This is the current release of the guideline.

This guideline updates a previous version: Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):645S-87S.

Thrombosis in neonates and children

Prevention
Treatment

Cardiology
Critical Care
Emergency Medicine
Family Practice
Hematology
Internal Medicine
Neurology
Pediatrics

Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Nurses
Patients
Physicians
Psychologists/Non-physician Behavioral Health Clinicians
Social Workers

To provide evidence-based guidelines on the treatment of neonates and children with thrombosis

Neonates and children with thrombosis

1. Vitamin K antagonists (VKA)
2. Unfractionated heparin (UFH)
3. Low molecular weight heparin (LMWH) therapy
4. Aspirin
5. Dipyridamole
6. Clopidogrel
7. Monitoring
   • Anti-factor Xa assay
   • Activated partial thromboplastin time (aPTT)
   • International normalized ratio (INR)
   • Duration of anticoagulation therapy
   • Radiological (for children with cerebral sinovenous thrombosis [CSVT])
8. Thrombolysis (urokinase, tissue plasminogen activator [tPA])
9. Plasminogen (fresh frozen plasma)
10. Thrombectomy
11. Surgical intervention
12. Inferior vena cava filter placement
13. Umbilical artery catheter placement
14. Intravenous (IV) gamma globulin, warfarin (for children with Kawasaki's disease)
15. IV hydration, exchange transfusion and long-term transfusion program (in children with sickle cell disease)
16. Revascularization (for children with moyamoya)
17. Fresh frozen plasma, protein C concentrate, liver transplantation (for protein C deficiency)
18. Supportive care

• Mortality
• Incidence of thrombosis
• Recurrent thromboembolism
• Incidence of major and minor hemorrhage

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, or C). See "Grades of recommendations for antithrombotic agents" in the "Availability of Companion Documents" field and the "Rating Scheme for the Strength of the Recommendations." field.

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Summarizing Evidence

The electronic searches also included searches 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.

Expert Consensus (Consensus Development Conference)

Group-Specific Recommendations

In general, the guideline developers have endeavored to make their recommendations as specific as possible for patient subgroups differing according to risk. Whenever valid prognostic data were available, the guideline developers used them to estimate absolute effects and made recommendations accordingly. Unfortunately, reliable prognostic indexes are not usually available, limiting the extent to which such group-specific recommendations are possible.

Acknowledge Values and Preferences and Resource Use Underlying Recommendations

Under ideal circumstances, knowledge of average patient values and preferences would be available for every recommendation, the panel members would summarize these values and preferences, and they would be integrated into the recommendations that guideline developers make. The guideline developers asked all chapter chairs before beginning the searches for the relevant literature to identify recommendations that they believed were particularly sensitive to patients' values and preferences. Moderate-quality evidence regarding values and preferences bearing directly on the recommendations proved available for only the chapter that addresses antithrombotic therapy in patients with atrial fibrillation. The panelists bore in mind what average patient values and preferences may be; the process, however, is speculative.

The guideline developer's main strategy for dealing with this unsatisfactory situation is to make the values and preferences underlying the recommendations explicit whenever the panelists believed that value and preference issues were crucial for a recommendation.

In addition, the guideline developers involved three consultants with expertise in the area of values and preferences to collaborate with the chairs of two chapters and try to ensure that the guidelines adequately represented the views of patients. This collaboration led to extensive discussions among the chapter authors and the consultants and the reflection of these discussions in the associated values and preference statements.

Finalizing and Harmonizing Recommendations

After having completed the steps the guideline developers have described above, the guideline authors formulated draft recommendations before the conference, which laid the foundation for authors to work together and critique the recommendations. Figure 1 in the methodology companion (see "Availability of Companion Documents" field) shows the process of guideline development and review. Drafts of chapters that included draft recommendations were usually distributed for peer review to at least two panel members and were always reviewed by at least one panel editor before the conference. Written critiques were prepared and returned to the authors for revision of their work. At the plenary conference, a representative of each chapter presented potentially controversial issues in their recommendations. Chapter authors met to integrate feedback and consider related recommendations in other chapters 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 provided critical feedback. The editors of this supplement harmonized the chapters and resolved remaining disagreements between chapters through facilitated discussion. All major correspondence and discussions at the meeting were recorded in written and audio protocols and are publicly available.

*The guideline developers use the wording recommend for strong (Grade 1) recommendations and suggest for weak (Grade 2) recommendations.

For these guidelines, the guideline developers implemented recommendations of a recent American College of Chest Physicians (ACCP) task force on integrating resource allocation in clinical practice guidelines by restricting resource expenditure consideration to a small number of recommendations for which they were particularly relevant. The guideline developers relied on two consultants with expertise in economic assessment to help with the process of considering costs in those small numbers of recommendations that we considered very important to the decision.

Recommendations highly sensitive to resource allocation now include value and preference statements regarding how cost issues were integrated.

Refer to "Strategies for incorporating resource allocation and economic considerations" (see "Availability of Companion Documents" field) of the original guideline document for details of the cost analyses.

External Peer Review
Internal Peer Review

The American College of Chest Physicians (ACCP) Health Science Policy (HSP) established a process for the thorough review of all ACCP evidence-based clinical practice guidelines. After final review by the editors, the guidelines underwent review by appropriate NetWorks of the ACCP (for these guidelines, the Cardiovascular and Pulmonary Vascular NetWorks), the HSP, and the Board of Regents. The latter two have the right of approval or disapproval but usually work with the guideline authors and editors to make necessary revisions before final approval. Each group identified primary reviewers who read the full set of chapters as well as individual committee members who were responsible for reviewing one or more chapters. The reviewers considered both content and methodology as well as whether there was balanced, not biased, reporting and adherence to HSP processes. Finally, the CHEST editor-in-chief read and forwarded the manuscripts for nonbiased, independent, external peer review before acceptance for publication.

None provided

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

Appropriate monitoring and management of neonates and children receiving antithrombotic therapy

• Adverse effects of heparin: One cohort study reported bleeding in 1.5% (95% confidence interval [CI], 0.0–8.3%) of children treated with unfractionated heparin (UFH) for deep venous thrombosis (DVT)/pulmonary embolus (PE). A more recent study reports a major bleeding rate of 24% in children in pediatric intensive care units receiving UFH.
• Adverse effects of low molecular weight heparin (LMWH): Although the risk of major bleeding in neonates remains uncertain, studies have reported the risk of bleeding in neonates as part of larger patient populations. One pilot study reported no bleeding in seven infants < 2 months of age (0%; 95% CI, 0–47%). In a larger series, 4 of 37 infants had major bleeding (10.8%; 95% CI, 3–25.4%). Bleeding occurred locally (at the site of subcutaneous catheters in two newborns with little subcutaneous tissue), and into preexisting abnormalities in the central nervous system (CNS) in a further two newborns. These data suggests that subcutaneous catheters should be used with caution in newborns with little subcutaneous tissue. In a single institution cohort study of 146 courses of therapeutic enoxaparin given to children, major bleeds occurred in 4.8% (95% CI, 2–9.6%) of patients. In a randomized trial (n = 37) of reviparin, major bleeding occurred in 8.1% of patients (95% CI, 1.7–21.9%). There are no data on the frequency of osteoporosis, heparin induced thrombocytopenia (HIT), or other hypersensitivity reactions in children exposed to LMWH.
• Adverse Effects of vitamin K antagonists (VKAs): Bleeding is the main complication of VKA therapy. The risk of serious bleeding in children receiving VKAs for mechanical prosthetic valves is < 3.2% per patient-yr (13 case series). In one large cohort (391 warfarin-years, variable target range), the bleeding rate was 0.5% per patient-year.
• Adverse effects of aspirin: Neonates may be exposed to aspirin due to maternal ingestion (e.g., treatment for preeclampsia). Clearance of aspirin is slower in neonates, potentially placing them at risk for bleeding for longer periods of time. However, in vitro studies have not demonstrated an additive effect of aspirin on the hypofunction of newborn platelets, and evidence linking maternal aspirin ingestion to bleeding in newborns is weak. In neonates, additive antiplatelet effect must be considered if concurrent indomethacin therapy is required. In older children, aspirin rarely causes important hemorrhage, except in the presence of an underlying hemostatic defect or in children also treated with anticoagulants or thrombolytic therapy.
• Adverse Effects of Thrombolytic Therapy: Thrombolytic therapy has significant bleeding complications in children. Early literature reviews (including 255 patients) reported an incidence of bleeding requiring treatment with packed red blood cells (RBCs) of approximately 20% in pediatric patients. A more recent study reported bleeding in 68% of patients, with bleeding requiring transfusion occurring in 39%.

• Anticoagulation is contraindicated in active bleeding
• There are well-defined contraindications to thrombolytic therapy in adults. Clinicians should consider similar problems in children as relative but not absolute contraindications to thrombolytic therapy.

Limitations of These Guideline Development Methods

Limitations of these guidelines include the limited quantity and quality of available studies for some patient groups. Second, it is possible that some authors followed this methodology more closely than others, although the development process was centralized by an evidence-based practice center (EPC) and supervised by the editors. Third, it is possible that the guideline developers missed relevant studies in spite of the comprehensive searching process. Fourth, despite their efforts to begin centralizing the methodologic evaluation of all studies to facilitate uniformity in the validity assessments of the research incorporated into these guidelines, resources were insufficient to conduct this evaluation for all but a few of the recommendations in each chapter. Fifth, the guideline developers performed only few statistical pooling exercises of primary study results. Finally, sparse data on patient preferences and values represent additional limitations inherent to most guideline development methods.

An implementation strategy includes local educational programs and tools offered through the American College of Chest Physicians (ACCP) Board of Governors and select other locations. The Veterans Administration (VA) will also participate in a pilot project.

Getting Better
Living with Illness
Staying Healthy

Effectiveness
Safety

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

2001 Jan (revised 2008 Jun)

American College of Chest Physicians - Medical Specialty Society

American College of Chest Physicians

American College of Chest Physicians (ACCP) Expert Panel on Antithrombotic and Thrombolytic Therapy

Primary Authors: Paul Monagle, MD, MBBS, MSc, FCCP; Elizabeth Chalmers, MD; Anthony Chan, MBBS; Gabrielle deVeber, MD, MHSc; Fenella Kirkham, MBBC; Patricia Massicotte, MD, MSc; and Alan D. Michelson, MD

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

Participants: Giancarlo Agnelli, MD; Pierre Amarenco, MD; Jack E. Ansell, MD; Collin Baigent; Shannon M. Bates, MD; Kenneth A. Bauer, MD; Richard C. Becker, MD; Peter B. Berger, MD; David Bergqvist, MD, PhD; Rebecca J. Beyth, MD; Christopher P. Cannon, MD; Elizabeth A. Chalmers, MB, ChB, MD; Anthony K.C. Chan, MBBS; Clifford W. Colwell, Jr., MD; Anthony J. Comerota, MD; Deborah Cook, MD; Mark A. Crowther, MD; James E. Dalen, MD; Gabrielle deVeber, MD, MHSc; Maria Benedetta Donati, MD, PhD; James D. Douketis, MD; Andrew Dunn, MD; J. Donald Easton, MD; Michael Ezekowitz, MD; Margaret Fang; William H. Geerts, MD, FCCP; Alan S. Go, MD; Samuel Z. Goldhaber, MD, FCCP; Shaun D. Goodman, MD; Michael Gould, MD, FCCP; Ian A. Greer, MD; Andreas Greinacher, MD; David Gutterman, MD, FCCP, HSP; Jonathan L. Halperin, MD; John A. Heit, MD; Elaine M. Hylek, MD; Alan Jacobson, MD; Roman Jaeschke, MD, PhD; Amir K. Jaffer, MD; Susan Kahn; Clive Kearon, MBBCh, PhD; Fenella Kirkham, MBBC; Andreas Koster, MD, PhD; Michael R. Lassen, MD; Mark N. Levine, MD, MSc; Sandra Zelman Lewis, PhD; A. Michael Lincoff, MD; Gregory YH Lip, MD; Christopher Madias, MD; Warren J. Manning, MD; Daniel B. Mark, MD; M. Patricia Massicotte, MD, MSc; David Matchar, MD; Thomas W. Meade, DM, FCCP; Venu Menon, MD; Tracy Minichiello, MD; Paul Monagle, MBBS, MSc, MD, FCCP; Christopher M. O'Connor, MD; Patrick O'Gara, MD; E. Magnus Ohman, MD; Ingrid Pabinger, MD; Gualtiero Palareti, MD; Carlo Patrono, MD; Stephen G. Pauker, MD; Graham F. Pineo, MD; Jeffrey J. Popma, MD; Gary Raskob, PhD; Gerald Roth, MD; Ralph L. Sacco, MD; Deeb N. Salem, MD, FCCP; Charles-Marc Samama, MD, FCCP; Meyer Michel Samama, MD; Sam Schulman, MD, PhD; Daniel Singer, MD; Michael Sobel, MD; Shoshanna Sofaer, DrPH; Alex C. Spyropoulos, MD FCCP; Ph. Gabriel Steg, MD; Philip Teal, MD; Raymond Verhaeghe, MD; David A. Vorchheimer, MD; Theodore E. Warkentin, MD; Jeffrey Weitz, MD

Dr. Professor Monagle discloses that he has received grant monies from the University of Melbourne, the National Health and Medical Research Council of Australia, Roche, and Stago.

Dr. Chan reveals no real or potential conflicts of interest or commitment.

Dr. Massicotte discloses that she has received grant monies from the Canadian Institutes for Health Research. She has also received consultant fees from Bristol-Myers Squibb, Sanofi-Aventis, Berlin Heart, Boehringer Ingelheim, Bayer, Pfizer, and Azai.

Dr. Chalmers reveals no real or potential conflicts of interest or commitment.

Dr. Michelson discloses that he has received grant monies from Accumetrics, Arena Pharmaceuticals, Dade Behring, GL Synthesis, Lilly, Daiichi Sankyo, McNeil Consumer Healthcare, Sanofi-Aventis, and Bristol-Myers Squibb. He has also served on an advisory committee for Lilly, Daiichi Sankyo, Sanofi-Aventis, and Bristol-Myers Squibb.

Dr. deVeber reveals no real or potential conflicts of interest or commitment.

Professor Kirkham reveals no real or potential conflicts of interest or commitment.

American College of Clinical Pharmacy - Medical Specialty Society
American Society of Health-System Pharmacists - Professional Association

This is the current release of the guideline.

This guideline updates a previous version: Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):645S-87S.

None available

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 was updated by ECRI Institute on December 9, 2008. The updated information was verified by the guideline developer on January 7, 2009.

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