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Antithrombotic Therapy in Children FREE TO VIEW

Paul Monagle, MBBS; Alan D. Michelson, MD; Edward Bovill, MD; Maureen Andrew, MD, Chair
Author and Funding Information

Correspondence to: Maureen Andrew, MD, Pediatric Thrombosis and Haemostasis Program, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada; e-mail: christine.warner@sickkids.on.ca

Chest. 2001;119(1_suppl):344S-370S. doi:10.1378/chest.119.1_suppl.344S
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Antithrombotic therapy is required for the prevention and treatment of thromboembolic complications in specific pediatric patient populations. Recommendations for antithrombotic therapy in children have been loosely extrapolated from recommendations for adults because thromboembolic events in children were rare enough to hinder the testing of specific therapeutic modalities, yet were common enough to present significant management dilemmas that required therapeutic intervention.12 However, the optimal prevention and treatment of thromboembolisms (TEs) in children likely differ from those of adults because of important ontogenic features of hemostasis that affect both the pathophysiology of the thrombotic processes and the response to antithrombotic agents.

Advances in tertiary-care pediatrics, paradoxically, have resulted in rapidly increasing numbers of children requiring antithrombotic therapy. Intervention trials are now both feasible and urgently needed to provide validated guidelines for antithrombotic therapy in children. Since the first publication of this article in the 1995 CHEST antithrombotic supplement,3at least five multinational, randomized, controlled intervention trials assessing specific aspects of anticoagulant therapy in children have been initiated, and one of these is now complete.46 Many more rigorous trials are needed. Until the results of these trials are available, modified adult guidelines remain the primary source for recommendations in children.

This article is divided into three parts. In the first section, the evidence showing that the interaction of antithrombotic agents with the hemostatic system of the young differs from that of adults is presented, as well as the indications, monitoring, therapeutic range, factors influencing dose-response relationships, and side effects of antithrombotic agents in children. In the second section, the specific indications for antithrombotic therapy in pediatric patients are discussed. In the third section, the current studies, ongoing difficulties, and key areas requiring further multicenter trials assessing aspects of anticoagulant therapy in children are briefly discussed. Many of the recommendations are extrapolated from clinical trials in adults and are interpreted within the context of the available information for pediatric patients.

MEDLINE searches of the literature were conducted from 1966 to 1999 using combinations of key words (eg, children, newborns, heparin, warfarin, aspirin, antiplatelet agents, thrombolysis, thrombosis, embolism, and mechanical and biological prosthetic heart valves) and were supplemented by additional references located through the bibliographies of listed articles. All articles were graded by design and methodology. Recommendations were based on the strength of the study methods and on a benefit-risk assessment.

Mechanism of Action

The anticoagulant activities of heparin, which are mediated by catalysis of antithrombin (AT), can be impaired in the presence of decreased plasma levels of AT. Some pediatric patients requiring heparin therapy have very low levels of AT, reflecting physiologic, congenital, and/or acquired etiologies. For example, plasma concentrations of AT are physiologically low at birth (approximately 0.50 U/mL) and increase to adult values by 3 months of age.79 Sick premature newborns, a population of children at significant risk for TEs, frequently have plasma levels of AT that are < 0.30 U/mL, potentially influencing their response to heparin therapy.910 Fetal reference ranges are now available and show that AT levels range from 0.20 to 0.37 U/mL at gestational ages of 19 to 38 weeks.11

Heparin functions as an antithrombotic agent by catalyzing the ability of AT to inactivate specific coagulation enzymes, of which thrombin is the most sensitive.1213 The capacity of plasmas from newborns to generate thrombin is both delayed and decreased compared to adults1415 and is similar to plasma from adults receiving therapeutic amounts of heparin therapy.16 Following infancy, the capacity of plasmas to generate thrombin increases but remains approximately 25% less than for adults throughout childhood.16 At heparin concentrations in the therapeutic range, the capacity of plasma to generate thrombin is delayed and decreased by 50 to 25% in newborns and children, respectively, compared to adults.14,16 These observations support the hypothesis that the optimal dosing of heparin will differ in pediatric patients from that of adults.

Therapeutic Range

Therapeutic doses of heparin are the amounts of heparin required to achieve the adult therapeutic range based on the activated partial thromboplastin time (APTT). The recommendations for standardizing APTT values to heparin levels in adults should be extrapolated to children. The recommended therapeutic range for the treatment of venous TEs in adults is an APTT that reflects a heparin level by protamine titration of 0.2 to 0.4 U/mL or an anti-factor(F) Xa level of 0.3 to 0.7 U/mL.17In pediatric patients, APTT values correctly predict therapeutic heparin concentrations approximately 70% of the time.18


The doses of heparin required in pediatric patients to achieve adult therapeutic APTT values have been assessed using a weight-based nomogram (in one prospective cohort study).18 A bolus dose of 50 U/kg was insufficient, resulting in subtherapeutic APTT values in 60% of children.18Bolus doses of 75 to 100 U/kg result in therapeutic APTT values in 90% of children (unpublished data). Maintenance heparin doses are age-dependent, with infants having the highest requirements (28 U/kg/h) and children > 1 year of age having lower requirements (ie, 20 U/kg/h) (Table 1 ). The doses of heparin required for older children are similar to the weight-adjusted requirements in adults (18 U/kg/h).19 The duration of heparin therapy for the treatment of deep venous thrombosis (DVT), again extrapolated from adult data, is a minimum of 5 days and 7 to 10 days for extensive DVT or pulmonary embolism (PE).2021 Oral anticoagulant (OA) therapy can be initiated on day 1 of heparin therapy, or later if 7 to 10 days of heparin therapy is required.22


There are at least two plausible explanations for the increased heparin requirement in young children. First, heparin is cleared more quickly in the young compared to adults in animal models23 and humans.2425 Second, the delay in diagnosis of TEs in children may result in more extensive disease at the time of presentation, accelerating heparin clearance.2627


An appropriate dosage adjustment of IV heparin therapy can be problematic. Nomograms are convenient to use and have been successful in achieving therapeutic APTT levels in a timely manner in adults.19,2829 A nomogram initially used in adults was adapted, tested, and modified for children (Table 1).,18,28 Heparin-dosing nomograms can be adapted into preprinted order sheets that facilitate rapid anticoagulation. Point-of-care APTT monitors are now available. However, to date and to our knowledge, there have been no studies validating the use of these instruments in children.

Adverse Effects

There are at least three clinically important adverse effects of heparin. First, bleeding, a major complication of heparin in adults, is discussed in detail elsewhere in this supplement (see page 108). One cohort study in children suggests that major bleeding from heparin therapy is not frequent in the treatment of DVT/PE in children.18 However, many children were treated with suboptimal amounts of heparin in this study,18 and there are case reports of major bleeding in children due to heparin. The risk of bleeding may increase when therapeutic doses of heparin are used more uniformly, particularly in children with serious underlying disorders. A second adverse effect is osteoporosis.30 There are only three case reports of pediatric heparin-induced osteoporosis, in two of which patients received concurrent steroid therapy.3032 The third patient received high-dose IV heparin therapy for a prolonged period.31 However, given the convincing relationship between heparin and osteoporosis in adults, long-term use of heparin in children should be avoided when other alternative anticoagulants are available. The third adverse effect is the association of thrombocytopenia with heparin therapy in pediatric patients.3334 There have been a number of case reports of pediatric heparin-induced thrombocytopenia (HIT) in the literature in patients ranging in age from 3 months to 15 years.3539 Five cases were due to therapeutic heparin, and one was due to prophylactic heparin to maintain a central venous line (CVL). However, there remain no well-designed studies to assess the incidence or natural history of HIT in children. A high index of suspicion is required to diagnose HIT in children, as many patients in the neonatal ICU or pediatric ICU who are exposed to heparin have multiple reasons for thrombocytopenia and/or thrombosis. Protocols for the use of danaparoid in adults have been adapted for children, but there is limited experience with their use (Table 2 ).,35,37,4041

Treatment of Heparin-Induced Bleeding

If anticoagulation therapy with heparin needs to be discontinued for clinical reasons, termination of the heparin infusion will usually suffice because of the rapid clearance of heparin. If an immediate effect is required, IV protamine sulfate rapidly neutralizes heparin activity by virtue of its positive charge. The dose of protamine sulfate required to neutralize heparin is based on the amount of heparin received in the previous 2 h (Table 3 ). Protamine sulfate can be administered in a concentration of 10 mg/mL at a rate not to exceed 5 mg/min. Patients with known hypersensitivity reactions to fish, and those who have received protamine-containing insulin or previous protamine therapy may be at risk of hypersensitivity reactions to protamine sulfate.

Potential Advantages of Low-Molecular-Weight Heparin For Children

Therapy with low-molecular-weight heparins (LMWHs) has several potential advantages over initial short-term heparin therapy for DVT or PE, as well as over the traditional 3 months of OAs. The potential advantages of LMWH for children include the following: predictable pharmacokinetics that result in minimal monitoring, which is critically important in pediatric patients with poor or nonexistent venous access; subcutaneous administration; lack of interference by other drugs or diet, such as those that exist for warfarin; reduced risk of HIT; and probable reduced risk of osteoporosis with long-term use, which occurs with heparin.

Mechanism of Action

Like heparin, the anticoagulant activities of LMWH are mediated by catalysis of AT.

Therapeutic Range

Therapeutic doses of LMWH are extrapolated from adults and are based on anti-factor Xa levels. The guideline for therapeutic LMWHs is an anti-factor Xa level of 0.50 to 1.0 U/mL in a sample taken 4 to 6 h following a subcutaneous injection.


The doses of LMWH required in pediatric patients to achieve adult therapeutic anti-factor Xa levels have been assessed for two LMWHs, enoxaparin (Lovenox; Aventis Pharma; Laval, Quebec) and reviparin (Clivarin; Knoll Pharmaceuticals; North Mount Olive, NJ). For both LMWHs, peak anti-factor Xa levels occur 2 to 6 h following an injection.4243 Children less than approximately 2 months of age or < 5 kg in weight have increased requirements per kilogram, which likely is due to a larger volume of distribution, but the pharmacokinetics are similar4243 (Table 4 ). A weight-adjusted nomogram was used to adjust LMWH doses into the therapeutic range (in two prospective cohort studies) (Table 5 ).,4243 The doses required for older children are similar to the weight-adjusted requirements for adults.40 Potentially, LMWH may be used for several months.44 However, when this route of treatment is chosen, sensitive tests of bone density should be considered to monitor for early signs of osteoporosis.


Plausible explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics42,45 and/or a decreased expression of anticoagulant activity of heparin in children due to decreased plasma concentrations of AT.79


Nomograms for the adjustment of therapeutic doses of LMWH have been validated (Table 5).4243

Treatment of LMWH-Induced Bleeding

If anticoagulation with LMWH needs to be discontinued for clinical reasons, termination of the subcutaneous injections will usually suffice. If an immediate effect is required, protamine sulfate has not been shown to completely reverse the activity of LMWH. Equimolar concentrations of protamine sulfate neutralize the anti-factor IIa activity but result in only partial neutralization of the anti-factor Xa activity. However, in animal models, bleeding is completely reversed by protamine sulfate.4649 The dose of protamine sulfate is dependent on the dose of LMWH used at the time of administration. If protamine sulfate is given within 3 to 4 h of the LMWH, then a maximal neutralizing dose is 1 mg protamine sulfate per 100 U (1 mg) LMWH administered IV in the last dose over 10 min.40 The same instructions for protamine sulfate administration for the reversal of heparin should be followed (Table 3).

Initial studies suggested that LMWH would cause less bleeding than unfractionated heparin for a similar antithrombotic effect. However, a review of clinical studies to date has failed to substantiate that claim.50In 1997, the US Food and Drug Administration (FDA) issued a warning concerning the danger of spinal hematoma occurring in adult patients undergoing epidural or lumbar punctures while receiving LMWH.51The results of preliminary studies show that a significant proportion of children have substantial anti-factor Xa plasma activity 12 h following a subcutaneous treatment dose of LMWH.52In a single institution cohort study, minor bleeding occurred in 26 of the 147 study patients (17%) receiving therapeutic doses of LMWH.53 Episodes of major bleeding occurred in seven patients (4%). The episodes of major bleeding consisted of two instances of GI bleeding, three instances of intracranial hemorrhage (ICH) (two patients had preexisting CNS structural abnormalities), and two thigh hematomas. The same study described 30 patients who received prophylactic LMWH, of whom 2 had minor bleeding. No major bleeding complications occurred. Further studies are required to determine the true bleeding risk from LMWH in children. Until such evidence is available, the risk of bleeding complications from LMWH should be considered to be similar to that for heparin for the equivalent antithrombotic effect. In particular, prior to lumbar punctures or epidural procedures, at least two doses of LMWH should be withheld and, if possible, anti-factor Xa levels should be determined prior to the procedure.

Age-Dependent Features

OAs function by reducing plasma concentrations of the vitamin K-dependent proteins. At birth, levels of the vitamin K-dependent coagulant factors (FII, FVII, FIX, and FX) and inhibitors (protein C [PC] and protein S [PS]) are at approximately 50% of adult values.79,5456 These levels are similar to those found in adults receiving OAs for the treatment of venous TEs.1516 A small number of newborns have evidence of a functional vitamin K deficiency state, which is indicated by significant levels of descarboxy vitamin K-dependent proteins at birth.57 Vitamin K deficiency significantly increases the sensitivity to OAs and, potentially, the risk of bleeding. Following the neonatal period, levels of the vitamin K-dependent proteins rapidly increase and are within the adult range of normal by 6 months.79 However, average values of the vitamin K-dependent proteins remain approximately 20% lower than adult values until the late teenage years.58

Decreased concentrations of the vitamin K-dependent coagulation proteins, particularly prothrombin, contribute to the delay and decreased amounts of thrombin generated in plasmas from newborns and children.1516 The pattern of thrombin generation in newborns is similar to that in plasma from adults receiving therapeutic amounts of OAs.59 Because of the potential risk of bleeding from further anticoagulation and the presence of borderline vitamin K status, OA therapy is avoided when possible during the first month of life.57,60 For older children receiving OAs, the capacity of their plasmas to generate thrombin is delayed and is decreased by 25% compared to plasmas from adults with similar international normalized ratios (INRs).59,61 The latter raises the issue of whether the optimal INR therapeutic range for children will be lower than that for adults. This hypothesis is further supported by the observation that plasma concentrations of a marker of endogenous thrombin generation, prothrombin fragment 1.2, is significantly lower in children than in adults at similar INR values.61

Therapeutic Range

The most commonly used test for monitoring OA therapy is prothrombin time (PT), which is reported as an INR. Unfortunately, most pediatric studies have not reported their PT results as INRs, which hinders the interpretation and generalizability of the results. Currently, therapeutic INR ranges for children are directly extrapolated from recommendations for adult patients because, to our knowledge, there are no clinical trials that have assessed the optimal INR range for children based on clinical outcomes. The recommended therapeutic target for the treatment of venous TEs is an INR of 2.5 with a range between 2.0 and 3.0. The recommended therapeutic range for children with mechanical prosthetic heart valves is an INR target of 3.0 (INR range, 2.5 to 3.5).62Low-dose OA therapy (INR target range, 1.4 to 1.9) is currently used in pediatric patients for a variety of reasons. First, children with a new thrombus and a long-term predisposing cause for recurrent TEs are treated with therapeutic doses of OA for 3 months followed by a low-dose regimen. Second, children with an old thrombus or significant risk for TE are treated initially with a low-dose regimen. Third, children with substantial bleeding risks, or those in whom monitoring is not possible, may be treated with low-dose warfarin. A single cohort study suggests that low-dose OA may provide an effective treatment strategy in selected children, but further evaluation is required before low-dose therapy can be widely recommended.63

Dose Response

Seven publications provide information on loading doses for OA therapy in children.1,6368 Five studies were case series, and two were cohort studies.1,63 An initial dose of 0.2 mg/kg, with subsequent dose adjustments made according to a nomogram using INR values, was evaluated in two prospective cohort studies.1,63 With this dosing regimen, all patients achieve their target INR range and 79% attain their target INR in < 7 days. The length of time required to achieve a minimal INR of 2.0 is age-dependent, ranging from a median of 5 days in infants to 3 days in teenagers. The overlap with heparin is approximately 5 days. Because of the length of time required to achieve a therapeutic range, higher loading doses of 0.3 and 0.4 mg/kg were tested but resulted in excessively high INR values on days 3 to 5 in at least 50% of children and cannot be generally recommended.63 Eight publications provide information on maintenance doses1,6367,6970 for OAs required to achieve an INR between 2.0 and 3.0 in children. Of these studies, five are case series and three are prospective cohort studies. Maintenance doses for OAs are age-dependent, with infants having the highest requirements and teenagers having the lowest requirements. The published age-specific, weight-adjusted doses for children vary due to the different study designs, patient populations, and, possibly, the small number of children studied. The largest cohort study (n = 262) found that infants required an average of 0.32 mg/kg and teenagers 0.09 mg/kg warfarin to maintain a target INR of 2 to 3.63 For adults, weight-adjusted doses for OAs are not precisely known but are in the range of 0.04 to 0.08 mg/kg for an INR of 2 to 3.71 In a single cohort study in children, the average dose requirement of OAs to maintain a target INR of 1.4 to 1.9 is 0.08 mg/kg with a range of 0.03 to 0.17 mg/kg.63 The mechanisms responsible for the age dependency of OA doses are not completely clear. Table 6 provides a nomogram for loading and monitoring OAs in children.,1 Guidelines for the duration1,72 of therapy with OAs in children reflect recommendations for adults with similar disorders. The optimal treatment for children with recurrent DVTs and PEs, beyond the initial treatment, is uncertain.


Monitoring OA therapy in children is difficult and requires close supervision with frequent dose adjustments.1,63 In contrast to adults, only 10 to 20% of children can be safely monitored monthly.1 Reasons contributing to the need for frequent monitoring include diet, medications, and primary medical problems.

Breast-fed infants are very sensitive to OAs due to the low concentrations of vitamin K in breast milk.7378 In contrast, some children are resistant to OAs due to impaired absorption,79 the requirements for total parenteral nutrition (TPN), which is routinely supplemented with vitamin K, and nutrient formulas, which are all supplemented with vitamin K (55 to 110 μg/liter) to protect against hemorrhagic diseases of the newborn.76,79

Most children are receiving multiple medications, both on a long-term basis, to treat their primary problems, or intermittently, to treat acquired problems (eg, infections). These medications influence the dose requirements for OAs in a manner similar to that of adults.71 The most commonly used medications in children that affect the INR are listed in Table 7 . Most children have serious primary problems that influence the biological effect and clearance of OAs, as well as the risk of bleeding.,1,63,68

The age distribution of children requiring OAs is skewed, with the two largest groups comprised of children < 1 year old and teenagers.1,63 Teenagers are not necessarily compliant with their medication,8081 and infants are a difficult group of patients to monitor due to poor venous access as well as complicated medical problems.66,8188

The problems with monitoring OAs in children have limited their use, even in conditions in which they are strongly indicated. Potential solutions for optimizing therapy with OAs in children include pediatric anticoagulation clinics, whole-blood PT/INR monitors used at home, and clinical trials to determine whether lower, safer INR ranges are as efficacious.

Whole-Blood Monitors for Children

Whole-blood monitors use various techniques to measure the time from the application of fresh samples of capillary whole blood to coagulation of the sample. The monitors include a batch-specific calibration code that converts the result into a calculated INR. There are two point-of-care monitors evaluated in the pediatric population (CoaguChek; Boehringer Mannheim; Mannheim, Germany; and ProTime Microcoagulation System; International Technidyne Corp; Edison, NJ). Both monitors were shown to be acceptable and reliable for use in the outpatient laboratory and in home settings. Parents and patients undertook a formal education program prior to using the monitors. The major advantages identified by families included reduced trauma of venipunctures, minimal interruption of school and work, ease of operation, and portability.

Adverse Effects of OAs

Bleeding is the main complication of OA therapy. Minor bleeding that is of minor clinical consequence (eg, bruising, nosebleeds, heavy menses, coffee-ground emesis, microscopic hematuria, bleeding from cuts and loose teeth, or ileostomy) occurs in approximately 20% of children receiving OAs.1,63 The risk of serious bleeding in children receiving OAs for mechanical prosthetic valves is < 3.2% per patient-year (13 case series). Significant bleeding complications occur in approximately 1.7% of children receiving OAs for other indications.1,68

Nonhemorrhagic complications of OAs, such as tracheal calcification or hair loss, have been described on rare occasions in young children.89Although OAs do not appear to affect bone density in adults,9091 OAs do cause bony abnormalities in the fetus and are an integral part of the warfarin embryopathy. Because of the potential risk for adverse effects on bone formation in rapidly growing children, a cross-sectional study assessing bone density was performed in 33 children who had received OAs for > 1 year.92 This study suggests that long-term OA therapy may influence bone density in growing children. This observation requires confirmation by further studies. Further studies are urgently required to define bone disease in children that has been induced by OAs and to assess potentially effective prevention strategies.

Treatment of OA-Induced Bleeding

Vitamin K1 is the antidote for OAs. The dose to be administered and the concurrent use of vitamin K1-dependent factor replacement (ie, either fresh frozen plasma [FFP] or prothrombin complex concentrates) are dependent on the clinical problem. Table 8 provides guidelines for the reversal of OA therapy in children with no bleeding and in those with significant bleeding.

There are an increasing number of antithrombotic agents used in adults, the majority of which have been tested in large clinical trials. However, there are almost no data on these drugs in children. Danaparoid is used frequently in adults with HIT, although there remain only a handful of case reports of use in children.35,37,41 Lepirudin is approved for the treatment of HIT in a number of countries.93To our knowledge, there are no published data on the use of hirudin or lepirudin in children. There is limited experience with the use of argatroban in adults,9496 but to our knowledge, there are no published data on the use of argatroban in children.

In addition to pharmacologic therapy, venous interruption devices (eg, inferior vena cava [IVC] filters) are used for specific clinical indications in adults. The most common indication for the use of IVC interruption is to prevent a PE in the presence of a contraindication to anticoagulant therapy in a patient with or at high risk for proximal DVT.97104 In the only randomized trial of filter placement, the rate of PE was reduced. However, the reduced rate of PE was associated with an increase in DVT in the group receiving filters. The overall survival rate was not different in the two groups.105Only a handful of anecdotal reports of successful and failed IVC filters in children have been published.106107 In contrast to adults, temporary filters often are used in children and are removed when the source of PE is no longer present.106 There are no specific guidelines for the use of filters in children and the risk/benefit ratio needs to be considered individually in each case.

Age-Dependent Features

Compared to adult control subjects, neonatal platelets are hyporeactive to thrombin, adenosine diphosphate/epinephrine, and thromboxane A2.108109 This hyporeactivity of neonatal platelets is the result of a defect that is intrinsic to neonatal platelets.108109 Paradoxically, the bleeding time is short in newborns due to increased RBC size, high hematocrit, and increased levels and multimeric forms of von Willebrand factor.110112 No studies of platelet function in healthy children were identified except for the bleeding time, which, relative to adults, is prolonged throughout childhood in two of three studies.58,113114 These physiologic differences suggest that the optimal dosage of antiplatelet agents in newborns and children also may differ from that of adults.

Therapeutic Range, Dose Response, and Monitoring of Antiplatelet Agents

There is a need to monitor aspirin, the most commonly used antiplatelet agent. To our knowledge, there are no studies that compare different doses of aspirin in children. Empiric low doses of 1 to 5 mg/kg/d have been proposed as adjuvant therapy for Blalock-Taussig (BT) shunts, for some endovascular stents, and for some cerebrovascular events.69 For mechanical prosthetic heart valves, aspirin doses of 6 to 20 mg/kg/d were used in eight studies,6364,82,85,115118 either alone or in combination with 6 mg/kg/d dipyridamole in three divided doses.64 High-dose aspirin, 80 to 100 mg/kg/d, is used in the treatment of Kawasaki’s disease during the acute phase (up to 14 days), then 3 to 5 mg/kg/d for 7 weeks or longer if there is echocardiographic evidence of coronary artery abnormalities.119 The effects of aspirin last for approximately 7 days. The second most commonly used antiplatelet agent, for patients with mechanical prosthetic heart valves, is dipyridamole in doses of 2 to 5 mg/kg/d.82,116,118

Ticlopidine and clopidogrel are related compounds. Both drugs selectively inhibit adenosine diphosphate-induced platelet aggregation.120122 The antiplatelet effect of ticlopidine (and probably that of clopidogrel) is additive to that of aspirin.123Studies in adults have used ticlopidine at doses of 250 mg every 12 h, and clopidogrel at 75 mg daily.124128 There is no reported use in children, and dosage recommendations are unknown.

Glycoprotein (GP) IIb/IIIa antagonists are a new class of antiplatelet drugs that are now available in IV form (abciximab, tirofiban, and eptifibatide) and may soon be available in oral form.129 These drugs, which are chimeric antibody fragments (abciximab), peptides (eptifibatide), or nonpeptide small molecules (tirofiban), act by binding to the platelet surface GPIIb-IIIa complex, thereby inhibiting fibrinogen-mediated platelet aggregation. Because fibrinogen binding to the platelet GPIIb-IIIa complex is the final common pathway of platelet aggregation, these drugs are powerful antiplatelet agents.129However, to our knowledge, there are as yet no reports of their use in children. Although GPIIb-IIIa antagonist therapy may need to be monitored, the optimal assays are still under investigation.130 The appropriate therapeutic ranges for these assays may prove to be different in children, because of the age-dependent differences in platelet function described above.

Adverse Effects of Antiplatelet Agents

Newborns may be exposed to antiplatelet agents due to maternal ingestion (aspirin as treatment for preeclampsia) or therapeutically (indomethacin as medical therapy for patent ductus arteriosus).131135 The clearance of both salicylate and indomethacin is slower in newborns, 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 clinically important bleeding in newborns is weak. Indomethacin does prolong the bleeding time in newborns, but the evidence linking indomethacin to ICH is weak.

In older children, aspirin rarely causes clinically important hemorrhaging, except in the presence of an underlying hemostatic defect or in children also treated with anticoagulants or receiving 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’s syndrome, this appears to be a dose-dependent effect of aspirin.136142

Treatment of Bleeding Due to Antiplatelet Agents

Antiplatelet agents alone rarely cause serious bleeding in children. More frequently, antiplatelet agents are one of several other causes of bleeding such as an underlying coagulopathy and antithrombotic agents. Transfusions of platelet concentrates and/or the use of products that enhance platelet adhesion (eg, plasma products containing high concentrations of von Willebrand factor or deamino-8-d-arginine vasopressin) may be helpful.

Mechanism of Action of Thrombolytic Agents

The actions of thrombolytic agents are mediated by converting endogenous plasminogen to plasmin. At birth, plasma concentrations of plasminogen are reduced to 50% of adult values (ie, 21 mg/100 mL).78,143The decreased levels of plasminogen in newborns slow the generation of plasmin144and reduce the thrombolytic effects of streptokinase (SK), urokinase (UK), and tissue plasminogen activator (tPA) in an in vitro fibrin clot system.146 A similar response occurs in children with acquired plasminogen deficiency.147 Supplementation of plasmas with plasminogen increases the thrombolytic effect of all three agents.145,147148


There are well-defined contraindications to thrombolytic therapy in adults. These include a history of stroke, transient ischemic attacks, other neurologic disease, and hypertension.149 Similar problems in children should be considered as relative, but not absolute, contraindications to thrombolytic therapy.

Choice of Thrombolytic Agent

To our knowledge, there are no studies that compare the cost, efficacy, and safety of different thrombolytic agents in children. Although SK is the cheapest of the three agents, it has the potential for allergic reactions and may be less effective in children with physiologic or acquired deficiencies of plasminogen. UK was widely used for pediatric patients, but a US FDA warning has substantially diminished the use of UK in North America.150

tPA has become the agent of choice in children for several reasons, including the US FDA warning regarding UK, experimental evidence of improved clot lysis in vitro compared to UK and SK, fibrin specificity, and low immunogenicity.145 However, tPA is considerably more expensive than either SK or UK, and the increased in vitro clot lysis by tPA has not been extended into clinical trials in children. There is minimal or no experience with other thrombolytic agents in children.

Therapeutic Range and Monitoring of Thrombolytic Agents

There is no therapeutic range for thrombolytic agents. The correlation between hemostatic parameters and efficacy/safety of thrombolytic therapy is too weak to have useful clinical predictive value.149 However, in patients with bleeding, the choice and doses of blood products used can be guided by appropriate hemostatic monitoring. The most useful single assay is the fibrinogen level, which usually can be obtained rapidly and helps to determine the need for cryoprecipitate and/or plasma replacement. A commonly used lower limit for fibrinogen level is 100 mg/dL. The APTT may not be helpful in the presence of low fibrinogen levels, concurrent heparin therapy, and the presence of fibrin/fibrinogen degradation products.149 Measurement of fibrin/fibrinogen degradation products and/or D-dimers is helpful in determining whether a fibrinolytic effect is present.

Dose Response

Thrombolytic agents are used in low doses, usually to restore catheter patency (Table 9 ), and in higher doses to lyse large-vessel TEs or PEs. Table 10 presents the most commonly used dose regimens for thrombolytic therapy in pediatric patients with arterial or venous TEs. These protocols come from case series.148,151The optimal doses for each condition for UK, SK, and tPA are not known for pediatric patients. Based on the Thrombolysis in Myocardial Infarction II trial, doses of 150 mg recombinant tPA caused more bleeding into the CNS than 100 mg152 (1.5% vs 0.5%, respectively). These data suggest that there is an upper dose limit that is based on safety.

Route of Administration

To our knowledge, there are no published studies that compare local to systemic thrombolytic therapy in children. From 1966 to 1997, there were 70 cases reported in the English-language literature of local thrombolytic therapy in children, excluding femoral artery thrombosis following cardiac catheter and low-dose thrombolysis to unblock CVLs. Complete or partial lysis was achieved in 70% of cases, with major bleeding occurring in 11% of children. A retrospective cohort reported successful lysis in only one of seven patients, with five major complications in three patients.153At this time, there is no evidence to suggest that there is an advantage of local over systemic thrombolytic therapy in children with thrombotic complications. In addition, the small vessel size in children may increase the risk of local vessel injury with new thrombus formation. Local therapy may be appropriate for catheter-related TEs when the catheter is already in situ. There are isolated case reports of thrombolysis via multiple-lumen catheter use in children.154 There are no reported cases of pulse-spray thrombolysis in children.

Adverse Effects of Thrombolytic Therapy

Based on a review of the pediatric literature (255 patients) and on two retrospective cohort studies, the incidence of bleeding requiring treatment with packed RBCs occurs in approximately 20% of pediatric patients.148 The most frequent problem was bleeding at sites of invasive procedures that required treatment with blood products. A review of the literature155 specifically examined the incidence of ICH during thrombolytic therapy in children. There was no information about concurrent heparin administration in this study. In total, ICH was found in 14 of 929 patients (1.5%) analyzed. When subdivided according to age, ICH was identified in 2 of 468 children (0.4%) after the neonatal period, in 1 of 83 term infants (1.2%), and in 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 the control arm, which did not receive thrombolytic therapy. The incidence of ICH in adults receiving thrombolytic therapy also varies with age and the indication for thrombolysis. The incidence of ICH in adults is between 0.3% and 1.0% when treating acute myocardial syndromes, but it may be as high as 20% in the treatment of acute stroke.156157

Treatment of Bleeding Due to Thrombolytic Therapy

Before thrombolytic therapy is used, the correction of other concurrent hemostatic problems, such as thrombocytopenia or vitamin K deficiency, is advised. Clinically mild bleeding, which is usually oozing from a wound or puncture site, can be treated with local pressure and supportive care. Major bleeding from a local site can be treated by stopping the infusion of the thrombolytic agent, administering a cryoprecipitate (usual dose, 1 bag per 5 kg), and administering other blood products as indicated. If the bleeding is life threatening, an antifibrinolytic agent also can be used.

Although the general indications for antithrombotic therapy in pediatric patients are similar to adults, the frequency of specific disease states and underlying pathologic conditions differ. For example, myocardial infarctions and cerebrovascular accidents are two of the more common indications for antithrombotic therapy in adults and are the least common in children.71 The current indications for antithrombotic therapy in children are provided in Table 11 .