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Antithrombotic Therapy in Children

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{at}sickkids.on.ca

	Introduction

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

 
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.^{1 2} 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,³ at 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.^{4 5 6} 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.

	Heparin Therapy in Pediatric Patients

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

 
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.^{7 8 9} 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.^{9 10} 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.^{12 13} The capacity of plasmas from newborns to generate thrombin is both delayed and decreased compared to adults^{14 15} 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.¹⁷ In pediatric patients, APTT values correctly predict therapeutic heparin concentrations approximately 70% of the time.¹⁸

Doses
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.¹⁸ Bolus 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).^{20 21} 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

Monitoring
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 28 29} 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.^{30 31 32} 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.^{33 34} 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.^{35 36 37 38 39} 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 40 41}

	Low-Molecular-Weight Heparin Therapy in Pediatric Patients

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

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.

Doses
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.^{42 43} 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 similar^{42 43} (Table 4 ). A weight-adjusted nomogram was used to adjust LMWH doses into the therapeutic range (in two prospective cohort studies) (Table 5 ).^{42 43} 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.

Monitoring
Nomograms for the adjustment of therapeutic doses of LMWH have been validated (Table 5) .^{42 43}

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.^{46 47 48 49} 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.⁵⁰ In 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.⁵¹ The 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.⁵² In 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.

	OA Therapy in Pediatric Patients

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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.^{7 8 9 54 55 56} These levels are similar to those found in adults receiving OAs for the treatment of venous TEs.^{15 16} 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.^{7 8 9} 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.^{15 16} 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).⁶² Low-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 63 64 65 66 67 68} 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 doses^{1 63 64 65 66 67 69 70} 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 duration^{1 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.

Breast-fed infants are very sensitive to OAs due to the low concentrations of vitamin K in breast milk.^{73 74 75 76 77 78} 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 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.⁸⁹ Although OAs do not appear to affect bone density in adults,^{90 91} 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.

	Alternative Antithrombotic Therapy in Children

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

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.^{97 98 99 100 101 102 103 104} 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.¹⁰⁵ Only a handful of anecdotal reports of successful and failed IVC filters in children have been published.^{106 107} 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.

	Antiplatelet Therapy in Pediatric Patients

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

 
Age-Dependent Features
Compared to adult control subjects, neonatal platelets are hyporeactive to thrombin, adenosine diphosphate/epinephrine, and thromboxane A₂.^{108 109} This hyporeactivity of neonatal platelets is the result of a defect that is intrinsic to neonatal platelets.^{108 109} 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.^{110 111 112} 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.^{58 113 114} 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,^{63 64 82 85 115 116 117 118} 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.^{120 121 122} The antiplatelet effect of ticlopidine (and probably that of clopidogrel) is additive to that of aspirin.¹²³ Studies in adults have used ticlopidine at doses of 250 mg every 12 h, and clopidogrel at 75 mg daily.^{124 125 126 127 128} 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.¹²⁹ However, 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).^{131 132 133 134 135} 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.^{136 137 138 139 140 141 142}

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.

	Thrombolytic Agents

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

 
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).^{7 8 143} The decreased levels of plasminogen in newborns slow the generation of plasmin¹⁴⁴ and reduce the thrombolytic effects of streptokinase (SK), urokinase (UK), and tissue plasminogen activator (tPA) in an in vitro fibrin clot system.^{145 146} A similar response occurs in children with acquired plasminogen deficiency.¹⁴⁷ Supplementation of plasmas with plasminogen increases the thrombolytic effect of all three agents.^{145 147 148}

Contraindications
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.^{148 151} The 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.

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.^{156 157}

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.

	Indications for Antithrombotic Therapy in Pediatric Patients

TOP Introduction Heparin Therapy in Pediatric... Low-Molecular-Weight Heparin... OA Therapy in Pediatric... Alternative Antithrombotic... Antiplatelet Therapy in... Thrombolytic Agents Indications for Antithrombotic... Key Areas That Urgently... Recommendations References

 
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 .

Clinical Features:
Despite the protective effects of age, increasing numbers of children are developing DVT and PE as secondary complications of their underlying disorders. In contrast to adults, in whom DVT and PE are idiopathic in 40% of patients, only 5% of cases of DVT and PE are idiopathic in children.^{72 178} Ninety-five percent of cases of DVT and PE in pediatric patients are secondary problems to serious diseases such as prematurity, cancer, trauma/surgery, congenital heart disease, and systemic lupus erythematosus.^{72 163 164 169 179 180} Less than 1% of cases of DVT in neonates are idiopathic.¹⁶⁴ Congenital prethrombotic disorders alone account for < 10% of cases of DVT and PE in children.^{72 169} The frequency of congenital prethrombotic disorders in children with secondary DVT is uncertain (Table 12 ).^{163 164 181 182 183 184} The greatest risk for developing DVT and PE occurs in infants < 1 year of age and in teenagers.^{72 163 164 169} DVT in the lower extremities is the most frequent non-CVL-related TE in children.¹⁶⁹ The clinical presentations and treatments for DVT and PE in children are similar to those for the adult.^{72 162 169 185}

The incidence of CVL-related TEs reported in the literature varies, reflecting different underlying disorders, diagnostic tests, and indexes of suspicion. For example, the incidence of CVL-related TEs in children receiving long-term TPN varies from 1%, based on clinical diagnosis,^{198 199} to 35%, based on ventilation-perfusion scans or echocardiography, to 75%, based on venography.¹⁹⁵ In a prospective cohort, 18% of children in an intensive-care setting with CVLs in place for 48 h developed CVL-related DVT.²⁰⁰ The recently completed Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated With Asparaginase (PARKAA) study⁵ reported an incidence of 37% for venographically proven DVT in children with acute lymphoblastic leukemia (ALL) who were receiving asparaginase therapy, and it reported that ultrasound missed approximately 80% of those clots.⁶ In many patient populations, the incidence is not accurately known. This information is important in order to identify populations of children in whom prophylactic antithrombotic therapy should be tested in clinical trials.

A randomized controlled trial (RCT) comparing low-dose OAs (1 mg) with placebo in adults with CVLs showed that the incidence of DVT, based on venography, was safely reduced from 37 to 9.5%.²⁰¹ A similar study comparing 2,500 IU fragmin, an LMWH administered subcutaneously daily, to no therapy in adults with cancer and who had catheters showed a reduction in venographically identified thrombosis at 90 days from 62 to 6%. The relative risk reduction was 6.75 (95% confidence interval [CI], 1.05 to 43).²⁰² The complexity of the primary illness in most children with CVL-related DVT, and the intensity of their therapy, whether medical or surgical, increases the potential for bleeding complications from prophylactic anticoagulation. In addition, oral anticoagulation therapy or subcutaneous LMWH therapy is more difficult to administer in small children. The results of the recently closed Prophylaxis of Thromboembolism in Kids Trial (PROTEKT) will demonstrate safety and, potentially, efficacy, although further studies are required in children who are < 3 months old.

The patency of CVL is frequently maintained by intermittent boluses of heparin (200 to 300 U) daily, weekly, or monthly. For infants weighing < 10 kg, a lower dose of 10 U/kg is frequently used to avoid transient anticoagulation of the infant. There is only one small randomized trial assessing the need for prophylactic heparin.²⁰³ The study was conducted in children with cancer using echocardiography of the heart as the outcome measure, not venography.²⁰³ Although the study reported no benefit from flushing CVLs with heparin, the design and outcome measure limits the generalizability of this study. Local instillation of UK is historically the most commonly used therapy for treating a malfunctioning line that is blocked, although, as previously mentioned, the use of UK has decreased substantially since the FDA warning.¹⁵⁰ Based on several case series, patency is restored in approximately 80% of patients.

Congenital Prothrombotic Conditions
Congenital thrombophilia is usually defined as having the following features: (1) positive family history; (2) early age of onset of TE; (3) recurrent disease; and (4) multiple or unusual locations. Clinically, the most significant inherited prothrombotic conditions are deficiencies of AT, PC, and PS because of the large increase in relative risk these deficiencies confer. Activated PC resistance/factor V Leiden (FV-R506Q) and prothrombin G20210A (IIG20210A) polymorphism, while having less impact on individual risk, are significant because of their frequencies in certain populations. A large number of other candidate genes have been proposed as risk factors for congenital thrombophilia²⁰⁴ ; however, most of these candidates have not undergone careful segregation or population studies to define their pathogenic roles. In fact, some of the seemingly obvious candidates, such as abnormalities in fibrinolysis, do not appear to confer heritable risk.²⁰⁵ These latter studies, however, are hampered by the low prevalence of most of these inherited abnormalities in the general population.

Another report²⁰⁶ demonstrated an increased risk for thrombosis in families with a second genetic abnormality. Most reports have described a combination of FV-R506Q with abnormalities of PC, PS, and AT. These findings begin to shed light on the marked variability in clinical expression of these syndromes. The effect of more severe deficiencies has long been evident from the severely affected neonates with homozygous PC and PS deficiencies. Once one moves away from the well-defined homozygous cases, the risk and severity of TEs appear to vary with the type and number of underlying genetic abnormalities (Table 12) .^{206 207 208 209}

The role of these congenital prothrombotic states in childhood thrombosis remains controversial. If one considers the deficiencies of AT, PC, and PS in addition to the factor V Leiden and prothrombin gene mutations, large family studies found negligible rates of thrombosis in children who were < 15 years of age.²¹⁰ A number of cohort studies have failed to identify AT deficiency in children with both arterial and venous TEs.^{211 212 213 214} Those studies that reported higher frequencies of AT deficiency did not distinguish between acquired and inherited deficiencies.²¹⁵ Cohort studies have reported conflicting results concerning the incidence of heterozygous PC deficiency in children with thromboembolic disease. From 1966 to 1999, there were 40 case reports of children with heterozygous PS deficiency and TEs during childhood. In these cases, 21 children had venous TEs, 11 had arterial TEs, and 5 had both venous and arterial TEs, and for 3 children the site of thrombosis was not clear.^{216 217 218 219 220 221 222 223 224 225 226} Eleven studies, the majority of which were case series or case control studies, have examined the frequency of the factor V Leiden mutation in children with TEs in a variety of clinical situations. These studies are summarized in Table 13 . Further studies assessed the relationship between childhood stroke (ie, arterial ischemic stroke and sinovenous thrombosis) and factor V Leiden mutation.^{211 215 230 231 235 236 237 238 239} The total number of children with heterozygous prothrombin 20210A and TEs reported in the literature is < 10,^{240 241} and there are no children reported with homozygous prothrombin 20210A and TEs.

Although there is agreement on the initial treatment of DVTs and PEs in children with anticoagulants and on the need for prophylaxis in high-risk situations, there is a paucity of information on the risks and benefits of long-term prophylaxis vs careful monitoring with intermittent prophylaxis for children with known prethrombotic conditions. Further studies are required.

Homozygous PC or PS Deficiency
In contrast to heterozygous PC or PS deficiency, homozygous PC/PS deficiency presents within hours of birth with purpura fulminans, cerebral and/or ophthalmic damage that occurred in utero, and, on rare occasions, large-vessel TEs. Purpura fulminans is an acute, lethal syndrome of rapidly progressive hemorrhagic necrosis of the skin due to dermal vascular thrombosis.^{242 243 244} An international database of mutations in the PC gene lists only 17 cases, and approximately 25 further kindreds are reported in the literature.^{245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277} At least one case of purpura fulminans due to homozygous PS deficiency has been reported.²⁷⁰ All patients presenting at birth with purpura fulminans had undetectable levels of PC or PS. Homozygous PC deficiency may be present with large-vessel TEs during childhood or early adult life. PC levels in these patients ranged from 0.05 to 0.20 U/mL.²⁶⁸ These children usually presented with DVT following a minor secondary insult and developed OA-induced skin necrosis.

Short-term Treatment:
Numerous forms of therapy have been used in individual patients, including FFP, PC concentrate, cryoprecipitate, prothrombin complex concentrate, heparin, LMWH, aspirin, sulfinpyrazone, corticosteroids, vitamin K, aprotinin, and AT concentrate. One approach is to initiate treatment with 10 to 20 mL/kg FFP every 12 h.²⁷⁵ Plasma PC levels achieved with these doses of FFP varied from 15 to 32% at 30 min after infusion, and from 4 to 10% at 12 h.²⁵⁶ Doses of PC concentrate administered in the literature have ranged from 20 to 60 U/kg. A dose of 60 U/kg resulted in peak PC levels above 0.60 U/mL.²⁷⁸ The replacement of PC should be continued until the clinical lesions resolve, which is usually 6 to 8 weeks.

The one newborn with homozygous PS deficiency was treated with both FFP and cryoprecipitate, which contain similar amounts of PS.²⁷⁰ A pharmacokinetic study was performed following the infusion of 10 mL/kg FFP, and a recovery of PS at 2 h of 0.23 U/mL and at 24 h of 0.14 U/mL was reported. The PS was entirely in the C4b-bound fraction on crossed immunoelectrophoresis. The approximate half-life of PS in this infant was 36 h.

Long-term Treatment:
The modalities used for long-term management of infants with homozygous PC deficiency include OA therapy, intermittent PC replacement with PC concentrate, and liver transplantation.²⁶⁷ PC replacement may not prevent further TEs in the presence of a risk factor such as a CVL. Currently, the majority of children are treated with OAs. When therapy with OAs is initiated, the infant should continue receiving PC (or PS) replacement until the INR is between approximately 3.0 and 4.5 to avoid skin necrosis. To some extent, these patients need to be titrated for the lowest dose that prevents skin necrosis.²⁶⁸ Patients with homozygous PC or PS deficiency, but with detectable plasma concentrations, also have been treated with LMWH.^{44 268} The latter approach avoids the risk of OA-induced skin necrosis and likely decreases the risk of bleeding associated with high doses of OAs.²⁶⁸

Arterial Thromboembolic Disease
Etiology:
The most common etiology of arterial TEs in children is catheter use. This includes cardiac catheterization and central or peripheral arterial lines in the intensive-care setting. Non-catheter-related arterial TEs are rare and occur in patients with Takayasu’s arteritis,^{279 280 281} in arteries from transplanted organs,^{282 283 284 285 286} in giant coronary aneurysms secondary to Kawasaki’s disease,^{119 287 288} as complications of some forms of congenital heart disease, and in cerebral vessels from local lesions or lesions that are embolic from cardiac or other locations.

Cardiac Catheterization:
In the absence of prophylactic anticoagulation, the incidence of symptomatic TEs following cardiac catheterization via the femoral artery is approximately 40% (Table 14 ).²⁸⁹ Younger children (ie, those < 10 years of age) have an increased incidence of TEs compared to older children.²⁸⁹ Prophylactic anticoagulation therapy with aspirin does not significantly reduce the incidence of arterial TEs.²⁹⁰ However, anticoagulation therapy with 100 to 150 U/kg heparin reduces the incidence from 40 to 8%.²⁸⁹ The results from a more recent, small randomized trial²⁹¹ suggested that a 50-U/kg bolus of heparin may be as efficacious as 100 U/kg when given immediately after arterial puncture; however, this study was underpowered, and one could not recommend 50 U/kg as the optimal prophylaxis at this time. Recent advances in interventional catheterization have resulted in the use of larger catheters and sheaths that may increase the risk of TEs. Further heparin boluses are frequently used in prolonged procedures (ie, those > 60 min), especially during interventional catheterizations; however, the benefits of this practice are not known. A short limb and claudication are the long-term consequences of femoral artery TEs in children.