after stopping aspirin treatment. Recovery ratios
BD vacutainer and then incubated at 37 C for 1 h. The blood
of AA- and ADP-induced aggregation ([Xn-X1/baseline-
was spun at 2000 g for 15 min and the serum was removed from
X1] · 100%; Xn represent PLAA, PLADP of day 2–6, 8, 10
thecellularelementsandstoredat)80 CuntilassayedforTXB2.
and 12 after aspirin and clopidogrel withdrawal; X1 represent
Platelet aggregation Platelet aggregation studies were AA- or ADP-induced aggregation on day 1 after aspirin and
performed using a Chronolog 560VS/490-2D aggregometer clopidogrel withdrawal; baseline represent AA- or ADP-
(Chronolog Corporation, Havertown, PA, USA). induced platelet aggregation before taking aspirin and
Immediately after preparation of PRP, 500 lL was clopidogrel) after aspirin and clopidogrel withdrawal were
transferred into each of the three test tubes, with 500 lL compared using two-factor repeated measurements ANOVA.
PPP set as a control. After 2 min of warming, PRP and PPP Similarly, the recovery curves of plasma TXB2, serum TXB2
were put in testing places and were warmed for a further and urinary 11-dH-TXB2 after withdrawal of aspirin were
2 min. Final concentrations of agonists were: AA 1 mM, ADP compared with the recovery of AA-induced platelet aggrega-
5 lM and collagen 1 lg mL)1, respectively. The aggregated tion (PLAA) after withdrawal of aspirin and with the recovery
plasma samples were stored at )80 C until assayed for TXB2. of ADP-induced platelet aggregation (PLADP) after the with-
drawal of clopidogrel. All analyzes were performed using SAS
Rapid platelet function assay The rapid platelet function 9.1.3 (SAS Institute Inc., Cary, NC, USA) and STATA11
assay (RPFA) is a semi-quantitative platelet function test which (StataCorp LP, College Station, TX, USA). A two-sided
measures turbidimetric platelet aggregation as an increase of P-value < 0.05 was considered statistically significant.
n 7 8 5 5 7 7 6 6
Males (%) 3 (43) 6 (75) 3 (60) 2 (40) 5 (71) 3 (43) 2 (33) 2 (33)
Age (years) 39 ± 7 25 ± 1 36 ± 10 36 ± 9 38 ± 9 35 ± 9 43 ± 8 34 ± 8
Weight (kg) 77.4 ± 13.5 63.1 ± 6.1 73.9 ± 9.4 61.6 ± 5.9 64.1 ± 7.9 61.1 ± 9.0 77.4 ± 11.9 64.1 ± 6.1
Results A
2500
100
PLAA (%) Plasma TXB2 (ng ml–1)
40
Recovery of platelet function after stopping
aspirin Compared with baseline levels, PLAA was
20
maximally suppressed on day 1 after completion of aspirin
treatment (2.4 ± 1.6% vs. 83.6 ± 4.6%, P < 0.0001) and
0
remained fully inhibited on day 2. Platelet function began to Baseline 1 2 3 4 5 6 8 10 12 14
Days after stopping aspirin
recover on day 3 and returned to baseline levels by day 4 B
(84.6 ± 4.0% vs. 83.6 ± 4.6%, P = 1.0) (Fig. 2A). ADP and
ADP-induced platelet aggregation (%)
10 20 30 40 50 60 70 80
clopidogrel The recovery of PLAA after stopping aspirin was donor platelets (75.7 ± 9.6% vs. 76.0 ± 15.5%, P = 1.00)
significantly more rapid than that of plasma TXB2 (Fig. 3B).
(P < 0.0001), serum TXB2 (P < 0.0001) and urinary 11-
dH-TXB2 (P = 0.0023), and the recovery of PLADP after Reversal of the anti-platelet effects of the combination of
stopping clopidogrel (P = 0.0086). In contrast, the recovery aspirin and clopidogrel Among subjects treated with the
curves of PLADP after stopping clopidogrel were similar to that combination of aspirin and clopidogrel, suppression of PLAA
of plasma TXB2, serum TXB2 and urinary 11-dH-TXB2 after was fully reversed compared with controls after adding 20%
stopping aspirin (P = 0.64, 0.18 and 0.86, respectively). donor platelets (73.7 ± 13.9% vs. 84.3 ± 4.8%, P = 0.57)
(Fig. 3C). Plasma TXB2 was fully inhibited to 15.84 ng mL)1
and did not return to control levels (1545.50 ng mL)1) until all
Cohort 2: reversal of the anti-platelet effects of aspirin and
the platelets were replaced by the donor platelets (Fig. 3C).
clopidogrel using donor platelets
Similarly, PLADP was fully reversed only after the addition of
Reversal of the anti-platelet effects of aspirin Among 90% or more donor platelets (Fig. 3D).
subjects treated with aspirin, suppression of PLAA was fully
reversed compared with controls after mixing with 30%
Discussion
uninhibited control platelets (84.4 ± 9.1% vs. 78.4 ± 13.7%,
P = 0.99) (Fig. 3A). A similar reversal pattern was evident for The present results indicate that the patterns of recovery of
collagen and ADP-induced platelet aggregation (Appendix 4). thromboxane production after stopping aspirin and of PLADP
In contrast, plasma TXB2 concentrations did not approximate after stopping clopidogrel are similar, with full recovery taking
control levels until all the platelets were replaced by the approximately 10 days. In contrast, the recovery of PLAA after
uninhibited donor platelets (Fig. 3A). stopping aspirin is much more rapid, with complete recovery
occurring within 4 days. Differences between aspirin and
Reversal of the anti-platelet effects of clopidogrel Among clopidogrel in the rate of recovery of platelet aggregation after
subjects treated with clopidogrel, suppression of PLADP was stopping treatment are paralleled by differences in the propor-
fully reversed only after mixing with 90% or more uninhibited tion of untreated control platelets required in mixing studies to
A B
2500
100
PLAA (%)
ADP-induced platelet aggregation (%)
AA-induced platelet aggregation (%)
0 10 20 30 40 50 60 70 80 90 100
0 10 20 30 40 50 60 80 100 Proportion of non-clopidogrelized platelets (%)
Proportion of non-aspirinated platelets (%)
C D
2500
100
0 10 20 30 40 50 60 70 80
0 10 20 30 40 50 60 70 80 90 100
0 10 20 30 40 50 60 80 100 Proportion of non-aspirinated and non-clopidogrelized platelets (%)
Proportion of non-aspirinated and non-clopidogrelized platelets (%)
Fig. 3. Reversal of the anti-platelet effects of aspirin (A), clopidogrel (B) and the combination of aspirin and clopidogrel (C and D) compared with
controls. (A) Demonstrates reversal of AA-induced platelet aggregation (PLAA) and plasma thromboxane B2 (TXB2) (n = 5 pairs). (B) Demonstrates
reversal of ADP-induced platelet aggregation (PLADP) (n = 7 pairs). (C) Demonstrates reversal of PLAA and plasma TXB2 (n = 6 pairs). (D) Dem-
onstrates reversal of PLADP (n = 6 pairs). Error bars represent two standard errors above and below the mean.
reverse their anti-platelet effects, where reversal of inhibition of bleeding in patients receiving dual anti-platelet therapy with a
AA-induced aggregation by aspirin is achieved when the combination of aspirin and clopidogrel is of particular concern
mixture contains 30% non-aspirinated platelets whereas inhi- in those who require urgent cardiac or non-cardiac surgery
bition of PLADP is achieved when the mixture contains at least [3,15]. Some of these patients are also at a high risk for
90% uninhibited platelets. thromboembolic events, for example stent thrombosis [15]. In
The similar patterns of recovery of thromboxane production such patients, one option to optimize the risk/benefit ratio
after stopping aspirin and of PLADP after stopping clopidogrel might be to stop clopidogrel 5 or more days before surgery, but
are explained by the irreversible platelet-inhibitory effects of the to continue aspirin until the time of surgery and to transfuse
drugs. Aspirin permanently inhibits the cyclooxygenase activity platelets immediately before surgery to fully reverse the anti-
of prostaglandin H-synthase-1 (also referred to as COX-1), platelet effects of aspirin. This approach requires testing in
thereby blocking platelet thromboxane production [8], and the clinical studies.
active metabolite of clopidogrel permanently inhibits the The present study has potential limitations. First, the
platelet P2Y12 receptor, thereby blocking ADP-induced plate- number of subjects was small and we included only healthy
let aggregation [9]. Full recovery of platelet thromboxane controls. However, in post hoc sample size calculations (based
production and PLADP does not occur until permanently on means and standard deviations observed in our study) we
inhibited platelets are replaced by de novo newly synthesized have confirmed that our sample size provides at least 80%
platelets, usually after 10 days (When platelet turnover is power to demonstrate a significant difference between inhib-
normal, approximately 10% of platelets are replaced each day ited and uninhibited platelets (as measured by platelet
[10]). The recovery of PLAA 4 days after stopping aspirin aggregation testing) at a given time point, even after
coincides with the replacement of approximately 40% of adjustment for multiple testing; and there is no reason to
aspirinated platelets with newly released non-aspirinated expect different results in patients with established cardiovas-
platelets. This finding is consistent with in vitro mixing studies cular disease [11,13] compared with healthy controls. Second,
that demonstrated reversal of PLAA when the mixture although our data provide the best available evidence to date
contained only 30% non-aspirinated platelets. Both lines of for the rate of recovery of platelet function after stopping
evidence indicate that in aspirin-treated subjects, only 30% to aspirin and clopidogrel and the reversal of their antiplatelet
40% uninhibited platelets are required to produce sufficient effects using uninhibited platelets, there are only limited data
thromboxane A2 to achieve a normal aggregation response, by on the association between in vitro platelet function and
activating the thromboxane A2 receptor of their own and the clinical events.
adjacent aspirinated platelets. Thromboxane from non-platelet In conclusion, aspirin permanently inhibits platelet throm-
sources (e.g. monocytes, endothelial cells) can also stimulate boxane production and clopidogrel permanently inhibits
platelets in the presence of aspirin because aspirin selectively PLADP for the life of the platelet. The platelet aggregation
blocks COX-1 and does not inhibit the platelet thromboxane response to AA recovers within 4 days of stopping aspirin,
receptor [8]. whereas the platelet aggregation response to ADP recovers
Our results demonstrating rapid recovery of platelet function within 10 days of stopping clopidogrel. These findings are
after stopping aspirin are consistent with those reported by paralleled by the observations in in vitro mixing experiments
Zisman et al. [11] who found that PLAA normalized within that the platelet inhibitory effects of aspirin are reversed with
3 days of stopping aspirin and by Feldman et al. [12] who 30% non-aspirinated platelets in the mixture, compared with
reported that serum TXB2 levels remained suppressed for at the requirement for at least 90% uninhibited platelets in the
least 7 days after stopping aspirin. Likewise, delayed recovery mixture to completely reverse the anti-platelet effects of
of PLADP after stopping clopidogrel in the present study is clopidogrel. The effect of clopidogrel on platelet function
similar to the rate of recovery reported in other studies as lasts longer than that of aspirin because thromboxane from
measured using the VerifyNow P2Y12 assay [13] and bleeding non-aspirinated platelets is able to activate aspirinated
time [14]. However, none of these previous studies explored the platelets whereas platelets that are still inhibited by the
effects of mixing with uninhibited platelets on the platelet active metabolite of clopidogrel do not aggregate normally in
inhibitory effects of aspirin and clopidogrel. response to ADP. Based on the present results, stopping
The present results have potential implications for the peri- aspirin for 7–10 days is longer than required for the recovery
operative management of aspirin and clopidogrel. First, if of platelet function in patients treated with aspirin and is
normal hemostasis is required, stopping of aspirin for 4 days sufficient for the recovery of platelet function in patients
and clopidogrel for 10 days before surgery should ensure full treated with clopidogrel.
recovery of the platelet aggregation response. Second, it seems
reasonable to expect that the dose of platelets required to
reverse the anti-aggregatory effects of aspirin is lower than the
Acknowledgements
dose required to reverse the anti-aggregatory effects of
clopidogrel. However, the present study cannot provide This work was carried out in the Thrombosis service, Hamilton
guidance on the dose of platelets that may be required because General Hospital, Hamilton, Ontario, Canada. This work was
our observations are based on in vitro-mixing studies. Third, supported by a grant from the New Investigator Funding of
Data are expressed as mean ± standard deviation. Recovery aspirin indicates recovery of the anti-platelet effects of aspirin; Recovery clopidogrel indicates recovery of the anti-platelet effects of
PLCOLL (%)
Hamilton Health Science (NIF-08200[R]), Hamilton, Canada,
12.6
11.8
12.8
8.7
4.9
6.7
8.3
6.6
9.5
5.2
and a grant from the National Natural Science Funding of
67.1 ±
43.2 ±
53.2 ±
60.9 ±
59.1 ±
64.8 ±
65.5 ±
64.8 ±
67.9 ±
72.5 ±
China (81170181).
–
Recovery clopidogrel (n = 8)
Disclosure of Conflict of Interests
11.0
18.1
14.3
13.6
13.5
17.8
PLADP (%)
7.6
9.3
9.6
9.2
73.8 ±
24.6 ±
30.2 ±
34.3 ±
45.8 ±
59.8 ±
61.1 ±
61.4 ±
72.0 ±
74.4 ±
The authors state that they have no conflict of interest.
–
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10.0
2.8
8.6
6.9
6.7
3.6
4.2
6.3
4.9
5.7
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65.6 ±
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±
±
±
±
±
±
±
±
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273.0
110.7
126.6
133.0
175.2
309.5
328.8
342.1
304.3
64.2
83.9
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255.7
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±
±
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642.3
734.0
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1022.4
1227.4
1448.6
1756.6
1738.2
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20.6
19.1
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5.8
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±
±
±
±
±
±
±
±
±
±
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40.6
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56.5
77.4
77.9
83.5
86.5
84.3
86.7
80.0
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7.6
7.3
6.4
7.1
7.1
4.6
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±
±
±
±
±
±
±
±
±
±
±
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76.1
61.9
60.9
61.2
67.1
77.1
78.3
73.7
76.2
81.0
72.4
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35.9
4.6
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1.3
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5.6
3.8
4.4
5.2
2.4
9.2
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17.
±
±
±
±
±
±
±
±
±
±
±
14.7
84.6
82.3
83.2
86.2
84.8
84.5
87.4
2.4
2.1
175: 552–3.
–
–
–
–
–
1.4
1.7
1.2
5.9 ±
7.9 ±
7.7 ±
5.3 ±
4.5 ±
–
–
–
13 Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng
Appendix 1
Appendix 3
Appendix 2
0
528 C. Li et al
Baseline 1
2
3
PLAA (%)
Days after stopping aspirin (d)
12
Urinary 11-DH-TXB2 (ng/ml)
14
0 100 200 300 400 500
immediately prior to ingestion of the first dose of aspirin.
Appendix 4
Reversal of the anti-platelet effects of 7-day aspirin and/or clopidogrel treatment by control platelets (Cohort 2).
Con-PRP/Stu-PRP PLAA PLADP PLCOLL Plasma TXB2 PLAA PLADP PLCOLL PLAA PLADP PLCOLL Plasma TXB2
(v/v) (%) (%) (%) (ng mL)1) (%) (%) (%) (%) (%) (%) (ng mL)1)
0/1.0 4.0 ± 0.7 62.0 ± 8.3 22.4 ± 7.3 11.3 ± 19.9 58.1 ± 30.0 22.6 ± 9.4 70.3 ± 16.7 4.2 ± 1.2 44.7 ± 7.5 18.7 ± 10.8 15.8 ± 19.1
0.1/0.9 34.0 ± 44.8 68.6 ± 12.6 44.0 ± 17.3 143.2 ± 100.4 74.0 ± 12.8 29.4 ± 9.3 75.4 ± 12.6 32.8 ± 34.6 48.2 ± 6.5 33.2 ± 18.2 147.6 ± 42.6
0.2/0.8 63.0 ± 38.1 71.2 ± 15.3 64.2 ± 17.7 305.1 ± 97.2 80.9 ± 8.0 37.0 ± 12.0 77.0 ± 6.9 73.7 ± 13.9 52.0 ± 5.9 57.8 ± 10.7 372.6 ± 69.1
0.3/0.7 84.4 ± 9.1 75.8 ± 13.0 64.8 ± 19.7 524.6 ± 127.7 81.6 ± 3.6 45.4 ± 10.0 76.3 ± 9.4 81.3 ± 6.0 55.7 ± 10.1 66.0 ± 9.1 532.9 ± 74.3
0.4/0.6 86.0 ± 9.2 79.6 ± 13.9 71.8 ± 11.8 – 80.9 ± 5.6 54.7 ± 14.5 83.0 ± 7.9 83.7 ± 2.3 61.8 ± 8.4 77.2 ± 7.2 –
0.5/0.5 86.8 ± 8.7 79.0 ± 17.2 75.2 ± 18.9 862.0 ± 195.0 83.3 ± 6.0 57.1 ± 12.1 85.0 ± 8.1 84.3 ± 4.1 66.5 ± 8.0 77.2 ± 3.4 841.6 ± 142.7
0.6/0.4 86.8 ± 10.1 77.4 ± 15.2 75.8 ± 14.2 – 82.6 ± 5.4 63.3 ± 10.0 82.1 ± 4.3 83.8 ± 5.8 67.8 ± 9.2 75.2 ± 1.8 –
0.7/0.3 – – – – 85.6 ± 4.1 71.6 ± 10.3 85.1 ± 4.7 86.7 ± 4.8 74.3 ± 7.6 82.0 ± 4.2 –
0.8/0.2 85.0 ± 11.2 73.8 ± 8.4 80.0 ± 11.9 1350.5 ± 573.6 83.4 ± 5.4 68.4 ± 11.1 82.1 ± 4.3 87.5 ± 5.0 74.3 ± 8.7 82.2 ± 6.5 1240.1 ± 179.2
0.9/0.1 – – – – 85.0 ± 5.7 75.7 ± 9.6 83.4 ± 6.6 86.7 ± 5.4 77.7 ± 6.7 83.7 ± 2.6 –
1.0/0 78.4 ± 13.7 70.6 ± 7.5 81.0 ± 7.1 1826.5 ± 237.5 85.6 ± 7.5 76.0 ± 15.5 82.4 ± 10.6 84.3 ± 4.8 79.2 ± 6.6 88.3 ± 7.1 1545.5 ± 196.2
Data are expressed as mean ± standard deviation. Reversal aspirin indicates reversal of the anti-platelet effects of aspirin; Reversal clopidogrel indicates reversal of the anti-
platelet effects of clopidogrel; Reversal aspirin and clopidogrel indicates reversal of the anti-platelet effects of aspirin and clopidogrel. Con-PRP, control platelet-rich plasma;
Stu-PRP, study platelet-rich plasma.