Treatments for children
Most of the recommendations on antithrombotic therapy in children are based on the extrapolation of results from randomised studies of adults or from small cross sectional, and mainly retrospective, clinical studies of children. Although antithrombotic therapy in children usually follows the same indications as in adults, the distribution of diseases requiring antithrombotic therapy differs in the paediatric population. For example, some predisposing factors for thromboembolism are encountered only in paediatric populations. Most of the indications for antithrombotic therapy in children arise because of an underlying medical disorder or an intervention for the management of the disorder. Management of antithrombotic therapy in children differs from that in adults because of ongoing changes in physiology that may alter the thrombotic process and potentially influence the response of the body to antithrombotic therapy.
Drug treatments
Antiplatelet treatment
Aspirin, dipyramidole, and indomethacin are probably the most used antiplatelet treatments among children. Low doses of aspirin (antiplatelet doses) usually have minimal side effects in children, but in general aspirin should not be prescribed to children aged <16 years unless there are compelling clinical indications. The particular concerns about Reye's syndrome usually seem to be related to higher doses of aspirin (>40 mg/kg).
Heparin
Heparin is probably the most commonly used antithrombotic drug in children. Varying concentrations of antithrombin in the body during different developmental stages mean that the therapeutic concentration of heparin in children has to be maintained by regular checks of the activated partial thromboplastin time (APTT) or anti-Xa concentrations. The recommended therapeutic level of APTT is the one which corresponds to a heparin concentration of 0.2-0.4 U/ml or an anti-Xa concentration of 0.3-0.7 U/ml.
Adjusting low molecular weight heparin in children
| Anti-Xa level (U/ml) | Hold next dose? | Dose change? | Repeat anti-Xa measurement |
| <0.35 | No | Increase by 25% | 4 hours after next dose |
| 0.35-0.49 | No | Increase by 10% | 4 hours after next dose |
| 0.5-1.0 | No | No | Next day, then 1 week later, and monthly thereafter while receiving reviparin-Na treatment (4 hours after morning dose) |
| 1.1-1.5 | No | Decrease by 20% | Before next dose |
| 1.6-2.0 | 3 hours | Decrease by 30% | Before next dose then 4 hours after next dose |
| >2.0 | Until anti-Xa 0.5 U/ml | Decrease by 40% | Before next dose, then every 12 hours until anti-Xa level <0.5 U/ml |
In children, the advantages of low molecular weight heparin over unfractionated heparin are similar to those in adults. In addition, low molecular weight heparin may be preferred for children with difficult venous access because regular blood checks to monitor the therapeutic levels are not mandatory. The recommended therapeutic dose of a low molecular weight heparin is the one that reflects the plasma anti-Xa concentrations of 0.5-1.0 U/ml four to six hours after injection.
Oral anticoagulants
Certain problems are associated with the use of oral anticoagulants in children. Sensitivity to oral anticoagulants changes during different phases of life, especially during infancy, because of varying concentrations of vitamin K and vitamin K dependent proteins in the body. Neonates (during the first month of life) are especially sensitive because of their relative deficiency of vitamin K, and therefore warfarin should be avoided in such patients if possible. However, formula fed infants are resistant to oral anticoagulants because of a high concentration of vitamin K in their diet. In general, young children need more oral anticoagulation for each kilogram of body weight than older children and adults. Poor venous access (for international normalised ratio (INR) checks) and non-compliance are added problems of anticoagulation in children.
Recommended therapeutic ranges and duration of anticoagulation for a variety of disorders in children are usually similar to those for adults.
Thrombolytic treatment
Thrombolytic treatment is used primarily for maintaining catheter patency and in the management of thromboembolism that threatens the viability of the affected organ. Thrombolytic drugs are used locally or systemically and their concentration can be monitored with plasma fibrinogen levels or total clotting time. Decreased plasma plasminogen levels in newborns may reduce the thrombolytic actions of the drugs. Thrombolytic drugs pose similar risks to children as to adults.
Venous thromboembolism
Venous thromboembolism in children usually occurs secondary to an underlying disorder, such as in the upper arm secondary to a central venous line being inserted. Such lines are usually placed for intensive care management and treatment of cancer. The patency of these lines is traditionally maintained through therapeutic local instillation of urokinase for blocked lines or prophylactic intermittent boluses of heparin (which have doubtful efficacy).
Established venous thromboembolism requires removal of the predisposing factor and anticoagulation similar to that in adults (standard heparin for five days followed by maintenance with oral anticoagulation for at least three months). Oral anticoagulation can be started on the same day as heparin. Low molecular weight heparin is a useful option for maintaining anti-Xa level of 0.5-1.0 U/ml. Patients with a first recurrence of venous thromboembolism or with an initial episode with continuing risk factors either could be closely monitored for any early signs of thromboembolism or should be given anticoagulant drugs prophylactically after the period of initial therapeutic anticoagulation for the episode. Patients with a second recurrence of venous thromboembolism or with a first recurrence with continuing risk factors should be given anticoagulants for life, as in adults.
Arterial thromboembolism
The usual predisposing factors include placement of central and peripheral arterial catheters for cardiac catheterisation and intensive care settings. A bolus of heparin (50-150 U/kg) at the time of arterial puncture and continuous low dose heparin infusion are common methods for cardiac and umbilical artery catheterisation, respectively.
Commonly used drugs in children that affect INR values
| Drug | Usual effect on INR |
| Amiodarone | Increase |
| Aspirin | Increase or no change |
| Amoxicillin | Slight increase |
| Cefaclor | Increase |
| Carbamazepine | Decrease |
| Phenytoin | Decrease |
| Phenobarbital | Decrease |
| Cloxacillin | Increase |
| Prednisone | Increase |
| Co-trimoxazole | Increase |
| Ranitidine | Increase |
Prosthetic heart valves
Oral anticoagulation is needed in children with mechanical heart valves. An INR of 2.5-3.5 is recommended as the target range. Patients who are predisposed to high risk of thromboembolism despite anticoagulation treatment and those with thromboembolism while taking warfarin could benefit from the addition of antiplatelet drugs, such as aspirin (6-20 mg/kg/day) or dipyridamole (2-5 mg/kg/day), to oral anticoagulation.
Other cardiac disorders
No universally accepted guidelines or randomised trials exist for the antithrombotic therapy in patients undergoing operations where there is risk of thromboembolism (such asBlalock-Taussig shunts, Fontan operations, and endovascular stents). A variety of antithrombotic regimens have been used after these operations, including intraoperative heparin only and intraoperative heparin followed by oral anticoagulation or aspirin.
Common thrombophilic disorders
Inherited
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Activated protein C resistance (factor V Leiden mutation)
Inherited hyperhomocysteinaemia
Raised factor VIII levels
Prothrombin gene G20210 A variant
Acquired
Antiphospholipid syndrome
Acquired hyperhomocysteinaemia
Hereditary prothrombotic states
Deficiencies of protein C, protein S, or antithrombin III and factor V Leiden mutation can lead to thromboembolism especially in the presence of a secondary risk factor. Homozygous deficiency of these proteins could lead to fatal purpura fulminans in newborns, which is treated immediately by rapid replacement of these factors with fresh frozen plasma or protein concentrates. This is followed by careful initiation of lifelong oral anticoagulation to maintain the INR at higher levels of 3.0-4.5. Heterozygous patients could be given prophylactic antithrombotic therapy during exposure to secondary risk factors or be followed up with close observation.
Antithrombotic therapy in thrombophilia and miscellaneous conditions
A detailed discussion of management of thrombophilic disorders is beyond the scope of this article. The guidelines on the management of these disorders are based on small and non-controlled series of patients because of the paucity of randomised trials (as reviewed by the Haemostasis and Thrombosis Task Force in 2001).
Guidelines for antithrombotic therapy in inherited thrombophilia*
| Indication | Treatment |
| Primary prophylaxis | |
| Any surgery | Unfractionated heparin subcutaneously 5000 IU three times daily |
| Malignancy or orthopaedic surgery | Unfractionated heparin subcutaneously 5000 IU three times daily, possibly with replacement of deficient factors |
| Pregnancy | Unfractionated heparin subcutaneously 5000 IU three times daily |
| Pregnancy in antithrombin III deficiency | Therapeutic dose of unfractionated heparin to prolong APTT or dose adjusted warfarin (INR 2.0-3.0), except during first trimester and latter part of third trimester, when unfractionated heparin is used |
| Puerperium (for 4-6 weeks) | Unfractionated heparin subcutaneously 5000 IU three times daily or dose adjusted warfarin (INR 2.0-3.0) |
| Secondary prophylaxis | |
| First episode of thrombosis | Dose adjusted warfarin for 6 months |
| First episode of life threatening thrombosis, multiple deficiencies, continuing predisposing factor | Lifelong oral anticoagulation |
| Recurrent thrombosis | Lifelong oral anticoagulation |
| Treatment of established thrombosis | |
| Treatment of acute thrombosis | Unfractionated heparin to prolong APTT followed by oral anticoagulation treatment, possibly with replacement of the deficient factors |
*For full guidelines see Haemostasis and Thrombosis Task Force, Br J Haematol 2001;114:512-28
Low molecular weight heparins are increasingly used as alternatives to unfractionated heparin
Inherited thrombophilic disorders are genetically determined, and most of the affected patients are heterozygotes. Homozygotes are extremely rare. Antithrombin III, protein C, and protein S are produced in the liver and act by inactivating coagulation factors. Deficiency of these proteins could lead to uncontrolled activation of the coagulation cascade and therefore thromboembolism.
Activated protein C resistance is the commonest inherited thrombophilic disorder and accounts for 20-50% of cases. Antithrombin III deficiency is the rarest of the mentioned inherited thrombophilic disorders but carries the highest thrombogenic risk. High plasma concentration of homocysteine is linked to genetic enzyme deficiencies and low plasma concentrations of folate and vitamin B-6, and an investigation of vitamin B-12 metabolism is warranted.
Though thrombophilic disorders predispose patients to thromboembolism, the routine use of anticoagulation for primary prophylaxis entails greater risks than benefit (except probably in homozygotes). Therefore primary prophylaxis is warranted only in the presence of a second risk factor, and for as long as the risk factor lasts. Common predisposing factors that require prophylaxis include surgery, immobilisation, pregnancy and the puerperium, and oral contraception.
Special caution is needed when giving anticoagulation to patients with protein C deficiency. Because protein C is a vitamin K dependent factor, the administration of warfarin could lead to sudden decrease in protein C before any noticeable decrease in coagulation factors. This could cause enhanced thrombosis and diffuse skin necrosis. This adverse response can be avoided by gradual initiation of oral anticoagulation with low doses of warfarin, preferably overlapped by adequate heparinisation. In cases of severe deficiency, replacement of protein C is indicated before starting warfarin.
Little evidence exists to support the use of antithrombotic agents in hyperhomocysteinaemia. Although replacement of folic acid and vitamin B-6 has been shown to reduce plasma homocysteine levels, no study has found reduction in thromboembolic events with this intervention.
Recommendations from the College of American Pathologists consensus conference XXXVI: diagnostic issues in thrombophilia
Patients, and especially asymptomatic family members, should provide informed consent before thrombophilia testing is performed
Individuals testing positive for a thrombophilia need counselling on: Risks of thrombosis to themselves and their family members Importance of early recognition of the signs and symptoms of venous thromboembolism that would require immediate medical attention Risks and benefits of antithrombotic prophylaxis in situations in which their risk of thrombosis is increased, such as surgery or pregnancy
Laboratory testing for other inherited and acquired thrombophilias should be considered even after the identification of a known thrombophilia because more than one thrombophilia could coexist, compounding the risk for thrombosis in many cases
When available, World Health Organization (WHO) standards, or standards that can be linked to the WHO standard, should be used to calibrate funtional and antigenic assays
Effect of age and sex should always be taken into consideration when interpreting the results of antigenic and functional assays
Before concluding that a patient has an inherited thrombophilia, diagnostic assays for function or antigen should be repeated after excluding acquired aetiologies of the defect
Antiphospholipid syndrome
The long term prognosis for this syndrome is influenced by the risk of recurrent thrombosis. As with other thrombophilic disorders, primary prophylaxis is not indicated in the absence of other risk factors. A patient with one episode of thrombosis is at considerable risk of further thrombosis and should be given lifelong anticoagulation with warfarin as secondary prophylaxis. The target INR should be 2.0-3.0 (although some authorities advocate a higher INR level (⩾3.0)). Patients with this syndrome may be relatively resistant to warfarin and so will need high doses. However, some authorities believe that the antiphospholipid antibodies interfere with the generation of the INR and lead to spurious results. Consequently, other routes to monitoring anticoagulation may be needed.
Low molecular weight heparin is used increasingly in patients with various thrombophilia and seems to be safe and reliable.
Kawasaki disease
Aspirin continues to be used in Kawasaki disease despite a lack of unequivocal evidence from randomised trials of its benefit in reducing coronary artery aneurysm or thrombosis. Aspirin is used in anti-inflammatory doses (50-100 mg/kg/day) during the acute stage of the disease, followed by antiplatelet doses (1-5 mg/kg/day) for seven weeks or longer.
Further reading
Cumming AM, Shiach CR. The investigation and management of inherited thrombophilia. Clin Lab Haem 1999;21:77-92
Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001;119:S344-70
Streif W, Mitchell LG, Andrew M. Antithrombotic therapy in children. Curr Opin Pediatr 1999;11:56-64
Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guideline: investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28
Figure.
Indications for antithrombotic therapy in children
Figure.
Effect of age on dose of warfarin needed to sustain an international normalised ratio (INR) of 2.0-3.0 in 262 children. Younger children required significantly more warfarin than older children (P<0.001)
Figure.
Protocol for oral anticoagulation treatment to maintain an INR ratio of 2.0-3.0 for children
Acknowledgments
The figure showing effect of age on dose of warfarin in 262 children is adapted from Streif W et al, Curr Opin Pediatr 1999;11:56-64. The diagram of protocol for oral anticoagulation for children and the tables showing adjustment of low molecular weight heparin in children and commonly used drugs in children are adapted from Monagle P et al, Chest 2001;119:S344-70. The guidelines for antithrombotic therapy in inherited thrombophilia are adapted from the Haemostasis and Thrombosis Task Force, Br J Haemotol 2001;114:512-28. The box of recommendations from the College of Amercian Pathologists consensus conference on diagnostic issues in thrombophilia is adapted from Olson JD, Arch Pathol Lab Med 2002;126:1277-80.
Footnotes
Bernd Jilma is associate professor in the department of clinical pharmacology, Vienna University Hospital, Vienna, Austria. Sridhar Kamath is research fellow and Gregory Y H Lip is professor of cardiovascular medicine at the haemostasis, thrombosis, and vascular biology unit, university department of medicine, City Hospital, Birmingham.
The ABC of antithrombotic therapy is edited by Gregory Y H Lip and Andrew D Blann, senior lecturer in medicine, haemostasis, thrombosis, and vascular biology unit, university department of medicine, City Hospital, Birmingham. The series will be published as a book in spring 2003.