Aspirin Resistance in Single-Ventricle Physiology:
Aspirin Prophylaxis Is Not Adequate to Inhibit
Platelets in the Immediate Postoperative Period
Arshid Mir, MD, Summer Frank, MPH, Janna Journeycake, MD, Joshua Wolovits, MD,
Kristine Guleserian, MD, Lisa Heistein, MD, and Matthew Lemler, MD
Department of Pediatrics, Section of Pediatric Cardiology, and Department of Biostatistics and Epidemiology, University of Oklahoma
Health Sciences Center, Oklahoma City, Oklahoma; and Department of Pediatrics, and Department of Surgery, Children Medical
CONGENITAL HEART
Center Dallas, University of Texas Southwestern Medical Center, Dallas, Texas
Background. Incidence of thrombosis after initial stage
1 single-ventricle palliation is high. Most centers use
aspirin as an antiplatelet agent to prevent thrombosis in
surgically placed shunts. We hypothesize there is a sig-
nificant incidence of aspirin resistance in infants after
stage 1 palliation and this resistance can be overcome by
an increased aspirin dose.
Methods. This is a prospective observational study
of 20 patients with single-ventricle physiology who
required single-ventricle palliation with a controlled
source of pulmonary blood flow (Norwood/Sano,
Norwood/Blalock-Taussig [BT] shunt or BT shunt
alone). Aspirin resistance was determined using throm-
boelastography with platelet mapping (TEG) and urine
thromboxane (UTX). The UTX level of less than 1,500
pg/mL and TEG value of more than 50% were used to
define as adequate platelet inhibition. The UTX was
measured prior to starting aspirin (20 mg/day) and
TEG and UTX were obtained after 5 days of aspirin
therapy A repeat UTX was measured for patients who
were determined to be aspirin resistant by TEG (<50%
arachidonic acid inhibition) after doubling the dose (40
mg/day). Clinical variables including patient diagnosis,
age of surgery, and cardiopulmonary bypass require-
ment, weight, hemoglobin, and platelet count were
C hildren with cyanotic congenital heart disease who
have undergone surgical palliation with a systemic-
to-pulmonary artery shunt are at significant risk for
thromboembolic complications [1]. The incidence of
thrombotic complications after the initial stage 1 pallia-
tion has been shown to be as high as 25% to 40%. Addi-
tionally Manlhoit and colleagues [2] speculate that the
prevalence of thrombosis in these patients is likely higher
than reported because of insufficient clinical testing and
lack of clinical suspicion. Aspirin has been effectively
Accepted for publication Feb 10, 2015.
Presented at the Poster Session of the Forty-ninth Annual Meeting of The
Society of Thoracic Surgeons, Los Angeles, CA, Jan 26–30, 2013.
Address correspondence to Dr Mir, Department of Pediatrics, Section of
Pediatric Cardiology, University of Oklahoma Health Sciences Center,
Oklahoma City, OK 73104; e-mail: arshid-mir@ouhsc.edu.
Ó 2015 by The Society of Thoracic Surgeons
Published by Elsevier
assessed to determine their association with aspirin
resistance.
Results. Eighty percent of patients were aspirin resis-
tant using TEG (95% CI, 56% to 94%) and none of the
patients achieved a UTX level of less than 1,500 pg/mL.
Aspirin resistant patients did not respond to an increased
dose of aspirin between the fifth and tenth days of ther-
apy (p [ 0.820). Patients did, however, respond to aspirin
treatment when comparing the baseline UTX measure-
ment with those recorded on the fifth day (p [ 0.008) and
the tenth day (p [ 0.0361) of aspirin therapy. The UTX
levels did not differ between those who were and those
who were not aspirin resistant by TEG at any of the
measurement times. The clinical variables were not
associated with aspirin resistance status.
Conclusions. There is a high incidence of aspirin
resistance in the immediate postoperative period after
single-ventricle shunt palliation. Aspirin might not be an
adequate agent for shunt prophylaxis in this patient
population. Further studies are needed to identify at-risk
patients who might benefit from additional testing and
specific anticoagulation.
(Ann Thorac Surg 2015;99:2158–65)
Ó 2015 by The Society of Thoracic Surgeons
used to prevent thrombus formation and shunt occlusion
in these patients. Aspirin use is associated with a greater
than sevenfold reduction in the risk of shunt thrombosis
and a decreased risk of death among patients undergoing
a systemic-to-pulmonary artery shunt, including the
Norwood procedure [3]. However, shunt thrombosis
continues to result in significant morbidity and mortality
despite the use of aspirin [4]. We reported [5] a significant
response to aspirin in patients with congenital heart dis-
ease; however, aspirin resistance was identified in 26% of
children with congenital heart disease and 39% of those
with cyanotic defects using platelet function analyzer
(PFA-100; Siemens AG, Munich, Bavaria).
There continues to be a paucity of evidence involving
the optimal dose and the effectiveness of aspirin in the
neonatal period. Empirically, most centers use heparin
followed by low dose aspirin to prevent thrombosis in
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Ann Thorac Surg MIR ET AL 2159
2015;99:2158–65 ASA RESISTANCE IN SV PATIENTS AND SHUNTS

patients with Blalock-Taussig shunts (BT shunt) [6]. The TEG was obtained after 5 days of aspirin therapy.
However, the optimal dose of aspirin for single-ventricle Aspirin resistance was defined as less than 50% AA in-
patients with systemic-to-pulmonary shunts has not been hibition. In patients who met the definition of aspirin
determined. resistance, the dose was doubled (40 mg/day).
The purpose of the present study was to assess the
incidence of aspirin resistance acutely after placement of
systemic-to-pulmonary artery shunts during the early
Laboratory Measures
postoperative period using urine thromboxane (UTX) and THROMBOELASTOGRAPH PLATELET MAPPING ASSAYS. The

thromboelastography with platelet mapping (TEG) [7–9].
The secondary aim was to determine the change in UTX
in patients with aspirin resistance to an increased dose of
aspirin. We hypothesized that we would observe a high
thromboelastograph hemostasis analyzer (Haemoscope
Corporation, Niles, IL) is a point of care assay that
gives numeric and graphical information concerning the
rate and strength of clot formation [7, 9]. Blood samples
for thromboelastography and platelet mapping were

incidence of aspirin resistance in the immediate post-
operative period and that this incidence would be over-
come by increasing the dose of aspirin. Aspirin resistance
was defined as an inability of aspirin to adequately inhibit
platelet function measured by TEG after exposure to
aspirin (ASA). Thromboelastography is a cyclooxygenase
(COX-1) specific method to assess for ASA resistance
by measuring arachidonic acid (AA) inhibition in blood
[7–10]. Urine thromboxane is a COX-1 nonspecific
method to assess for aspirin responsiveness by mea-
surement of 11-dehydrothromboxane B2 in urine [8].
Material and Methods
Study Design
This study was approved by the Institutional Review
Board of the University of Texas Southwestern Medical
Center. All families approached provided full informed
consent to participate in this study. Infants with a single-
ventricle physiology who required palliation with a
controlled source of pulmonary blood flow were pro-
spectively enrolled in this study. Twenty consecutive
patients were enrolled and underwent a Norwood and BT
shunt (n ¼ 9), Norwood Sano (n ¼ 5), or a BT shunt (n ¼ 6)
(Table 1).
According to our protocol, we started heparin on the
first postoperative day and continued until the initiation
of aspirin. Aspirin was started on postoperative day 3 to 5
enterally (20 mg), depending on the hemodynamic sta-
bility and feeding status of the patient. The UTX was
measured on 3 occasions; prior to starting aspirin, 5 days
after starting aspirin, and 5 days after increasing the dose.
CONGENITAL HEART
obtained through an existing line in the immediate
postoperative period. Four milliliters of blood was
collected in a test tube and reconstituted with appro-
priate reagents according to manufacturer protocol
(Haemoscope Corporation, TEG TM Guide to Platelet
Mapping, monitor antiplatelet therapy). Percentage
platelet inhibition is defined by the extent of non-
response of the platelet thromboxane receptor to the
exogenous AA as measured by TEG maximum ampli-
tude. The percentage platelet inhibition is calculated by
the TEG-PM software. The percentage inhibition
resulting from aspirin can also be calculated. Percent
platelet inhibition ranges from 0% to 100%, with 0%
showing no platelet inhibition and 100% showing
complete platelet inhibition. A percent platelet inhibi-
tion of greater than 50% was used to define adequate
platelet inhibition in our study based on data from
several adult studies [7].
URINE THROMBOXANE. Urinary 11-dehydrothromboxane B2
is a direct metabolite of in vivo thromboxane A2 [8].
Ten milliliters of urine was collected in a tube provided
by the manufacturer (AspirinWorks, Broomfield, CO)
and analysis was performed with the commercially
available enzyme-linked immunosorbent assay obtained
from AspirinWorks. Results from the test were not
immediately available and the initial decision regarding
the dose change was made on the basis of TEG.
However, UTX greater than 1,500 pg/mL have been
previously used to define aspirin resistance in adult
studies [8]. Results were normalized to urine creatinine
to reflect change in renal function and were reported as
11-dt B2 pg/mg creatinine.

Table 1. Summary of Diagnosis Categories by Diagnosis, Aspirin Resistance, and Cardiopulmonary Bypass Requirement Status
Aspirin Resistanta Bypass Requiredb

Overall No Yes No Yes

Frequency Frequency Frequency Frequency Frequency
Diagnosis Categories (%) (%) (%) (%) (%)

Double inlet left ventricle 3 (15.00) 1 (25.00) 2 (12.50) 1 (16.67) 2 (14.29)

Heterotaxy 3 (15.00) 0 3 (18.75) 2 (33.33) 1 (7.14)
Hypoplastic left heart syndrome 11 (55.00) 3 (75.00) 8 (50.00) 0 11 (78.57)
Pulmonary atresia with intact ventricular septum 1 (5.00) 0 1 (6.25) 1 (16.67) 0
Tricuspid atresia 2 (10.00) 0 2 (12.50) 2 (33.33) 0
a
Fisher exact p value ¼ 1.00. b
Fisher exact p value ¼ 0.0017.
 2160 MIR ET AL Ann Thorac Surg
ASA RESISTANCE IN SV PATIENTS AND SHUNTS 2015;99:2158–65

Statistical Analysis

p Value

0.9673
0.9028
0.5429
0.0728
0.1466
0.0026
Demographic and clinical patient characteristics were
compared between aspirin resistant and non-resistant
subjects by Mann-Whitney U and Fisher exact statistical

(184,00–227,000)
tests. Similar comparisons were made between subjects

(25th%-75th%)
requiring a cardiopulmonary bypass and those who did

(5.00–9.00)

(38.0–39.0)

(14.4–15.4)
(2.84–3.50)
Yes (n ¼ 14)

(123–139)
Median
not. The proportion of aspirin resistant patients was
estimated and 95% confidence interval constructed using

Bypass Required
the exact binomial test. To determine the change in UTX

132

206,500
8.00

38.0

15.0
3.04
and TEG in patients with aspirin resistance to an
increased dose of aspirin, analysis was restricted to only
those patients with a percent platelet inhibition of less
CONGENITAL HEART

than 50%. Repeated measures analysis of variance

(141,000–314,000)
(ANOVA) was used to determine if UTX levels changed

(25th%–75th%)
from baseline, fifth, and tenth day of aspirin therapy. The

(5.00–17.0)
(0.00–0.00)
(38.0–38.0)

(13.3–14.4)
(2.49–3.26)
No (n ¼ 6)
Table 2. Summary of Continuous Variables Overall and by Aspirin Resistance and Cardiopulmonary Bypass Requirement Status

Median
UTX was not normally distributed. Therefore, the natural
log of UTX was used in the analysis and then back-
transformed by exponentiating least squares means and

7.00
0.00
38.0
280,000
13.7
3.15
the bounds of 95% confidence intervals. The UTX levels
were also compared between groups based on aspirin
resistance status and cardiopulmonary bypass require-
ment. The variance of the residuals of the UTX levels was

p Value

0.5431
0.5771
0.3329
0.7796
0.2836
0.4812
not stable. Therefore, the Mann-Whitney U test was used
to compare UTX levels between these groups. Statistical
analyses were performed using SAS version 9.3 (SAS

(189,500–312,000)
Institute, Cary, NC). Two-tailed values of p less than 0.05
were considered statistically significant.
(25th%–75th%)
Yes (n ¼ 16)

(5.00–9.00)

(38.0–38.5)

(13.7–15.3)
(2.77–3.45)
(0.00–136)
Median

Results
ASA Resistant

Subjects
8.00
115
38.0
220,500
14.7
3.04
Twenty consecutive patients were enrolled. Median age
at time of surgery was 6 days (range, 4 to 75 days). The
median weight at the time of surgery was 3.08 kg (range,
(182,000–217,000)

2.3 to 4.9) (Table 2). There were 10 boys and 10 girls. For
the 14 patients who underwent cardiopulmonary bypass
(25th%–75th%)

(5.00–52.5)

(38.0–39.0)

(13.5–15.2)
(2.90–4.07)
No (n ¼ 4)

(65.5–141)

the median time spent on the bypass was 123 minutes

Median

Hb ¼ hemoglobin.

(range, 97 to 148 minutes). Six shunts were done without

cardiopulmonary bypass.
All patients were able to complete the study; however,
132

184,000
17.5

38.5

14.5
3.18

there were 2 deaths, 1 patient died prior to discharge and

the other patient died after discharge from the hospital.
The etiology of the deaths was not determined. No
(184,000–280,000)

bleeding or thrombotic complications were encountered.

CPB ¼ cardiopulmonary bypass;

No allergic or any other adverse events were related to

(25th%–75th%)

(5.00–13.0)

(38.0–39.0)

(13.7–15.3)
(2.77–3.45)
(0.00–136)

aspirin therapy. The demographic and clinical charac-

(n ¼ 20)
Median
Overall

teristics of patients are shown in Tables 1 and 2; sum-

marized in all patients, in patients who were and were not
aspirin resistant, and in those who did and did not
8.00
124
38.0
213,500
14.7
3.09

require a cardiopulmonary bypass.

Laboratory Aspirin Resistance (by TEG and UTX)

Age at surgery (days)

Eighty percent of patients were ASA resistant as assessed

by TEG (95% CI, 56% to 94%). None of the patients ach-
Preoperative Hb
Gestational age

ieved a UTX level less than 1,500 pg/mL. Figure 1 shows

ASA ¼ aspirin;
Weight (kg)

the change in UTX measurement over time in aspirin

CPB time
Variables

resistant patients. Aspirin resistant patients did not

Platelet

respond to an increased dose of aspirin between the fifth

and tenth days of therapy (p ¼ 0.820). Patients did,
Ann Thorac Surg
2015;99:2158–65
Fig 1. Box plot of urine thromboxane by measurement time.
(ASA ¼ aspirin; * ¼ mean of the values.)
however, respond to aspirin treatment when comparing
the baseline UTX measurement with those recorded on
the fifth day (p ¼ 0.008) and the tenth day (p ¼ 0.0361) of
aspirin therapy. Table 3 shows the repeated measures
ANOVA models comparing the UTX at 3 different mea-
surement times.
Urine Thromboxane Level and ASA Resistance Groups
as Demonstrated by TEG
The UTX levels did not differ between those who were
and those who were not aspirin resistant as determined
by TEG at either measurement times. Table 4 provides a
summary of UTX levels at baseline and after 5 and 10
days of therapy in aspirin resistant and aspirin sensitive
patients. Figure 2 shows a box plot of UTX over the 3
measurement times by aspirin resistance status.
Urine Thromboxane Levels and Need for
Cardiopulmonary Bypass
The UTX levels did not differ between those who did and
those who did not need cardiopulmonary bypass. Table 5
summarizes the UTX levels at the 3 measurement times
by cardiopulmonary bypass status. Figure 3 shows the
box plot of UTX by cardiopulmonary bypass requirement
status and measurement time.
Table 3. Summary of Repeated Measures Analysis of Variance Models Comparing the Mean Urine Thromboxane (UTX) Levels at
the 3 Measurement Times
Untransformed
UTX Measurement Mean of UTX
Baseline 20,289.00
Day 5 of ASA therapy 9,346.50
Day 10 of ASA therapya 10,815.00
a
At this measure, the dosage of ASA differed between ASA resistant (10 mg/kg) and ASA responsive (5 mg/kg) patients.
ASA ¼ aspirin; CI ¼ confidence interval.
MIR ET AL 2161
ASA RESISTANCE IN SV PATIENTS AND SHUNTS
Comment
Aspirin resistance as assessed by different platelet
aggregation tests and UTX levels has been shown to
predict adverse clinical outcomes in several adult studies
[10–13] with high UTX level shown to predict increased
risk of stroke, myocardial infarction, and death [13].
Aspirin has been proven to decrease the risk of throm-
bosis in pediatric patients [3]; however, despite the use of
ASA recent studies indicate that the risk of thrombosis
during the early postoperative period is unacceptably
high [2, 14–16].
To the best of our knowledge this is the first study to
CONGENITAL HEART
investigate ASA resistance in the acute postoperative
period after first stage single-ventricle palliation with an
aortic to pulmonary artery shunt. Our study demon-
strates that only 20% of infants are responsive to aspirin
at currently used doses as measured by TEG. The level of
resistance observed in this study is higher than previ-
ously described. We speculate that the higher incidence is
mainly due to age, single-ventricle physiology, presence
of cyanosis, and the complexity of the procedure. This is
supported by Cholette and colleagues [17] who reported a
6% incidence of symptomatic thrombus after pediatric
cardiac surgery; however, when patients less than 4
months of age were analyzed separately the incidence of
thrombus increased to 66%. Heistein and colleagues [5]
have previously shown a higher incidence of ASA resis-
tance in cyanotic versus acyanotic patients (39.5% vs
17%). These patients were 3 months to 18 years of age.
This is supported by Emani and colleagues [18]) who
reported a higher incidence of aspirin unresponsiveness
in neonates (57%) with 5 mg/kg of aspirin compared with
their overall cohort which showed a 10% incidence of
aspirin unresponsiveness. A recent study has shown that
single-ventricle palliation by itself is a risk factor for
thrombosis [15]. The findings in our study are concurrent
with these studies, which show a high incidence in aspirin
resistance in neonates with single ventricles.
Our study raises several important questions about the
optimal dosage of ASA in these cyanotic patients and
whether ASA is effective in this patient population at the
doses currently used. The possible mechanisms for
aspirin resistance in this patient population include
immaturity of the neonatal coagulation system, inade-
quate aspirin dose, poor absorption caused by marginal
cardiac output, genetic factors, and inflammation due to
Least Squares Back Transformed
Mean Log UTX Mean Log UTX (95% CI)
9.69 16089.14 (11,544.91–22,424.29)
8.95 7694.8 (5,520.92–10,724.65)
9.09 8825.5 (6,332.18–12,300.56)
 2162 MIR ET AL
ASA RESISTANCE IN SV PATIENTS AND SHUNTS
Table 4. Summary of Urine Thromboxane (UTX) Measurement by Aspirin (ASA) Resistance Status
No (n ¼ 4)
Median
UTX Measurement (25th%–75th%)
Baseline 11,270 (9,064.5–20,090)
Day 5 of ASA therapy 9,111 (6,228–12,060)
Day 10 of ASA therapyb 6,754.5 (5,051–10,606.5)
a b
p value from the Wilcoxon-Mann-Whitney test. At this measure, the dosage of ASA differed between ASA resistant (10 mg/kg) and ASA responsive
(5 mg/kg) patients.
CONGENITAL HEART
surgery [19–27]. Eighteen of the 20 patients in our study
were less than 30 days old. Previous studies have shown
that neonates tend to have an immature coagulation
system with low levels of antithrombin, protein C, and
protein S (20% to 60% of adult values) and low levels of
contact factors and vitamin K-dependent factors (<70% of
adult values) [22, 23]. Neonates have also shown a high
resistance to anticoagulation. Initiation of cardiopulmo-
nary bypass causes a further decrease (50%) in circulating
coagulation factors [20, 22]. Platelets are activated by
exposure to a synthetic surface as well as by deep hypo-
thermic circulatory arrest. These activated platelets pro-
vide important binding sites for specific coagulation
factors and the activation periods tend to last longer for
cyanotic patients. The length of these derangements (in
days) differs between patients and can put them at risk
for thrombosis. Conversely, coagulation abnormalities
might be inherent in some of these patients or due to
other unknown factors not currently identified.
Patients after stage 1 palliation are typically desaturated
(targeted oxygen saturation is 75% to 85%) and normal
saturations are not achieved until they undergo their final
surgical (Fontan) palliation. Cyanosis has been shown
to be associated with liver hypoperfusion, subclinical
hepatic dysfunction, and impaired metabolism of
Fig 2. Box plot of urine thromboxane by aspirin (ASA) resistance status
and measurement time. (ASA resistant: —— ¼ yes; – - - – ¼ no; * ¼ mean
of the values.)
Ann Thorac Surg
2015;99:2158–65
ASA Resistant
Yes (n ¼ 16)
Median
(25th%–75th%) p Valuea
13,393 (10,000–26,864.5) 0.4586
7,077.5 (4,524.5–11,200.5) 0.6755
9,450 (5,306.5–15,710) 0.4871
coagulation proteins and low grade inflammation [27]. A
longitudinal study looking at patients with hypoplastic
left heart syndrome found lower protein C levels; this has
been shown to correlate with lower oxygen saturation and
risk of thrombosis [28]. These derangements might be
more pronounced in neonates because of immaturity of
hepatic pathway and hypoxia, which could explain
resistance to antiplatelet agents in this time period. In
addition, surgery and especially cardiopulmonary bypass
incite inflammatory response marked by an increase in
inflammatory markers. Studies have shown that patients
with increased preoperative inflammatory markers might
be at the highest risk for shunt thrombosis [17].
Our study has several important limitations. Our
sample size was small and reflects our practice in post-
operative management with timing and mode of admin-
istration of ASA. No tests to confirm optimal absorption
of ASA in the immediate postoperative period were
performed. Because systemic blood flow is especially
tenuous in the immediate postoperative period, subopti-
mal absorption with low serum levels might cause ASA
insensitivity. However, in our institution aspirin is started
only when feeds are tolerated when absorption of aspirin
is likely improved. Additionally increasing the ASA
several days later had no effect on sensitivity. The cutoff
values used to define aspirin resistance were based on
adult data. Normal cutoff values for urine thromboxane
are higher in pediatric patients and even higher in neo-
nates [29]. In our study, values for urine thromboxane
were inordinately high and approached the maximum
reading based on recommendations for the manufacturer
for dilutions (>20,000 pg/mL). Although further dilutions
were pursued for research purposes, the accuracy beyond
the prescribed dilutions is less predictable. As there is
platelet activation and resistance to anticoagulation in the
immediate postoperative period, a longer term follow-up
would have been ideal to document differences in the
aspirin resistance over time. Although we show there is a
high laboratory evidence of aspirin resistance, the actual
risk of thrombosis is possibly much lower and this has
been shown in some recent studies [18]. With the lack of
follow-up to show any clinical correlation in this study,
clinical decision making cannot be inferred from the
findings of this study. Although several different platelet
aggregation tests are available to measure aspirin resis-
tance, there is a wide variability in literature regarding
Ann Thorac Surg
2015;99:2158–65
Table 5. Summary of Urine Thromboxane (UTX) Measurement by Cardiopulmonary Bypass Requirement Status
No (n ¼ 6)
Median
UTX Measurement (25th%–75th%)
Baseline 11,250 (7,018–30,679)
Day 5 of ASA therapy 8,575.5 (6,467–14,354)
Day 10 of ASA therapyb 6,551.5 (4,000–13,973)
a b
p value from Wilcoxon-Mann-Whitney test. At this measure, the dosage of aspirin (ASA) differed between ASA resistant (10 mg/kg) and ASA
responsive (5 mg/kg) patients.
the incidence of aspirin resistance using different tests.
Currently there is no gold standard for assessing the
incidence of aspirin resistance with any of the commer-
cially available tests. The TEG-PM is available in most
pediatric cardiothoracic surgical programs because it is
used intraoperatively and postoperatively to assess the
need for blood transfusion and clotting factors replace-
ment. Although there are limited data on the use of TEG
in pediatric patients and the high incidence of aspirin
resistance might reflect some variability of TEG in
neonatal patients, there are several adult studies which
have shown good correlation of TEG with other platelet
aggregation tests [7, 8]. A repeat TEG would have been
useful to see the change in aspirin resistance with
increased aspirin dose but was not done because of
difficultly in blood draws in these high-risk patients once
central lines are removed. Some recent studies have
shown that increased aspirin dose can lower the aspirin
unresponsiveness in these patients [18].
In conclusion, this study shows a high incidence of
laboratory ASA resistance in single-ventricle patients’
status post stage 1 palliation. This study raises important
questions as to whether ASA is an adequate prophylaxis
in this patient population at the currently used doses.
Further studies are needed to validate this finding in a
Fig 3. Box plot of urine thromboxane by cardiopulmonary bypass
requirement status and measurement time. (ASA ¼ aspirin; ASA
resistant: —— ¼ yes; – - - – ¼ no; * ¼ mean of the values.)
MIR ET AL 2163
ASA RESISTANCE IN SV PATIENTS AND SHUNTS
Bypass Required
Yes (n ¼ 14)
Median
(25th%–75th%) p Valuea
13,203.5 (11,111–23,050) 0.5170
7077.5 (4,000–9,766) 0.3973
9450 (5,971–15,320) 0.3973
CONGENITAL HEART
larger cohort of patients. Risk stratification in this patient
population with laboratory markers which are reliable,
reproducible, and easily accessible is needed. A certain
subgroup of this patient population might benefit from
additional anticoagulation.
This study was funded by the Children’s Clinical Research
Advisory council (CCRAC) from the Department of Pediatrics at
Children Medical Center Dallas.
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ASA RESISTANCE IN SV PATIENTS AND SHUNTS
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INVITED COMMENTARY
Thrombosis in neonates undergoing complex cardiac
surgery, particularly single-ventricle palliation, is a major
cause of morbidity and mortality. The problem is com-
pounded by a lack of a rational approach to anti-
coagulation management and monitoring. The study by
Mir and colleagues [1] highlights important deficiencies
in thrombosis prophylaxis with aspirin in single-ventricle
neonates. Specifically, the study found that a significant
proportion of patients undergoing therapy with aspirin at
20 mg per day after stage 1 palliation were unresponsive
to aspirin. Although some of these patients responded to
an increasing dose of aspirin, some of these patients were
truly aspirin “resistant”; increasing the dose of aspirin did
not result in appropriate platelet inhibition.
There are several important messages from this
manuscript. First, 20 mg per day of aspirin is likely
insufficient dosing for a 3 to 4 kg neonate undergoing
stage 1 palliation. A recent study from our institution
supports this finding, and our dosing for neonates
has changed to 40.5 mg/day [2]. Second, the study dem-
onstrates variability in aspirin responsiveness for a given
dose of aspirin. An important question that the Mir
study does not address is, “Does unresponsiveness pre-
dict thrombosis after stage 1 palliation?”. If it does,
then tailored therapy based upon platelet reactivity
Ó 2015 by The Society of Thoracic Surgeons
Published by Elsevier
Ann Thorac Surg
2015;99:2158–65
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coagulation system. Prog Pediatr Cardiol 2005;21:87–115.
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dergoing cardiac surgery for complex cardiac defects show
imbalance between pro- and anti-thrombotic activity. Crit
Care 2006;10:R165.
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fects in neonates during cardiopulmonary bypass. Ann
Thorac Surg 1992;54:541–6.
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thrombogenesity in patients with cyanotic congenital heart
disease. Circ J 2007;71:948–53.
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response to cardiopulmonary bypass in children. Ann
Thorac Surg 2006;81:S2347–54.
25. Carvalho MV, Maluf MA, Catani R, et al. Cytokines and
pediatric open heart surgery with cardiopulmonary bypass.
Cardiol Young 2001;11:36–43.
26. Seghaye MC. The clinical implications of the systemic in-
flammatory reaction related to cardiac operations in children.
Cardiol Young 2003;13:228–39.
27. Chan AK, Leaker M, Burrows FA, et al. Coagulation and
fibrinolytic profile of paediatric patients undergoing cardio-
pulmonary bypass. Thromb Haemost 1997;77:270–7.
28. Odegard KC, Zurakowski D, DiNardo JA, et al. Prospective
longitudinal study of coagulation profiles in children
with hypoplastic left heart syndrome from stage I through
Fontan completion. J Thorac Cardiovasc Surg 2009;137:
934–41.
29. Varnell CD Jr, Goldstein SL, Yee DL, et al. Age-related dif-
ferences in urinary 11-dehydroxythromboxane B2 between
infants, children, and adolescents: another example of
developmental hemostasis? Pediatr Blood Cancer 2014;61:
2074–6.
testing may mitigate the risk of thrombosis. Our practice
has been to perform testing either with the VerifyNow
(Accriva Corp, San Diego, CA) or thromboelastography
platelet mapping (TEG-PM) in all pediatric patients who
are considered to be at high risk for thrombosis. Unre-
sponsiveness is managed by increase in the dose of
aspirin followed by retesting. If the patient is determined
to be resistant, clopidogrel is administered, again with
testing to confirm inhibition.
Finally, even if aspirin inhibits platelet arachidonic acid
activity sufficiently, there are patients in whom such inhi-
bition may simply not be enough to prevent thrombosis.
Of note, aspirin testing has not been demonstrated to
prevent adverse outcomes (stent thrombosis) in adults
after coronary intervention [3]. Patients undergoing aor-
topulmonary shunting may remain at risk for thrombosis
despite aspirin. In these patients alternative agents such
as clopidogrel or even parenteral GPIIb/IIIa inhibitors
(not currently approved for pediatric use) should be
considered.
Clearly there is a lot of work to be done to optimize
our anticoagulation management. Newer agents are
becoming available, and the technology to measure the
activity of these agents is improving. Tailored anti-
coagulation management in these high-risk pediatric
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