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Minerva Pediatrica 2018 February;70(1):67-78 DOI: 10.23736/S0026-4946.17.05131-3

REVIEW

Antithrombotic treatment in neonates and children C. Heleen van OMMEN * Department of Pediatric Hematology, Sophia Children’s Hospital ErasmusMC, Rotterdam, The Netherlands *Corresponding author: C. Heleen van Ommen, Department of Pediatric Hematology, Sophia Children’s Hospital ErasmusMC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands. E-mail: [email protected]

A B S TRACT Despite the increasing incidence of venous thromboembolic disease in pediatric patients, it remains a rare complication in childhood. Particularly neonates and adolescents are at risk for development of venous thrombosis. Spontaneous thrombotic events are sporadic, the majority of children have multiple coexisting risk factors, including central venous catheter, asphyxia, congenital heart disease, infection, malignancy, surgery and hypovolemia. Most thrombi are diagnosed by ultrasonography. Recommendations for management of pediatric thrombosis are typically extrapolated from adult studies, despite many differences between adults and children, including developmental hemostasis. This review will focus on the management of venous thrombosis in neonates and children, and discuss the use of the available antithrombotic agents in both age categories with reference to those differences. (Cite this article as: van Ommen CH. Antithrombotic treatment in neonates and children. Minerva Pediatr 2018;70:67-78. DOI: 10.23736/S0026-4946.17.05131-3) Key words: Venous thrombosis - Anticoagulants - Thrombolytic therapy.

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ore and more neonates and children develop venous thromboembolic events (VTE) as result of the increased number of children with chronic underlying diseases and hypercoagulability, medical and technologic developments and increased awareness.1 VTE is typically diagnosed in hospitalized children, especially critically ill neonates with central venous catheters and older children with a combination of risk factors.2, 3 These risk factors may include catheters, malignancy, cardiac disease, infection, surgery, immobility, obesity and oral contraceptives. Due to the decreased rate of thrombotic events in children as compared to adults, large clinical trials regarding management of VTE are lacking in both neonates and children. Most of the recommendations of current guidelines for the treatment of pediatric VTE are extrapolated from adult studies despite several differences

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between VTE in adults and children.4 These age-dependent differences include variances in volume of distribution, binding and clearance of the drugs as well as variances in hemostatic proteins, which differs both qualitatively and quantitatively in neonates and young infants from those in older children and adults.5 This review will focus on the management of VTE in neonates and children, and discuss the use of the available antithrombotic agents in both age categories relating to those differences. Developmental hemostasis Maureen Andrew was the first who showed that the hemostatic system develops over time from neonatal to adult system.6, 7 Although all components are present at birth, important differences exist among preterm and term neonates, older children and adults.8 These

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van OMMEN ANTITHROMBOTIC TREATMENT IN NEONATES AND CHILDREN

differences may have important consequences for the management of pediatric thrombotic events. Platelets are the central elements of the primary hemostasis. The number, size and ultrastructure of platelets do not differ much between neonates and adults.9 Nevertheless, neonatal platelets show decreased responses to agonists.10 Despite this platelet hyporeactivity, bleeding times and closure times (using a platelet function analyzer [PFA-100]) in healthy term neonates were shorter than those in adults.11-13 This discrepancy might be explained by higher hematocrit, higher concentrations of plasma Von Willebrand Factor (VWF) levels, and a greater percentage of large VWF multimers with increased adhesive activity in neonates compared to adults.7, 14, 15 Even in premature neonates with more prominent platelet hyporeactivity, results of bleeding time, PFA-100 and platelet adhesion studies showed shorter or comparable closure times to those of adults.14 However, when the term or preterm neonate becomes ill, they seem to lack reserve capacity and the hemostatic equilibrium can easily be unbalanced, predisposing them to bleeding or thrombotic complications. In case of thrombocytopenia, adults can increase both megakaryocyte ploidy and megakaryocyte number to improve the quantity of platelets, whereas neonates can only increase megakaryocyte number in the bone marrow.16 The infusion of hyper-reactive adult platelets have been shown to lead to a hypercoagulable state in vitro, which might contribute to the risk of thrombosis in neonates.17 Secondary hemostasis consists of the cascade of coagulation factors that ends in the formation of insoluble fibrin. In fetal life, these coagulation factors are synthesized by the liver and endothelial cells of the fetus and all factors are measurable in the plasma at about 20 weeks’ gestation. The concentrations gradually increase until birth.8 At birth, plasma levels of most pro- and anticoagulant factors are approximately 50% of normal adult values, which are reflected in the prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT).18 The low levels

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of anticoagulant factors are similar to those of patients with heterozygous deficiencies of antithrombin, protein C or protein S, thus delaying the diagnosis of congenital thrombophilia.19 Furthermore, the decreased levels of antithrombin might influence the efficacy of heparin in neonates. Heparin binds to antithrombin and increases the ability of antithrombin to inactivate especially thrombin and factor (F)Xa by 100- to 1000-fold. In neonates, the low antithrombin levels may challenge the ability to achieve a sufficient anticoagulant effect using both unfractionated (UFH) and lowmolecular-weight heparin (LMWH). During the fibrinolytic process, tissue plasminogen activator (t-PA) and urokinase convert plasminogen into plasmin, which breaks down fibrin, releasing fibrin degradation products, including D-dimer. At birth, plasma levels of most components of the fibrinolytic system differ from older children and adults.20 Clot lysis by thrombolytic agents may be limited due to decreased plasminogen levels in neonates, as shown in some in vitro studies.21, 22 Andrew et al revealed that administration of plasminogen improved fibrinolysis in cord plasma to adult values.21 Antithrombotic agents Unfractionated heparin The anticoagulant function of UH is accomplished by potentiating the inhibitory effects of antithrombin on several coagulation factors, in particular FIIa and FXa. UH is administered intravenously. Due to its short half-life and an available antidote (protamine sulfate), UH is still frequently used in critically ill neonates and children on the intensive care units for treatment of thrombosis. To treat thrombosis, UH is usually started with a bolus dose of 75 U/kg over 10 minutes.23 This bolus dose can be reduced, if there is an increased bleeding risk, for example in neonates. Neonates need higher maintenance dosages (mean 28 U/kg/h) than older children (mean 20 U/kg/h) to reach therapeutic heparin concentrations, which is the result of increased clearance, larger volume

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ANTITHROMBOTIC TREATMENT IN NEONATES AND CHILDREN

of distribution and lower levels of antithrombin.23 In neonates and critically ill children with heparin resistance due to low antithrombin levels, UH dose requirements might be decreased by replacing antithrombin.24, 25 The effect of antithrombin supplementation on bleeding or thrombotic risk is unknown, however. After antithrombin supplementation, it is crucial to monitor UH frequently to decrease heparin dosage accordingly and prevent bleeding complications. Monitoring UH treatment in neonates and children is challenging. The standard monitoring tests include APTT and anti-FXa assay. Frequent blood sampling is required due to the variability in the dose response of UH. In addition, APTT and anti-FXa levels often do not correlate well with each other and/or with the heparin concentration.26 As with other anticoagulants, no clinical outcome studies have been performed to determine the therapeutic target range for UH in the pediatric population. Therefore, the therapeutic range is extrapolated from that in adults (anti-FXa level between 0.3-0.7 U/mL). Especially in neonates and infants, the therapeutic target range might be lower compared to adults due to decreased thrombin generation in this age group.27 Accordingly, while in the study of Schechter et al. only 15 of 100 neonates reached therapeutic target levels within 24 hours and 17% did not reach them at all, thrombus resolution rate was still high (70%) and none of the thrombi progressed.28 Bleeding complications are reported to occur in about 2% of the pediatric patients.23 In critically ill patients, the incidence might be higher.29 Heparin-induced thrombocytopenia (HIT) is a serious complication although the incidence in children is lower than reported in adult patients.30, 31 Low-molecular-weight heparin The shorter polysaccharide chains of LMWHs, which also act through potentiating the anticoagulant effect of antithrombin, have a more predictable dose-response and require fewer dose adjustments and less monitoring than UH. Furthermore, they have a longer

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half-life, can be administered subcutaneously once or twice daily, which allows outpatient management. In addition, due to reduced binding to platelet factor 4, the risk of HIT is decreased compared to UH.30 Therefore, LMWH has become the first choice for initial treatment of pediatric thrombosis. One randomized controlled trial assessed the efficacy and safety of LMWH (reviparin) compared to heparin and vitamin K antagonists (VKAs) for the treatment of pediatric VTE (REVIVE Trial).32 After 6 months, recurrent VTE and major bleeding risk was 12.5% in the heparin/VKA group and 5.6% in the LMWH group. Unfortunately, this study was underpowered due to premature closure. Enoxaparin is the most frequently used and studied LMWH. In neonates, data about LMWH are still limited. In a review of Malowany et al., the mean dose of enoxaparin ranged from 1.48 to 2.27 mg/kg per 12 h in all neonates.33 Similar to UH, preterm neonates require higher dosages of LMWH to achieve the therapeutic range.33-35 Therefore, a starting dose of 2 mg/kg per 12 h in preterm and 1.7 mg/kg per 12 h in term neonates is suggested. In children, the starting dose is 1.0 mg/kg per 12 h.4, 36 In contrast to adults, it is recommended to monitor LMWH in pediatric patients at least once. More frequent testing is recommended in neonates, critically ill children and patients with renal insufficiency.37 As in UH, the therapeutic target range of 0.5-1.0 U/mL, 4 hours after LMWH dose, is extrapolated from adult studies. The neonatal therapeutic target level might be lower due to reduced thrombin potential compared to adults.38 In the study of Lulic-Botica et al. thrombus resolution occurred in 80% of the affected neonates while about 60% of maintenance anti-FXa levels were below the therapeutic range.39 Major bleeding complications do not occur very often: in a systemic review the pooled incidence rate of major bleeding events on LMWH treatment was 0.050 (95% Confidence Interval [CI], 0.031-0.078).40 The antidote protamine sulfate is only partly effective. An important disadvantage of (long-term) LMWH is frequent subcutaneous injections, which are painful and may cause skin hematomas, especially

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in case of therapeutic LMWH dosages. Injection pain can be diminished by the use of local anesthetics, such as lidocaine cream. Fondaparinux Fondaparinux is a synthetic pentasaccharide that inhibits FXa by binding to antithrombin. It is given subcutaneously and has a long half-life permitting once-daily dosing. It may be an alternative to LMWH in the initial treatment of thrombosis in children. An antidote, however, is not available. A fondaparinuxspecific anti-Xa assay is needed to monitor fondaparinux. Blood for anti-FXa levels should be drawn 3 hours post dose. The target range is between 0.5-1 mg/L. Only two pediatric studies have been published: one prospective, pharmacokinetic and safety study in 24 patients aged 1 to 18 years and one longterm follow-up study.41, 42 Pharmacokinetic modeling showed that a once-daily dose of fondaparinux at 0.1 mg/kg was safe and resulted in similar concentrations that were effective in adults.42 At follow-up, 14 of the 22 (64%) evaluable children had complete resolution, 6/22 (27%) had partial resolution and 2/22 (9%) had no change. Recurrent VTE occurred in 2 patients (9%), and major bleedings in 3 patients (14%). Direct thrombin inhibitors: argatroban and bivalirudin Argatroban and bivalirudin directly inhibit FII and do not need antithrombin for their anticoagulant function. An important disadvantage is their continuous intravenous administration. Pediatric experience is limited and large pediatric studies are lacking. Argatroban is studied in 18 children (1.6 weeks to 16 years old), who required an alternative anticoagulant for suspicion of or at risk for HIT or other conditions requiring nonheparin anticoagulation.43 After pharmacometric analyses, an initial argatroban dose of 0.75 ug/kg/min appeared to provide adequate and safe levels of anticoagulation, i.e. APTT of 1.5-3 times the initial baseline value. As argatroban is metabolized in the liver, dose

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reduction is necessary in hepatic impairment (0.2 ug/kg/min). Based on this small study, argatroban is FDA approved for the treatment of HIT in children. Bivalurudin has been evaluated in two pediatric VTE studies.44, 45 A dose-finding study was performed in 16 infants less than 6 months of age with venous thrombosis. The initial bolus dosing was divided into three patients cohorts: 0.25 mg/kg, 0.125 mg/kg and 0.5 mg/ kg. The initial infusion rate was divided into two patient cohorts: 0.25 mg/kg/h and 0.125 mg/kg/h. APTT was used to monitor bivalirudin treatment, targeting an APTT of 1.5-2.5 times baseline APTT. After the bolus dosing, 12 of the 13 evaluable patients had therapeutic APTT values. After initiation of the continuous infusion, the first measured APTT was therapeutic in 15 of the 16 patients. As a bolus dose of 0.125 mg/kg and initial infusion rate of 0.125 mg/kg/h were the lowest effective dosages, this study suggested to use these dosages for treatment of thrombosis in infants less than 6 months.45 In children between 6 months and 18 years old, two-thirds of 18 participating patients had APTT values in the therapeutic range, following the aforementioned dosage scheme.44 After 48 to 72 hours, nine patients (50%) had complete or partial thrombus resolution. No major bleeding complication occurred. No antidote is available for both direct thrombin inhibitors. Vitamin K antagonists VKAs function by competitively inhibiting the vitamin K-dependent carboxylation of the clotting factors II, VII, IX and X. Different VKAs are available of which warfarin, acenocoumarol and phenprocoumon are most frequently prescribed. Of these three VKAs, phenprocoumon has the longest half-life of 110-130 hours. The half-life of warfarin varies from 36 to 42 hours and acenocoumarol has the shortest half-life of about 6.5 hours.46 The most important advantage of all VKAs is the oral route of administration. As a consequence, VKAs have been frequently used for prevention and treatment of thrombosis in both adults

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and children for decades. In neonates and infants, the use of VKA can be challenging due to its narrow therapeutic index requiring frequent monitoring, and its drug and food interactions. Hence, in these age groups LMWHs are frequently prescribed instead of VKAs. As it usually takes more than 5 days before VKAs reach a therapeutic effect, a period of overlap is needed with heparin or fondaparinux. Loading dose of warfarin is 0.2 mg/kg. In children with liver disease and Fontan patients, a lower loading dose of 0.1 mg/kg is advised.37 Monitoring of VKA occurs via the international normalized ratio (INR), which should be in the therapeutic range for 2 consecutive days before heparin or fondaparinux can be discontinued. The target INR range depends on the clinical situation, but is usually between 2 and 3. Initial and maintenance dosages are age-dependent for all types of VKAs.47, 48 Bleeding is the main complication. Streif et al. reported two major bleeding events in a prospective study of 319 consecutive children with warfarin.48 No major bleeding and 6 clinically relevant non major bleedings occurred in 107 children with phenprocoumon or acenocoumarol in the study of Spoor et al.47 Bleeding can be reversed by vitamin K or prothrombin complex concentrates. Direct oral anticoagulants Direct oral anticoagulants (DOACs) are excellent alternatives for VKAs, because they have several advantages including more predictable dose response, fixed dosing, no requirement for monitoring, no food and minimal drug interactions. Furthermore, specific antidotes for DOACs are being developed.49 In adults, DOACs and VKAs have similar efficacy in the treatment of acute VTE. The risk of major bleeding seems to be reduced with DOACS.50 In contrast to the traditional anticoagulant agents such as heparin and VKA, DOACs will be extensively studied in the pediatric population in large development programs. Currently, dabigatran, apixaban, rivaroxaban and edoxaban are studied in pediatric patients with VTE in phase III trials.

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Thrombolytic therapy Thrombolytic therapy is a vital therapy in selected pediatric patient groups with life-, organ- or limb-threatening thromboembolic events.4 Thrombolytic agents are plasminogen activators that enhance fibrinolysis by converting plasminogen to plasmin. They cause faster thrombus resolution than heparin therapy. However, thrombolysis is more frequently associated with bleeding complications than UH or LMWH. The thrombolytic agents include urokinase, streptokinase and recombinant tPA (r-tPA). r-tPA is the most used agent in children due to its fibrin specificity and affinity and low immunogenicity.51 Several casereports and small case-series have reported successful thrombolysis in both neonates and children. Relative contraindications include known allergy, active bleeding, cerebral ischemia, bleeding or surgery within the previous 30 days, invasive procedures within the previous 3 days, other surgery within the previous 7 to 14 days, uncontrolled hypertension, and seizures within the previous 2 days.25, 52 The fibrinogen level and the platelet count should be maintained above 1.0 g/L and 50 – 100 x 109/L, respectively, to minimize bleeding complications. The precise r-tPA dosage is unknown. Two systemic r-tPA dosing regimens are frequently used: a standard- and low-dose regimen. The standard-dose regimen consists of 0.1-0.5 mg/kg/h for 6 hours. A second course can be administered if the clot remains unaffected.4, 53 The low-dose regimen of 0.010.06 mg/kg/h may be given for longer periods of time.54, 55 Wang et al. showed that either standard or low-dose regimen resulted in complete lysis of 28 of 29 acute thrombi.56 Neonates required 0.06 mg/kg per hour. As vitro studies showed that clot lysis of neonatal clots may be limited due to decreased plasminogen levels, supplementation of plasminogen using fresh frozen plasma is suggested in neonates before start of thrombolysis.21, 22 A specific laboratory test to monitor thrombolysis is not available. The thrombolytic effect may be assessed by observing a rise in fibrin degradation products or D-dimer and a drop in fibrinogen.

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The most severe complication of thrombolysis is bleeding. The reported bleeding rates in pediatric patients varies from 0 to 40% due to variances in dosing regimens and patient populations.52, 53 The incidence of intracerebral hemorrhages seem to be higher in preterm neonates than in term neonates and children after the neonatal period.57 Furthermore, low-dose r-tPA regimens seem to be associated with fewer bleeding complications than high-dose regimens.52, 56, 58 Neonatal venous thrombosis The incidence of neonatal VTE was estimated to be 75 cases per 10 000 hospital admissions in the United States in 2007.1 All neonatal thrombi are provoked, in more than 90% of the neonates by the insertion of a central venous catheter.2, 59 In addition, the neonatal hemostatic equilibrium can be easily disturbed due to lack of reserve capacity by underlying conditions such as asphyxia, congenital heart disease, infection and hypovolemia.60 The clinical presentation depends on the VTE location and size. The majority of the neonatal catheter-related thrombi are situated in the hepatic system (35%), right atrium (28%) and superior or inferior vena cava or subclavian vein (25%).61 About 25% of the thrombi is asymptomatic and diagnosed by screening for other purposes.62 Swelling of the affected limb is reported in 10% to 50% and limb discoloration in 34% of the neonates.62-64 Incidentally, vena cava syndrome or chylothorax may occur when the catheter is positioned in the upper venous system.65, 66 In addition, catheter dysfunction and persistent sepsis or thrombocytopenia should raise suspicion of catheter-related thrombosis.60 Ultrasound is the most common imaging modality used to diagnose neonatal catheter-related VTE. Neonatal renal vein thrombosis (RVT) is the most frequent noncatheter-related VTE in neonates. A German registry reported the incidence of symptomatic RVT in neonates to be about 2.2 per 100.000 live births.67 Casereports and small case-series showed that both neonatal and maternal factors are associated

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with neonatal RVT, including dehydration, sepsis, asphyxia, preeclampsia and maternal diabetes.68 RVT seems to occur more frequently in males compared to females, and the majority of neonatal RVT are unilateral, with a left-sided predominance. About 40% of patients have thrombus extension in the inferior caval vein.69 The mortality rates are low, but long-term kidney dysfunction is common. A review showed kidney atrophy on 71% of neonates, hypertension in 20% and chronic kidney disease requiring replacement therapy in 3% (usually sequelae of bilateral RVT).68 Neonatal cerebral sinovenous thrombosis (CSVT) is a rare, but serious disease. The reported incidence is 0.6-12 per 100 000 live births.70 It occurs more often in males. CSVT is a multifactorial disease and many risk factors, including pre-eclampsia, chorioamnionitis, gestational diabetes, complicated delivery, meconium aspiration, infection, and congenital heart disease, have been identified. The patients typically develop symptoms within 48 hours after birth. These symptoms are often subtle and mainly consist of seizures.71 About three quarter of the patients develop some kind of deficit. Motor impairment are observed in 2080% of the patients. Cognitive outcome is abnormal in 25-73% of all patients. 15% to 40% of the patients develop postneonatal epilepsy.70 Antithrombotic management in neonates Due to lack of large prospective studies in neonates, treatment recommendations include: 1) observation and supportive treatment; 2) anticoagulant agents, including LMWH and UH; 3) thrombolytic agents; and 4) thrombectomy. Thrombectomy, however, is very rarely reported, as experience with microsurgery is limited.72 As the most important complication of antithrombotic therapy is intracranial bleeding, especially in preterm neonates, the (bleeding) risks and benefits of all these options should be considered in each neonate before treating the patient. In catheter-related thrombosis, the catheter should be removed if it is no longer required or dysfunctional. It is advised to remove the cath-

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eter after 3 to 5 days of anticoagulation to decrease risk of embolization, although evidence is lacking.4 Catheter-related thrombosis in neonates may be divided in thrombi located in veins or in the right atrium, as most thrombi are located in the hepatic or caval veins and right atrium.61 Thrombi located in veins may be nonocclusive or occlusive. Occlusive vein thrombosis should be treated with anticoagulants. As spontaneous resolution is more likely in nonocclusive vein thrombosis, it is reasonable to hold back anticoagulants in these thrombi and follow them by ultrasonography or echocardiography for progression.73, 74 If progression occurs, anticoagulant therapy (LMWH or UH) should be started, like in occlusive vein thrombosis. Dose recommendations are shown in Table I.4, 23, 25, 33, 56 Supportive care only may be an option for small catheter-related thrombosis in the right atrium, as well.75, 76 If ultrasonography reveals progression of the thrombosis, anticoagulant treatment should be started immediately. Larger right atrium clots, however, should be treated with anticoagulants directly. To determine at which clot size anticoagulation should be started may be problematic. It seems rational to treat thrombosis with sizes which may completely occlude the pulmonary valve. Critical clot sizes in children according to their expected pulmonary valve size based on their weight have been published.77 Thrombolysis should be reserved for organ-, limb- or

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life-threatening occlusions of the veins as well as high-risk right atrium thrombosis. Right atrium thrombosis may be considered highrisk if it: 1) restricts the outflow from the right atrium; 2) extends via the tricuspid valve or patent foramen ovale with risk of embolization to lungs or brain; 3) causes severe arrhythmias; 4) causes hemodynamic instability; 5) is pedunculated, mobile, or snake-shaped and mobile; and 6) progresses despite adequate therapeutic heparin levels.77 The American College of Chest Physicians (ACCP) guideline recommends to treat neonatal catheter-related thrombosis for a maximum of 3 months.4 If ultrasonography or echocardiography shows resolution of the thrombosis at an earlier stage, anticoagulation may be stopped. A proposed management algorithm is shown in Figure 1. Optimal treatment for neonatal RVT is unknown. The ACCP guideline suggests supportive care or anticoagulation in neonates with unilateral RVT and thrombolytic therapy in neonates with bilateral RVT causing kidney failure.4 It is not clear, however, whether anticoagulation and/or thrombolytic therapy influences the short-term bleeding risk, the long-term sequelae, the recurrence risk and/or mortality.78 Neonatal CSVT may progress, if anticoagulation is not initiated.79 Anticoagulation seems to be safe, even in the presence of a thalamic bleeding.80 Therefore, the ACCP guideline

Table I.—Anticoagulant and thrombolytic therapy in neonates. Medication

Dosing

Monitoring

LMWH Preterm neonates: 2.0 mg/kg/12 h sc Enoxaparin 33 Term neonates: 1.7 mg/kg/12 h sc UH 23, 25

r-TPA 4, 56

Exclude ICH by US Check anti-FXa level 4 h after dose; target anti-FXa level: 0.5-1.0 U/mL Check platelets regularly Loading: 25-100 U/kg in 10 min IV Exclude ICH by US Start maintenance: 28 U/kg/h IV Check APTT or anti-FXa level 4 h after loading dose and every change in therapy; target APTT: 60-85 sec, corresponding to heparin level by anti-FXa of 0.3-0.7 U/mL Check platelets regularly Start low-dose: 0.06 mg/kg/h IV Check CBC, APTT, PT, fibrinogen, D-dimers daily Start standard-dose: 0.1 mg/kg/h IV Exclude ICH by US daily For periods of 6 h or continuous infusion for longer Transfuse with FFP daily periods with increasing doses if no improvement Maintain fibrinogen >1.0 g/L and platelets >50-100 x 109/L Max. dose: 0.5 mg/kg/h Check thrombus resolution once to twice daily

LMWH: low-molecular weight heparin; UH: unfractionated heparin; r-TPA: recombinant tissue plasminogen activator; ICH: intracranial hemorrhage; US: ultrasonography; CBC: complete blood count; APTT: activated partial thromboplastin time; PT: prothrombin time; FFP: fresh frozen plasma; IV: intravenously; sc: subcutaneously; max: maximum.

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Central venous catheter thrombosis

Vein thrombosis

Limb- or organthreatening

r-TPA

Occlusive thrombosis

Nonocclusive thrombosis

US/EC control

Extension

Anticoagulation

Atrial thrombosis

High-risk thrombosis

Small size thrombosis

r-TPA

US/EC control

Large size thrombosis

Extension

Anticoagulation

Continue anticoagulation for 6 weeks to 3 months, follow thrombus resolution

Figure 1.—Management of catheter-related venous thrombosis in neonates. r-TPA: recombinat tissue plasminogen activator; US: ultrasonography; EC: echocardiography.

recommends to administer anticoagulation for 6 to 12 weeks. Anticoagulation should not be started in the presence of a large intracranial bleeding. However, if subsequent imaging shows progression of CSVT, anticoagulation may still be initiated. Venous thrombosis in older children In older children, VTE most frequently develops in adolescents with 94 cases per 10 000 hospital admissions in the USA in 2007.1 Most children have underlying conditions, such as malignancies, sepsis, surgery and heart disease. About 33 to 48% of the thrombi is catheter-related.81 Typically, multiple coexisting risk factors are present. In contrast to adults, pediatric thrombosis rarely occurs spontaneously. National registries recorded spontaneous VTE in 2-8.5% of the patients, particularly in adolescents.81 As in neonates, the symptoms depend on the location of the thrombosis. The clinical diagnosis of VTE is most frequently confirmed by ultrasonography. However, diagnosis of VTE in the upper venous system may be hampered as result of the impossibility of

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compressing the veins due to the thoracic cage, the limited view of the distal subclavian veins due to the presence of the clavicle and the difficulty to discriminate large collaterals from normal vasculature. Imaging tests for CSVT include computed tomography and magnetic resonance imaging. Diagnosis of pulmonary embolism (PE) is usually made by computed tomography. Mortality rate directly related to VTE ranges from 1% to 3.7%.82-84 Recurrent VTE occurs in 6.5% to 11% of the patients.82-84 The recurrence risk is higher in children with spontaneous thrombosis.85 The incidence of the post-thrombotic syndrome fluctuates between 10% to 70%. A meta-analysis revealed a mean frequency of 26% (95% CI: 23-28%).86 Antithrombotic management in older children The antithrombotic management in older children did not differ much from that in adults, as large randomized-controlled trials are lacking in the pediatric population. However, nowadays most adult patients with VTE are treated with one of the new DOACs. In the pediatric population, DOACs are still in clinical development and only used in the setting of phase III trials. It is likely, though, that in future, the use of DOACs for treatment of pediatric VTE will rise due to the aforementioned advantages. Thus, pediatric venous thrombosis (including CSVT and PE) is still treated with traditional anticoagulants. Dose recommendations are shown in Table II.4, 23, 37, 42-45, 47, 56, 87 The initial treatment of VTE consists of UH or LMWH, which is followed by LMWH or VKAs. LMWH is the preferred initial agent. Nevertheless, in critically ill children and children requiring emergent procedures, UH is frequently used due to its short half-life and available antidote. Thrombolytic therapy is reserved for children with life-, organ- or limbthreatening VTE (Figure 2). Treatment with VKA can be initiated on day 2 after the start of heparin therapy. Heparin therapy should be continued until INR is in the therapeutic range for two consecutive days. In some patients, follow-up treatment with LMWH is more con-

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Table II.—Anticoagulant and thrombolytic therapy in older children. Medication

Dosing

Monitoring

LMWH Enoxaparin 87

1 mg/kg/12 h sc

UH 23

Loading: 75 U/kg in 10 min IV Start maintenance: 20 U/kg/h IV

Fondaparinux 42

0.1 mg/kg/day sc

Bivalirudin 44, 45

0.125 mg/kg IV, followed by 0.125 mg/kg/h IV HIT: 0.75 ug/kg/min IV 0.2 ug/kg/min IV (hepatic impairment) Warfarin: 0.2 mg/kg orally Phenprocoumon/Acenocoumarol: >5 years: 0.15 mg/kg orally 1-5 years: 0.10 mg/kg orally >5 years: 0.05 mg/kg orally Low-dose: 0.01-0.06 mg/kg/h IV Standard-dose: 0.1-0.5 mg/kg/h IV For periods of 6 h or continuous infusion for longer periods with increasing doses if no improvement

Argatroban 43 VKA 37, 47

r-TPA 4, 56

Check anti-FXa level 4 h after dose; target anti-FXa level: 0.5-1.0 U/mL Check platelets regularly Check APTT or anti-FXa level 4 h after loading dose and every change in therapy; target APTT: 60-85 sec, corresponding to heparin level by anti-FXa of 0.3-0.7 U/mL Check platelets regularly Check anti-FXa level (Fondaparinux-based anti-Xa assay); target anti-FXa level: 0.5-1 mg/L 3h after dose Check APTT; target APTT: 1.5-2.5 times baseline APTT Check APTT; target APTT: 1.5-3 times baseline APTT Check INR Lower loading dose in patients with liver disease and Fontan circulation Check CBC, APTT, PT, fibrinogen, D-dimers daily Maintain fibrinogen >1.0 g/L and platelets >50-100 x 109/L Check thrombus resolution once to twice daily

LMWH: low-molecular weight heparin; UH: unfractionated heparin; r-TPA: recombinant tissue plasminogen activator; CBC: complete blood count; APTT: activated partial thromboplastin time; PT: prothrombin time; IV: intravenously; sc: subcutaneously; HIT: heparin-induced thrombocytopenia; INR: international normalized ratio.

Venous thrombosis Limb-, organor life-threatening Anticoagulation r-TPA followed by anticoagulation Continue anticoagulation for 3 months Consider indefinite anticoagulation in patients with idiopathic thrombosis, recurrent thrombosis and patients with persisting risk factor, including antiphospholipid syndrome

In the Kids-DOTT (Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in Children, [NCT00687882]) Trial, children with a first-episode, provoked VTE are randomized to short-duration (6 weeks) or standard-duration (12 weeks) anticoagulation. Long-term anticoagulant treatment should be considered in patients with idiopathic and/or recurrent VTE, and patients with a persistent risk factor, including antiphospholipid syndrome.

Figure 2.—Management of venous thrombosis in older children. r-TPA: recombinant tissue plasminogen activator.

venient, for example in patients with acute lymphoblastic leukemia. LMWH can be easily stopped and restarted before and after lumbar punctures which are often performed in these patients. The total duration of antithrombic treatment in children with VTE is 3 months. In children with provoked thrombosis, a shorter period of anticoagulation might be sufficient.

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