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DOI 10.1007/s00246-010-9672-2
REVIEW
Received: 3 January 2010 / Accepted: 8 February 2010 / Published online: 6 March 2010
Springer Science+Business Media, LLC 2010
Abstract Platelets play a critical role in normal physio- healing, inflammation, and innate immunity [26]. Platelets
logic processes such as hemostasis, wound healing, inflam- respond to vascular injury by adhering to the endothelium
mation, and innate immunity. However, they also play a role via platelet glycoprotein (GP) interaction with extracellular
in the pathologic process of thrombosis. Although anti- matrix proteins (e.g., von Willebrand factor, collagen,
platelet therapy is most commonly used to prevent throm- fibrinogen) [26]. After platelet adhesion, a series of signal
botic events for adults with atherosclerotic vascular disease, transduction events occur, culminating in platelet activa-
children with certain types of congenital heart disease, tion. Once activated, platelets bind to fibrinogen via GP 2b/
stroke, and Kawasaki disease also are at risk for thrombosis 3a receptors and release their granules into the cytoplasm.
and may benefit from antiplatelet therapy. Unfortunately, These granules include agonists such as adenosine
very little data on the efficacy and safety of antiplatelet diphosphate (ADP) and serotonin, as well as adhesive
therapy for pediatric patients are available. As a conse- molecules such as von Willebrand factor, fibronectin, and
quence, consistent clinical practice among pediatric practi- coagulation factors 5, 7, 11, and 13. Platelet activation and
tioners is lacking. Furthermore, much of what is practiced granule secretion subsequently result in platelet aggrega-
results from extrapolation from adult studies, which may be tion, thrombin generation, and leukocyte recruitment.
problematic because many aspects of platelet biology differ Besides their normal physiologic roles, platelets also
between children and adults. This review discusses aspects participate in the pathologic processes of thrombosis and
of antiplatelet therapy for pediatric patients. inflammation [26]. Agents that inhibit platelet function are
therefore useful tools in treating individuals who present
Keywords Antiplatelet therapy Congenital cardiac with platelet-related pathologies.
defects Kawasaki disease Pediatric Stroke Several antiplatelet agents currently are available for
use. The most widely used and well established of these is
aspirin. Aspirin, after its absorption in the proximal gas-
Platelets, anucleate blood cells formed by megakaryocyte trointestinal tract, inhibits platelet function by irreversibly
fragmentation, are a critical component of several impor- binding to cyclooxygenase (COX)-1. The inhibition of
tant physiologic processes including hemostasis, wound COX-1 blocks the conversion of arachidonic acid to
thromboxane A2 (TXA2), a potent amplifier of platelet
aggregation in response to stimuli such as collagen, ADP,
and thrombin [44]. Dipyridamole is an agent that inhibits
J. S. Li (&)
adenosine uptake into platelets. This results in increased
Division of Pediatric Cardiology, Department of Pediatrics,
Duke University Medical Center and Duke Clinical Research local concentrations of adenosine, which act on the platelet
Institute, P.O. Box 17969, Durham, NC 27705, USA A2 receptor, thereby stimulating platelet adenylate cyclase
e-mail: jennifer.li@duke.edu and increasing platelet cyclic-30 ,50 -adenosine monophos-
phate (cAMP) levels. Via this mechanism, platelet aggre-
J. W. Newburger
Department of Cardiology, Children’s Hospital Boston, gation is inhibited in response to various stimuli, including
Boston, MA, USA platelet-activating factor (PAF), collagen, and ADP.
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Pediatr Cardiol (2010) 31:454–461 455
Other currently available oral antiplatelet agents are the have shown that compared with platelets derived from
thienopyridines clopidogrel, prasugrel, and ticlopidine. The adults, those derived from neonates display a decreased
most commonly used agent in this class is clopidogrel, response to platelet agonists such as collagen, thrombin,
which, after hepatic metabolism, irreversibly binds to the ADP, and epinephrine [24, 45, 46]. A decreased platelet
purinergic P2Y12 receptor on platelets [20], thus preventing response also is observed in neonates compared with adults
binding of ADP [44]. Recently, ticagrelor, an oral, and older children when platelet function is measured with
reversible, direct-acting P2Y12 inhibitor, has been evalu- the collagen/epinephrine and collagen/ADP cartridges of
ated in a large adult clinical trial [63]. the Platelet Function Analyzer-100 (PFA-100, Dade Beh-
Another category of antiplatelet agents are the intrave- ring, Inc., Deerfield, IL) [6, 23, 48]. These findings suggest
nous GP 2b/3a inhibitors abciximab, eptifibatide, and tir- that neonates may require lower weight-adjusted doses of
ofiban. These agents reversibly (eptifibatide and tirofiban) or antiplatelet agents to achieve the same level of platelet
irreversibly (abciximab) bind to platelet GP 2b/3a receptors, inhibition as for adults and older children.
which prevents their cross-linking with fibrinogen and Another point of distinction between pediatric and adult
blocks the last common pathway of platelet aggregation [33]. patients is the underlying condition that necessitates anti-
Antiplatelet therapy is most commonly used as primary platelet use. Among adults, antiplatelet therapy is most
or secondary prevention against thrombotic events for commonly prescribed for the primary or secondary pre-
adults with atherosclerotic vascular disease. Children also vention of ischemic complications resulting from athero-
may benefit from antiplatelet therapy if they experience sclerotic coronary artery, cerebrovascular, or peripheral
other thrombosis-predisposing conditions (Table 1). How- arterial disease [19]. Children are likely to require anti-
ever, very few studies of this population have been con- platelet therapy to prevent thrombotic complications
ducted. The lack of clinical studies leads to extrapolation of resulting from certain types of congenital heart defects,
results from studies conducted with adults and an incon- stroke, sickle-cell disease, and Kawasaki disease (Table 1).
sistent clinical practice strategy for pediatric patients. In Pediatric antiplatelet therapy use is associated with
this review, we discuss important aspects of antiplatelet significant safety concerns. One concern is that young
therapy for pediatric patients and present data regarding its children, particularly those learning to walk, are prone to
use for children susceptible to thrombosis. falling, potentially putting them at risk for excess bruising
or, more seriously, intracranial hemorrhage. Older children
also are at risk for such events, particularly if they partic-
Important Considerations for Antiplatelet Therapy ipate in contact sports. When aspirin is used for patients
for Pediatric Patients with a viral infection, they are at a small risk for the
development of Reye’s syndrome, a serious condition
Several factors should be considered when antiplatelet characterized by acute central nervous system and liver
therapy is initiated for children. Several in vitro studies dysfunction [3, 22]. The incidence of this disease has fallen
precipitously in the last 10 to 15 years for reasons not
completely understood [53].
Table 1 Conditions that predispose pediatric patients to thrombosis
A potential consequence of excess bruising and bleeding
Cardiac surgery or interventional procedures to correct or palliate in pediatric patients receiving antiplatelet therapy is that it
• Single-ventricle palliative procedures involving a shunt (hypoplastic may decrease medication adherence. In adult patients, it is
left heart syndrome, tricuspid atresia, pulmonary atresia with intact
septum, other complex single-ventricle physiology)
known that those who experience minor or ‘‘nuisance’’
• Complex tetralogy of Fallot or pulmonary atresia/ventricular septal
bleeding are less likely to be adherent to their antiplatelet
defect after shunt palliation therapy [49]. Although no specific data exist for children
• Valve defects necessitating prosthetic mechanical valves receiving antiplatelet therapy, it is possible that a parent or
• Intracardiac devices or stents caregiver who is uncomfortable with these side effects may
Ischemic stroke secondary to stop giving the child antiplatelet therapy. Older children
• Congenital heart disease and young adults, who have more autonomy over their
• Infection medication adherence, also may stop taking their anti-
• Metabolic disease platelet therapy to avoid the easy bruising and minor
• Sickle-cell disease
bleeding episodes.
• Thrombophilia (congenital or acquired)
In studies of pediatric drug compliance, clear and open
communication between physicians and caregivers as well
• Vasculitis
as between physicians and older children has been shown
Kawasaki disease
to increase medication adherence [8, 35, 60, 67]. Thus, it is
• Particularly those with coronary artery aneurysms
important that the clinician clearly educate caregivers as
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well as older children and adolescents on the need for secondary to thromboembolus originating from the device.
antiplatelet therapy (i.e., how it helps the patient), possible Another study showed that aspirin may not be sufficient to
side effects (e.g., bruising, bleeding), and the importance of prevent occlusion in children who receive fenestrated
continued therapy (i.e., what may happen if medication is Amplatzer devices. However, this study included only four
not received regularly). patients who received aspirin [29].
Aspirin also has been used to prevent thrombosis after
pediatric stent placement [28]. In a retrospective review of
Evidence Supporting Antiplatelet Therapy for Pediatric nine patients, four of whom were 18 years old or younger,
Patients aspirin therapy was administered for at least 1 year after
implantation of balloon-expandable stents for coarctation of
Whereas a large volume of clinical data supports the effi- the aorta, and no patient showed evidence of thromboem-
cacy and safety of antiplatelet therapy in adults, evidence bolism after an average follow-up period of 18 months [11].
for children is considerably more limited. Furthermore, In another retrospective review, 24 patients (14 age
much of the available data is derived from small, retro- 18 years or younger) received aspirin after undergoing
spective studies conducted at single sites. hybrid pulmonary artery stent implantation secondary to
congenital heart disease and did not demonstrate any epi-
Evidence for Antiplatelet Therapy for Pediatric Patients sodes of stent thrombosis over a mean follow-up period of
With Cardiac Defects 19 months [36]. As pediatric device placement becomes a
more common practice, future studies should evaluate the
One of the most common uses of antithrombotic therapy is comparative effectiveness of various antithrombotic regi-
to treat children with congenital heart disease who have mens in lowering the risk of thromboembolic events in this
undergone valve replacement. Several small, uncontrolled at-risk population of children as well as their relative safety
studies have reported the efficacy and safety of aspirin (e.g., bleeding).
therapy in preventing long-term complications in children Infants and children who require systemic-to-pulmonary
with mechanical heart valves [5, 27, 30, 47, 55, 62, 65]. shunts to palliate congenital heart defects such as hypo-
Because no randomized controlled trials with pediatric plastic left heart syndrome, pulmonary atresia, and com-
patients have been performed, the treatment of infants and plex single-ventricle physiology represent another pediatric
children with mechanical valves is derived from studies population at risk for thrombotic events. Only a few, rel-
conducted with adults. In the absence of high-quality atively small studies have assessed the benefit of aspirin in
studies with sufficient sample size, pediatric cardiologists reducing adverse events in shunt recipients. Some studies
generally manage patients according to the guidelines for have not shown any benefit of aspirin in reducing shunt
adults published by the American College of Chest Phy- thrombosis. However, these studies were small and likely
sicians (ACCP) [38, 50] or the American College of Car- underpowered [1, 7, 13]. Conversely, other studies have
diology/American Heart Association [4, 64]. shown aspirin use to be beneficial [32, 41].
Another group of pediatric patients requiring thrombo- In a large, multicenter, prospective study conducted with
embolic protection involves the patients who undergo 1,004 infants who received systemic-to-pulmonary artery
implantation of cardiac devices such as ventricular assist shunts at a median age of 8 days, the infants who received
devices (VADs), septal defect occluders, and stents. We aspirin (dose range, \20 to [40 mg/day) were 87% less
found little published data on the best way to prevent and likely to experience shunt thrombosis within 1 year of sur-
treat thrombotic complications in pediatric patients who gery than the infants who did not receive aspirin (hazard
receive these devices. A single case report describes the ratio, 0.13; 95% confidence interval, 0.03–0.59; p = 0.008).
successful use of repeated 150-mg clopidogrel boluses to The aspirin recipients also were significantly less likely to
clear device-related thrombi in a 15-year-old boy who experience death within 1 year (v2 = 68.71; p\0.001) [32].
received a DeBakey VAD child (MicroMed Cardiovascu- As children a with single-ventricle approach the Fontan
lar, Inc.; Houston, TX, USA) [58]. Children who undergo procedure, they remain at high risk of thromboembolic
transcatheter closure of secundum atrial septal defects with complications [40].
the Amplatzer Septal Occluder (AGA Medical Corporation, Despite this high risk, we found very little published
Plymouth, MN, USA) often are treated with aspirin. [16]. literature on the use of antithrombotic therapy for these
In a study of 236 consecutive patients (median age, patients after the Fontan procedure. In one retrospective
4.9 years) treated with aspirin after implantation, no study of 72 patients who received aspirin 81 mg/kg/day
thrombotic complications were noted during a median after Fontan surgery, no thrombotic events were recorded.
follow-up period of 2.3 years [15]. One child experienced a However, because all the patients were treated at the same
cerebral infarct 4 to 5 years after implantation, most likely institution and no data were presented on the rates of
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Pediatr Cardiol (2010) 31:454–461 457
thrombotic events for the patients who did not receive (PICOLO) trial, 92 young children ages 0 to 24 months
aspirin, it is difficult to determine whether the lack of with cardiac disease were randomized to receive placebo or
thrombotic events was due to aspirin protection [25]. clopidogrel 0.01, 0.10, 0.15, or 0.20 mg/kg/day. Via
In another retrospective study investigating 87 survivors platelet aggregometry, clopidogrel 0.20 mg/kg/day was
of Fontan surgery, the rates of thromboembolic complica- identified as the dose that provided a level of platelet
tions were similar for the patients who received aspirin (1.6 inhibition similar to that achieved with 75 mg/day for
events/100 patient-years) and those who received warfarin adults. Notably, none of the patients experienced serious
(1.1 events/100 patient-years) but much higher for those hemorrhagic events, and only four patients (2 in the pla-
who received no antithrombotic therapy (4.2 events/100 cebo group and 1 each in the clopidogrel 0.01 and 0.20 mg/
patient-years) [54]. Recently, the results of a multicenter, kg/day groups) experienced minor bleeding [31]. The
randomized trial comparing aspirin with anticoagulation results of PICOLO underscore the importance of con-
(heparin followed by warfarin) for 111 Fontan recipients ducting randomized clinical trials with children, particu-
(mean age, 3.8 years) were presented at the 2008 Scientific larly dose-finding studies, because the 0.20-mg/kg/day
Sessions of the American Heart Association [39]. During a clopidogrel dose identified in PICOLO is five times lower
27-month follow-up period, thrombosis occurred for 24% than the 1-mg/kg/day dose extrapolated from adult studies.
of the heparin and warfarin recipients and 21% of the The ongoing Efficacy and Safety of Clopidogrel in
aspirin recipients (p = 0.47). The rate of major bleeding Neonates/Infants With Systemic-to-Pulmonary Artery
also was the same (1 event per group). These data suggest Shunt Palliation (CLARINET) trial is assessing the efficacy
that anticoagulation and antiplatelet therapies are similarly and safety of clopidogrel 0.20 mg/kg/day in the treatment
safe and effective in preventing thrombosis after Fontan of infants and young children with systemic-to-pulmonary
surgery. shunts [51].
Another therapeutic option for patients at risk for
thrombotic complications is clopidogrel, either as mono-
therapy or in combination with aspirin. Data on the efficacy Pediatric Stroke
and safety of clopidogrel for children are just beginning to
emerge. In one retrospective analysis of 15 children The etiology of pediatric stroke is highly variable and
(median age, 3.5 years) who received clopidogrel for either includes embolism secondary to congenital heart disease,
a congenital or acquired heart condition, no thrombotic cerebral vasculopathy, sickle-cell disease, prothrombotic
events were observed during treatment [14]. One patient in disorders, and acute illness leading to systemic infection
this study experienced a major bleeding event. However, and dehydration [2]. Due to the relative rarity of the disease
this patient was receiving both aspirin and warfarin in as well as disease heterogeneity, little evidence exists on
addition to clopidogrel. whether antithrombotic therapy after pediatric ischemic
The safety and efficacy of pediatric clopidogrel use for stroke is safe or beneficial. In one prospective study of 135
children with congenital heart disease was assessed in two children ages 6 to 18 months with ischemic stroke who
larger retrospective analyses [14]. In a single-center, ret- were followed up for a mean of 36 months, the rates of
rospective analysis of 90 children (median age, 6.7 years) recurrent stroke were similar for the 49 patients who
receiving various doses of clopidogrel, it had a favorable received aspirin and the 86 patients who received low-
safety and tolerability profile because only two children, molecular-weight heparin (8% and 10%, respectively;
both of whom also received aspirin, experienced major p = 0.76) [57]. Because no patient in either group expe-
bleeding. An additional three patients receiving aspirin plus rienced drug-related adverse events such as major bleeding,
clopidogrel experienced minor bleeding [34]. the authors concluded that neither treatment was superior
In another single-site, retrospective analysis of 46 children in treating children with ischemic stroke.
(median age, 3.9 years) receiving clopidogrel (0.1–0.7 mg/ Data from a large health care provider network showed
kg/day) for heart disease, no thrombotic events were observed that among 95 children who experienced an index stroke, 3
[37]. Although most of the patients in this cohort experienced of the 32 patients treated with aspirin, 3 of the 11 patients
skin bruising, clopidogrel was relatively well tolerated treated with anticoagulation, and 9 of 46 patients treated
because only two patients, both receiving concomitant war- without any antithrombotic treatment experienced recur-
farin, experienced major bleeding complications. An addi- rent stroke [17]. These numbers are too small to conclude
tional patient experienced hematologic abnormalities that definitively whether one agent is more effective than
resolved after clopidogrel withdrawal [37]. another in preventing recurrent stroke. Unfortunately, we
To date, only one randomized clinical trial of clopido- are unaware of any ongoing randomized clinical trials
grel use in children has been published [31]. In the dose- assessing the efficacy and safety of antithrombotic therapy
finding Platelet Inhibition in Children on Clopidogrel for pediatric patients experiencing ischemic stroke. The
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458 Pediatr Cardiol (2010) 31:454–461
ongoing Aspirin Prophylaxis in Sickle-Cell Disease study the regression of those that have already formed. In the
is assessing the safety and efficacy of aspirin in preventing retrospective analysis, the six patients treated with abcix-
ischemic stroke in children with sickle-cell anemia. How- imab had a significantly smaller maximal aneurysm lumen
ever, it is a small (projected enrollment of 40) and non- diameter and a greater percentage decrease in lumen size at
randomized study [61]. both the early and late follow-up assessment compared
Limited evidence from one small prospective study with the nine patients who did not receive abciximab [66].
suggests that clopidogrel, either alone or in conjunction Although one abciximab recipient experienced lower gas-
with aspirin, may be beneficial for children experiencing trointestinal bleeding, the event was transient and did not
ischemic stroke [56]. In this study of 17 children treated require treatment. Future prospective studies, ideally ran-
with clopidogrel, at a dosage of approximately 1 mg/kg/ domized trials, are needed to establish the true efficacy and
day, no drug-related adverse events were observed. Two safety of abciximab for children with acute or subacute
patients experienced intracranial hemorrhage during ther- Kawasaki disease and coronary aneurysms.
apy, but both were receiving concomitant aspirin, a therapy
combination shown to increase the risk of bleeding in
adults experiencing ischemic stroke [9]. More studies on Recommendations for the Treatment of Pediatric
the safety and efficacy of antiplatelet agents would be Patients at Risk for Thrombosis
helpful in determining the circumstances under which they
are safe and the effective treatment options for children Despite the lack of conclusive data and the paucity of
who experience ischemic stroke. randomized clinical trials, several guidelines for the use of
antiplatelet therapy for children have been published [38,
42, 43]. The most comprehensive up-to-date guidelines are
Kawasaki Disease those recently published by the ACCP (the ACCP guide-
lines pertaining to antiplatelet therapy can be found in
One pediatric condition for which aspirin therapy has been Table 2). Although these guidelines cover the spectrum of
more thoroughly studied is Kawasaki disease. Kawasaki conditions that necessitate antithrombotic use for children,
disease, the leading cause of acquired heart disease in they also reflect the overall lack of data because many of
children, is an acute, systemic vasculitis of unknown origin their recommendations are assigned a low level of evi-
that results in coronary artery aneurysm formation in dence. To increase the confidence with which antiplatelet
approximately 15% to 25% of cases. Both the antiinflam- therapy can be administered safely for infants and children,
matory and antiplatelet properties of aspirin are used in more studies, particularly randomized and controlled trials,
treating Kawasaki disease. The results of two large are necessary.
metaanalyses have shown that the combination of aspirin
and intravenous gamma globulin (IVIG) is superior to
aspirin alone in preventing coronary abnormalities [10, 59]. Conclusions
Although high-dose aspirin often is used to treat Kawa-
saki disease in the acute phase, data from the aforemen- Pediatric patients with a variety of conditions, including
tioned metaanalyses [10, 59] and an additional retrospective congenital and acquired heart disease and ischemic stroke,
analysis of 70 children [52] suggest that low-dose aspirin often are treated with antithrombotic therapy to prevent
has efficacy similar to that of high-dose aspirin in the acute adverse clinical events. Although children differ from
phase. Hsieh et al. [21] reported the rates for IVIG resis- adults in many respects, including their platelet biology and
tance, fever duration, and incidence of coronary artery the underlying conditions that necessitate antiplatelet use,
abnormalities in children who did not receive any aspirin few studies have assessed the optimal dosing, efficacy, and
until their fever was resolved and compared these rates with safety of antiplatelet regimens in the pediatric population.
those in published series that used a higher dose of aspirin. The minimal evidence available suggests that antiplatelet
Although data inferences are limited by the retrospective therapy is beneficial for certain pediatric patients, including
study design, the comparability in these outcome rates those who receive systemic-to-pulmonary shunts, undergo
suggest that high- or intermediate-dose aspirin may provide Fontan surgery, receive heart valves or cardiac assist
little benefit in the acute phase of Kawasaki disease. devices, or experience ischemic stroke or Kawasaki disease.
Evidence from a single case study [12] and a small These findings are reflected in the current guidelines out-
retrospective analysis [66] suggests that adding the GP 2b/ lined by the ACCP. However, future prospective studies are
3a inhibitor abciximab to IVIG and aspirin in the acute needed for better delineation of platelet response variability
phase of Kawasaki disease is beneficial in preventing the as well as the overall benefits and risks of antiplatelet
formation of additional coronary aneurysms and promoting therapies in neonates, infants, and older children.
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Pediatr Cardiol (2010) 31:454–461 459
Table 2 American College of Chest Physicians’ guidelines for antiplatelet therapy in neonates and children [38]a
Recommendation Grade
For children with mechanical prosthetic valves, VKA therapy should be implementedb 1A
For children with mechanical prosthetic valves who experience thrombotic events while receiving VKA therapy or who cannot 2C
tolerate VKA therapy, ASA should be used
Antiplatelet therapy, either ASA (1–5 mg/kg/day) or DP (3–10 mg/kg/day), should be instituted within 72 h of VAD placement 2C
For children who have an MBT shunt, postoperative ASA (1–5 mg/kg/day) or no antithrombotic therapy should be used compared 2C
with prolonged therapy using LMWH or VKA
For children who undergo the Norwood procedure, UFH immediately after the procedure, with or without ongoing antiplatelet 2C
therapy, should be used
For children who undergo Fontan surgery, ASA (1–5 mg/kg/day) or therapeutic UFH followed by VKAs should be used 1B
In the absence of a documented ongoing cardioembolic source, no anticoagulation or ASA therapy should be given to neonates with 1B
first AIS
For neonates with recurrent AIS, anticoagulant or aspirin therapy may be given 2C
For children with AIS not secondary to sickle-cell disease, cardioembolism, or dissection, UFH, LMWH, and ASA (1–5 mg/kg/day) 1B
are all acceptable options that should be used for 2 years or longer
Children who experience recurrent AIS or TIA while taking ASA should be switched to either clopidogrel or anticoagulant therapy 2C
(VKA or LMWH)
For children with Kawasaki disease, high-dose ASA (80–100 mg/kg/day) should be given as an antiinflammatory agent for up to 1B
14 days, followed by low-dose ASA (1–5 mg/kg/day) for 6–8 weeks as prevention against CAA
VKA vitamin K antagonist, ASA aspirin, DP dipyridamole, VAD ventricular assist device, LMWH low-molecular-weight heparin, UFH
unfractionated heparin, AIS acute ischemic stroke, CAA coronary artery aneurysm, TIA transient ischemic attack, MBT modified Blalock-Taussig
a
For a full description of the grading system, see Guyatt et al. [18]. Briefly, grade 1 recommendations are strong recommendations, whereas
grade 2 recommendations are weak recommendations; ‘‘A’’ indicates high-quality evidence, ‘‘B’’ moderate-quality evidence, and ‘‘C’’ low-
quality evidence
b
The pediatric recommendation is modeled after the adult recommendation
Acknowledgments This article was written and edited by the Cardiovascular Anesthesiologists endorsed by the Society for
authors, who take full responsibility for its content. Editorial assis- Cardiovascular Angiography and Interventions and the Society of
tance with searching the literature, coordinating revisions, and cre- Thoracic Surgeons. J Am Coll Cardiol 48:e1–e148
ating tables in the preparation of this articlet was provided by Melanie 5. Bradley SM, Sade RM, Crawford FA Jr, Stroud MR (1997)
Leiby, PhD, of Wolters Kluwer, and funded by Sanofi-Aventis and Anticoagulation in children with mechanical valve prostheses.
Bristol-Myers Squibb, Inc. The authors did not receive any com- Ann Thorac Surg 64:30–34; discussion 35–36
pensation for this work. 6. Carcao MD, Blanchette VS, Dean JA, He L, Kern MA, Stain AM,
Sparling CR, Stephens D, Ryan G, Freedman J, Rand ML (1998)
The platelet function analyzer (PFA-100): a novel in vitro system
for evaluation of primary haemostasis in children. Br J Haematol
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