Antithrombotic Therapy in Children Paul Monagle, MBBS; Alan D. Michelson, MD; Edward Bovill, MD; and Maureen Andrew, MD, Chair Abbreviations: ALL ⫽ acute lymphoblastic leukemia; APTT ⫽ qjactivated partial thromboplastin time; AT ⫽ antithrombin; BT ⫽ Blalock-Taussig; CI ⫽ confidence interval; CVL ⫽ central venous line; DVT ⫽ deep venous thrombosis; FDA ⫽ Food and Drug Administration; FFP ⫽ fresh frozen plasma; GP ⫽ glycoprotein; HIT ⫽ heparin-induced thrombocytopenia; HUS ⫽ hemolytic-uremic syndrome; ICH ⫽ intracranial hemorrhage; INR ⫽ international normalized ratio; IVC ⫽ inferior vena cava; LMWH ⫽ lowmolecular-weight heparin; OA ⫽ oral anticoagulant; PARKAA study ⫽ Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated With Asparaginase; PC ⫽ protein C; PE ⫽ pulmonary thromboembolism; PROTEKT ⫽ Prophylaxis of Thromboembolism in Kids Trial; PS ⫽ protein S; PT ⫽ prothrombin time; RCT ⫽ randomized controlled trial; SK ⫽ streptokinase; TE ⫽ thromboembolism; TPA ⫽ tissue plasminogen activator; TPN ⫽ total parenteral nutrition; UK ⫽ urokinase (CHEST 2001; 119:344 –370S)

ntithrombotic therapy is required for the prevention A 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 – 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 secCorrespondence 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: [email protected]

344S

tion, 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 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.7–9 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 adults14,15 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 hepSixth ACCP Consensus Conference on Antithrombotic Therapy

arin 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

Pharmacokinetics 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.24,25 Second, the delay in diagnosis of TEs in children may result in more extensive disease at the time of presentation, accelerating heparin clearance.26,27 Table 1—Protocol for Systemic Heparin Administration and Adjustment for Pediatric Patients* I. Loading dose: Heparin 75 U/kg IV over 10 min II. Initial maintenance dose: 28 U/kg/h for infants ⬍ 1 year; 20 U/kg/h for children ⬎ 1 year. III. Adjust heparin to maintain APTT 60–85 s (assuming this reflects an anti-factor Xa level of 0.30 to 0.70): APTT, s

Bolus, U/kg

Hold, min

Rate Change, %

Repeat APTT

⬍ 50 50–59 60–85 86–95 96–120 ⬎ 120

50 0 0 0 0 0

0 0 0 0 30 60

⫹10 ⫹10 0 ⫺10 ⫺10 ⫺15

4h 4h Next day 4h 4h 4h

IV. Obtain blood for APTT 4 h after administration of the heparin loading dose and 4 h after every change in the infusion rate. V. When APTT values are therapeutic, a daily CBC and APTT. *Reproduced with permission of Michelson et al.3

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 –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 heparininduced thrombocytopenia (HIT) in the literature in patients ranging in age from 3 months to 15 years.35–39 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

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 CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

345S

Table 2—Protocol for the Use of Danaparoid in Pediatric Patients Orgaran consists mainly of heparan sulfate, a small quantity of dermatan sulfate, and a minor amount of chondroitin sulfate and does not contain any heparin fragments. Danaparoid has a much higher anti-factor Xa/anti-factor IIa ratio compared to heparin or LMWH. Danaparoid has a decreased cross-reactivity rate (⬍ 10%) with heparin-induced antibody as compared to LMWH (⬎ 90%)39 Loading dose: 30 U/kg body weight Initial maintenance dose: 1.2–2.0 U/kg/h Monitoring: Anti-factor Xa activity can be monitored immediately Danaparoid is predominantly removed from the circulation through the kidney. Consequently, danaparoid is contraindicated in patients with severe impaired renal function. Subcutaneous danaparoid is frequently used in adults,39 however, there is no published pediatric dose information.

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.

Low-Molecular-Weight Heparin Therapy in Pediatric Patients 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.

Table 3—Reversal of Heparin Therapy* Time Since Last Heparin Dose, min

Protamine Dose, mg/100 U heparin

⬍ 30 30–60 60–120 ⬎ 120

1.0 0.5–0.75 0.375–0.5 0.25–0.375

*Maximum dose of 50 mg. Infusion rate of a 10-mg/mL solution should not exceed 5 mg/min. Hypersensitivity reactions to protamine sulfate may occur in patients with known hypersensitivity reactions to fish or those previously exposed to protamine therapy or protamine-containing insulin. 346S

Table 4 —Dosing of Reviparin and Enoxaparin Weight-Dependent Dose of Reviparin* Treatment

⬍ 5 kg

⬎ 5 kg

Initial treatment dose Initial prophylactic dose

150 50

100 30

Age-Dependent Dose of Enoxaparin†

Initial treatment dose Initial prophylactic dose

⬍ 2 mo

⬎ 2 mo

1.5 0.75

1.0 0.5

*Values given as U/kg/dose q12h. †Enoxaparin has 110 anti-factor Xa U/mg.43 Values given as mg/kg/ dose q12h.

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 similar42,43 (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.

Pharmacokinetics 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.7–9 Sixth ACCP Consensus Conference on Antithrombotic Therapy

Table 5—Nomogram for Monitoring Reviparin/Enoxaparin in Pediatric Patients Anti-Factor Xa Level U/mL

Hold Next Dose?

Dose Change?

⬍ 0.35 0.35–0.49 0.5–1.0

No No No

Increase by 25% Increase by 10% No

1.1–1.5 1.6–2.0 ⬎ 2.0

No 3h Until anti-factor Xa 0.5 U/mL

Decrease by 20% Decrease by 30% Decrease by 40%

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 – 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

Repeat Anti-Factor Xa 4 h after next dose 4 h after next dose Next day, then 1 wk later and monthly thereafter while receiving reviparin-Na treatment (at 4 h after am dose) Before next dose Before next dose then 4 h after next dose Before next dose, if not ⬍ 0.5 u/mL, repeat q12h

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 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.7–9,54 –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.7–9 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 CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

347S

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 lowdose therapy can be widely recommended.63

Dose Response Seven publications provide information on loading doses for OA therapy in children.1,63– 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 agedependent, 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 doses1,63– 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 348S

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 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.73–78 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 ␮g/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

Table 6 —Protocol for Oral Anticoagulation Therapy to Maintain an INR Between 2 and 3 for Pediatric Patients* I. Day 1: if the baseline INR is 1.0 to 1.3: dose ⫽ 0.2 mg/kg orally II. Loading days 2–4: If the INR is: INR

Action

1.1–1.3 1.4–1.9 2.0–3.0 3.1–3.5 ⬎ 3.5

Repeat initial loading dose 50% of initial loading dose 50% of initial loading dose 25% of loading dose Hold until INR ⬍ 3.5, then restart at 50% less than previous dose

III. Maintenance oral anticoagulation dose guidelines: INR

Action

1.1–1.4 1.5–1.9 2.0–3.0 3.1–3.5 ⬎ 3.5

Increase by 20% of dose Increase by 10% of dose No change Decrease by 10% of dose Hold until INR ⬍ 3.5 then restart at 20% less than previous dose

*Reproduced with permission of Michelson et al.3 Sixth ACCP Consensus Conference on Antithrombotic Therapy

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,80,81 and infants are a difficult group of patients to monitor due to poor venous access as well as complicated medical problems.66,81– 88 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.

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 K1dependent 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 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

Adverse Effects of OAs Bleeding is the main complication of OA therapy. Minor bleeding that is of minor clinical consequence (eg, Table 7—Commonly Used Drugs in Children That Affect Their INR Values Drug

Effect on INR

Amiodarone Aspirin Amoxicillin Cefaclor Carbamazepine Phenytoin Phenobarbital Cloxacillin Prednisone Trimethoprim-sulfamethoxazole Ranitidine

Increase Increase or no change Slight increase Increase Decrease Decrease Decrease Increase Increase Increase Increase

Reproduced with permission of Michelson et al.3

Table 8 —Reversal of Oral Anticoagulation Therapy 1. No bleeding A. Rapid reversal of OAs is necessary, and the patient will require OAs again in the near future: give vitamin K1, 0.5 to 2 mg subcutaneously or IV (not intramuscularly), depending on the patient’s size. B. Rapid reversal of OAs is necessary and the patient will not require OAs again: vitamin K1 2–5 mg subcutaneously or IV (not intramuscularly). 2. Significant bleeding A. Significant bleeding that is not life-threatening and will not cause morbidity: treat with vitamin K1 as in 1A plus (20 mL/kg IV). B. Significant bleeding that is life-threatening and will cause morbidity: treat with vitamin K1 IV (5 mg) by slow infusion over 10–20 min because of the risk of anaphylactic shock. Consider giving prothrombin concentrate (containing factors II, VII, IX, and X) 50 U/kg IV rather than FFP (20 mL/kg IV).

CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

349S

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.93 To 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,94 –96 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.97–104 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 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 –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,63,64,82,85,115–118 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 350S

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 diphosphateinduced platelet aggregation.120 –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 –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).131–135 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 –142 Sixth ACCP Consensus Conference on Antithrombotic Therapy

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 deamino8-d-arginine vasopressin) may be helpful.

Thrombolytic Agents

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

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

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.

Table 9 —Guidelines for Local Instillation of tPA* Treatment

Single-Lumen CVL

tPA ⱕ 10 kg

0.5 mg diluted in 0.9% NaCl to volume required to fill line

tPA ⱖ 10 kg

1.0 mg in 1.0 mL 0.9% NaCl Use amount required to fill volume of line, to maximum of 2 mL in 2 mg

Double-Lumen CVL

SC Port

0.5 mg per lumen diluted in 0.9% NaCl to fill volume of line. Treat one lumen at a time 1.0 mg/mL Use amount required to fill volume of line, to a maximum of 2 mL (2 mg/lumen). Treat one lumen at a time

0.5 mg diluted with 0.9% NaCl to 3 mL 2.0 mg diluted with 0.9% NaCl to 3 mL

*SC ⫽ subcutaneous. CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

351S

Table 10 —Thrombolytic Therapy for Pediatric Patients* Low Dose for Blocked Catheters

Instillation Infusion

Regimen

Monitoring

UK (5,000 U/mL) 1.5–3 mL/lumen 2–4 h UK (150 U/kg/h) per lumen 12–48 h

None None Fibrinogen, TCT PT, APTT

Systemic Thrombolytic Therapy† Load, U/kg

Maintenance

UK

4,400 U/kg

4,400 U/kg/h 6–12 h

SK tPA

2,000 U/kg None

2,000 U/kg/h 6–12 h 0.1–0.6 mg/kg/h for 6 h

Monitoring Fibrinogen, TCT PT, APTT Same Same

*TCT ⫽ thrombin clotting time. †Start heparin therapy either during or immediately on completion of thrombolytic therapy. A loading dose of heparin may be omitted. The length of time for optimal maintenance is uncertain. Values provided are starting suggestions; some patients may respond to longer or shorter courses of therapy.

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.153 At 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 catheterrelated 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 352S

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 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.

Venous Thromboembolic Disease Incidence: The incidence of venous thromboembolic complications (ie, DVT and PE) is age-dependent, with the lowest risk occurring in children.17,158,159 Estimates of the incidence of DVT and PE in the general pediatric population are 0.07 events per 10,000 hospital admissions and 5.3 events per 10,000 hospital admissions, respectively.160 –162 Two prospective large-registry studies reported the incidence of symptomatic neonatal DVT to be 0.24 to 0.26 events per 10,000 births.163,164 Comparable incidences of DVT and PE in the adult population are approximately 2.5 to 5.0%.165–167 Other comparisons illustrating the lower risk of DVT and PE during childhood are the ⬍ 1% incidence of clinically apparent DVT and PE following lower limb or scoliosis surgery,168 and the low frequency of DVT and PE in children with heterozygote congenital prethrombotic states.72,169 Several mechanisms likely contribute to the protective effect of age for DVT and PE.170 These mechanisms include a reduced capacity to generate thrombin,15,16 an increased capacity of ␣2-macroSixth ACCP Consensus Conference on Antithrombotic Therapy

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

Table 11—Indications for Antithrombotic Agents in Pediatric Patients I. Treatment Venous thromboembolic complications Arterial thromboembolic complications II. Treatment: probable Myocardial infarction Some forms of stroke III. Prophylaxis Mechanical prosthetic heart valves Biological prosthetic heart valves Cardiac catheterization Central arterial catheters IV. Prophylaxis: probable Endovascular stents BT shunts Fontans Central venous catheters Atrial venous fibrillation V. Other Kawasaki’s disease Cardiopulmonary bypass Extra/corporeal membrane oxygenation Hemodialysis Continuous venovenous hemoperfusion

globulin to inhibit thrombin,171 the presence of a circulating anticoagulant at birth,172–174 and others, such as an enhanced antithrombotic potential by the vessel wall.175–177 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).163,164,181–184 The greatest

CVLs: Over 50% of cases of DVT in children and over 80% of cases in newborns occur in the upper venous system secondary to the use of CVLs.72,163,164,169 CVLs are placed for short-term intensive care or for long-term supportive care for children requiring TPN or therapy for cancer. Cases of CVL-related DVT are not trivial as they require repeat anesthesia for CVL replacement, provide a source for PE,186 –189 cause superior vena cava syndrome,186,189 –192 chylothorax,186,189,193,194 and eventual destruction of the upper venous system,195 and contribute to postphlebitic syndrome in both the upper and lower extremities. A cross-sectional study assessed the incidence of PE in children receiving TPN at home and reported an incidence of 35% and a mortality rate from PE of 12%.196 A prospective registry of 244 children with CVL-related DVT reported an incidence of postphlebitic syndrome of 9.5% and a DVTrelated mortality rate of 3.7%.197 Further study is required to document the true extent of long-term morbidity and mortality of patients with CVL-related DVT. 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 longterm 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 CVLrelated 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

Table 12—Frequency of Venous TE in Members of Families With Combined Thrombophilias* Associated With FV-R506Q Thrombophilia Protein C deficiency (6 families) Protein S deficiency (7 families) Antithrombim III deficiency (6 families)

Sole Defect

FV-R506Q Only

Neither Defect

Source of Extracted Data

No.

VTE, %

No.

VTE, %

No.

VTE, %

No.

VTE, %

23

70

34

35

20

10

30

7

Koeleman207/1994

18

72

21

19

21

19

44

2

Zoller et al208/1995

12

92

7

57

5

20

11

0

Van Boven et al209/1996

*VTE ⫽ venous TE; FV ⫽ factor V. Reprinted from Seligsohn and Zivelin with permission.206 CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

353S

order to identify populations of children in whom prophylactic antithrombotic therapy should be tested in clinical trials. A randomized controlled trial (RCT) comparing lowdose 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 fibrino-

354S

lysis, 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 –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.211–214 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 –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.211,215,230,231,235–239 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. The need to screen for prothrombotic disorders in children with thrombosis, especially in the presence of clinical risk factors, remains uncertain. The need to screen children with major illnesses or, for example, children about to have a CVL inserted is questionable. The results of the PARKAA study would not support routine screening.5 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 longterm prophylaxis vs careful monitoring with intermittent prophylaxis for children with known prethrombotic conditions. Further studies are required.

Sixth ACCP Consensus Conference on Antithrombotic Therapy

Table 13—Frequency of the Factor V Leiden Mutation in Children With Thrombosis* Study/Year Nowak-Gottl et al184/1996 Hausler et al227/1999 Gurgey228/1999 Aschka et al229/1996 Sifontes et al214/1996 Sifontes et al230/1998 Hagstrom et al231/1998 Sifontes et al212/1997 Mullen et al324/1996 Seixas et al233/1997 Ong et al234/1998

Location of TE and/or Patient Population

Heterozygote

Homozygote

ALL non-CVL TE VTE/ATE VTE/ATE VTE non-CNS TE non-CNS TE Cancer VTE PVT CPB

3/3 (100%) 2/8 (25%) 15/63 (23%) 29/125 (23%) 3/14 (21%) 5/34 (15%) 4/32 (13%) 1/32 (3%) 0/6 (0%) 0/20 (0%) 0/9 (0%)

0/3 (0%) 0 (0%) 5/63 (8%) 3/125 (2%) 0 (0%) 0 (0%) 0/32 (0%) 0/32 (0%) 0/6 (0%) 0/20 (0%) 0/9 (0%)

*PVT ⫽ portal vein thrombosis; CPB ⫽ cardiopulmonary bypass; ATE ⫽ arterial thromboembolism. See Table 12 for any abbreviations not used in text.

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, largevessel TEs. Purpura fulminans is an acute, lethal syndrome of rapidly progressive hemorrhagic necrosis of the skin due to dermal vascular thrombosis.242–244 An international database of mutations in the PC gene lists only 17 cases, and approximately 25 further kindreds are reported in the literature.245–277 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 C4bbound fraction on crossed immunoelectrophoresis. The approximate half-life of PS in this infant was 36 h.

Long-term Treatment: The modalities used for longterm 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 –281 in arteries from transplanted organs,282–286 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 CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

355S

Table 14 —Cardiac Catheterization in Children: Arterial Outcome Type of Study

Intervention

Patients, No.

Bleeding

TE

/1974

RCT

Freed et al289/1974

RCT

Saxena et al291/1997

RCT

Aspirin (15 mg/kg) Placebo Heparin (1 mg/kg) Placebo Heparin 50 IU/kg Heparin 100 IU/kg

37 58 37 40 183 183

0 0 0 0 0 0

8 14 2 10* 18 17

Study/yr Freed et al

290

*Indicates a p value ⬍ 0.05.

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. Umbilical Artery Catheterization: Umbilical arterial catheterization is necessary for the administration of supportive care that is critical to the survival of sick newborns (Table 15). Umbilical artery catheter tips are positioned either high (ie, at the level of T5 to T10) or low (ie, at the level of L3 to L5). The optimal position to minimize TEs remains uncertain. The position of the umbilical artery catheters may affect the frequency of both TEs and

ICHs.292–295 A low-dose continuous heparin infusion (3 to 5 U/h) is commonly used to maintain catheter patency. The effectiveness of heparin was assessed in one large trial296 and in five smaller randomized trials.297–301 The following three outcomes were assessed: patency; local thrombus; and ICH. Patency, which is likely linked to the presence of local thrombus, is prolonged by the use of low-dose heparin.296,298 –301 The incidence of local thrombus, detected by ultrasound, was not decreased in two randomized studies. However, the power of these studies was low.297,300 The incidence of ICH as an outcome was not increased in two randomized studies. However, the sample size in one study was small (15 per arm).301 In the other study, the odds ratio for ICH and heparin use was 1.49 (95% CI, 0.62 to 3.59).302 In two cohort studies, heparin was implicated as a risk factor for ICH in lowbirth-weight infants.303,304 One study was retrospective, and the 95% CI around the odds ratio of 3.9 was large (95% CI, 1.4 to 11.0), and the magnitude of the risk was uncertain.303 The second study reported a positive correlation between heparin dose and frequency of ICH;

Table 15—Umbilical Artery Catheterization*

Study/yr

Type of Study

Intervention

Jackson et al297/1987

RCT

Horgan et al300/1987

RCT

Rajani et al296/1979

RCT

David et al298/1981

RCT

Bosque and Weaver299/1986

RCT

Horgan et al300/1987

RCT

Ankola and Atakent301/1993

RCT

Chang et al302/1997

RCT

HB-PU PVC Heparin No heparin Heparin Saline solution Heparin No heparin Heparin (C) Heparin (I) Heparin No heparin Heparin No heparin Heparin No heparin

Patients, No. 61 64 59 52 32 30 26 26 18 19 59 52 15 15 5,558

Outcome Bleeding NR NR NR NR NR NR 0† 0† NR NR NR NR 4 ICH 5 ICH 19 ICH 17 ICH

Event 13 TE 23 TE 16 TE 18 TE 4 B‡ 19 B 3 B‡ 15 B 0 B‡ 8B 2 B‡ 10 B 2 B‡ 11 B † †

*B ⫽ blocked; HB-PU ⫽ heparin-bonded polyurethane; PVC ⫽ polyvinyl chloride; C ⫽ continuous; I ⫽ intermittent; NR ⫽ not reported. †No hemorrhage. ‡Indicates a p value ⬍ 0.05. 356S

Sixth ACCP Consensus Conference on Antithrombotic Therapy

however, severity of illness was also positively correlated with heparin dose, and the effect could not be differentiated.304 Large well-designed studies are required to determine whether low-dose heparin infusion affects the incidence of ICH.

Kawasaki’s Disease In patients with Kawasaki’s disease, aspirin is initially given in high doses (80 to 100 mg/kg/d, during the acute phase, for up to 14 days) as an anti-inflammatory agent, then in lower doses as an antiplatelet agent (3 to 5 mg/kg/d for ⱖ 7 weeks) to prevent coronary aneurysm thrombosis and subsequent infarction (the major cause of death in Kawasaki’s disease). Although no randomized controlled studies have been performed (to our knowledge), two cohort studies287,288 have suggested that aspirin can reduce the coronary involvement in patients with Kawasaki’s disease. A 1995 meta-analysis305 concluded that children treated with IV gamma globulin and aspirin had a significantly lower incidence of coronary artery aneurysms than those treated with aspirin alone. Much of the treatment difference in this analysis was due to one randomized study that demonstrated that the combination of IV gamma globulin and aspirin is more efficacious in this regard than aspirin alone.119 The meta-analysis made a number of conclusions about the optimal dosing of aspirin and gamma globulin. However, significant methodologic flaws in the analysis suggest that the conclusions should be viewed with some caution. Further studies are required.

Prosthetic Heart Valves in Children Biological Prosthetic Heart Valves in Children: Valvular heart diseases in childhood encompass a wide variety of abnormalities with greatly variable presentations. The valve lesion may be isolated, may be an integral part of more complex intracardiac lesions, or may be the result of treatment of the underlying congenital defect. TEs, either of the valve or due to a cerebrovascular accident, are some of the most serious complications of successful cardiac valve replacement. The failure of biological prosthetic heart valves in children poignantly illustrates the fallacy of extrapolating recommendations for adults to children without evaluation

in clinical trials. Commercially prepared biological prostheses became available in 1971 and achieved excellent early results in adult patients. Biological prosthetic heart valves rapidly became the “valve of choice” for the pediatric age group.306 Subsequently, the premature degeneration and calcification of porcine valves was identified in the majority of children.307–313 The accelerated failure of biological prosthetic heart valves in children was confirmed by many groups. Current recommendations are that, in general, mechanical prosthetic heart valves should be used in the mitral and aortic positions in children and biological prosthetic heart valves should be reserved for patients who require tricuspid or pulmonary valve replacements.314,315 Children with biological prosthetic heart valves are treated following adult recommendations and should be observed for evidence of valve dysfunction. Mechanical Prosthetic Heart Valves in Children: Antithrombotic therapy with OAs is clearly indicated for adults with mechanical prosthetic heart valves (Tables 16, 17, 18).316 –318 Alternatives to OAs have been pursued for children because of the issue of safe monitoring. No Therapy: With no antithrombotic therapy, TEs occurred at a rate of 5.7% per patient-year with St. Jude valves,83 and at rates of 6.8 to 27.3% per patient-year for other types of valves (Table 16).116 There was one death due to mitral valve thrombosis.83 Antiplatelet Agents: One cohort study reported no differences in survival or number of TEs in children with left-sided St. Jude valves treated with warfarin to maintain a PT of 1.5 times control, or aspirin (5 to 6 mg/kg) and dipyridamole (6 mg/kg).64 The linearized TE rates were 2.6% and 1.7% per patient-year, respectively (p ⫽ 0.6). Bleeding linearized event rates were 1.5% per patient-year in the warfarin group and 0 in the antiplatelet group (p ⫽ 0.09). Numerous case series have reported the use of empiric low doses of aspirin (6 to 20 mg/kg/d) and/or dipyridamole (2 to 5 mg/kg/d) for the prevention of TEs in the absence of therapy with OAs. With antiplatelet agents alone, TEs occurred at rates of 1.1 to 68% per patientyear, with three of eight studies having TE rates of ⬎ 5% per patient-year (Table 17). There was only one major

Table 16 —Thromboembolic and Hemorrhagic Complications of Mechanical Prosthetic Heart Valves With No Antithrombotic Therapy* Study/Year

Study Type

No.

Age

83

Valve Type

Sade et al /1988

Observational

48

5 mo–21 yr

St. Jude

Solymar et al116/1991

Observational

(186)‡

1–19 yr

Various

Position

TE/% pt-yr

HEM/% pt-yr

Deaths

Ao, M Ao ⫹ M overall Ao M ⱖ E2 valves

NR NR 5.7 6.8 20.0 27.3

0 0 0 0 0 0

1 M†

*HEM ⫽ hemorrhage; Ao ⫽ aortic; M ⫽ mitral; pt-yr ⫽ patient-year. See Table 15 for abbreviations not used in text. †The death was secondary to a mitral valve thrombosis. ‡The number of patients treated with no antithrombotic therapy could not be determined. Number refers to the entire patient population of the study.116 CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

357S

Table 17—Thromboembolic and Hemorrhagic Complications of Mechanical Prosthetic Heart Valves Treated With Antiplatelet Agents* Study/yr

Study Type

No.

Serra et al85/1987

Observational

24

McGrath et al86/1987

Observational

30

El Makhlouf et al82/1987

Observational

15

Bradley et al64/1985

Observational

10

Solymar et al116/1991

Observational (186)‡

Borkon et al117/1986

Observational

8

LeBlanc et al118/1993

Observational

20

Bradley et al64/1985

Observational

16

Dose

Age, yr

Valve Type

ASA mg/kg/d DIP 25/mg/kg ASA 900 mg/d DIP 150 mg/kg/d ASA 20 mg/kg/d DIP 5 mg/kg/d

50–20

St. Jude

4–20

St. Jude

2–6

Various

ASA 6.1 mg/kg/d DIP 1.9 mg/kg/d ASA 12 mg/kg/d DIP 3.0 mg/kg/d Not provided Not provided

⬍ 19

Various

ASA 10 mg/kg/d DIP 3 mg/kg/d ASA 5–6 mg/kg/d DIP 6 mg/kg/d

1–20

Various

3 wk–17

Various

1–17

Various

3–16

St. Jude

Position Ao M Ao, M ⱖ E2 valves Ao, M ⱖ E2 valves Overall Ao M Ao M ⱖ E2 valves Ao M Ao M Ao, M ⬎ 2 valves

TE/% pt-yr

HEM/% pt-yr

Deaths

68 19 32 NR NR NR 2.3 0 12 1.8 2.5 NR 0 1.1 0 1.7 1.7

NR NR 0† NR NR NR 0.1 0† 0† NR NR NR 0† 0† 0† 0† 0

0 0 0 1 Ao ⫹ M 0 0 0 0 0 0 2 CVA 0 0 1 M§ 0† 0† 2

*CVA ⫽ cerebral vascular accident; DIP ⫽ dipyridamole; ASP ⫽ aspirin. See Table 16 for abbreviations not used in text. †No hemorrhage. ‡The number of patients treated with antiplatelet agents could not be determined. Number refers to the entire patient population of the study.116 §Secondary to mitral valve thrombosis.

episode of bleeding, which was not fatal and did not result in long-term morbidity (Table 17). There were eight patients who died due to TEs for whom information on anticoagulant therapy could not be determined.82 Oral Anticoagulation Therapy: With OAs, the incidence of TEs was uniformly ⬍ 5% per patient-year (Table 18). There were five deaths due to TEs and two deaths due to bleeding.66,88,314,319 Three of the five patients had discontinued OA therapy, and the anticoagulant status of the other two patients could not be determined. With one exception, the rate of major bleeding was ⬍ 3.5% per patient-year (Table 18). In one study, two patients required blood transfusions (rate, 8.2% per patient-year) and recovered uneventfully.64 Adjuvant therapy with antiplatelet agents was used in one study.66 Based on information available for adults and children, a reasonable approach is to consider therapy with aspirin in combination with OAs for high-risk patients. High-risk patients include those with prior TEs, atrial fibrillation, a large left atrium, left atrial thrombi, ball valves, and mitral valves. Conclusion: The available data support the recommendation for oral anticoagulation therapy in children who have mechanical prosthetic heart valves. Problems of effectively monitoring OAs can be addressed through anticoagulation clinics for children1,63 and through the use of whole-blood monitors in the clinic and at home.320

Other Cardiac Disorders Antithrombotic therapy is currently used for several other congenital heart lesions or as a consequence of their surgical treatments 358S

BT Shunts: BT shunts are one form of palliative surgery used to enhance systemic blood flow, subclavian artery blood flow, and pulmonary artery blood flow in patients with severe or progressive cyanosis that is usually secondary to pulmonary stenosis.321,322 Modified Blalock shunts, in which a tube graft (Gore-Tex; W.L. Gore & Associates; Newark, DE) is taken from the side of the subclavian artery and anastomosed to the pulmonary artery, have been used since 1980. Because of the short length and very high flow, acute thrombosis is less common. Since 1980, 647 children with BT shunts were described in 21 case series. The incidence of thrombotic occlusion ranged from 1 to 17%. Many investigators used antithrombotic therapy, beginning with therapeutic doses of heparin followed by low-dose aspirin (1 to 10 mg/kg/d),323 although others324 have recommended intraoperative heparin with no further anticoagulation therapy. Fontan Operation: The Fontan procedure, or a modified version, is the definitive palliative surgical treatment for most congenital univentricular heart lesions. TEs remain a major cause of early and late morbidity and mortality. The reported incidences of venous TEs and stroke ranged from 3 to 16% and 3 to 19%, respectively, in retrospective cohort studies in which thrombosis was the primary outcome, and ranged from 1 to 7% in retrospective studies assessing multiple outcomes. TEs may occur anytime following Fontan procedures, but often present months to years later. No predisposing factors have been identified with certainty, although this may be due to inadequate power and the retrospective nature of the studies. Transesophageal echocardiography is more sensitive than transthoracic echocardiography for the diagnosis of intracardiac and central venous thrombosis. Despite Sixth ACCP Consensus Conference on Antithrombotic Therapy

Table 18 —Thromboembolic and Hemorrhagic Complications of Mechanical Prosthetic Heart Valves Treated With OAs* Study/yr

Study Type

No.

Age

Valve Type

Position

TE/% pt-yr

HEM/% pt-yr

Spevak et al87/1986 El Makhlouf et al82/1987 Harada et al88/1990 Stewart et al81/1987

Observational Observational Observational Observational

56 83 40 30

⬍ 5 yr 2–16 yr 4 mo–15 yr 6–17 yr

Various Various St. Jude Various

1.6 2.3 1.3 2.30

0.8 0 0 0.5

Bradley et al64/1985 Milano et al347/1986

Observational Observational

20 71

⬍ 19 yr 15 yr

Various Various

Ao, M Ao, M Ao, M Ao, M ⱖ E2 Ao, M Ao, M ⱖ E2

Schaffer et al348/1987

Observational

33

9–48 mo

St. Jude

Ao, M

Solymar et al116/1991

Observational (186)§

1–20 yr

Various

Ao, M ⱖ E2

Schaff et al115/1984 Borkon et al117/1986

Observational Observational

48 22

6 mo–18 yr 3 wk–17 yr

Starr St. Jude

Ao Ao, M Pulm

0 0.7 4.0 1.4 0.13 0.38 2.1 3.2 5.0 5.3 — 1.1

8.2 0 0 0 0 0 2.1 3.2 2.6 — —

Human et al349/1982 Antunes et al350/1989

Observational Observational

56 352

2–12 yr ⱕ 20 yr

Various Various

n⫽3 0.80.51.7

0 —

Woods et al66/1986

Observational

20¶

5 mo–16 yr

Various

1.80

Champsaur et al314/1997

Observational

54

1–17 yr

Various

M Ao, M ⱖ E2 Ao, M ⱖ E2 Ao ⬎ 2

0.3

0.9 0 0.3

Bradley et al64/1985

Observational

48

6 mo–18 yr

St. Jude

Ao, M

2.6

1.5

Deaths 4† 1 M‡

1 M‡

1 M‡

0 0 0

1 1 1 1 1

bleeding TE bleeding TE

*Pulm ⫽ pulmonary. See Table 16 for abbreviations not used in text. †The type of anticoagulant used could not be determined. ‡Death was due to a mitral valve thrombosis. §Parentheses indicate estimated number. ¶Patients were treated with a combination of warfarin and ASA.

aggressive therapy, thromboembolic events following Fontan procedures have a high mortality rate and respond to therapy in ⬍ 50% of cases. There is no consensus in the literature, or in routine clinical practice, as to the optimal type or duration of anticoagulation. Consequently, a wide variety of prophylactic anticoagulant regimens are in use. There is an ongoing large, multicenter, prospective trial of prophylactic anticoagulation therapy following Fontan procedures.325 The trial compares aspirin (5 mg/kg/d) to initial heparin therapy followed by warfarin (target INR, 2 to 3) as primary prophylaxis. Endovascular Stents: Endovascular stents are used increasingly to manage a number of congenital heart lesions, including branch pulmonary artery stenosis, pulmonary vein stenosis, and coarctation of the aorta, and are used to treat subsequent surgical stenosis.326 Although stents can be successfully used in infants who are ⬍ 1 year of age, the small vessel size increases the risk of thrombosis. To our knowledge, there are no studies assessing the role of anticoagulation or antiplatelet therapy to avoid stent occlusion in children. Heparin is commonly given at the time of stent insertion, followed by aspirin therapy. Further studies are required to determine the optimal prophylactic anticoagulation therapy required.

Other Cardiac Disorders: Other likely cardiac indications for anticoagulation in children are atrial fibrillation and myocardial infarction.327 There are only case reports describing antithrombotic therapy for these patients. In the absence of data, the use of guidelines for antithrombotic therapy in adult patients is recommended.

Other Disorders Antithrombotic therapy is used in several other disorders in pediatric patients that are not discussed in this article.232 Readers are referred to other references for antithrombotic therapy in cardiopulmonary bypass,328 –331 extracorporeal membrane oxygenation,332–334 and continuous venovenous hemoperfusion.335–337 Atrophie Blanche: Atrophie blanche (livedo vasculitis) is a superficial thrombotic disorder in which antiplatelet therapy may alleviate pain and decrease ulceration.338 Angina, Acute Myocardial Infarction, and Peripheral Artery Disease: Although these are the typical indications for aspirin therapy in adults, they occur rarely in children. To our knowledge, there are no published studies addressCHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

359S

ing the use of antiplatelet agents in these clinical settings in children. Hemolytic-Uremic Syndrome: Participation of platelets in the thrombotic microangiopathy of hemolytic-uremic syndrome (HUS) makes the use of antiplatelet agents an attractive possibility. Based on two case series,339,340 aspirin and dipyridamole have been proposed to result in a more rapid rise in the platelet count in children with HUS. However, a randomized study341 failed to confirm this hypothesis. Furthermore, there is no evidence that aspirin and dipyridamole favorably affect other outcome variables in children with HUS. A well-designed randomized study342 showed no benefit of dipyridamole and heparin treatment over symptomatic therapy alone. Similarly, antiplatelet agents have not been shown to be useful in the related disorder of childhood thrombotic thrombocytopenia purpura. Homocystinuria: In a case series, aspirin and dipyridamole were hypothesized to diminish the thromboembolic complications of homocystinuria in patients who are unresponsive to pyridoxine.343 However, two other case series did not support this hypothesis.344,345

Key Areas That Urgently Require Further Study Since the CHEST consensus conferences began in 1986, there has been a gradual progression of recommendations, with increasing numbers of strong recommendations for antithrombotic therapy in adults. The first guidelines for antithrombotic therapy in pediatric patients occurred in 1995 and were primarily based on adult guidelines and case series in children. Over the last 5 years, through numerous studies, there has been significant improvement in our understanding of the physiology of hemostasis during infancy and childhood, and of the implications for various antithrombotic therapies. In addition, large registries and prospective cohort studies have identified specific clinical questions that require intervention trials to determine optimal therapy. At the time the 1998 CHEST supplement was published, there were five multicenter, multinational randomized controlled trials assessing the optimal use of anticoagulants in children with or at risk for specific thromboembolic complications. The PARKAA study has been completed and has provided important information about the incidence of CVL-related TEs in children with ALL who are receiving l-asparaginase.6 The Fontan A study (an RCT comparing aspirin to heparin/warfarin as primary prophylaxis against TEs following Fontan surgery) and the PRECLUDE trial (an RCT of placebo vs warfarin anticoagulation [INR, 2.0 to 2.5] for primary thromboembolic prophylaxis in children with systemic lupus erythematosus and antiphospholipid antibodies) are ongoing. The Reviparin in Venous Thromboembolism trial and PROTEKT have stopped prior to planned recruitment targets and are unlikely to answer their primary questions but will provide valuable information on the diagnosis of DVT and the safety of using LMWH in children. 360S

The data from recent studies confirm that extrapolation of adult guidelines to infants and children is suboptimal. Determining the pharmacokinetics of various antithrombotic agents in infants and children, while important, does not determine the efficacy or safety of therapeutic regimens for the prevention or treatment of thromboembolic disease in children. There remains an urgent need for studies to determine safe and effective antithrombotic prophylaxis for CVLs, especially in small infants. The frequent, prolonged, off-label use of LMWH as a single agent to treat DVT in children needs adequate efficacy and safety study. The long-term impact of arterial thrombosis secondary to the use of vascular access devices needs to be proven prior to the consideration of more aggressive prophylactic regimes. The optimal anticoagulation therapy following many cardiac surgical procedures in children remains unclear. These studies will take many years to complete. There is now a collaborative international network capable of performing the needed studies. The challenge remains to convince both peer review agencies and pharmaceutical companies that pediatric trials require a specific dedicated approach.

Recommendations Venous Thromboembolic Disease in Children First TE: We recommend that children (⬎ 2 months of age) who have had an initial TE should be treated in the short term with doses of IV heparin that are sufficient to prolong the APTT to a range that corresponds to an anti-factor Xa level of 0.3 to 0.7 U/mL, or with doses of LMWH that are sufficient to achieve an anti-factor Xa level of 0.5 to 1.0 U/mL 4 h after an injection (grade 1C⫹). We recommend that initial treatment with heparin or LMWH should be continued for 5 to 10 days. For patients in whom subsequent OA therapy will be used, it can be started as early as day 1 and heparin/ LMWH therapy discontinued on day 6 if the INR is therapeutic on 2 consecutive days. For massive PEs or extensive DVTs, a longer period of heparin or LMWH therapy should be considered (grade 1C⫹). We recommend that anticoagulant therapy should be continued for at least 3 months using OAs to prolong the PT to a target INR of 2.5 (range, 2.0 to 3.0) or, alternatively, using LMWH to maintain an anti-factor Xa level of 0.5 to 1.0 U/mL (grade 2C). For children who have experienced an idiopathic TE, we recommend that treatment be continued for at least 6 months with either OAs or LMWH (grade 2C). Following the initial 3 months of therapy, for children with a first CVL-related DVT, we recommend prophylactic doses of OAs (INR, 1.5 to 1.8) or LMWH (anti-factor Xa levels, 0.1 to 0.3) as an option until the CVL is removed (grade 2C). Recurrent TE: For recurrent non-CVL-related TEs, following the initial 3 months of therapy Sixth ACCP Consensus Conference on Antithrombotic Therapy

(recommendation, 1 to 3 months), we recommend that indefinite therapy with either therapeutic or prophylactic doses of OAs or LMWH be used (grade 2C). For recurrent CVL-related TEs, following the initial 3 months of therapy, we recommend that prophylactic doses of OAs (INR, 1.5 to 1.8) or LMWH (anti-factor Xa level, 0.1 to 0.3) be continued until removal of the CVL. If the recurrence occurs while the patient is receiving prophylactic therapy, we recommend that therapeutic doses be continued until the CVL is removed or for a minimum of 3 months (all grade 2C). Primary Prophylaxis for Venous TE in Children: We do not recommend primary prophylaxis for children with CVLs in general at this time, because there is no evidence for the efficacy or safety of this approach (grade 2C). Remark: Short-term prophylactic anticoagulation therapy in high-risk situations such as immobility, significant surgery, or trauma is an option for children with known congenital prothrombotic disorders. However, to our knowledge, there are no published data on which to base a formal recommendation.

Venous Thromboembolic Disease in Newborns Remark: There are insufficient data to make specific recommendations about anticoagulation therapy in the treatment of newborns with DVTs and PEs. Options include conventional anticoagulation therapy in age-appropriate doses, short-term anticoagulation therapy, or close monitoring of the thrombus with objective tests and use of anticoagulation therapy if thrombus extension occurs. If anticoagulation therapy is used, we recommend a short course (10 to 14 days) of IV heparin that is sufficient to prolong the APTT to the therapeutic range that corresponds to an anti-factor Xa level of 0.3 to 0.7 U/mL, or, alternatively, a short course of LMWH that is sufficient to achieve an anti-factor Xa level at the low end of the adult therapeutic range (0.5 to 1.0 U/mL) may be used (all grade 2C compared to no treatment). Longer courses of anticoagulant therapy, up to 3 months, may be required dependent on the location and extent of the thrombus. The thrombus should be closely monitored with objective tests for evidence of extension or recurrent disease. If the thrombus extends following discontinuation of heparin therapy, we recommend oral anticoagulation therapy or extended LMWH therapy (grade 2C).

Thrombolytic Therapy for Venous Thromboembolic Disease Remark: There are insufficient data to make specific recommendations about the use of thrombolytic

agents in the treatment of venous TEs in neonates or children. Treatment needs to individualized. If thrombolytic therapy is used, in the presence of physiologic or pathologic deficiencies of plasminogen, we recommend supplementation with plasminogen (FFP) (grade 2C).

Congenital Prothrombotic Conditions Homozygous PC-Deficient and PS-Deficient Patients: We recommend that newborns with purpura fulminans due to a homozygous deficiency of PC or PS may be treated initially with replacement therapy (either FFP or PC concentrate) for approximately 6 to 8 weeks until the skin lesions have healed (grade 1C⫹). Following resolution of the skin lesions, and under cover of replacement therapy, we recommend that oral anticoagulation therapy be introduced with target INR values of approximately 3 to 4.5. Treatment duration with OAs is indefinite. We recommend that replacement therapy with PC concentrate for PCdeficient patients may be used for long-term prophylaxis or as salvage therapy for recurrent skin lesions or thrombosis (grade 2C). We recommend that for patients with homozygous PC and PS deficiency but with measurable plasma concentrations, LMWH is a therapeutic option (grade 2C).

Treatment of Arterial Thromboembolism Cardiac Catheterization: We recommend that newborns and children requiring cardiac catheterization via an artery should undergo IV heparin prophylaxis (grade 1A). We recommend heparin doses of 100 to 150 U/kg as a bolus (grade 2A compared with 50 U/kg). Remark: The initial dose and further administration of heparin therapy need further evaluation before definite recommendations can be given, in particular in small infants having procedural catheters. We recommend that clinicians not use aspirin alone (grade 1B). Arterial TE: We recommend that children or neonates with an arterial TE be treated with therapeutic doses of IV heparin (grade 1C). Remark: There are insufficient data to make a recommendation about the optimal duration of therapy. We recommend that children or neonates with limb-threatening or organ-threatening arterial TEs who fail to respond to initial heparin therapy, and who have no known contraindications, be treated with thrombolytic therapy (grade 1C). CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

361S

Remark: The use of surgery to treat arterial thrombosis in children should be individualized. There are insufficient data to make specific recommendations in children.

Treatment of Kawasaki’s Disease in Children In addition to IV gamma globulin (2 g/kg as a single dose), children with Kawasaki’s disease should receive aspirin, 80 to 100 mg/kg/d, during the acute phase (up to 14 days) as an anti-inflammatory agent, then aspirin, 3 to 5 mg/kg/d, for ⱖ 7 weeks to prevent the formation of coronary aneurysm thrombosis (grade 1C).

Prosthetic Heart Valves in Children Biological Prosthetic Heart Valves in Children: Children with biological prosthetic heart valves should be treated following adult recommendations and observed for evidence of valve dysfunction.

Mechanical Prosthetic Heart Valves in Children We recommend that children with mechanical prosthetic heart valves receive OA therapy (grade 1C⫹). We recommend levels of OA therapy that prolong the target INR to 3.0 (range, 2.5 to 3.5) (grade 1C⫹).346 For children with mechanical prosthetic heart valves who suffer systemic embolisms despite adequate therapy with oral anticoagulation therapy, we recommend the addition of aspirin, 6 to 20 mg/kg/d, to the regimen. Dipyridamole, 2 to 5 mg/kg/d, in addition to oral anticoagulation therapy is an alternative option (all grade 2C). When full-dose oral anticoagulation therapy is contraindicated, we recommend long-term therapy with OAs sufficient to increase the INR to 2.5 (range, 2.0 to 3.0) in combination with aspirin, 6 to 20 mg/kg/d, (grade 1C⫹) and dipyridamole, 2 to 5 mg/kg/d (grade 2C).

Other Cardiac Disorders BT Shunts: We recommend the initial treatment of patients with BT shunts with therapeutic amounts of heparin, followed by treatment with aspirin, at doses of 3 to 5 mg/kg/d, indefinitely (grade 2C). Remark: Further clinical investigation is needed before definitive recommendations can be made. Fontan Operations: We recommend aspirin or therapeutic amounts of heparin followed by oral anticoagulation therapy to achieve a target INR of 2.5 (range, 2 to 3) as therapeutic options (grade 2C). The optimal duration of prophylaxis is unknown. Patients 362S

with fenestrations may benefit from treatment until closure. Remark: Further clinical investigation is needed before definitive recommendations for primary postoperative prophylaxis can be made. ACKNOWLEDGMENT: We acknowledge the assistance of Lu Ann Brooker for conducting literature searches and for editing this article.

References 1 Andrew M, Marzinotto V, Brooker L, et al. Oral anticoagulant therapy in pediatric patients: a prospective study. Thromb Haemost 1994; 71:265–269 2 Massicotte P, Marzinotto V, Vegh P, et al. Home monitoring of warfarin therapy in children with a whole blood prothrombin time monitor. J Pediatr 1995; 127:389 –394 3 Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 1995; 108:506S–522S 4 Mitchell L, Abshire T, Hanna K. Supranormalizing antithrombin levels is safe in children with acute lymphoblastic leukemia treated with L-asparaginase: results of the PARKAA study [abstract]. Blood 1999; 94(suppl):27a 5 Mitchell L, Abshire T, Hanna K, et al. A prospective cohort determining the incidence of thrombotic events in children with acute lymphoblastic leukemia treated with L-asparaginase: results of the PARKAA study [abstract]. Blood 1999; 94(suppl):649a 6 Mitchell L, Chait P, Ginsberg J, et al. Comparison of venography with ultrasound for the detection of venous thrombosis in the upper body in children: results of the PARKAA study [abstract]. Blood 1999; 94(suppl):588a 7 Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70:165–172 8 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12:95–104 9 Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72:1651–1657 10 Shah J, Mitchell L, Paes B, et al. Thrombin inhibition is impaired in plasma of sick neonates. Pediatr Res 1992; 31:391–395 11 Reverdiau-Moalic P, Delahousse B, Bardos GBP, et al. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996; 88:900 –906 12 Hirsh J, Warkentin TE, Raschkle, et al. Heparin and low molecular weight heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998; 114(suppl):489S–510S 13 Hirsh J, Dalen J, Warkentin T, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1995; 108(suppl):258S–275S 14 Schmidt B, Ofosu F, Mitchell L, et al. Anticoagulant effects of heparin in neonatal plasma. Pediatr Res 1989; 25:405– 408 15 Andrew M, Schmidt B, Mitchell L, et al. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb Haemost 1990; 63: 27–30 16 Andrew M, Mitchell L, Vegh P, et al. Thrombin regulation in children differs from adults in the absence and presence of heparin. Thromb Haemost 1994; 72:836 – 842 Sixth ACCP Consensus Conference on Antithrombotic Therapy

17 Hirsh J. Heparin. N Engl J Med 1991; 324:1565–1574 18 Andrew M, Marzinotto V, Blanchette V, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35:78 – 83 19 Raschke R, Reilly B, Guidry J, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993; 119:874 – 881 20 Gallus A, Jackaman J, Tillett J, et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2:1293–1296 21 Hull RD, Raskob GE, Rosenbloom D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322:1260 –1264 22 Holmgren K, Andersson G, Fagrell B, et al. One-month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand 1985; 218:279 –284 23 Andrew M, Ofosu F, Schmidt B, et al. Heparin clearance and ex vivo recovery in newborn piglets and adult pigs. Thromb Res 1988; 52:517–527 24 McDonald MM, Jacobson LJ, Hay WW, et al. Heparin clearance in the newborn. Pediatr Res 1981; 15:1015–1018 25 Turner Gomes S, Nitschmann E, Benson L, et al. Heparin is cleared faster in children with congenital heart disease than adults [abstract]. J Am Coll Cardiol 1993; 21:59a 26 Hirsh J, van Aken W, Gallus A, et al. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976; 53:691– 695 27 Chiu H, van Aken W, Hirsh J, et al. Increased heparin clearance in experimental pulmonary embolism. J Lab Clin Med 1977; 90:204 –215 28 Cruickshank MK, Levine MN, Hirsh J, et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151:333–337 29 Elliot G, Hiltunen S, Suchyta M, et al. Physician-guided treatment compared with a heparin protocol for deep vein thrombosis. Arch Intern Med 1994; 154:999 –1004 30 Avioli L. Heparin induced osteoporosis: an appraisal. Adv Exp Med Biol 1975; 52:375–387 31 Sackler JP. Heparin induced osteoporosis. Br J Radiol 1973; 46:548 –550 32 Murphy M. Heparin therapy and bone fractures. Lancet 1992; 340:1098 –1099 33 Murdoch IA, Beattie RM, Silver DM. Heparin-induced thrombocytopenia in children. Acta Paediatr 1993; 82:495– 497 34 Spadone D, Clark F, James E, et al. Heparin-induced thrombocytopenia in the newborn. J Vasc Surg 1996; 15: 306 –311 35 Wilhelm M. Cardiopulmonary bypass in patients with heparin induced thrombocytopenia using Organon 10172. Ann Thorac Surg 1996; 61:920 –924 36 Potter C. Heparin induced thrombocytopenia in a child. J Pediatr 1992; 121:135–138 37 Klement D, Rammos S, von Kries R, et al. Heparin as a cause of thrombus progression: heparin-associated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts. Eur J Pediatr 1996; 155:11–14 38 Murdoch I, Beattie R, Silver D. Heparin-induced thrombocytopenia in children. Acta Paediatr 1993; 82:495– 497 39 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70:554 –561 40 Andrew M, deVeber G. Pediatric thrombembolism and stroke protocols. Hamilton, BC, Canada: Decker, 1997 41 Leaker M, Saxon BR. Heparin induced thrombocytopenia in

42

43

44

45 46 47

48 49 50 51 52

53 54 55

56 57 58 59

60

61

a young child managed with Orgaran for cardiopulmonary bypass surgery [abstract]. Blood 1998; 92(10 suppl 2):361b Massicotte P, Adams M, Marzinotto V, et al. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128:313–318 Massicotte MP, Adams M, Leaker M, et al. A nomogram to establish therapeutic levels of the low molecular weight heparin (LMWH), clivarine in children requiring treatment for venous thromboembolism (VTE) [abstract]. Thromb Haemost 1997; 282(suppl) Andrew M, Halton J, Massicotte M. Treatment of homozygous protein C deficiency in two children with low molecular weight heparin (LMWH) therapy [abstract]. Thromb Haemost 1995; 73:939 Andrew M, Ofosu F, Brooker L, et al. The comparison of the pharmacokinetics of a low molecular heparin in the newborn and adult pig. Thromb Res 1989; 56:529 –539 Hirsh J, Levine M. Low molecular weight heparin. Blood 1992; 79:1–17 Massonet-Castel S, Pelissier E, Bara L, et al. Partial reversal of low molecular weight heparin (PK 10169) anti Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis 1986; 16:139 –146 Harenberg J, Wurzner B, Zimmermann R, et al. Bioavailability and antagonization of the low molecular weight heparin CY 216 in man. Thromb Res 1986; 44:549 –555 Van Ryn-McKenna J, Cai L, Ofosu F, et al. Neutralization of enoxaparine induced bleeding by protamine sulfate. Thromb Haemost 1990; 63:271–274 Tait DP. Does low molecular weight heparin cause bleeding? Thromb Haemost 1997; 78:1422–1425 Public Health Service. Invasive procedures in pediatric patients on low molecular weight heparin. Rockville, MD: US Food and Drug Administration, 1997 Dix D, Charpentier K, Sparling C, et al. Determination of trough anti-factor Xa levels in pediatric patients on low molecular weight heparin (LMWH). Am J Pediatr Hematol Oncol 1998 Dix D, Marzinotto V, Leaker M, et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136:439 – 445 Hathaway W, Corrigan J. Report of scientific and standardization subcommittee on neonatal hemostasis. Thromb Haemost 1991; 65:323–325 Corrigan J. Normal hemostasis in fetus and newborn: coagulation. In: Polin R, Fox W, eds. Fetal and neonatal physiology. Philadelphia, PA: WB Saunders, 1992; 1368 – 1371 Hathaway WE, Bonnar J. Hemostatic disorders of the pregnant woman and newborn infant. New York, NY: Elsevier Science, 1987 Bovill E, Soll R, Lynch M, et al. Vitamin K1 metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate. Blood 1993; 81:77– 83 Andrew M, Vegh P, Johnston M, et al. Maturation of the hemostatic system during childhood. Blood 1992; 80:1998 – 2005 Massicotte M, Marzinotto V, Adams M, et al. Coumarin suppresses thrombin regulation to a greater extent in children compared to adults [abstract]. Thromb Haemost 1995; 73:1117 Schmidt B, Andrew M. Report of scientific and standardization subcommittee on neonatal hemostasis diagnosis and treatment of neonatal thrombosis. Thromb Haemost 1992; 67:381–382 Massicotte MP, Leaker M, Marzinotto V, et al. Enhanced CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

363S

62

63 64 65 66 67 68 69 70 71 72 73 74 75

76

77

78 79 80 81

82 83

thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80:570 –574 Fordyce M, Baker A, Staddon G. Efficacy of fixed minidose warfarin prophylaxis in total hip replacement. BMJ 1991; 303:219 –220 Streif W, Andrew M, Marzinotto V, et al. Analysis of warfarin therapy in pediatric patients: a prospective cohort study. Blood 1999; 94:3007–3014 Bradley LM, Midgley FM, Watson DC, et al. Anticoagulation therapy in children with mechanical prosthetic cardiac valves. Am J Cardiol 1985; 56:533–535 Carpentieri U, Nghiem QX, Harris LC. Clinical experience with an oral anticoagulant in children. Arch Dis Child 1976; 51:445– 448 Woods A, Vargas J, Berri G, et al. Antithrombotic therapy in children and adolescents. Thromb Res 1986; 42:289 –301 Doyle JJ, Koren G, Chen MY, et al. Anticoagulation with sodium warfarin in children: effect of a loading regimen. J Pediatr 1988; 113:1095–1097 Evans D, Rowlands M, Poller L. Survey of oral anticoagulant treatment in children. J Clin Pathol 1992; 45:707–708 Hathaway WE. Use of antiplatelet agents in pediatric hypercoagulable states. Am J Dis Child 1984; 138:301–304 Tait RC, Ladusans EJ, El-Metaal M, et al. Oral anticoagulation in paediatric patients: dose requirements and complications. Thromb Haemost 1996; 74:228 –231 Hirsh J. Oral anticoagulant drugs: review article. N Engl J Med 1991; 324:1865–1875 Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83:1251–1257 Aballi A, de Lamerens S. Coagulation changes in the neonatal period and in early infancy. Pediatr Clin North Am 1962; 9:785– 817 Shearer MJ, Barkhan P, Rahim S, et al. Plasma vitamin K1 in mothers and their newborn babies. Lancet 1982; 2:460 – 463 Greer FR, Mummah-Schendel LL, Marshall S, et al. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) status in newborns during the first week of life. Pediatrics 1988; 81:137–140 Haroon Y, Shearer MJ, Rahim S, et al. The content of phylloquinone (vitamin K1) in human milk, cow’s milk and infant formula foods determined by high-performance liquid chromatography. J Nutr 1982; 112:1105–1117 Von Kries R, Shearer MJ, McCarthy PT, et al. Vitamin K1 content of maternal milk: influence of the stage of lactation, lipid composition, and vitamin K 1 supplements given to the mother. Pediatr Res 1987; 22:513–517 Andrew M. The hemostatic system in the infant. In: Nathan D, Oski F, eds. Hematology of infancy and childhood. Philadelphia, PA: WB Saunders, 1992; 115–154 Lehman M, Kolb K, Barnhart G, et al. Warfarin absorption in a patient with short-bowel syndrome. Clin Pharm 1985; 4:325–326 Kumar S, Haigh J, Rhodes L, et al. Poor compliance is a major factor in unstable outpatient control of anticoagulant therapy. Thromb Haemost 1989; 62:729 –732 Stewart S, Cianciotta D, Alexson C, et al. The long-term risk of warfarin sodium therapy and the incidence of thromboembolism in children after prosthetic cardiac valves. J Thorac Cardiovasc Surg 1987; 93:551–554 El Makhlouf A, Friedli B, Oberhansli I, et al. Prosthetic heart valve replacement in children. J Thorac Cardiovasc Surg 1987; 93:80 – 85 Sade R, Crawford FJ, Fyfe D, et al. Valve prostheses in children: a reassessment of anticoagulation. J Thorac Cardiovasc Surg 1988; 95:553–561

364S

84 Rao S, Solymar L, Mardini M, et al. Anticoagulant therapy in children with prosthetic valves. Ann Thorac Surg 1989; 47:589 –592 85 Serra A, McNicholas K, Olivier H Jr, et al. The choice of anticoagulation in pediatric patients with the St. Jude Medical valve prostheses. J Cardiovasc Surg 1987; 28:588 –591 86 McGrath L, Gonzalez-Lavin L, Edlredge W, et al. Thromboembolic and other events following valve replacement in a pediatric population treated with antiplatelet agents. Ann Thorac Surg 1987; 43:285–287 87 Spevak P, Freed M, Castaneda A, et al. Valve replacement in children less than 5 years of age. J Am Cardiol 1986; 8:901–908 88 Harada Y, Imai Y, Kurosawa H, et al. Ten-year follow-up after valve replacement with the St. Jude Medical prosthesis in children. J Thorac Cardiovasc Surg 1990; 100:175–180 89 Hooshang T, Capitanio M. Tracheobronchial calcification: an observation in three children after mitral valve replacement and warfarin sodium therapy. Radiology 1990; 176: 728 –730 90 Piro L, Whyte M, Murphy W, et al. Normal cortical bone mass in patients after long term Coumadin therapy. J Clin Endocrinol Metab 1982; 54:470 – 473 91 Rosen H, Maitland L, Suttie J, et al. Vitamin K and maintenance of skeletal integrity in adults. Am J Med 1993; 94:62– 68 92 Massicotte P, Julian J, Webber C, et al. Osteoporosis: a potential complication of long term warfarin therapy [abstract]. Thromb Haemost 1999; (suppl):1333a 93 Greinacher A, Volpel H, Janssens U. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99:73– 80 94 Kikumoto R, Tamao Y, Tesuka T. Selective inhibition of thrombin by (2R,4R)-4methyl-1[N2- [(3-methyl-1,2, 3,4tetrahydro-8-quinolinyl) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid. Biochemistry 1984; 23:85–90 95 Yasuda T, Gold HK, Yaoita H. Comparative effects of aspirin, a synthetic thrombin inhibitor, and a monoclonal antiplatelet glycoprotein IIb/IIIa antibody on coronary artery reperfusion, reocclusion, and bleeding with recombinant tissue-type plasminogen activator in a canine preparation. J Am Coll Cardiol 1990; 16:714 –722 96 Gold HK, Torres FW, Garabedian HD. Evidence for a rebound coagulation phenomenon after cessation of a 4 hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993; 21:1039 – 1047 97 Rohrer MJ, Scheidler MG, Wheeler Brownell H. Extended indications for placement of an inferior vena cava filter. J Vasc Surg 1989; 10:44 –50 98 Golneke PJ, Garrett WV, Thompson JE. Interruption of the vena cava by means of the Greenfield filter: expanding the indications. Surgery 1988; 103:111–117 99 Cohen JH, Tenenbaum N, Citron M. Greenfield filter as primary therapy for deep venous thrombosis and/or pulmonary embolism in patients with cancer. Surgery 1991; 109: 12–15 100 Calligaro KD, Bergen WS, Hant MJ. Thromboembolic complications in patients with advanced cancer: anticoagulation versus Greenfield filter placement. Ann Vasc Surg 1991; 5:186 –189 101 Rogers FB, Shackford SR, Wilson J. Prophylactic vena cava filter insertion in severely injured trauma patients: Indications and preliminary results. J Trauma 1993; 35:637– 641 102 Rosethal D, McKinsey JF, Levy AM. Use of the Greenfield Sixth ACCP Consensus Conference on Antithrombotic Therapy

103

104 105

106

107 108 109 110 111

112

113 114 115 116 117

118 119 120 121

122

filter in patients with major trauma. Cardiovasc Surg 1994; 2:52–55 Webb LX, Rush PT, Fuller SB. Greenfield filter prophylaxis of pulmonary embolism in patients undergoing surgery for acetabular fracture. J Orthop Trauma 1992; 6:139 –145 Timsit JF, Reynaud P, Meyer G. Pulmonary embolectomy by catheter device in massive pulmonary embolism. Chest 1991; 100:655– 658 Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis: the Prevention du Risque D’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998; 338:409 – 415 Khong PL, John PR. Technical aspects of insertion and removal of an inferior vena cava IVC filter for prophylactic treatment of pulmonary embolus. Pediatr Radiol 1997; 27:239 –241 McBride WJ, Gadowski GR, Keller MS, et al. Pulmonary embolism in pediatric trauma patients. J Trauma 1996; 37:913–915 Rajasekhar D, Kestin A, Bednarek F, et al. Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72:957–963 Rajasekhar D, Barnard MR, Bednarek FJ, et al. Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997; 77:1002–1007 Ts’ao C, Green D, Schultz K. Function and ultrastructure of platelets of neonates; enhanced ristocetin aggregation of neonatal platelets. Br J Haematol 1976; 32:225–233 Katz JA, Moake JL, McPherson PD, et al. Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma. Blood 1989; 73:1851–1858 Weinstein MJ, Blanchard R, Moake JL, et al. Fetal and neonatal von Willebrand Factor (vWf) is unusually large and similar to the vWf in patients with thrombotic thrombocytopenic purpura. Br J Haematol 1989; 72:68 –72 Sanders J, Holtkamp C, Buchanan G. The bleeding time may be longer in children than in adults. Am J Pediatr Hematol Oncol 1990; 12:314 –318 Aversa L, Vasquez A, Penalver J, et al. Bleeding time in normal children. Am J Pediatr Hematol Oncol 1995; 17: 25–28 Schaff H, Danielson G, DiDonato R, et al. Late results after Starr-Edwards valve replacement in children. J Thorac Cardiovasc Surg 1984; 88:583–589 Solymar L, Rao PS, Mardini MK, et al. Prosthetic valves in children and adolescents. Am Heart J 1991; 121:557–568 Borkon AM, Soule L, Reitz BA, et al. Five year follow-up after valve replacement with the St. Jude Medical valve in infants and children. Circulation 1986; 74(suppl):I-110 –I115 LeBlanc J, Sett S, Vince D. Antiplatelet therapy in children with left-sided mechanical prostheses. Eur J Cardiothorac Surg 1993; 7:211–215 Newburger J, Takahashi M, Burns J, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341–347 Ito MK, Smith AR, Lee ML. Ticlopidine: a new platelet aggregation inhibitor. Clin Pharm 1992; 11:603– 617 Savi P, Heilmann E, Nurden P. Clopidogrel: an antithrombotic drug acting of the ADP-dependent activation pathway of human platelets. Clin Appl Thromb Hemost 1996; 2:35– 42 Herbert JM, Frehel D, Vallee E. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovasc Drug Rev 1993; 11:180 –198

123 Lecompte TP, Lecrubier C, Bouloux C. Antiplatelet effects of the addition of acetylsalicylic acid 40 mg daily to ticlopidine in human healthy volunteers. Clin Appl Thromb Hemostas 1997; 3:245–250 124 Hass WK, Easton JD, Adams HP. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high risk patients. N Engl J Med 1989; 321:501–507 125 Becquemin JP. Effect of ticlopidine on the long term patency of saphenous vein bypass grafts in the legs: Etude de la Ticlopidine apres Pontage Femoro-Poplite and the Association Universitaire de Recherche en Chirurgie. N Engl J Med 1997; 337:1726 –1731 126 Gershlick AH. Antiplatelet therapy following stent deployment. Heart 1997; 78:24 –26 127 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogril versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348:1329 –1339 128 Patrono C, Coller B, Dalen JE, et al. Platelet active drugs: the relationships among dose, effectiveness, and side effects. Chest 1998; 114(suppl):470S– 488S 129 Coller BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation 1995; 92:2373–2380 130 Coller BS. Monitoring platelet GPIIb/IIIa antagonist therapy. Circulation 1997; 96:3828 –3832 131 Bandstra ES, Montalvo BM, Goldberg RN. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988; 82:533–542 132 Ment LR, Duncan CC, Ehrenkranz RA. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants. J Pediatr 1985; 107:937–943 133 Ment LR, Duncan CC, Ehrenkranz RA. Randomized low dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr 1988; 112:948 –955 134 Ment LR, Ehrenkranz RA, Duncan CC. Intraventricular hemorrhage of the preterm neonate: prevention studies. Semin Perinatol 1988; 12:359 –372 135 Bada H, Korones S, Kolni H, et al. Partial plasma exchange transfusion improves cerebral hemodynamics in symptomatic neonatal polycythemia. Am J Med Sci 1986; 291:11–163 136 Porter J, Robinson P, Glasgow J, et al. Trends in the incidence of Reye’s syndrome and the use of aspirin. Arch Dis Child 1990; 65:826 – 829 137 Remington P, Shabino C, McGee H, et al. Reye syndrome and juvenile rheumatoid arthritis in Michigan. Am J Dis Child 1985; 139:870 – 872 138 Makela A, Lang H, Korpela P. Toxic encephalopathy with hyperammonaemia during high-dose salicylate therapy. Acta Neurol Scand 1980; 61:146 –151 139 Starko K, Ray C, Dominguez L, et al. Reye’s syndrome and salicylate use. Pediatrics 1980; 66:859 – 864 140 Halpin T, Holtzhauer F, Campbell R, et al. Reye’s syndrome and medication use. JAMA 1982; 248:687– 691 141 Young R, Toretti D, Williams R, et al. Reye’s syndrome associated with long-term aspirin therapy. JAMA 1984; 251:754 –756 142 Baum J. Aspirin in the treatment of juvenile arthritis. Am J Med 1983; 74:10 –15 143 Reverdiau-Moalic P, Gruel Y, Delahousse B, et al. Comparative study of the fibrinolytic system in human fetuses and in pregnant women. Thromb Res 1991; 61:489 – 499 144 Corrigan J, Sluth J, Jeter M, et al. Newborn’s fibrinolytic mechanism: components and plasmin generation. Am J Hematol 1989; 32:273–278 145 Andrew M, Brooker L, Paes B, et al. Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

365S

146

147

148 149 150 151 152

153 154 155

156 157 158

159 160 161 162 163 164 165 166

plasminogen concentration. Thromb Haemost 1992; 68: 325–330 Leaker M, Brooker L, Ofosu K, et al. Anisoylated streptokinase-plasminogen activator complex offers no advantage over streptokinase for fibrin clot lysis in cord plasma. Biol Neonate 1998 (in press) Leaker M, Superina R, Andrew M. Fibrin clot lysis by tissue plasminogen activator (tPA) is impaired in plasma from pediatric liver transplant patients. Transplantation 1995; 60:144 –147 Leaker M, Massicotte MP, Brooker L, et al. Thrombolytic therapy in pediatric patients: a comprehensive review of the literature. Thromb Haemost 1996; 76:132–134 Bovill E, Becker R, Tracy R. Monitoring thrombolytic therapy. Prog Cardiovasc Dis 1992; 34:279 –294 Public Health Service. Important drug warning regarding the use of Abbokinase (urokinase). Rockville, MD: US Food and Drug Administration, 1999 Wever M, Liem K, Geven W, et al. Urokinase therapy in neonates with catheter related central venous thrombosis. Thromb Haemost 1995; 73:180 –185 Gore J, Sloan M, Price T, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction, phase II, pilot and clinical trial. Circulation 1991; 83:448 – 459 Monagle P, Phelan E, Downie P, et al. Local thrombolytic therapy in children [abstract]. Thromb Haemost 1997; 504 Kaufman SL, Martin LG, Gilarsky BP, et al. Urokinase thrombolysis using a multiple side hole multilumen infusion catheter. Cardiovasc Intervent Radiol 1991; 14:334 –337 Zenz W, Arit F, Socia S, et al. Intracerebral hemorrhage during fibrinolytic therapy in children: a review of the literature of the last thirty years. Semin Thromb Hemost 1997; 23:321–332 Simoons ML, Maggioni AP, Knatterud G, et al. Individual risk assessment for intracranial hemorrhage during thrombolytic therapy. Lancet 1993; 342:1523–1528 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329:673– 682 Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318:1162–1173 Clagett G, Reisch J. Prevention of venous thromboembolism in general surgical patients. Ann Surg 1988; 208:227–240 Castaman G, Rodeghiero F, Dini E. Thrombotic complications during L-asparaginase treatment for acute lymphocytic leukemia. Haematologica 1990; 75:567–569 Wise RC, Todd JK. Spontaneous, lower-extremity venous thrombosis in children. Am J Dis Child 1973; 126:766 –769 Bernstein D, Coupey S, Schonberg S. Pulmonary embolism in adolescents. Am J Dis Child 1986; 140:667– 671 Nowak-Gottl U, von Kries R, Gobel U. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child 1997; 76:F163–F167 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96:939 –943 Coon W, Willis P, Keller J. Venous thromboembolism and other venous disease in the Tecumseh Community Health Study. Circulation 1973; 48:839 – 846 Gjores J. The incidence of venous thrombosis and its sequelae in certain districts in Sweden. Acta Chir Scand 1956; 206(suppl):1–10

366S

167 Carter C, Gent M. The epidemiology of venous thrombosis. In: Colman R, Hirsh J, Marder V, et al, eds. Hemostasis and thrombosis. basic principles and clinical practice. Philadelphia, PA: JB Lippincott, 1982; 805– 819 168 Uden A. Thromboembolic complications following scoliosis surgery in Scandinavia. Acta Orthop Scand 1979; 50:175– 178 169 David M, Andrew M. Venous thromboembolism complications in children: a critical review of the literature. J Pediatr 1993; 123:337–346 170 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients. Thromb Haemost 1995; 74(suppl):415– 425 171 Xu L, Delorme M, Berry L, et al. Alpha-2-macroglobulin remains as important as ATIII for thrombin regulation in cord plasma in the presence of endothelial cell surfaces. Pediatr Res 1995; 37:1– 6 172 Delorme M, Xu L, Berry L, et al. Anticoagulant dermatan sulfate proteoglycan (Decorin) in the term human placenta. Thromb Res 1998; 90:147–153 173 Andrew M, Mitchell L, Berry L, et al. An anticoagulant dermatan sulfate circulates in the pregnant woman and her fetus. J Clin Invest 1992; 89:321–326 174 Delorme M, Burrows R, Ofosu F, et al. Thrombin regulation in mother and fetus during pregnancy. Semin Thromb Hemost 1992; 18:81–90 175 Xu L, Delorme M, Berry L, et al. Thrombin generation in newborn and adult plasma in the presence of an endothelial surface [abstract]. Thromb Haemost 1991; 65:1230 176 Nitschman E, Berry L, Bridge L, et al. Morphological and biochemical features affecting the antithrombotic properties of the inferior vena cava in adult rabbits and rabbit pups. Pediatr Res 1998; 43:1– 6 177 Nitschmann E, Monagel P, Andrew M. Morphological and biochemical features affecting the antithrombotic properties of the aorta of adult rabbits and rabbit pups. Thromb Haemost 1998; 79:1034 –1040 178 Monagle PAM, Mahoney M, Ali K, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47:763–766 179 Berube C, David M, Laxer R, et al. The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus in children: a cross-sectional study. Lupus 1994; 3:360A 180 Montes de Oca MA, Babron MC, Bletry O, et al. Thrombosis in systemic lupus erythematosus: a French collaborative study. Arch Dis Child 1991; 66:713–717 181 Ehrenforth S, Junker R, Koch HG, et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood; the Childhood Thrombophilia Study Group. Eur J Pediatr 1999; 158(suppl):S97– S104 182 Nuss R, Hays T, Manco-Johnson MJ. Childhood thrombosis. Pediatrics 1995; 96:291–294 183 Nowak-Gottl U, Auberger K, Gobel U, et al. Inherited defects of the protein C anticoagulant system in childhood thrombo-embolism. Eur J Pediatr 1996; 155:921–927 184 Nowak-Gottl U, Koch D, Aschka B, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996; 92:992–998 185 Green R, Meyer T, Dunn M, et al. Pulmonary embolism in younger adults. Chest 1992; 101:1507–1511 186 Le Coultre C, Oberhansli I, Mossaz A, et al. Postoperative chylothorax in children: differences between vascular and traumatic origin. Paper presented at: 37th Annual InternaSixth ACCP Consensus Conference on Antithrombotic Therapy

187

188

189 190

191 192 193 194

195

196 197

198

199 200

201

202

203 204 205

tional Congress of the British Association of Paediatric Surgeons, July 25–27, 1990 Rockoff M, Gang DL, Vancanti JP. Fatal pulmonary embolism following removal of a central venous catheter. J Pediatr Surg 1984; 19:307–309 Mulvihill SJ, Fonkalsrud EW. Complications of superior versus inferior vena cava occlusion in infants receiving central total parenteral nutrition. J Pediatr Surg 1984; 19:752–757 Mollitt DL, Golladay ES. Complications of TPN catheterinduced vena caval thrombosis in children less than one year of age. J Pediatr Surg 1983; 18:462– 467 Tanaka K, Takao M, Yada I, et al. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989; 3:181–188 Graham L, Gumbiner CH. Right atrial thrombus and superior vena cava syndrome in a child. Pediatrics 1984; 73:225– 229 Bertrand M, Presant CA, Klein L, et al. Iatrogenic superior vena cava syndrome: a new entity. Cancer 1984; 54:376 –378 Kramer SS, Taylor GA, Garfinkel DJ, et al. Lethal chylothoraces due to superior vena caval thrombosis in infants. Am J Radiol 1981; 137:559 –563 Dhande V, Kattwinkel J, Alford B. Recurrent bilateral pleural effusions secondary to superior vena cava obstruction as a complication of central venous catheterization. Pediatrics 1983; 72:109 –113 Andrew M, Marzinotto V, Pencharz P, et al. A crosssectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr 1995; 126:358 –363 Dollery CM, Sullivan ID, Bauraind O, et al. Thrombosis and embolism in long-term central venous access for parenteral nutrition. Lancet 1994; 344:1043–1045 Massicotte MP, Dix D, Monagle P, et al. Central venous catheter related thrombosis (CVL-related DVT) in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133:770 –776 Marsh D, Wilkerson S, Cook L, et al. Right atrial thrombus formation screening using two-dimensional echocardiograms in neonates with central venous catheters. Pediatrics 1988; 81:284 –286 Warner B, Gorgone P, Schilling S, et al. Multiple purpose central venous access in infants less than 1,000 grams. J Pediatr Surg 1987; 22:820 – 822 Beck C, Dubois J, Grignon A, et al. Incidence and risk factors of catheter related deep vein thrombosis in a pediatric intensive care unit: a prospective study. J Pediatr 1998; 133:237–241 Bern MM, Lokich JJ, Wallach SR, et al. Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 1990; 112:423– 428 Monreal M, Alastrue A, Rull M, et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices: prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75:251–253 Stockwell M, Adams M, Andrew M, et al. Central venous catheters for out-patient management of malignant disorders. Arch Dis Child 1983; 58:633– 663 Miletich J, Prescott S, White R, et al. Inherited predisposition to thrombosis. Cell 1993; 72:477– 480 Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151:1721–1731

206 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78:297–301 207 Koeleman B. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84:1031–1035 208 Zoller B, Berntsdotter A, Carcia de Frutos P, et al. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85:3518 –3523 209 Van Boven HH, Reitsma PH, Rosendaal FR, et al. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75:417– 421 210 Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81:198 –202 211 Nowak-Gottl U, Strater R, Dubbers A, et al. Ischemic stroke in infancy and childhood: role of Arg506 to Gln mutation in the factor V gene. Blood Coagul Fibrinolysis 1996; 7:684 – 688 212 Sifontes MT, Nuss R, Hunger SP, et al. The factor V Leiden mutation in children with cancer and thrombosis. Br J Haematol 1997; 96:484 – 489 213 Nuss R, Hays T, Chudgar U, et al. Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary embolism. J Pediatr Hematol Oncol 1997; 19:202–207 214 Sifontes MT, Nuss R, Jacobson LJ, et al. Thrombosis in otherwise well children with the factor V Leiden mutation. J Pediatr 1996; 128:324 –328 215 deVeber G, Monagle P, Chan A, et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol 1998; 55:1539 –1543 216 Blanco A, Bonduel M, Penalva L, et al. Deep vein thrombosis in a 13 year old boy with hereditary protein S deficiency and a review of the pediatric literature. Am J Hematol 1994; 45:330 –334 217 Witt O, Pereira PL, Tillmann W. Severe cerebral venous sinus thrombosis and dural arteriovenous fistula in an infant with protein S deficiency. Childs Nerv Sys 1999; 15:128 –130 218 Zimmerman AA, Watson RS, Williams JK. Protein S deficiency presenting as an acute postoperative arterial thrombosis in a four year old child. Anesth Analg 1999; 88:535–537 219 Charuvanji A, Laothamatas J, Torcharus K, et al. Moyamoya disease and protein S deficiency: a case report. Pediatr Neurol 1997; 17:171–173 220 Zoller B, He X, Dahlback B. Homozygous APC-resistance combined with inherited type I protein S deficiency in a young boy with severe thrombotic disease. Thromb Haemost 1995; 73:743–745 221 Simioni P, Battistella PA, Drigo P, et al. Childhood stroke associated with familial protein S deficiency. Brain Dev 1994; 16:241–245 222 Horowitz I, Galvis A, Gomperts E. Arterial thrombosis and protein S deficiency. J Pediatr 1992; 121:934 –937 223 Prats J, Garaizar C, Zuazo E, et al. Superior sagittal sinus thrombosis in a child with protein S deficiency. Neurology 1992; 42:2303–2304 224 O’Sullivan J, Chatuverdi R, Bennett MK, et al. Protein S deficiency: early presentation and pulmonary hypertension. Arch Dis Child 1992; 67:960 –961 225 Pan EY, Gomperts ED, Millen R, et al. Bone mineral density and its association with inherited protein S deficiency. Thromb Res 1990; 58:221–231 226 De Stefano V, Leone G, Ferrelli R, et al. Severe deep vein thrombosis in a 2 year old child with protein S deficiency. Thromb Haemost 1987; 58:1089 227 Hausler M, Duque D, Merz U, et al. The clinical outcome CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

367S

228

229 230 231

232 233 234 235

236 237 238 239

240 241

242 243 244 245

246 247

after inferior vena cava thrombosis in early infancy. Eur J Pediatr 1999; 158:416 – 420 Gurgey A. Clinical manifestations in thrombotic children with factor V Leiden mutation. Pediatr Hematol Oncol 1999; 16:233–237 Aschka I, Aumann V, Bergmann F, et al. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr 1996; 155:1009 –1014 Sifontes MT, Nuss R, Hunger SP, et al. Activated protein C resistance and the factor V Leiden mutation in children with thrombosis. Am J Hematol 1998; 57:29 –32 Hagstrom JM, Walter J, Bluebond-Langner R, et al. Prevalence of the factor V Leiden mutation in children and neonates with thromboembolic disease. J Pediatr 1998; 133:777–781 Fabri D, Belangero VM, Annichino-Bizzacchi JM, et al. Inherited risk factors for thrombophilia in children with nephrotic syndrome. Eur J Pediatr 1998; 157:939 –942 Seixas CA, Hessel G, Ribeiro CC, et al. Factor V Leiden is not common in children with portal vein thrombosis. Thromb Haemost 1997; 77:258 –261 Ong BC, Zimmerman AA, Neufeld EJ, et al. Prevalence of factor V Leiden in a population of patients with congenital heart disease. Can J Anaesth 1998; 45:1176 –1180 McColl MD, Chalmers EA, Thomas A, et al. Factor V Leiden, prothrombin 20210G-A and the MTHFR C677T mutation in childhood stroke. Thromb Haemost 1999; 81: 690 – 694 Ganesan V, McShane MA, Liesner R, et al. Inheritied prothrombotic states and ischemic stroke in childhood. J Neurol Neurosurg Psychiatry 1998; 65:508 –511 Zenz W, Bodo Z, Plotho J, et al. Factor V Leiden and prothrombin gene G20210A variant in children with ischemic stroke. Thromb Haemost 1998; 80:763–766 Bonduel M, Sciuccati G, Hepner M, et al. Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol 1999; 56:967–971 Vielhaber H, Ehrenforth S, Koch HG, et al. Cerebral venous sinus thrombosis in infancy and childhood: role of genetic and acquired risk factors of thrombophilia. Eur J Pediatr 1998; 157:555–560 Young G, Krohn KA, Packer RJ. Prothrombin G20210A mutation in a child with spinal cord infarction. J Pediatr 1999; 134:777–779 Stier C, Potzsch B, Muller-Berghaus G, et al. Severe thrombophilia in a pediatric patients with end-stage renal disease: detection of the prothrombin gene G20210A mutation. Nephrol Dial Transplant 1998; 13:2130 –2132 Auletta M, Headington J. Purpura fulminans: a cutaneous manifestation of severe protein C deficiency. Arch Dermatol 1988; 124:1387–1391 Adcock D, Brozna J, Marlar R. Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis. Semin Thromb Hemost 1990; 16:333–340 Adcock D, Hicks M. Dermatopathology of skin necrosis associated with purpura fulminans. Semin Thromb Hemost 1990; 16:283–292 Pescatore P, Horellou H, Conard J, et al. Problems of oral anticoagulation in an adult with homozygous protein C deficiency and late onset of thrombosis. Thromb Haemost 1993; 69:311–315 Marlar R, Sills R, Groncy P, et al. Protein C survival during replacement therapy in homozygous protein C deficiency. Am J Hematol 1992; 41:24 –31 Deguchi K, Tsukada T, Iwasaki E, et al. Late-onset homozygous protein C deficiency manifesting cerebral infarction as the first symptom at age 27. Intern Med 1992; 31:922–925

368S

248 Yamamoto K, Matsushita T, Sugiura I, et al. Homozygous protein C deficiency: identification of a novel missense mutation that causes impaired secretion of the mutant protein C. J Lab Clin Med 1986; 119:682– 689 249 Auberger K. Evaluation of a new protein C concentrate and comparison of protein C assays in a child with congenital protein C deficiency. Ann Hematol 1992; 64:146 –151 250 Grundy C, Melissari E, Lindo V, et al. Late-onset homozygous protein C deficiency. Lancet 1991; 338:575–576 251 Ozkutlu S, Saraclar M, Atalay S, et al. Two-dimensional echocardiographic diagnosis of tricuspid valve noninfective endocarditis due to protein C deficiency (lesion mimicking tricuspid valve myxoma). Jpn Heart J 1991; 32:139 –145 252 Marlar RA, Neuman A. Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies. Semin Thromb Hemost 1990; 16:299 –309 253 Tripodi A, Franchi F, Krachmalnicoff A, et al. Asymptomatic homozygous protein C deficiency. Acta Hematol 1990; 83:152–155 254 Petrini P, Segnestam K, Ekelund H, et al. Homozygous protein C deficiency in two siblings. Pediatr Hematol Oncol 1990; 7:165–175 255 Marlar R, Adcock D, Madden R. Hereditary dysfunctional protein C molecules (type II): assay characterization and proposed classification. Thromb Haemost 1990; 63:375–379 256 Marlar R, Montgomery R, Broekmans A. Report on the diagnosis and treatment of homozygous protein C deficiency. Thromb Haemost 1989; 61:529 –531 257 Ben-Tal O, Zivelin A, Seligsohn U. The relative frequency of hereditary thrombotic disorders among 107 patients and thrombophilia in Israel. Thromb Haemost 1989; 61:50 –54 258 Tuddenham E, Takase T, Thomas A, et al. Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 1989; 53:475– 484 259 Hartman R, Manco-Johnson M, Rawlings J, et al. Homozygous protein C deficiency: early treatment with Warfarin. Am J Pediatr Hematol Oncol 1989; 11:395– 401 260 Vukovich T, Auberger K, Weil J, et al. Replacement therapy for a homozygous protein C deficiency-state using a concentrate of human protein C and S. Br J Haematol 1988; 70:435– 440 261 Gladson C, Groncy P, Griffin J. Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. Arch Dermatol 1987; 123:1701a–1706a 262 Casella J, Bontempo F, Markel H, et al. Successful treatment of homozygous protein C deficiency by hepatic transplantation. Lancet 1988; 1:435– 438 263 Manco-Johnson M, Marlar R, Jacobson L, et al. Severe protein C deficiency in newborn infants. J Pediatr 1988; 113:359 –363 264 Peters C, Casella J, Marlar R, et al. Homozygous protein C deficiency: observations on the nature of the molecular abnormality and the effectiveness of warfarin therapy. Pediatrics 1988; 81:272–276 265 Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317:991–996 266 Rappaport E, Speights V, Helbert B, et al. Protein C deficiency. South Med J 1987; 80:240 –242 267 Marlar R, Montgomery R, Broekmans A. Diagnosis and treatment of homozygous protein C deficiency: report of the Working Party on Homozygous Protein C and Protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989; 114:528 –534 268 Monagle P, Andrew M, Halton J, et al. Homozygous protein C deficiency: description of a new mutation and successful Sixth ACCP Consensus Conference on Antithrombotic Therapy

269

270 271 272

273 274 275 276 277 278

279 280 281 282

283 284 285 286

287 288 289

treatment with low molecular weight heparin. Thromb Haemost 1998; 79:756 –761 Hattenbach LO, Beeg T, Kreuz W, et al. Ophthalmic manifestation of congenital protein C deficiency. J AAPOS 1999; 3:188 –190 Mahasandana C, Suvatte V, Chuansumvita A, et al. Homozygous protein S deficiency in an infant with purpura fulminans. J Pediatr 1990; 117:750 –753 Tarras S, Gadia C, Meister L, et al. Homozygous protein C deficiency in a newborn: clinicopathologic correlation. Arch Neurol 1988; 45:214 –216 Branson H, Katz J, Marble R, et al. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2:1165– 1168 Seligsohn U, Berger A, Abend M, et al. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310:559 –562 Sills R, Marlar R, Montgomery R, et al. Severe homozygous protein C deficiency. J Pediatr 1984; 105:409 – 413 Estelles A, Garcia-Plaza I, Dasi A, et al. Severe inherited “homozygous” protein C deficiency in a newborn infant. Thromb Haemost 1984; 52:53–56 Marciniak E, Wilson H, Marlar R. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood 1985; 65:15–20 Yuen P, Cheung A, Hsiang J, et al. Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics 1986; 77:670 – 676 Dreyfus M, Magny J, Bridey F, et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325:1565–1568 Hong C, Yun Y, Choi J, et al. Takayasu arteritis in Korean children: clinical report of seventy cases. Heart Vessels 1992; 7:91–96 Zheng D, Fan D, Liu L. Takayasu arteritis in China: a report of 530 cases. Heart Vessels 1992; 7:32–36 Wiggelinkhuizen J, Cremin B, Cywes S. Spontaneous recanalization of renal artery stenosis in childhood Takayasu arteritis: a case report. S Afr Med J 1980; 57:96 –98 Hall T, McDiarmid S, Grant E, et al. False-negative duplex Doppler studies in children with hepatic artery thrombosis after liver transplantation. AJR Am J Roentgenol 1990; 154:573–575 Flint E, Sumkin J, Zajko A, et al. Duplex sonography of hepatic artery thrombosis after liver transplantation. AJR Am J Roentgenol 1988; 151:481– 483 Lerut J, Gordon R, Tzakis A, et al. The hepatic artery in orthotopic liver transplantation. Helv Chir Acta 1988; 55: 367–378 LeBlanc J, Culham J, Chan K, et al. Treatment of grafts and major vessel thrombosis with low-dose streptokinase in children. Ann Thorac Surg 1986; 41:630 – 635 Samara E, Voss B, Pederson J. Renal artery thrombosis associated with elevated cyclosporine levels: a case report and review of the literature. Transplant Proc 1988; 20:119 – 123 Koren G, Rose V, Lavi S, et al. Probable efficacy of high-dose salicylates in reducing coronary involvement in Kawasaki disease. JAMA 1985; 254:767–769 Daniels S, Specker P, Capannari TE, et al. Correlates of coronary artery aneurysm formation in patients with Kawasaki disease. Am J Dis Child 1987; 141:205–207 Freed M, Keane J, Rosenthal A. The use of heparinization to prevent arterial thrombosis after percutaneous cardiac catheterization in children. Circulation 1974; 50:565–569

290 Freed M, Rosenthal A, Fyler D. Attempts to reduce arterial thrombosis after cardiac catheterization in children: use of percutaneous technique and aspirin. Am Heart J 1974; 87:283–286 291 Saxena A, Gupta R, Kumar RK, et al. Predictors of arterial thrombosis after diagnostic cardiac catheterization in infants and children randomized to two heparin doses. Cathet Cardiovasc Diagn 1997; 41:400 – 403 292 Schick RM, Jolesz F, Barnes PD, et al. MR diagnosis of dural venous sinus thrombosis complicating L-asparaginase therapy. Comput Med Imaging Graph 1989; 13:319 –327 293 Lott J, Connor G, Phillips J. Umbilical artery catheter blood sampling alters cerebral blood flow velocity in preterm infants. J Perinatol 1996; 16:341–345 294 Fletcher M, Brown D, Landers S, et al. Umbilical artery catheter use: report of an audit by study group for complications of perinatal care. Am J Perinatol 1994; 11:94 –99 295 Rand T, Weninger M, Kohlhauser C, et al. Effect of umbilical artery catheterization in mesenteric hemodynamics. Pediatr Radiol 1996; 26:435– 438 296 Rajani K, Goetzman B, Wennberg R, et al. Effect of heparinization of fluids infused through an umbilical artery catheter on catheter patency and frequency of complications. Pediatrics 1979; 63:552–556 297 Jackson J, Truog W, Watchko J, et al. Efficacy of thromboresistant umbilical artery catheters in reducing aortic thrombosis and related complications. J Pediatr 1987; 110:102–105 298 David R, Merten D, Anderson J, et al. Prevention of umbilical artery catheter clots with heparinized infusates. Dev Pharmacol Ther 1981; 2:117–126 299 Bosque E, Weaver L. Continuous versus intermittent heparin infusion of umbilical artery catheters in the newborn infant. J Pediatr 1986; 108:141–143 300 Horgan MJ, Bartoletti A, Polansky S, et al. Effect of heparin infusates in umbilical arterial catheters on frequency of thrombotic complications. J Pediatr 1987; 111:774 –778 301 Ankola P, Atakent Y. Effect of adding heparin in very low concentration to the infusate to prolong the patency of umbilical artery catheters. Am J Perinatol 1993; 10:229 –232 302 Chang G, Lueder S, DiMichele D, et al. Heparin and the risk of intraventricular hemorrhage among very low birth weight infants. J Pediatr 1997; 131:362–366 303 Lesko S, Mitchell A, Eopstein M, et al. Heparin use a risk factor for intraventricular hemorrhage in low birth weight infants. N Engl J Med 1986; 314:1156 –1160 304 Malloy MH, Cutter FR. The association of heparin exposure with intraventricular hemorrhage among very low birth weight infants. J Perinatol 1995; 15:185–191 305 Durongpisitkul K, Fururaj VJ, Park JM, et al. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995; 96:1057–1061 306 Sade R, Ballenger J, Hohn A, et al. Cardiac valve replacement in children: comparison of tissue with mechanical prostheses. J Thorac Cardiovasc Surg 1979; 78:123–127 307 Brown J, Dunn J, Spooner E, et al. Late spontaneous disruption of a porcine xenograft mitral valve: clinical, hemodynamic, echocardiographic, and pathologic findings. J Thorac Cardiovasc Surg 1978; 75:606 – 611 308 Geha A, Laks H, Stansel H Jr, et al. Late failure of porcine valve heterografts in children. J Thorac Cardiovasc Surg 1979; 78:351–364 309 Silver M, Pollock J, Silver M, et al. Calcification in porcine xenograft valves in children. Am J Cardiol 1980; 45:685– 689 310 Dunn J. Porcine valve durability in children. Ann Thorac Surg 1981; 32:357–368 311 Williams WG, Pollack JC, Geiss DM, et al. Experience with CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT

369S

312 313

314 315

316 317 318 319 320

321 322 323 324 325

326 327 328 329

330

aortic and mitral valve replacement in children. J Thorac Cardiovasc Surg 1981; 81:326 –333 Miller D, Stinson E, Oyer P, et al. The durability of porcine xenograft valves and conduits in children. Circulation 1982; 66(suppl):I172–I185 Odell J. Calcification of porcine bioprostheses in children. In: Cohn L, Gallucci V, eds. Cardiac bioprostheses: Proceedings of the Second International Symposium. New York, NY: Yorke Medical Books, 1982; 231 Champsaur G, Robin J, Trone F, et al. Mechanical valve in aortic position is a valid option in children and adolescents. Eur J Cardiothorac Surg 1997; 11:117–122 Yankah AC, Alexi-Meskhishvili V, Weng Y, et al. Performance of aortic and pulmonary homografts in the right ventricular outflow tract in children. J Heart Valve Dis 1995; 4:392–395 Turpie A, Gent M, Laupacis A, et al. Comparison of aspirin with placebo in patients treated with warfarin after heart valve replacement. N Engl J Med 1993; 329:524 –529 Rajah S, Sreeharan N, Joseph A, et al. Prospective trial of dipyridamole and warfarin in heart valve patients [abstract]. Acta Thera (Brussels) 1980; 6:54 Turpie A, Gunstensen J, Hirsh J, et al. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; 1:1242–1245 Aoyagi S, Funkunaga S, Suzuki S, et al. Obstruction of mechanical valve prosthesis: clinical diagnosis and surgical or nonsurgical treatment. Jpn J Surg 1996; 26:400 – 406 van Wersch JWJ, van Mourik-Alderliesten CH, Coremans A. Determination of markers of coagulation activation and reactive fibrinolysis in patients with mechanical heart valve prosthesis at different intensities of oral anticoagulation. Blood Coagul Fibrinolysis 1992; 3:183–186 Taussig H. Long-time observations on the Blalock-Taussig operation: IX. Single ventricle (with apex to the left). Johns Hopkins Med J 1976; 139:69 –76 Truccone N, Bowman F Jr, Malm J, et al. Systemicpulmonary arterial shunts in the first year of life. Circulation 1974; 49:508 –511 Tamisier D, Vouhe P, Vernant F, et al. Modified BlalockTaussig shunts: results in infants less than 3 months of age. Ann Thorac Surg 1990; 49:797– 801 Mullen JC, Lemermeyer G, Bentley MJ. Modified BlalockTaussig shunts: to heparinize or not to heparinize? Can J Cardiol 1996; 12:645– 647 Monagle P, Cochrane A, McCrindle B, et al. Thromboembolic complications after Fontan procedures: the role of prophylactic anticoagulation [editorial]. J Thorac Cardiovasc Surg 1998; 115:493– 498 Zahn E, Lima V, Benson L, et al. Use of endovascular stents to increase pulmonary blood flow in pulmonary atresia with ventricular septal defect. Am J Cardiol 1992; 70:411– 412 Peeters S, Vandenplas Y, Jochmans K, et al. Myocardial infarction in a neonate with hereditary antithrombin III deficiency. Acta Paediatr 1993; 82:610 – 613 Andrew M, MacIntyre B, Williams W, et al. Heparin therapy during cardiopulmonary bypass requires ongoing quality control. Thromb Haemost 1993; 70:937–941 Babacan MK, Tasdemir O, Yakut C, et al. Heparin need of the patients with cyanotic congenital heart disease during cardiopulmonary bypass. J Cardiovasc Surg 1989; 30:348 – 350 Akl B, Vargas G, Neal J, et al. Clinical experience with the activated clotting time for the control of heparin and protamine therapy during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1980; 79:97–102

370S

331 Freedman JE, Loscalzo J, Benoit SE, et al. Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis. J Clin Invest 1996; 97:979 – 987 332 Whittlesey G, Drucker D, Salley S, et al. ECMO without heparin: laboratory and clinical experience. J Pediatr Surg 1991; 26:320 –325 333 Green T, Isham-Schopf B, Irmiter R, et al. Inactivation of heparin during extracorporeal circulation in infants. Clin Pharmacol Ther 1990; 48:148 –154 334 Wilson J, Bower L, Fackler J, et al. Aminocaproic acid decreases the incidence of intracranial hemorrhage and other hemorrhagic complications of ECMO. J Pediatr Surg 1993; 28:536 –541 335 Zobel G, Trop M, Muntean W, et al. Anticoagulation for continuous arteriovenous hemofiltration in children. Blood Purif 1988; 6:90 –95 336 Zobel G, Beitzke A, Stein J, et al. Continuous arteriovenous hemofiltration in children with postoperative cardiac failure. Br Heart J 1987; 58:473– 476 337 Leone M, Jenkins R, Golper T, et al. Early experience with continuous arteriovenous hemofiltration in critically ill pediatric patients. Crit Care Med 1986; 14:1058 –1063 338 Suarez S, Paller A. Atrophie blanche with onset in childhood. J Pediatr 1993; 123:753–755 339 Arenson E, August C. Preliminary report: treatment of the hemolytic-uremic syndrome with aspirin and dipyridamole. J Pediatr 1975; 86:957–961 340 Thorenson C, Rossi E, Green D, et al. The treatment of the hemolytic-uremic syndrome with inhibitors of platelet function. Am J Med 1979; 66:711–716 341 O’Regan S, Chesney RW, Mongeau J-G, et al. Aspirin and dipyridamole therapy in the hemolytic-uremic syndrome. J Pediatr 1980; 97:473– 476 342 van Damme-Lombaerts R, Proesmans W, Van Damme B, et al. Heparin plus dipyridamole in childhood hemolytic-uremic syndrome: a prospective, randomized study. J Pediatr 1988; 113:913–918 343 Harker L, Slichter S, Scott C, et al. Homocystinemia: vascular injury and arterial thrombosis. N Engl J Med 1974; 291:537–543 344 Uhlemann E, TenPas JH, Lucky A, et al. Platelet survival and morphology in homocystinuria due to cystathionone synthase deficiency. N Engl J Med 1976; 295:1283–1286 345 Schulman JD, Agarwal B, Mudd SH, et al. Pulmonary embolism in a homocystinuric patient during treatment with dipyridamole and acetylsalicylic acid. N Engl J Med ; 299:661 346 Stein P, Grandison D, Hua T, et al. Therapeutic levels of oral anticoagulation with warfarin in patients with mechanical prosthetic heart valves: review of literature and recommendations based on international normalized ratio. Postgrad Med J 1994; 70(suppl):S72–S83 347 Milano A, Vouhe PR, Baillot-Vernant F, et al. Late results after left-sided cardiac valve replacement in children. J Thorac Cardiovasc Surg 1986; 92:218 –225 348 Schaffer MS, Clarke DR, Campbell DN, et al. The St. Jude Medical cardiac valve and children: role of anticoagulant therapy. J Am Coll Cardiol 1987; 9:235–239 349 Human DG, Joffe HS, Fraser CB, et al. Mitral valve replacement in children. J Thorac Cardiovasc Surg 1982; 83:873– 877 350 Antunes MJ, Vanderdonck KM, Sussman MJ. Mechanical valve replacement in children and teenagers. Eur J Cardiothorac Surg 1989; 3:222–228

Sixth ACCP Consensus Conference on Antithrombotic Therapy