Antiplatelet Activity of Aspirin in Infants After Aortopulmonary and Cavopulmonary Shunts

Background: Aortopulmonary and cavopulmonary shunts ("shunts") are surgically placed to
provide pulmonary blood flow in infants with congenital heart disease who require the shunt
for survival. Thrombosis occurs in about 17% of these shunted infants (Li et al, 2007;
Monagle et al, 2012) with an associated morbidity of 23% and mortality of 7%.(Li et al,
2007) One study reported a third of all deaths were from shunt thrombosis.(Fenton, 2003)
Despite insufficient evidence to guide appropriate dosing, current thromboprophylaxis
guidelines recommend aspirin (ASA) for thrombus prevention in these high-risk infants. No
therapeutic monitoring exists to ensure consistent and effective anticoagulation and prevent
over-anticoagulation to minimize bleeding complications. Previous studies examining the
effectiveness of ASA in shunt thrombosis prevention have conflicting results. The most
recent large, prospective observational study showed a significant association between ASA
use and lower risk of thrombosis and death (Li et al, 2007), but the study was limited by
lack of standardized ASA dosing and failure to include adverse events. To further complicate
the picture, adult studies have described a phenomenon termed "ASA resistance," where
thrombosis occurs despite ASA therapy.(Frelinger et al, 2008; Heistein et al, 2008;
Szczeklik et al, 2005; Frelinger et al, 2006) ASA resistance has not been adequately studied
in the pediatric population leading to a knowledge gap between therapeutic dosing and the
adequate prevention of thrombosis combined with minimization of bleeding complications.
Thromboelastography with Platelet Mapping (TEG-PM) is a blood test that specifically
evaluates the percentage of inhibition of the arachidonic acid pathway targeted by ASA. It
can be used for serial monitoring of the adequacy of anticoagulation with ASA in shunted
infants and to provide evidence of safe and effective dosages for its use in other pediatric
populations.

Hypothesis and Specific Aims:

Hypothesis: The investigators hypothesize that ASA dosing by current guidelines (1-5
mg/kg/day) favors protection from bleeding complications and fails to achieve adequate
inhibition of the arachidonic acid pathway to prevent thrombosis.

Specific Aim 1: The primary aim is to determine the percentage of infants treated with ASA
after shunt surgery who have adequate (> 70%) inhibition of the arachidonic acid pathway as
measured by TEG-PM.

Outcome: The percentage of arachidonic inhibition, as measured by TEG-PM, at 3 designated
time points after starting ASA postoperatively. Therefore, TEG-PM will be measured at these
designated time points:

1. After the third dose of ASA

2. At the first post-operative cardiology clinic visit (between 2 and 4 weeks after
hospital discharge)

3. At a follow-up cardiology clinic visit 3-6 months after the initiation of ASA

Specific Aim 2: The secondary aim is to describe the frequency of bleeding and thrombotic
events while on ASA.

Outcome: The number of bleeding and thrombotic events from initiation of ASA therapy to end
of study will be documented.

ASA administration: ASA will be initiated by the cardiac intensive care unit attending
physician postoperatively, at a dose of 1-5 mg/kg/day, but no less than 20 mg per day; the
initiation of ASA at 1-5 mg/kg/day is standard of care and recommended by the College of
Chest Physicians (Monagle et al, 2012), albeit with limited evidence for its use. TEG-PM
results obtained for research purposes will be available only to the research team. The dose
of ASA will not be adjusted by results from the research TEG-PM. However, if bleeding or
thrombosis occurs, TEG-PM is obtained by local practice and ASA dosing adjusted by the
treating physician. If the dose of ASA is changed while the patient is hospitalized, TEG-PM
will be obtained 2 hours after the third (adjusted or restarted) dose.

Inclusion Criteria:

- Undergoing cardiac surgery for a shunt and planned treatment with aspirin

- Age 2.0 days to 12 months

- Consent of parent or guardian

Exclusion Criteria:

- Known or suspected congenital or acquired coagulation disorders (such as hemophilia,
von Willebrands disease, Glansmans thrombasthenia).

- History of aspirin use within 7 days of surgery.

- Platelet count < 50K prior to surgery.

- Weight < 2.5 kg.

- Prematurity defined as gestational age < 37 weeks.