This is the current release of the guideline.

This guideline updates a previous version: Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001 Jan;119(1 Suppl):344S-370S.

• Thromboembolic disorders, including the following:
  • Venous thromboembolic complications
  • Arterial thromboembolic complications
  • Myocardial infarction
  • Some forms of strokes
• Conditions, diseases, or interventions that predispose a patient to thromboembolism, including the following:
  • Mechanical or biological prosthetic heart valves
  • Cardiac catheterization
  • Central arterial catheters
  • Umbilical arterial catheterization (UAC)
  • Stage 1 Norwood procedure
  • Endovascular stents
  • Blalock-Taussig shunts
  • Fontan surgery
  • Central venous catheters
  • Atrial venous fibrillation
  • Kawasaki's disease
  • Cardiopulmonary bypass
  • Hemodialysis
  • Purpura fulminans
  • Dilated cardiomyopathy

Management
Prevention
Treatment

Cardiology
Critical Care
Emergency Medicine
Family Practice
Pediatrics
Pulmonary Medicine

Physicians

• To detail the evidence showing that the interaction of antithrombotic agents with the hemostatic system of young patients differs from that of adult patients
• To describe the mechanisms of action, therapeutic ranges, dose regimes, monitoring requirements, factors influencing dose-response relationships, and side effects of antithrombotic, antiplatelet, and thrombolytic agents in neonates and children
• To discuss background information regarding the biological rationale related to specific antithrombotic agents, and evidence regarding appropriate administration and side effects, and to review evidence regarding thromboembolic markers
• To provide evidence-based clinical practice guidelines to assist clinicians in preventing and effectively treating thrombotic disorders in specific pediatric patient populations

Pediatric patients who are candidates for antithrombotic therapy

Note: Throughout this article, the term pediatric patients is used to refer to all neonates and children (i.e., from birth to 16 years of age). The term neonates refers to infants from birth to 28 days of age corrected for gestational age. The term children refers to patients 28 days to 16 years of age.

Prevention or Treatment

Pharmacotherapy

1. Low-molecular-weight heparin (LMWH) such as, reviparin and enoxaparin
2. Unfractionated heparin (UFH)
3. Protamine sulfate to reverse heparin therapy
4. Vitamin K antagonists (VKAs)
5. Reversal of oral anticoagulation therapy with vitamin K1
6. Aspirin therapy
7. Oral anticoagulation therapy in combination with aspirin therapy and/or dipyridamole
8. Thrombolytic agents (tissue plasminogen activator (tPA), streptokinase, urokinase)

   Note: The following antithrombotic and antiplatelet therapies are considered but not recommended: danaparoid (Orgaran), ticlopidine and clopidogrel, and glycoprotein (GP) IIb/IIIa antagonists (abciximab, tirofiban, and eptifibatide).

Other Related Treatment

1. Treatment of bleeding:
   • Transfusions of platelet concentrates and/or the use of products that enhance platelet adhesion
   • Stopping an infusion of the thrombolytic agent, followed by administering a cryoprecipitate, other blood products as indicated, or anti-fibrinolytic agent
2. Fresh frozen plasma (FFP) or protein C concentrate

Management

Oral Anticoagulation Monitoring

1. International normalized ratio (INR)
2. Activated partial thromboplastin time (aPTT)
3. Anti-factor Xa levels
4. Pediatric anticoagulation clinics
5. Whole-blood prothrombin time/international normalized ratio (INR) monitors for home use

Effectiveness and safety of treatments, as evidenced by the following:

• Rates of thromboembolic complications
• Rates of hemorrhagic complications
• Mortality
• Recurrence rates
• Patency

Hand-searches of Published Literature (Primary Sources)
Searches of Electronic Databases

Not stated

Weighting According to a Rating Scheme (Scheme Given)

The rating scheme framework captures the trade-off between benefits and risks (1 or 2) (and the methodological quality of the underlying evidence (A, B, C+, or C). See "Rating Scheme for the Strength of the Recommendations."

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Summarizing Evidence

The electronic searches also included searching for systematic reviews. If authors were satisfied with a recent high-quality systematic review, evidence from that review provided a foundation for the relevant recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever possible, the evidence base of the recommendations. Pooling offers the advantage of obtaining more precise estimates of treatment effects and allows for a greater generalizability of results. However, pooling also bears the risk of spurious generalization. In general, the summary estimates of interest were the different types of outcomes conveying benefit and downsides (i.e., risk, burden, and cost).

Expert Consensus (Consensus Development Conference)

The strength of any recommendation depends on the following two factors: the trade-off between the benefits and the risks, burdens, and costs; and the strength of the methodology that leads to the treatment effect. The guideline developers grade the trade-off between benefits and risks in the two categories: 1, in which the trade-off is clear enough that most patients, despite differences in values, would make the same choice; and 2, in which the trade-off is less clear, and individual patients’ values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large treatment effects, and the risks and costs of therapy are small, treatment for average patients with compatible values and preferences can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically rigorous studies providing Grade A evidence and recommendations may still be weak (Grade 2). Uncertainty may come from less precise estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the balance of positive and negative impacts of treatment on the strength of recommendations. In situations in which there is doubt about the value of the trade-off, any recommendation will be weaker, moving from Grade 1 to Grade 2.

Grade 1 recommendations can only be made when there is a relatively clear picture of both the benefits and the risks, burdens, and costs, and when the balance between the two clearly favors recommending or not recommending the intervention for the typical patient with compatible values and preferences. A number of factors can reduce the strength of a recommendation, moving it from Grade 1 to Grade 2. Uncertainty about a recommendation to treat may be introduced if the following conditions apply: (1) the target event that is trying to be prevented is less important (confident recommendations are more likely to be made to prevent death or stroke than asymptomatic deep vein thrombosis); (2) the magnitude of risk reduction in the overall group is small; (3) the probability of the target event is low in a particular subgroup of patients; (4) the estimate of the treatment effect is imprecise, as reflected in a wide confidence interval (CI) around the effect; (5) there is substantial potential harm associated with therapy; or (6) there is an expectation for a wide divergence in values even among average or typical patients. Higher costs would also lead to weaker recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater the influence of individual patient values in decision making. Virtually all patients, if they understand the benefits and risks, will take aspirin after experiencing a myocardial infarction (MI) or will comply with prophylaxis to reduce the risk of thromboembolism after undergoing hip replacement. Thus, one way of thinking about a Grade 1 recommendation is that variability in patient values is unlikely to influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual patient values may influence treatment decisions even among patients with average or typical preferences.

Grade 2 recommendations are those in which variation in patient values or individual physician values will often mandate different treatment choices, even among average or typical patients. An alternative, but similar, interpretation is that a Grade 2 recommendation suggests that clinicians conduct detailed conversations with patients to ensure that their ultimate recommendation is consistent with the patient's values.

*These situations include RCTs with both lack of blinding and subjective outcomes, where the risk of bias in measurement of outcomes is high, or RCTs with large loss to follow-up.

While conference participants agreed that recommendations should reflect economic considerations, incorporating costs is fraught with difficult challenges. For most recommendations, formal economic analyses are unavailable. Even when analyses are available, they may be methodologically weak or biased. Furthermore, costs differ radically across jurisdictions, and even sometimes across hospitals within jurisdictions.

Because of these challenges, the guideline developers consider economic factors only when the costs of one therapeutic option over another are substantially different within major jurisdictions in which clinicians make use of these recommendations. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that are designated as Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations. Furthermore, recommendations change (either in direction or with respect to grade) only when the guideline developers believe that costs are high in relation to benefits. Instances in which costs have influenced recommendations are labeled in the "values and preferences" statements associated with the recommendation.

External Peer Review
Internal Peer Review

The guideline authors formulated draft recommendations prior to the conference that served as the foundation for authors to work together and critique the recommendations. Drafts of all articles including draft recommendations were available for review during the conference. A representative of each article presented potentially controversial issues in their recommendations at plenary meetings. Article authors met to integrate feedback, to consider related recommendations in other articles, and to revise their own guidelines accordingly. Authors continued this process after the conference until they reached agreement within their groups and with other author groups who had provided critical feedback. Finally, the editors of this supplement harmonized the articles and resolved remaining disagreements through facilitated discussion.

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Appropriate use of antithrombotic therapy in selected pediatric populations may help clinicians prevent, manage, and treat thromboembolic complications, while minimizing the risk of adverse effects, such as bleeding, heparin induced thrombocytopenia, and osteoporosis.

• Heparin. Further studies are required to determine the true frequency of heparin-induced bleeding in children. There are only three case reports of pediatric heparin-induced osteoporosis, and in two of them patients received concurrent steroid therapy. The third received high-dose intravenous (IV) heparin therapy for a prolonged period. However, given the convincing relationship between heparin and osteoporosis in adults, the long-term use of heparin in children should be avoided when other alternative anticoagulant agents are available. There have been a number of case reports of pediatric heparin-induced thrombocytopenia (HIT) in the literature, and the patients described in those case reports range in age from 3 months to 15 years.
• Low-molecular-weight heparin (LMWH). Although the risk of major bleeding is not precisely known in neonates, there are studies reporting the risk of bleeding in neonates as part of larger patient populations. There are no data on the frequency of osteoporosis, HIT, or other hypersensitivity reactions secondary to LMWH use in children.
• Vitamin K Antagonists (VKAs). Bleeding is the main complication of VKAs. The risk of serious bleeding in children receiving VKAs for mechanical prosthetic valves is <3.2% per patient-year (13 case series). Nonhemorrhagic complications of VKAs, such as tracheal calcification or hair loss, have been described on rare occasions in young children. Two cohort studies have described reduced bone density in children who have received warfarin for >1 year. However, these were uncontrolled studies, and the role of the underlying disorders in reducing bone density remains unclear.
• Aspirin. The clearance of aspirin is slower in neonates potentially placing them at risk for bleeding for longer periods of time. In neonates, additive antiplatelet effect must be considered if concurrent indomethacin therapy is required. In older children, aspirin rarely causes clinically important hemorrhaging, except in the presence of an underlying hemostatic defect or in children who also have been treated with anticoagulant or thrombolytic therapy. The relatively low doses of aspirin used as antiplatelet therapy, compared to the much higher doses used for anti-inflammatory therapy, seldom cause other side effects. For example, although aspirin is associated with Reye syndrome, this appears to be a dose-dependent effect of aspirin and is usually associated with doses of >40 mg/kg.
• Thrombolytic Therapy. Thrombolytic therapy has been reported to have significant bleeding complications in children, occurring in 68% of patients, with bleeding requiring transfusion in 39%. The prolonged duration of thrombolytic infusion was associated with increased bleeding. Earlier literature reviews (including 255 patients) had concluded that the incidence of bleeding requiring treatment with packed red blood cells (RBCs) was approximately 20% in pediatric patients. The most frequent problem was bleeding at sites of invasive procedures that required treatment with blood products. Another review reported intracranial hemorrhage (ICH) in 14 of the 929 (1.5%) analyzed. When subdivided according to age, ICH was identified in 2 of 468 children (0.4%) after the neonatal period, 1 of 83 term infants (1.2%), and 11 of 86 preterm infants (13.8%). However, in the largest study of premature infants included in this review, the incidence of ICH was the same in patients in the control arm of the study, who had not received thrombolytic therapy.

• Danaparoid sodium (Orgaran) is predominantly removed from the circulation through the kidneys. Consequently, its use is contraindicated in patients with severe impaired renal function.
• There are well-defined contraindications to thrombolytic therapy in adults. These include a history of stroke, transient ischemic attacks, other neurologic disease, and hypertension. Similar problems in children should be considered as relative, but not absolute, contraindications to thrombolytic therapy.

Interpreting the Recommendations

Clinicians, third-party payers, institutional review committees, or the courts should not construe these guidelines in any way as absolute dictates. In general, anything other than a Grade 1A recommendation indicates that the article authors acknowledge that other interpretations of the evidence, and other clinical policies, may be reasonable and appropriate. Even Grade 1A recommendations will not apply to all circumstances and all patients. For instance, the guideline developers have been conservative in their considerations of cost and have seldom downgraded recommendations from Grade 1 to Grade 2 on the basis of expense. As a result, in jurisdictions in which resource constraints are severe, alternative allocations may serve the health of the public far better than some of the interventions that are designated as Grade 1A. This will likely be true for all less industrialized countries and, with the increasing promotion of expensive drugs with marginal benefits, may be increasingly true for wealthier nations.

Similarly, following Grade 1A recommendations will at times not serve the best interests of patients with atypical values or preferences or of those whose risks differ markedly from those of the usual patient. For instance, consider patients who find anticoagulant therapy extremely aversive, either because it interferes with their lifestyle (e.g., prevents participation in contact sports) or because of the need for monitoring. Clinicians may reasonably conclude that following some Grade 1A recommendations for anticoagulation therapy for either group of patients will be a mistake. The same may be true for patients with particular comorbidities (e.g., a recent gastrointestinal bleed or a balance disorder with repeated falls) or other special circumstances (e.g., very advanced age) that put them at unusual risk.

The guideline developers trust that these observations convey their acknowledgment that no recommendations or clinical practice guidelines can take into account the often compelling and unique features of individual clinical circumstances. No clinician, and no body charged with evaluating a clinician’s actions, should attempt to apply these recommendations in a rote or blanket fashion.

Limitations of Guideline Development Methods

The limitations of these guidelines include the possibility that some authors followed this methodology more closely than others, although the development process was centralized and supervised by the editors. Second, it is possible that the guideline developers missed relevant studies despite the comprehensive searching process. Third, the guideline developers did not centralize the methodological evaluation of all studies to facilitate uniformity in the validity assessments of the research incorporated into these guidelines. Fourth, if high-quality meta-analyses were unavailable, the guideline developers did not statistically pool primary study results using meta-analysis. Finally, sparse data on patient preferences and values, resources, and other costs represent additional limitations that are inherent to most guideline development methods.

Guideline Implementation Strategies

A full review of implementation strategies for practice guidelines is provided in the companion document titled "Antithrombotic and Antithrombolytic Therapy: From Evidence to Application." The review suggests that there are few implementation strategies that are of unequivocal, consistent benefit, and that are clearly and consistently worth resource investment. The following is a summary of the recommendations (see "Major Recommendations" for a definition of the recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend that appreciable resources be devoted to distribution of educational material (Grade 2B).

They also suggest that:

• Few resources be devoted to educational meetings (Grade 2B)
• Few resources be devoted to educational outreach visits (Grade 2A)
• Appreciable resources be devoted to computer reminders (Grade 2A)
• Appreciable resources be devoted to patient-mediated interventions to encourage uptake of the guidelines (Grade 2B)
• Few resources be devoted to audit and feedback (Grade 2B)

Getting Better
Living with Illness
Staying Healthy

Effectiveness
Safety

Not applicable: The guideline was not adapted from another source.

2001 Jan (revised 2004 Sep)

American College of Chest Physicians - Medical Specialty Society

Funding was provided through an unrestricted educational grant by AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

American College of Chest Physicians Consensus Panel on Antithrombotic and Thrombolytic Therapy

Primary Authors: Paul Monagle, MBBS, MSc, MD, FCCP; Anthony Chan, MBBS; Patti Massicotte, MD, MSc; Elizabeth Chalmers, MDChB, MD; Alan D. Michelson, MD

Committee Co-Chairs: Jack Hirsh, MD, FCCP (Chair); Gregory W. Albers, MD; Gordon H. Guyatt, MD, MSc; Holger J. Schünemann, MD, MSc, PhD, FCCP

Participants: Giancarlo Agnelli, MD; Amin Al-Ahmad, MD; Pierre Amarenco, MD; Jack E. Ansell, MD; Shannon M. Bates, MD; Richard C. Becker, MD; Peter B. Berger, MD; David Bergqvist, MD, PhD, FRCS; Rebecca J. Beyth, MD, MSc; Stewart Brower, MLIS; Harry R. Buller, MD; Henry I. Bussey, PharmD, FCCP; Christopher P. Cannon, MD, FACC; Elizabeth A. Chalmers, MB, ChB, MD, MRCP(UK). FRCPath; Anthony K.C. Chan, MD; G. Patrick Clagett, MD; Barry Coller, MD; Clifford W. Colwell, MD; Deborah Cook, MD, MSc; James E. Dalen, MD, MPH, FCCP; J. Donald Easton, MD; Michael Ezekowitz, MD; Garret A. Fitzgerald, MD; William H. Geerts, MD, FCCP; Jeffrey S. Ginsberg, MD, FCCP; Alan S. Go, MD; Shaun D. Goodman, MD, FACC; Ian A. Greer, MD, FRCP, FRCOG; Andreas Greinacher, MD; Jeremy Grimshaw, MD, PhD; Cindy Grines, MD; Jonathan L. Halperin, MD; Robert A. Harrington, MD; John Heffner, MD, MPH; John A. Heit, MD; Judith S. Hochman, MD, FACC; Dieter Horstkotte, MD, FESC; Russell D. Hull, MBBS, MSc, FCCP; Elaine Hylek, MD; Thomas M. Hyers, MD, FCCP; Mark R. Jackson, MD; Alan Jacobson, MD; Roman Jaeschke, MD, MSc; Ajay Kakkar BSc, PhD; Clive Kearon, MD, PhD, FCCP; Matthew Kraay; Michael R. Lassen, MD; Mark N. Levine, MD, MSc; Alessandro Liberati, MD; Gregory YH Lip, MD, FESC, FACC; Warren J. Manning, MD; M. Patricia Massicotte, MD, MSc, FRCPC, MSc; Thomas W. Meade, MD; Venu Menon, MD, FACC; Alan D. Michelson, MD; Nancy Miller, RN; Paul Monagle, MBBS, MSc, MD, FRACP, FRCPA, FCCP; Heather Munger, MLS; Christopher M. O’Connor, MD; Martin O’Donnell, MD; E. Magnus Ohman, MD, FCCP; Carlo Patrono, MD; Stephen G. Pauker, MD; Graham F. Pineo, MD; Leon Poller, MD; Jeffrey J. Popma, MD; Martin H. Prins, MD; Robert Raschke, MD, MS; Gary Raskob, PhD; Joel G. Ray, MD, MSc; Gerald Roth, MD; Ralph L. Sacco, MD; Deeb N. Salem, MD, FCCP; Meyer M. Samama, MD; Andrew Schafer; Sam Schulman, MD, PhD; Daniel Singer, MD; Michael Sobel, MD; Paul D. Stein, MD, FCCP; Marco Tangelder, MD; Victor F. Tapson, MD, FCCP; Philip Teal, MD; Raymond Verhaeghe, MD; David A. Vorchheimer, MD; Theodore E. Warkentin, MD; Jeffrey Weitz, MD; Robert G. Wilcox, MD

Dr. Chan has received research funding from Leo Pharma and Pfizer, and has received honoraria for his participation on the advisory boards from Aventis Pharma, Bayer, and Wyeth.

Dr. Massicotte has received research funding from Leo Pharma and Pfizer and AstraZeneca and has received honoraria for her participation on the advisory boards and/or as a speaker at educational events from AstraZeneca, Aventis Pharma, Lifescan, Leo Pharma, Sanofi-Synthelabo-Organon, and Bristol-Myers Squibb.

Dr. Michelson has received research funding from Centocor, Lilly, Bristol-Myers Squibb and Sanofi-Synthelabo.

This is the current release of the guideline.

This guideline updates a previous version: Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001 Jan;119(1 Suppl):344S-370S.

This summary was completed by ECRI on July 30, 2001. The information was verified by the guideline developer on October 31, 2001.This NGC summary was updated by ECRI on December 9, 2004. The updated information was verified by the guideline developer on January 12, 2005. This summary was updated by ECRI on March 6, 2007 following the U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin sodium). This summary was updated by ECRI Institute on June 22, 2007 following the U.S. Food and Drug Administration (FDA) advisory on heparin sodium injection. This summary was updated by ECRI Institute on September 7, 2007 following the revised U.S. Food and Drug Administration (FDA) advisory on Coumadin (warfarin). This summary was updated by ECRI Institute on March 14, 2008 following the updated FDA advisory on heparin sodium injection.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.