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Antithrombotic Therapy in Children*

The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Correspondence to: Paul Monagle, MBBS, MSc, MD, FCCP, Division of Laboratory Services, Royal Children’s Hospital, Department of Paediatrics, University of Melbourne, c/o Royal Children’s Hospital, Flemington Rd, Parkville, Melbourne, VIC, Australia 3052; e-mail: paul.monagle{at}wch.org.au

	Abstract

TOP Abstract Introduction Antithrombotic Therapy in... Heparin and LMWH in... Surgical Therapy Summary of Recommendations References

 
This article about antithrombotic therapy in children is part of the 7th American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh the risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this article are the following. In neonates with venous thromboembolism (VTE), we suggest treatment with either unfractionated heparin or low-molecular-weight heparin (LMWH), or radiographic monitoring and anticoagulation therapy if extension occurs (Grade 2C). We suggest that clinicians not use thrombolytic therapy for treating VTE in neonates, unless there is major vessel occlusion that is causing the critical compromise of organs or limbs (Grade 2C). For children (ie, > 2 months of age) with an initial VTE, we recommend treatment with IV heparin or LMWH (Grade 1C+). We suggest continuing anticoagulant therapy for idiopathic thromboembolic events (TEs) for at least 6 months using vitamin K antagonists (target international normalized ratio [INR], 2.5; INR range, 2.0 to 3.0) or alternatively LMWH (Grade 2C). We suggest that clinicians not use thrombolytic therapy routinely for VTE in children (Grade 2C). For neonates and children requiring cardiac catheterization (CC) via an artery, we recommend IV heparin prophylaxis (Grade 1A). We suggest the use of heparin doses of 100 to 150 U/kg as a bolus and that further doses may be required in prolonged procedures (both Grade 2 B). For prophylaxis for CC, we recommend against aspirin therapy (Grade 1B). For neonates and children with peripheral arterial catheters in situ, we recommend the administration of low-dose heparin through a catheter, preferably by continuous infusion to prolong the catheter patency (Grade 1A). For children with a peripheral arterial catheter-related TE, we suggest the immediate removal of the catheter (Grade 2C). For prevention of aortic thrombosis secondary to the use of umbilical artery catheters in neonates, we suggest low-dose heparin infusion (1 to 5 U/h) (Grade 2A). In children with Kawasaki disease, we recommend therapy with aspirin in high doses initially (80 to 100 mg/kg/d during the acute phase, for up to 14 days) and then in lower doses (3 to 5 mg/kg/d for 7 weeks) [Grade 1C+], as well as therapy with IV gammaglobulin within 10 days of the onset of symptoms (Grade 1A).

Key Words: antithrombotic • child • heparin • pediatric • thromboembolism

	Introduction

TOP Abstract Introduction Antithrombotic Therapy in... Heparin and LMWH in... Surgical Therapy Summary of Recommendations References

 
The prevention and treatment of thromboembolic complications in specific pediatric populations requires antithrombotic therapy. Recommendations for antithrombotic therapy in pediatric patients have been extrapolated from recommendations for adults, because thromboembolic events (TEs) in pediatric patients were rare enough to hinder testing of specific therapeutic modalities, yet were common enough to present significant management dilemmas that required therapeutic intervention.¹²

Advances in tertiary care pediatrics have paradoxically 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 neonates and children. Since the first publication of this article in the 1995 CHEST antithrombotic supplement,³ < 10 multinational randomized controlled intervention trials assessing specific aspects of anticoagulant therapy in children have been initiated, and most of these have failed to enroll an adequate number of patients to answer the primary study question.⁴⁵⁶ The majority of the articles published in the available literature to support the recommendations in this publication are uncontrolled studies, case reports, or in vitro experiments. Unfortunately, there has not been a dramatic improvement in the quality of evidence since the first publication of this article.

This article is divided into three parts. The first section details the evidence showing that the interaction of antithrombotic agents with the hemostatic system of young patients differs from that of adult patients. This section describes the mechanisms of action, therapeutic ranges, dose regimes, monitoring requirements, factors influencing dose-response relationships, and side effects of antithrombotic, antiplatelet, and thrombolytic agents in neonates and children. The second section discusses background information regarding the biological rationale related to specific antithrombotic agents, and evidence regarding appropriate administration and side effects, and it reviews evidence regarding thrombophilic markers. The final section provides the evidence and recommendations for antithrombotic therapy in pediatric patients.

Throughout this article, the term pediatric patients is used to refer to all neonates and children (ie, from birth to 16 years of age). The term neonates refers to infants from birth to 28 days of age corrected for gestational age. The term children refers to patients 28 days to 16 years of age. Comprehensive literature searches were performed as per the American College of Chest Physicians guidelines for this publication (Table 11A ), and recommendations were based on the American College of Chest Physicians grades of recommendation.

	Antithrombotic Therapy in Pediatric Patients

TOP Abstract Introduction Antithrombotic Therapy in... Heparin and LMWH in... Surgical Therapy Summary of Recommendations References

While numerous studies have defined appropriate diagnostic strategies in adults with a range of TEs, the optimal diagnostic strategies in children who have experienced TEs remain controversial and, in many cases, unproven. In particular, there are physiologic, pathologic, and practical reasons why the simple extrapolation of adult diagnostic strategies is insufficient. A full discussion of optimal diagnostic strategies for TEs in neonates and children is beyond the scope of this article. Readers can consult several recent studies and reviews.^{67891011121314151617181920212223242526272829}

In summary, the management of TEs in children differs significantly from the management of TEs in adults. While there are no formal studies to support a recommendation, the authors suggest that, where possible, pediatric hematologists with experience in treating TEs manage pediatric patients with TEs. When this is not possible, a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (eg, the 1–800-NO CLOTS service or other national referral centers) provides a reasonable compromise.

	Heparin and LMWH in Neonates and Children

TOP Abstract Introduction Antithrombotic Therapy in... Heparin and LMWH in... Surgical Therapy Summary of Recommendations References

 
Heparin
Unfractionated heparin (UFH) [also called standard heparin] remains a commonly used anticoagulant in pediatric patients. A recent report³⁰ has suggested that in a tertiary pediatric hospital, approximately 15% of inpatients are exposed to UFH each day.

Mechanism of action
The anticoagulant activities of heparin, which are mediated by the catalysis of antithrombin (AT), can be impaired in the presence of decreased plasma levels of AT. Plasma concentrations of AT are physiologically low at birth (approximately 0.50 U/mL) and do not increase to adult values until 3 months of age.³¹³²³³ Sick premature neonates frequently have plasma levels of AT of < 0.30 U/mL.³³³⁴ 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.³⁵

Heparin exerts antithrombotic activity by catalyzing the ability of AT to inactivate specific coagulation enzymes, in particular thrombin.³⁶ The capacity of plasmas from neonates to generate thrombin is both delayed and decreased compared to that in adults,³⁸³⁹ and it is similar to plasma from adults receiving therapeutic amounts of heparin.³⁸ Following infancy, the capacity of plasma to generate thrombin increases but remains approximately 25% less than that for adults throughout childhood.⁴⁰ Both an increased sensitivity and a resistance to the anticoagulant activities of UFH have been reported in vitro in plasma from neonates.³⁸⁴⁰ Increased sensitivity to UFH is observed in systems based on assays that are dependent on thrombin generation (eg, activated partial thromboplastin time [aPTT]).⁴¹ One study⁴² of the in vitro effects of UFH (0.25 U/mL) on neonates, children, and adults found that thrombin generation was delayed and reduced in children compared to that in adults, and was virtually absent in neonates. Resistance to UFH has been observed⁴¹⁴³⁴⁴ in systems based on assays that measure the inhibition of exogenously added factor Xa (FXa) or thrombin and that are dependent on plasma concentrations of AT.

The paradox of UFH sensitivity and resistance in plasma from neonates reflects the ratio of AT to prothrombin in the assay system.⁴¹ The in vivo antithrombotic effects of UFH in newborn piglets show that decreased concentrations of AT limit the antithrombotic effects of UFH.⁴⁵ This resistance to UFH can be overcome by increasing either the dose of UFH or the AT concentration.⁴⁵

Therapeutic range
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-FXa level of 0.35 to 0.7 U/mL.⁴⁶ The aPTT therapeutic ranges are universally calculated using adult plasma, and whether extrapolation of these to pediatric patients is valid is unknown. Baseline aPTTs in pediatric patients, especially neonates, are often increased compared to those in adults, and so the therapeutic ranges represent a reduced relative increment in aPTT values in pediatric patients receiving heparin therapy compared to those in adults. In the absence of further information, the extrapolation of the adult therapeutic ranges remains necessary. In pediatric patients, aPTT values correctly predict therapeutic heparin concentrations approximately 70% of the time.⁴⁷

Doses
The doses of heparin required in pediatric patients to achieve adult therapeutic aPTT values have been assessed using a weight-based nomogram (one prospective cohort study).⁴⁷ Bolus doses of 75 to 100 U/kg result in therapeutic aPTT values in 90% of children. Maintenance heparin doses are age-dependent, with infants (up to 2 months of age, corrected for gestational age) having the highest requirements (average dose, 28 U/kg/h), and children > 1 year of age having lower requirements (average dose, 20 U/kg/h). The doses of heparin required for older children are similar to the weight-adjusted requirements in adults (ie, 18 U/kg/h).⁴⁸

Pharmacokinetics
Studies of UFH in newborns are limited but show that the clearance is faster than that for older children due to a larger volume of distribution,⁴⁹⁵⁰ and that the dose of UFH required to achieve a therapeutic aPTT is also increased compared to that in older children.⁴⁷ Pharmacokinetic studies in piglets also show that the clearance of UFH is faster than for that adult pigs due to a larger volume of distribution.⁴⁵ Heparin protein binding in newborns also may be different from that in older children and adults, although this remains to be proven.

Monitoring
The appropriate dosage adjustment of IV heparin therapy can be problematic.⁴⁸⁵¹ Heparin dosing nomograms have been validated in children (Table 2 ).⁴⁷

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

Mechanism of action
At similar anti-FXa concentrations, UFH inhibits free-thrombin generation to a greater degree than does LMWH in neonates, children, and adults. In vitro, thrombin generation is similar in adults and children at the same concentration of LMWH. However, at a LMWH concentration of 0.25 U/mL thrombin generation was delayed and reduced by approximately half in newborns compared to adults. These differences were matched by reductions in the rates of prothrombin consumption.⁴²

Therapeutic range
Therapeutic doses of LMWH are extrapolated from adults and are based on anti-FXa levels. The guideline for therapeutic LMWHs is an anti-FXa level of 0.50 to 1.0 U/mL in a sample taken 4 to 6 h following a subcutaneous injection. The clinical significance of the in vitro data described previously has not been established.

Doses
The doses of LMWH required in pediatric patients to achieve adult therapeutic anti-FXa levels have been assessed for enoxaparin, reviparin, dalteparin, and tinzaparin (Table 4 ).^64656669 In general, peak anti-FXa levels occur 2 to 6 h following a subcutaneous LMWH injection. Infants who are less than approximately 2 to 3 months of age or weight < 5 kg have increased requirements per kilogram, which likely is due to a larger volume of distribution. Alternative explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics⁶⁹ and/or a decreased expression of the anticoagulant activity of heparin in children due to decreased plasma concentrations of AT. IV dosing has been reported in one neonate, and the administration of enoxaparin, 1 mg/kg q8h, was required to maintain therapeutic anti-FXa levels.⁶⁷

Treatment of LMWH-induced bleeding
Equimolar concentrations of protamine sulfate neutralize the anti-factor IIa activity but result in only partial neutralization of the anti-FXa activity.⁷⁰ However, in animal models, bleeding is completely reversed by protamine sulfate.^71727374 The dose of protamine sulfate is dependent on the dose of LMWH used at the time of administration. Repeat doses of protamine may be required after subcutaneous LMWH. Protocols for reversal have been published.⁷¹

VKAs in neonates and children
VKAs function as anticoagulants by reducing the functional plasma concentration of vitamin-K dependent factors (ie, factors II, VII, IX, and X). The vitamin K-dependent factors are decreased physiologically in newborns to levels that are frequently achieved in adults receiving therapeutic amounts of VKAs with target INRs of 2 to 3. VKAs are problematic in newborns for several other reasons. First, infant formula is supplemented with vitamin K to prevent hemorrhagic disease of the newborn, which makes formula-fed infants resistant to VKAs. In contrast, breast milk has low concentrations of vitamin K, making breast-fed infants very sensitive to VKAs.⁷⁵⁷⁶ The latter can be compensated for by feeding breast-fed neonates 1 to 2 oz formula each day. Second, VKAs are available only in tablet form. Although the tablets can be dissolved in water for administration to newborns, there are no stability data or critical assessments of this practice. Third, VKAs require frequent monitoring in newborns because of the rapidly changing physiologic values of the vitamin K-dependent proteins, the frequent changes in medications, and the changes in diet. Poor venous access becomes an issue for these newborns. Fourth, although there is substantial information on the use of VKAs in children who are > 3 months of age, there is essentially no efficacy or safety information on their use in neonates.

Therapeutic range
For children receiving VKAs, the capacity of their plasmas to generate thrombin is delayed and decreased by 25% compared to plasmas from adults with similar INRs.⁷⁸ The latter situation raises the issue of whether the optimal INR therapeutic range for children will be lower than that for adults. This hypothesis is further supported by the observation that plasma concentrations of a marker of endogenous thrombin generation, prothrombin fragment 1.2, are significantly lower in children compared to those in adults at similar INR values.⁷⁸

Despite this, current therapeutic INR ranges for children are directly extrapolated from recommendations for adult patients because no clinical trials have assessed the optimal INR range for children based on clinical outcomes.

Dose response
An initial dose of 0.2 mg/kg, with subsequent dose adjustments made according to a nomogram using INR values, was evaluated in a prospective cohort study (Table 5 ).¹ The published age-specific, weight-adjusted doses for children vary due to the different study designs and patient populations, and possibly the small number of children studied. The largest cohort study (319 patients) found that to maintain a target INR of 2 to 3 infants required an average of 0.33 mg/kg warfarin and that teenagers required 0.09 mg/kg warfarin.⁷⁹ For adults, the weight-adjusted doses for VKAs are not precisely known but are in the range of 0.04 to 0.08 mg/kg for an INR of 2 to 3.³⁷ The mechanisms responsible for the age dependency of VKA doses are not completely clear.

Point-of-care monitoring in neonates and children
Whole-blood monitors use various techniques to measure the time from the application of fresh samples of capillary whole blood to the coagulation of the sample, and to report an INR value. The monitors include a batch-specific calibration code that converts the result into a calculated INR. There are two "point-of-care" monitors that have been evaluated in the pediatric population (CoaguChek; Boehringer-Mannheim; Mannheim, Germany; and ProTime Microcoagulation System; International Technidyne Corp; Edison, NJ). Both monitors have been 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 from venipunctures, minimal interruption of school and work, ease of operation, and portability.²⁷⁷⁸⁰ At this time, no studies have demonstrated the accuracy of point-of-care monitors for heparin or LMWH therapy.

Adverse effects of VKAs
Bleeding is the main complication of VKAs. The risk of serious bleeding in children receiving VKAs for mechanical prosthetic valves is < 3.2% per patient-year (13 case series).⁸¹ In one large cohort study (391 warfarin years, variable target range),⁷⁹ the bleeding rate was 0.5% per patient-year. In a randomized trial (41 patients; target INR range, 2 to 3 [for 3 months]),⁶⁹ bleeding occurred in 12.2% of patients (95% CI, 4.1 to 26.2). Nonhemorrhagic complications of VKAs, such as tracheal calcification or hair loss, have been described on rare occasions in young children.⁸²⁸³ Two cohort studies⁸⁴ have described reduced bone density in children who have received warfarin for > 1 year. However, these were uncontrolled studies, and the role of the underlying disorders in reducing bone density remains unclear.⁸⁴

Treatment of VKA-induced bleeding
In the presence of a high INR (usually > 8) and no significant bleeding, vitamin K may be used to reverse the effects of excess anticoagulation. There are only limited data available in children, but IV vitamin K in doses of 30 µg/kg have been used previously.⁸⁵ In the presence of significant bleeding, immediate reversal using fresh-frozen plasma (FFP), prothrombin complex concentrates, or recombinant factor VIIa may be required.

Alternative thrombin inhibitors
A small number of case reports^5658626386 have documented the use of danaparoid sodium, hirudin, and argatroban in pediatric patients. The most common indication has been for the management of HIT. No further data are available at this time. A standard protocol for danaparoid sodium (Orgaran) use is available (Table 6 ).⁸¹

An in vitro method using a device (PFA-100; Dade International; Miami, FL) for assessing primary hemostasis that utilizes citrated whole blood has been studied.¹⁰² This instrument measures the time required for a platelet plug to occlude an aperture (150 µm) in a membrane that has been coated with fibrillar type I collagen in the presence of either epinephrine (10 µM) or ADP (50 µM) [ie, called closure time]. Platelets are activated by exposure to these agonists and by high shear stress as the blood is aspirated through the membrane aperture. Closure times correlate with hematocrit, quantitative and functional levels of von Willebrand factor, and the number and functional activity of platelets.¹⁰⁴¹⁰⁵, Cord blood samples from term neonates have shorter closure times than do samples from older children or adults.^103106107 The shorter closure time correlates with the higher hematocrit and increased von Willebrand factor activity (measured by the ristocetin cofactor assay) in cord blood.¹⁰⁶

Aspirin
Aspirin remains the most common antiplatelet agent used in children.

Therapeutic range, dose response, and monitoring.
Evidence from studies of adults^9596979899 has suggested there is significant interindividual variation in the dose of aspirin required for effective antiplatelet therapy. The dose of aspirin required for the optimal inhibition of platelet aggregation is not known, although empiric low doses of 1 to 5 mg/kg/d have been proposed.¹⁰¹ Pediatric doses of aspirin are not based on studies of the effect on platelet function in pediatric patients.¹⁰⁰ In the use of the device for assessing primary hemostasis (the PFA-100), the antiplatelet action of aspirin prolongs the closure time with the epinephrine cartridge but not with ADP. The device has been shown to quantify an individual’s response to aspirin therapy and to be effective in monitoring the compliance of aspirin therapy in adult patients.¹¹⁰ It will likely be useful for documenting adequate aspirin therapy in pediatric patients.⁸¹

Adverse effects.
Neonates may be exposed to aspirin as a result of maternal ingestion (eg, treatment for preeclampsia). The clearance of aspirin is slower in neonates, 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. In neonates, additive antiplatelet effect must be considered if concurrent indomethacin therapy is required.

In older children, aspirin rarely causes clinically important hemorrhaging, except in the presence of an underlying hemostatic defect or in children who also have been treated with anticoagulant or 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 syndrome, this appears to be a dose-dependent effect of aspirin and is usually associated with doses of > 40 mg/kg.^{108109111112113114}

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 other antithrombotic agents. Transfusions of platelet concentrates and/or the use of products that enhance platelet adhesion (plasma products containing high concentrations of von Willebrand factor, or des-amino-D-arginine vasopressin may be helpful.

Other antiplatelet agents
The second most commonly used antiplatelet agent in children is dipyridamole in doses of 2 to 5 mg/kg/d.^115116117

Ticlopidine and clopidogrel are thienopyridines. Both drugs selectively inhibit ADP-induced platelet aggregation via the inhibition of the P2Y₁₂ receptor.^118119120 The antiplatelet effect of ticlopidine and clopidogrel is additive to that of aspirin.¹²¹ There has been no reported use in children, and dosage recommendations are unknown.

The clinically available glycoprotein (GP) IIb-IIIa antagonists are IV abciximab, eptifibatide (Integrilin; Millennium; Cambridge, MA), and tirofiban (Aggrastat; Merck; Whitehouse Station, NJ).¹²² These drugs, which are either chimeric antibody fragments (abciximab), peptides (eptifibatide), or nonpeptide small molecules (tirofiban), act by binding to platelet surface GPIIb-IIIa (integrin -IIbß₃), thereby blocking fibrinogen-mediated platelet aggregation. Because fibrinogen binding to the platelet GPIIb-IIIa is the final common pathway of platelet aggregation, these drugs are powerful antiplatelet agents.¹²² In one study,¹²³ children with Kawasaki disease who were treated with abciximab in addition to standard therapy demonstrated greater regression in coronary aneurysm diameter at early follow-up than did patients who received standard therapy alone. This study compared abciximab to historical control subjects, and all patients received additional anticoagulation therapy.

Thrombolytic agents and thrombectomy in neonates and children
Background.
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 (21 mg/100 mL).^3132124 The decreased levels of plasminogen in newborns slows the generation of plasmin¹²⁵ and reduces the thrombolytic effects of streptokinase (SK), urokinase (UK), and tissue plasminogen activator (tPA) in an in vitro fibrin clot system.¹²⁸ A similar response occurs in children with acquired plasminogen deficiency. The supplementation of plasmas with plasminogen increases the thrombolytic effect of all three agents.¹²⁷¹²⁸

There are no studies that compare the efficacy, safety, or cost of different thrombolytic agents in children. Although SK is the cheapest of the three agents, SK has the potential for allergic reactions and may be less effective in children with physiologic or acquired deficiencies of plasminogen.

tPA has become the agent of choice in pediatric patients for several reasons, including the Food and Drug Administration warning regarding UK, experimental evidence of improved clot lysis in vitro compared to that using UK and SK, fibrin specificity, and low immunogenicity.¹²⁹¹³⁶ However, tPA is considerably more expensive than either SK or UK, and the increased in vitro clot lysis by tPA has not been demonstrated in clinical trials in children. There is minimal or no experience with the use of other thrombolytic agents in children.

Success rates for tPA in pediatric patients vary in the literature. A prospective study¹³⁰ using 0.5 mg/kg/h systemic tPA for 6 h concurrently with heparin (10 U/kg/h) and FFP supplementation prior to tPA infusion reported complete thrombosis resolution in 13 of 20 patients (65%) [arterial thrombosis, 12 patients; venous thrombosis, 1 patient], partial resolution in 4 patients (20%) [arterial thrombosis, 1 patient; venous thrombosis, 3 patients], and no response in 3 patients (15%) [arterial thrombosis, 1 patient; venous thrombosis, 2 patients]. Zenz et al¹³¹ reported using a dose of 0.5 mg/kg/h for the first hour followed by 0.25 mg/kg/h until clot lysis occurred or treatment had to be stopped because of bleeding complications. Complete clot lysis was achieved in 16 of 17 patients within 4 to 11 h after the start of treatment. In one patient, only partial lysis occurred. After complete lysis, rethrombosis developed in one patient 15 h after the end of treatment.

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.¹²⁶ Similar problems in children should be considered as relative but not absolute contraindications to thrombolytic therapy.

Therapeutic range and monitoring of thrombolytic agents.
There is no therapeutic range for thrombolytic agents. The correlation between hemostatic parameters and the efficacy/safety of thrombolytic therapy is too weak to have useful clinical predictive value.¹²⁶ However, in patients with bleeding, the choice and doses of blood products can be guided by appropriate hemostatic monitoring. The single most useful 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.¹²⁶ Measurements of fibrinogen degradation products and/or d-dimers are helpful in determining whether a fibrinolytic effect is present.

Dose response.
Thrombolytic agents are used in low doses, usually to restore catheter patency, and in higher doses to lyse large-vessel TEs or PEs. Table 7 presents the most commonly used local and systemic dose regimens for thrombolytic therapy in pediatric patients. These protocols come from case series.¹²⁷¹³² The optimal doses for UK, SK, and tPA are not known for pediatric patients. Based on the results of the Thrombolysis in Myocardial Infarction II trial,¹³³ doses of 150 mg recombinant t-PA caused more bleeds into the CNS than did doses of 100 mg (1.5% vs 0.5%, respectively). These data suggest that there is an upper dose limit based on safety.

Adverse effects of thrombolytic therapy.
Thrombolytic therapy has been reported¹³⁶ to have significant bleeding complications in children, occurring in 68% of patients, with bleeding requiring transfusion occurring in 39%. The prolonged duration of thrombolytic infusion was associated with increased bleeding. Zenz et al,¹³¹ in a prospective study using the protocol described earlier, reported bleeding requiring transfusion in 3 of 17 patients (18%) who had been treated for between 4 and 11 h, and minor bleeding in 9 of 17 patients (54%). Another recent prospective study¹³⁰ using a defined protocol, the key features of which were (1) concurrent heparin therapy (10 U/kg/h), (2) fixed tPA infusions at 0.5mg/kg/h for 6 h with no extensions beyond 6 h, and (3) FFP (10 mL/kg) given a half-hour before each tPA infusion to ensure adequate plasminogen and fibrinogen levels, reported bleeding requiring transfusion in 2 of 20 patients (10%), and minor bleeding episodes in 6 patients (30%) [ie, venipuncture sites and epistaxis]. Earlier literature reviews¹²⁷ (including 255 patients) had concluded that the incidence of bleeding requiring treatment with packed RBCs was approximately 20% in pediatric patients. The most frequent problem was bleeding at sites of invasive procedures that required treatment with blood products. In another review, Zenz et al¹³⁷ reported intracranial hemorrhage (ICH) in 14 of the 929 patients (1.5%) analyzed. There was no information provided about concurrent heparin administration in this study. When subdivided according to age, ICH was identified in 2 of 468 children (0.4%) after the neonatal period, 1 of 83 term infants (1.2%; 95% CI, 0.3 to 6.5%), and 11 of 86 preterm infants (13.8%; 95% CI, 6.6 to 21.7%). However, in the largest study of premature infants included in this review, the incidence of ICH was the same in patients in the control arm of the study, who had not received thrombolytic therapy. A retrospective analysis of 16 newborns who received tPA reported one death from bleeding.¹³⁸

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, or 5 to 10 mL/kg), and administering other blood products as indicated. If the bleeding is life-threatening, an antifibrinolytic agent also can be used.

	Surgical Therapy

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In addition to pharmacologic therapy, venous interruption devices (ie, inferior vena cava [IVC] filters) are used for specific clinical indications in adults. A handful of anecdotal reports¹³⁹ of successful and failed IVC filters in children have been published. In contrast to adults, temporary IVC filters are often used in children and are removed when the source of PE is no longer present.¹⁴⁰ Recently, the safety of temporary IVC filters has been described in a case series of 10 patients.¹⁴¹ 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.

Surgical thrombectomy is rarely used as treatment in children. The common situations in which thrombectomy is reported include IVC thrombosis in association with intravascular extension of Wilm tumor, acute thrombosis of Blalock-Taussig (BT) shunts, life-threatening intracardiac thrombosis immediately after complex cardiac surgery, prosthetic valve thrombosis, and peripheral arterial thrombosis secondary to vascular access in neonates. There are no controlled data to compare the value of conservative therapy, and it is unlikely that such data will become available. In most cases, concurrent or subsequent anticoagulation therapy was used.^{142143144145146} There are no specific guidelines for the use of thrombectomy in children, but there is general consensus that in many situations the TE recurrence rate and the risk of long-term vascular damage are high. However, the risk/benefit ratio needs to be considered individually in each case.

Thrombophilia Markers
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) TE in multiple or unusual locations. Clinically, the most significant inherited prothrombotic conditions are deficiencies of AT, protein C (PC), and protein S (PS) because of the large increase in relative risk (RR) that these deficiencies confer. Activated PC resistance/factor V Leiden (FV-R506Q) and prothrombin G20210A (IIG20210A) polymorphisms, 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 proposed¹⁴⁷ as risk factors for congenital thrombophilia. However, most of these candidates have not undergone careful segregation or population studies to define their pathogenic role. In fact, some of the seemingly obvious candidates such as abnormalities in fibrinolysis do not appear to confer thrombotic risk.¹⁴⁸ However, these latter studies are hampered by the low prevalence of most of these inherited abnormalities in the general population.

Some reports¹⁴⁹ have 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. Apart from the well-defined homozygous cases, the risk and severity of TEs appear to vary with the type and number of underlying genetic abnormalities.^149150151152

Thrombophilia markers in neonates with thrombosis
Homozygous prothrombotic disorders usually present in newborns with severe clinical manifestations that may have developed antenatally and require specific urgent therapy. The diagnosis of heterozygous congenital prothrombotic disorders in neonates can be problematic because physiologic values are significantly decreased compared to those in older children and adults.³¹³³⁹² This issue is further confounded by the presence of acquired disorders that are present in > 80% of neonates with systemic TEs, and these disorders frequently have a consumptive component resulting in further decreases in these proteins. Although neonates with heterozygote inhibitor deficiencies rarely develop TEs, 20% of neonates with TEs are heterozygote for a congenital prothrombotic disorder.¹⁵³ Whether the presence of these prothrombotic markers should affect the duration of anticoagulation therapy and subsequent secondary prophylaxis remains undetermined. In addition, heterozygous inhibitor deficiencies have been implicated in other neonatal conditions such as porencephaly. Further studies are required to confirm these associations.¹⁵⁴

Thrombophilia markers in children with thrombosis
The reported incidence of congenital prothrombotic disorders in children with venous TEs varies from < 1 to > 60%.^{150151152154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185186} If one considers the deficiencies of AT, PC, and PS in addition to the factor V Leiden and prothrombin gene mutations, large family studies have found negligible rates of thrombosis in children < 15 years.¹⁸⁷ A number of cohort studies^163165167180 have failed to identify AT deficiency in children with both arterial and venous TEs. Those studies that have reported higher frequencies of AT deficiency have not distinguished between acquired and inherited deficiencies.¹⁶⁴ In children with cancer and venous TEs, the reported incidence of thrombophilias is 3%.¹⁸⁰¹⁸⁸ There is a similar disparity between studies concerning thrombophilia and childhood stroke.^{162163164168169170189190191} The variability in incidence reported in all of these studies reflects small sample sizes, variability in study design, differing definitions of prothrombotic disorders, and different patient selection.¹⁹² Most recently, a prospective study¹⁹³ of an unselected cohort of children with venous thrombosis found that, with the exception of teenagers with spontaneous thrombosis, inherited thrombophilic markers did not contribute significantly to the pathogenesis of venous thrombosis in children.

Screening for congenital prothrombotic disorders in children with venous TEs is of unproven benefit, regardless of the presence or absence of acquired risk factors. At this time, the uniform screening of children with major illnesses, or of those who require central venous lines (CVLs) in order to provide prophylactic therapy for the treatment of congenital prothrombotic disorders cannot be recommended. The contribution of congenital prothrombotic disorders to the occurrence of venous TE in pediatric patients remains to be clarified. Few children develop thrombosis due to a heterozygote congenital prothrombotic condition without also having an acquired risk factor.^{147161186194195196197198199200201}Neonates who present with purpura fulminans or severe spontaneous thrombosis need to have homozygous thrombin inhibitor deficiencies excluded.

1.0 Specific Indications for Antithrombotic Therapy
The following section describes the evidence for the use of anticoagulation therapy in specific clinical circumstances. In addition, there remain a number of less common clinical situations in neonates and children in which the question of optimal antithrombotic management is important, however, the literature consists of only a few case reports, such that there are insufficient data to distinguish between any of the potential therapeutic options. One example of such a situation is portal vein thrombosis, which, in neonates, most commonly occurs secondary to the placement of an umbilical vein catheter (UVC), with or without infection.^202203204 In older children, portal vein thrombosis is related to liver transplantation, intra-abdominal sepsis, splenectomy, sickle cell anemia, and the presence of antiphospholipid antibodies.^{205206207208209210211212} In approximately 50% of children with portal vein thrombosis, an underlying etiology is not identified.^206213214 In contrast to adults with portal vein thrombosis, which is most frequently secondary to cirrhosis, liver function is usually normal in children.²¹⁰ These differences in etiology and pathophysiology reduce the usefulness of the extrapolation of therapeutic guidelines for adults with portal vein thrombosis, and yet the infrequency of its occurrence in children significantly hinders obtaining evidence that would permit informed pediatric guidelines for therapy.

1.1 Systemic venous thrombosis in neonates
Background
An international registry of symptomatic venous thromboembolism (VTE) in neonates reported an incidence of 2.4 per 1,000 admissions to neonatal ICUs.²¹⁵ A German prospective, nationwide, 2-year registry¹⁵³ reported an incidence of symptomatic neonatal TE (which included CNS events) to be 0.51 per 10,000 births, with approximately half of the cases being VTE and half being arterial thrombosis.

Over 80% of cases of VTE in newborns are secondary to the placement of CVLs.²¹⁵ CVLs are usually placed either into umbilical veins (ie, UVC) or into the upper venous system through peripheral veins from the arm or through major vessels such as jugular veins. Currently, UVCs or CVLs are used extensively in premature and full-term infants who require supportive care in the form of fluids, drugs, or total parenteral nutrition (TPN). There are several mechanisms by which CVLs cause TEs, including damage to vessel walls,²¹⁶ disrupted blood flow, the infusion of substances such as TPN that damage endothelial cells,²¹⁷ and thrombogenic catheter materials.²¹⁸

There are several studies^219220221222 that have assessed the incidence of UVC-related VTE. Autopsy studies^219222223224 have estimated the incidence of UVC-related VTE at 20 to 65% of neonates who die with a UVC in place. Clinical studies²²² have estimated the incidence of UVC-related VTE to be approximately 13%.

There are numerous studies²²⁵ reporting the risk of CVL TE based on the loss of CVL patency and/or the results of objective tests. Although there is no definitive study determining the incidence of CVL-related VTE in neonates, the published studies clearly identify CVLs as the most important risk factor.

The clinical symptoms/complications of VTE can be classified as acute or chronic. The acute clinical symptoms, besides the loss of CVL patency, include swelling, pain, discoloration of the related limb, swelling of the face and head with superior vena cava syndrome,²²⁶ and respiratory compromise with PE.¹⁵³²¹⁵ The chronic clinical symptoms/complications include prominent collateral circulation in the skin over the chest, back, neck, and face, the repeated loss of CVL patency requiring treatment with local thrombolytic therapy, the repeated requirement for CVL replacement, the eventual loss of venous access, CVL-related sepsis, chylothorax,²²⁷²²⁸ chylopericardium,²²⁹ recurrent VTE necessitating long-term anticoagulation therapy with its associated risk of bleeding,²³⁰ and post-thrombotic syndrome (PTS).²³¹ Specific long-term sequelae of UVC-related VTE include portal hypertension,²³² splenomegaly,²³³ gastric and esophageal varices, major bleeding related to the varices,¹⁵³²³⁴ and hypertension.²³⁵

There is no published information on the incidence of recurrent VTE in neonates. There is also no published information on the incidence of PTS in neonates. Potentially, neonates are at an increased risk for PTS because the fibrinolytic system is physiologically suppressed. The long-term follow-up of neonates with VTE is critically important to determine the frequency and severity of PTS.

Treatment of venous TE in neonates
There are insufficient data to make strong recommendations about anticoagulation therapy in the treatment of newborns with DVT and pulmonary thromboembolism. The options include conventional anticoagulation therapy in age-appropriate doses, short-term anticoagulation therapy, or close monitoring of the thrombus with objective tests and the use of anticoagulation therapy if thrombus extension occurs. The treatment in each neonate should be individualized with due consideration to the risk/benefit ratio.

Recommendations: Neonates With VTE
1.1.1. We suggest treatment with either UFH or LMWH, or radiographic monitoring and anticoagulation therapy if extension occurs (Grade 2C).

1.1.2. We suggest that if clinicians elect anticoagulation therapy, they administer UFH or LMWH, and subsequently administer LMWH for 10 days to 3 months (Grade 2C).

1.1.3. We suggest that clinicians adjust the dose of UFH to prolong the aPTT corresponding to an anti-FXa level of 0.35 to 0.7 U/mL (Grade 2C).

1.1.4. We suggest that clinicians adjust the dose of LMWH to achieve an anti-FXa level of 0.5 to 1.0 U/mL. (Grade 2C).

1.1.5. We suggest that if the thrombus extends following the discontinuation of heparin therapy, clinicians administer VKAs or extended LMWH therapy (Grade 2C).

1.1.6. We suggest that clinicians not use thrombolytic therapy for treatment of VTE in neonates unless there is major vessel occlusion that is causing a critical compromise of organs or limbs (Grade 2C). If thrombolytic therapy is used, we suggest supplementation with plasminogen (FFP) immediately prior to thrombolysis (Grade 2C).

1.1.7. We suggest that, in general, clinicians should remove either CVLs or UVCs that are in situ. However, if either CVLs or UVCs are still in place at the completion of the above therapy, we suggest prophylactic dosing with LMWH to prevent recurrent VTE until such time as the CVL or the UVC is removed (both Grade 2C).

1.2 Systemic venous thromboembolic disease in children
Background
The estimated incidence of symptomatic VTE in children is 5.3 per 10,000 hospital admissions. Several mechanisms likely contribute to the protective effect of age for VTE. These include a reduced capacity to generate thrombin,³⁹⁴⁰ increased capacity of ₂-macroglobulin to inhibit thrombin,²³⁶ and the enhanced antithrombotic potential of the vessel wall.²³⁷²³⁸ Ninety-five percent of VTEs in children are secondary to serious conditions such as cancer, trauma/surgery, congenital heart disease (CHD), and systemic lupus erythematosus.^{215230239240241} The age groups at greatest risk for VTE are infants < 1 year of age and teenagers.^215230242 Most children have several risk factors for VTEs, with the most common risk factor being the presence of a CVL. The most frequent non-CVL-associated VTE is in a lower limb.²⁴²

Over 50% of VTEs in children occur in the upper venous system secondary to the use of CVLs.^215230242 The incidence of CVL-related VTEs reported in the literature varies, reflecting different underlying conditions, the use of different diagnostic tests, and different indexes of suspicion. For example, the incidence of CVL-related VTE in children receiving long-term TPN varies from 1% (based on clinical diagnosis)²⁴³²⁴⁴ to 35% (based on ventilation-perfusion scans or echocardiography), to 75% (based on venography).²⁴⁵ In a prospective cohort,²⁴⁶²⁴⁷ 18% of children in an intensive care setting with CVLs in place for 48 h developed CVL-related VTE. The recently completed Prophylactic Antithrombin Replacement in Kids With ALL Treated With L-Asparaginase (PARKAA) study¹⁷ reported a 37% incidence of venographically proven VTE in asymptomatic children with acute lymphoblastic leukemia who were receiving L-asparaginase therapy. In many patient populations, the incidence is not accurately known.

Radiographically detected, asymptomatic, CVL-related VTEs in children are of clinical importance for a number of reasons. First, there is increasing evidence that CVL-related VTEs are associated with CVL-related sepsis. In a meta-analysis,²⁴⁸ prophylactic UFH therapy reduced CVL-related VTE (RR, 0.43; 95% CI, 0.23 to 0.78), and in addition decreased bacterial colonization (RR, 0.18; 95% CI, 0.06 to 0.60) and probably CVL-related bacteremia (RR, 0.26; 95% CI, 0.07 to 1.03). Second, CVL-related VTEs are the most common source for PE in children,²⁴⁹ which may be fatal.²⁵⁰ The long-term consequences may be significant, although their frequency is unknown. Case reports^153155199 have documented sudden death resulting from the rupture of an intrathoracic collateral vessel thought to be due to a previous CVL placement.

In the Canadian registry, consisting of 405 patients (mean follow-up, 2.86 years), recurrent venous TEs occurred in approximately 8% of children.²⁵⁰ In the Dutch study,¹⁵³ the recurrence rate was 7% at the 1-year follow-up.

PTS has been estimated²³¹ to be present in up to 65% of children post-VTE, but clinically significant PTS occurs in approximately 10 to 20% of children.²³⁴²⁵⁰ There is, as yet, no properly validated outcome measure for PTS in children.

Evidence
There has been one multicenter randomized trial of anticoagulation for venous thrombosis in children.⁶ The REVIVE (Reviparin In Venous Thromboembolism) trial randomized children (ie, those > 3 months of age) with a first DVT to receive either UFH and then VKAs (target INR, 2.5) for 3 months, or an LMWH (reviparin) to a target anti-FXa level of 0.5 to 1.0 U/mL for 3 months.⁶ The outcome measures were recurrence during next 3 months after treatment. The study stopped prior to the completion of target recruitment, making the study underpowered (78 patients) to answer the primary question. However, the recurrence rates were 5.6% in the reviparin arm and 12.5% in the UFH/VKA arm. The study also reported major bleeding rates of 5.6% in the reviparin arm and 12.5% in the UFH/VKA arm.

The early closure of the REVIVE study, and the subsequently described Prophylaxis of Thromboembolism in Kids Trial (PROTEKT) study,⁵ highlight the difficulties of performing multicenter randomized trials in pediatric patients. Both studies were closed early. The primary reason for the premature closure by the sponsor was slow recruitment rates for each study. However, the initial inclusion and exclusion criteria were modeled on adult antithrombotic studies, and precluded many clinically relevant patients. Furthermore, consent rates were low, reflecting the cautiousness of parents (and many pediatricians) with respect to randomized trials. The following recommendations are based mostly on data from adult studies, and the relevant evidence can be found in the related articles in this volume.

Recommendations
First TE for children > 2 months of age
1.2.1. We recommend treatment with IV heparin that is sufficient to prolong the aPTT to a range that corresponds to an anti-FXa level of 0.35 to 0.7 U/mL, or treatment with LMWH that is sufficient to achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection (Grade 1C+).

1.2.2. We recommend initial treatment with heparin or LMWH for 5 to 10 days (Grade 1C+). For patients in whom subsequent VKAs will be used, we recommend beginning oral therapy as early as day 1 and discontinuing heparin/LMWH on day 6 if the INR is in the therapeutic range on two consecutive days (Grade 1C+). For massive PEs or extensive DVTs, we recommend a longer period of heparin or LMWH therapy (Grade 1C+).

1.2.3. We suggest continuing anticoagulant therapy for idiopathic TEs for at least 6 months, using VKAs to achieve a target INR of 2.5 (INR range, 2.0 to 3.0) or alternatively using LMWH to maintain an anti-FXa level of 0.5 to 1.0 U/mL (Grade 2C). Underlying values and preferences: The suggestion to use anticoagulation therapy to treat idiopathic DVTs in children for at least 6 months rather than on a lifelong basis places a relatively high value on avoiding the known risk of bleeding secondary to anticoagulant therapy in young active adults and places less importance on the unknown risk of recurrence in the absence of an ongoing clinical precipitating factor.

1.2.4. We suggest that, for secondary TEs, anticoagulant therapy be continued for at least 3 months using VKAs to achieve a target INR of 2.5 (INR range, 2.0 to 3.0) or alternatively using LMWH to maintain an anti-FXa level of 0.5 to 1.0 U/mL (Grade 2C).

1.2.5. We suggest that in the presence of ongoing risk factors, such as active nephrotic syndrome, ongoing asparaginase therapy, or a lupus anticoagulant, anticoagulant therapy, in either therapeutic or prophylactic doses, continue until the risk factor has resolved (Grade 2C).

1.2.6. We suggest that clinicians not use thrombolytic therapy routinely for venous TE in children (Grade 2C). Treatment needs to be individualized, and needs to be based on the size and location of the thrombus, and on the degree of organ compromise. If thrombolytic therapy is used, in the presence of physiologic or pathologic deficiencies of plasminogen, we suggest supplementation with plasminogen (FFP) [Grade 2C].

Recurrent idiopathic TEs in children
1.2.7. We recommend indefinite therapy with either therapeutic or prophylactic doses of VKAs (Grade 1C+). We suggest LMWH as an alternative if VKA therapy is too difficult (Grade 2C).

Recurrent secondary TEs in children
1.2.8. We suggest that, following the initial 3 months of therapy, anticoagulation therapy be continued for at least a further 3 months, or until the removal of any precipitating factors (Grade 2C).

CVL-related thrombosis
There are two aspects to the management of CVL-related thrombosis. First, management of the CVL itself and, second, anticoagulation therapy.

1.2.9. We suggest that if the CVL is no longer required, or is nonfunctioning, it be removed (Grade 2C). We suggest at least 3to 5 days of anticoagulation therapy prior to its removal. If CVL access is required and the CVL involved is still functioning, we suggest that the CVL remain in situ (Grade 2C). Anticoagulation therapy should be given as described in recommendations 1.2.1 to 1.2.6.

1.2.10. For children with a first CVL-related DVT after the initial 3 months of therapy, we suggest that prophylactic doses of VKAs (INR range, 1.5 to 1.8) or LMWH (anti-FXa level range, 0.1 to 0.3) be given until the CVL is removed (Grade 2C).

1.2.11. For children with recurrent CVL-related TEs after the initial 3 months of therapy, we suggest prophylactic doses of VKAs (INR range, 1.5 to 1.8) or LMWH (anti-FXa level range, 0.1 to 0.3) be continued until the removal of the CVL. If the recurrence occurs while the patient is receiving prophylactic therapy, we suggest continuing therapeutic doses until the CVL is removed or for a minimum of 3 months (Grade 2C).

1.3 Renal vein thrombosis
Background
Renal vein thrombosis (RVT) is the most common non-catheter-related VTE in neonates and is responsible for approximately 10% of all VTEs in neonates. Almost 80% of all RVTs present within the first month and usually within the first week of life.^{9153254255256257} Some neonates develop RVTs in utero.²⁵⁴ The incidences of RVT in male and female neonates are similar, both sides of the body are affected equally, and RVTs occur bilaterally in 24% of cases.²⁵⁴

The etiologies of RVT are diverse and reflect the prevalence of pathologic conditions, which include perinatal asphyxia, shock, polycythemia, cyanotic CHD, diabetic mothers, dehydration, and septicemia. These disorders result in reduced renal blood flow, increased blood viscosity, hyperosmolality, and hypercoagulability.²⁵⁴

Neonates usually present with a flank mass, hematuria, proteinuria, thrombocytopenia, and nonfunction of the involved kidney. However, in one series²⁵⁸ of 23 cases, of which 83% were diagnosed in the first month after birth, the complete triad was seen in only 13% of neonates. Clinical findings suggestive of associated acute IVCrelated VTE include cold, cyanotic, and edematous lower extremities. Chronic obstruction is characterized by the dilation of collateral veins over the abdomen and upper thighs, as well as bilateral PTS.

The outcome of RVT has changed from a frequently lethal complication to one in which > 85% of neonates survive, mostly due to improvements in supportive care and more sensitive diagnostic techniques, widening the spectrum of diagnosed cases. A total of 58 neonates with renal venous thrombosis have been followed for 0.1 to 17 years by four different investigator teams. Persistent hypertension was found in 28% of all children, and 21% had residual renal tubular defects.²⁵⁹ In another study,²⁶⁰ 26 of 39 affected kidneys were atrophic. Unfortunately, there are no recent studies assessing long-term morbidity such as hypertension and loss of renal function.

Evidence
The only data on the treatment of RVTs have come from case reports and small series. Therefore, the use of anticoagulant or thrombolytic therapy is controversial.²⁶¹ There are no data to confirm that active treatment improves the long-term outcome in the absence of acute renal failure.^{262263264265266267}

Recommendations
1.3.1. For unilateral RVT in the absence of uremia, and in the absence of extension into the IVC, we suggest supportive care with careful monitoring of the RVT for extension (Grade 2C). Alternatively, we suggest anticoagulation therapy with UFH or LMWH (Grade 2C).

1.3.2. For unilateral RVT that extends into the IVC, we suggest anticoagulation therapy with UFH or LMWH for 6 weeks to 3 months (Grade 2C).

Remark: The therapeutic range is the same as that for venous thrombosis.

1.3.3. For bilateral RVT with various degrees of renal failure, we suggest therapy with UFH (and not LMWH) and thrombolytic therapy (Grade 2C).

1.4 CVL prophylaxis
A number of randomized trials have compared thromboprophylaxis vs no treatment for the prevention of CVL-related DVT in adults with cancer. Therapy with both fixed-dose warfarin (1 mg)²⁶⁸ and dalteparin (2,500 U)²⁶⁹ resulted in significant risk reduction when using venography as the study end point. In a study comparing clinical end points, Verso and Agnelli²⁷¹ reported no difference in symptomatic thrombosis between patients receiving dalteparin (5,000 U) or placebo. Mismetti et al²⁷⁰ compared therapy with nadroparin (2,850 U) and warfarin (1 mg), and found no significant difference in thrombosis frequency. Thromboprophylaxis for adults with cancer and CVLs has recently been reviewed.²⁷¹

There has been one multicenter randomized trial of thromboprophylaxis for CVL-related DVT in children. The PROTEKT study randomized 186 children with a new CVL (short-term or long-term) to receive either the standard of care or LMWH (ie, reviparin, 30 U/kg subcutaneously bid) until the CVL was removed or for 30 d