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"Emergency medicine" 7 (70) 2015

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Thromboprophylaxis and Antithrombotic Therapy in Children and Newborns

Authors: Filyk O.V.
Lviv National Medical University named after Danylo Halytskyi, Department of Anesthesiology and Intensive Care, Lviv, Ukraine

Categories: Medicine of emergency

Sections: Clinical researches

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Summary

У статті наведено дані про фізіологічні особливості системи гемостазу в дітей різних вікових груп. Наведено епідеміологічні дані щодо частоти виявлення тромбозів та їх основних причин у дітей. Розглянуто показання до тромбопрофілактики та схеми, а також оптимальні стратегії щодо мене-джменту тромбозів у дітей відповідно до міжнародних рекомендацій.

В статье приведены данные о физиологических особенностях системы гемостаза у детей разных возрастных групп. Приведены эпидемиологические данные о частоте выявления тромбозов и их основных причин у детей. Рассмотрены показания к тромбопрофилактике и ее схемы, а также оптимальные стратегии менеджмента тромбозов у детей, основанные на международных рекомендациях.

The article presents the data on physiological characteristics of hemostasis system in children of different age groups. The epidemiological data on the incidence of thromboses and their main causes in children are presented. Indications and schemes of thromboprophylaxis were shown, as well as optimal strategies for the management of thrombosis in children according to international guidelines.


Keywords

тромбопрофілактика, гепарин, діти.

тромбопрофилактика, гепарин, дети.

thromboprophylaxis, heparin, children.

Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children.
The hemostatic system is incompletely developed at birth and matures throughout infancy. Both full-term and preterm neonates are born with low levels of most procoagulant proteins including all the contact activation factors and vitamin K-dependent factors. Similarly, levels of the major anticoagulant proteins are low at birth. Although often characterized as ‘immature’, the neonatal hemostatic system is nevertheless functionally balanced with no tendency toward coagulopathy or thrombosis. At birth, plasma concentrations of plasminogen are near 50% of adult values (21 mg/100 mL). The decreased levels of plasminogen in newborns slows the generation of plasmin and reduces the thrombolytic effects of streptokinase, urokinase and tissue plasminogen activator (tPA) in an in vitro fibrin clot system. A similar response occurs in children with acquired plasminogen deficiency. Supplementation with plasminogen increases the thrombolytic effect of all three agents. Compared with adult controls, neonatal platelets are hyporeactive to thrombin, adenosine diphosphate/epinephrine, and thromboxane A2. This hyporeactivity of neonatal platelets is the resultof a defect intrinsic to neonatal platelets. Paradoxically, the bleeding time is short in newborns because of increased RBC size, high hematocrit levels, and increased levels of multimeric forms of von Willebrand factor. 
The incidence of venous thromboembolism (VTE) is increasing in children as a result of therapeutic advances and improved clinical outcome in primary illnesses that previously caused mortality. VTE is mostly diagnosed in hospitalized children, especially sick newborns with central venous catheters and older children with a combination of risk factors. Infants older than 3 months and teenagers are the largest groups developing VTE. The most important triggering risk factors are the presence of central venous lines, cancer and chemotherapy. Pathological conditions such as severe infection, sickle cell disease, trauma and antiphospholipid syndrome are associated with the presence of a hypercoagulable state in children. The thrombotic risk in otherwise healthy children with a single identified thrombophilic defect appears to be extremely low. Venous thromboembolism in pediatric patients is mainly caused by combinations of prothrombotic risk factors for venous thromboembolic events and associated with underlying clinical conditions and a triggering risk factor. In addition, recurrence of VTE after withdrawal of anticoagulant treatment occurs in about 20% of patients after re-exposure to a triggering risk factor.
This article based on Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines and Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease: A Scientific Statement From the American Heart Association.
Thromboembolism (TE) in pediatric patients is rare and makes management studies a challenge, resulting in limited direct evidence. In children near 50% of all drugs used are unlicensed or off-label, refl ecting the paucity of specifi c trials in children. Thus, most recommendations are based on extrapolation from adults.
The use of antithrombotic drugs in pediatric patients differs from adults. First, the epidemiology of TE in pediatric patients differs from that seen in adults. Second, the hemostatic system is a dynamic, evolving entity that likely affects not only the frequency and natural history of TEs in children but also the response to therapeutic agents. Third, the distribution, binding, and clearance of antithrombotic drugs are age dependent.
Experts suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). Experts suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, experts suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). Experts suggest, for children receiving vitamin K antagonists (VKAs), that the drug be monitored to a target international normalized ratio (INR) of 2.5 (range, 2.0-3.0), except in the setting of prosthetic cardiac valves where experts suggest adherence to the adult recommendations (Grade 2C) . Experts suggest that INR monitoring with point-of-care monitors be made available where resources make this possible (Grade 2C). Experts suggest that when aspirin is used for antiplatelet therapy in children, it is used in doses of 1 to 5 mg/kg per day (Grade 2C). 
The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.

Bibliography

1. Antithrombotic Therapy and Prevention of Thrombosis. — 9th ed. — American College of Chest Physicians Evidence-Based Clinical Practice Guidelines / Paul Monagle, Anthony K. C. Chan, Neil A. Goldenberg [et al] // CHEST. — 2012. — Vol. 141 (2). — P. e737S-e801S. 
2. Outcome of Pediatric Thromboembolic Disease: A Report from the Canadian Childhood Thrombophilia Registry / Paul Monagle, Margaret Adams, Michael Mahoney, Kaiser Ali [et al] // Pediatric Research. — 2000. Vol. 47. — P. 763-766; doi:10.1203/00006450-200006000-00013.
3. Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease: A Scientific Statement From the American Heart Association / Therese M. Giglia, M. Patricia Massicotte, James S. Tweddell, Robyn J. Barst // Circulation. — 2013. — Vol. 128. — P. 2622-2703; doi: 10.1161/01.cir.0000436140.77832.7a.
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