Antithrombotic Therapy in Neonates and Children
Summarized from the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)*
Click on a topic below for pertinent treatment recommendations and other relevant information. For the full Guidelines reference, click here. Recommendations for the following are included in the Guidelines but NOT below: renal thromboembolism, VAD, neonatal AO thrombus, anticoagulation with dialysis, Kawasaki disease, cerebral venous sinus thrombosis, or any thrombotic stroke therapy, or neonates with Protein C deficiency.
Stage 1 Norwoods in Neonates
Glenn or BCPS in Children
Fontan Surgery in Children
Endovascular Stents in Children
Cardiomyopathy in Neonates and Children
Primary Pulmonary Hypertension
Biological Prosthetic Heart Valves
Mechanical Prosthetic Heart Valves
- We suggest that CVLs or umbilical venous catheter (UVCs) associated with confirmed thrombosis be removed, if possible, after 3 to 5 days of anticoagulation (Grade 2C).
- We suggest either initial anticoagulation, or supportive care with radiologic monitoring (Grade 2C); however, we recommend subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 1B).
- We suggest anticoagulation should be with either: (1) LMWH given twice daily and adjusted to achieve an anti-FXa level of 0.5 to 1.0 U/mL; or (2) UFH for 3 to 5 days adjusted to achieve an anti-FXa of 0.35 to 0.7 U/mL or a corresponding aPTT range, followed by LMWH. We suggest a total duration of anticoagulation of between 6 weeks and 3 months (Grade 2C).
- We suggest that if either a CVL or a UVC is still in place on completion of therapeutic anticoagulation, a prophylactic dose of LMWH be given to prevent recurrent VTE until such time as the CVL or UVC is removed (Grade 2C).
- We recommend against thrombolytic therapy for neonatal VTE unless major vessel occlusion is causing critical compromise of organs or limbs (Grade 1B).
- We suggest that if thrombolysis is required, the clinician use tissue plasminogen activator (tPA) and supplement with plasminogen (fresh frozen plasma) prior to commencing therapy (Grade 2C).
- To maintain umbilical artery catheter (UAC) patency, we suggest prophylaxis with a low-dose UFH infusion via the UAC (heparin concentration 0.25 to 1 U/mL) [Grade 2A].
- For neonates with UAC-related thrombosis, we suggest therapy with UFH orLMWHfor at least 10 days (Grade 2C).
- For neonates with UAC-related thrombosis, we recommend UAC removal (Grade 1B).
- For neonates with UAC-related thrombosis with potentially life-, limb-, or organ-threatening symptoms, we suggest thrombolysis with tPa. When thrombolysis is contraindicated, we suggest surgical thrombectomy (Grade 2C).
- We suggest UACs placement in a high position rather than a low position (Grade 2B).
- We recommend anticoagulant therapy with either UFH or LMWH (for additional information see Section 1.2, DVT in Children) [Grade 1B].
- We recommend initial treatment with UFH or LMWH for at least 5 to 10 days (Grade 1B). For patients in whom clinicians will subsequently prescribe VKAs, we recommend beginning oral therapy as early as day 1 and discontinuing UFH/ LMWH on day 6 or later than day 6 if the international normalized ratio (INR) has not exceeded 2.0 (Grade 1B). After the initial 5- to 10-day treatment period, we suggest LMWH rather than VKA therapy if therapeutic levels are difficult to maintain on VKA therapy or if VKA therapy is challenging for the child and family (Grade 2C).
- We suggest children with idiopathic thromboembolism (TE) receive anticoagulant therapy 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
- In children with secondary thrombosis in whom the risk factor has resolved, we suggest anticoagulant therapy be administered 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).
- In children who have ongoing, but potentially reversible risk factors, such as active nephrotic syndrome or ongoing l-asparaginase therapy, we suggest continuing anticoagulant therapy in either therapeutic or prophylactic doses until the risk factor has resolved (Grade 2C).
- For children with recurrent idiopathic thrombosis, we recommend indefinite treatment with VKAs to achieve a target INR of 2.5 (INR range, 2.0 to 3.0) [Grade 1A].
- For children with recurrent secondary TE with an existing reversible risk factor for thrombosis, we suggest anticoagulation until the removal of the precipitating factor but for a minimum of 3 months (Grade 2C).
- If a CVL is no longer required, or is nonfunctioning, we recommend it be removed (Grade 1B). We suggest at least 3 to 5 days of anticoagulation therapy prior to its removal (Grade 2C). If CVL access is required and the CVL is still functioning, we suggest that the CVL remain in situ and the patient be anticoagulated (Grade 2C).
- For children with a first CVL-related DVT, we suggest initial management as for secondary TE as previously described. We suggest, after the initial 3 months of therapy, that prophylactic doses of VKAs (INR range, 1.5 to 1.9) or LMWH (anti-FXa level range, 0.1 to 0.3) be given until the CVL is removed (Grade 2C). If recurrent thrombosis occurs while the patient is receiving prophylactic therapy, we suggest continuing therapeutic doses until the CVL is removed but at least for a minimum of 3 months (Grade 2C).
- In children with DVT, we suggest that thrombolysis therapy not be used routinely (Grade 2C). If thrombolysis is used, in the presence of physiologic or pathologic deficiencies of plasminogen, we suggest supplementation with plasminogen (Grade 2C). 1.4.1. If life-threatening VTE is present, we suggest thrombectomy (Grade 2C).
- We suggest, following thrombectomy, anticoagulant therapy be initiated (Grade 2C).
- In children > 10 kg body weight with lower- extremity DVT and a contraindication to anticoagulation, we suggest placement of a temporary inferior vena cava (IVC) filter (Grade 2C).
- We suggest temporary IVC filters be removed as soon as possible if thrombosis is not present in the basket of the filter, and when the risk of anticoagulation decreases (Grade 2C).
- In children who receive an IVC filter, we recommend appropriate anticoagulation for DVT (see Section 1.2) as soon as the contraindication to anticoagulation is resolved (Grade 1B).
- In children with cancer, we suggest management of VTE follow the general recommendations for management of DVT in children. We suggest the use of LMWH in the treatment of VTE for a minimum of 3 months until the precipitating factor has resolved (eg, use of asparaginase) [Grade 2C].
- We suggest clinicians not use primary antithrombotic prophylaxis in children with cancer and central venous access devices (Grade 2C).
- For children with VTE, in the setting of antiphospholipid antibodies (APLAs), we suggest management as per general recommendations for VTE management in children.
- In children with CVLs, we recommend against the use of routine systemic thromboprophylaxis (Grade 1B).
- In children receiving long-term home total parenteral nutrition, we suggest thromboprophylaxis with VKAs with a target INR of 2.5 (range 2.0–3.0) [Grade 2C].
- For blocked CVLs, we suggest tPA or recombinant urokinase to restore patency (Grade 2C). If 30 min following local thrombolytic instillation CVL patency is not restored, we suggest a second dose be administered. If the CVL remains blocked following two doses of local thrombolytic agent, we suggest investigations to rule out a CVL-related thrombosis be initiated (Grade 2C).
- For pediatric patients with a femoral artery thrombosis, we recommend therapeutic doses of IV UFH (Grade 1B). We suggest treatment for at least 5 to 7 days (Grade 2C).
- We recommend administration of thrombolytic therapy for pediatric patients with limbthreatening or organ-threatening (via proximal extension) femoral artery thrombosis who fail to respond to initial UFH therapy and who have no known contraindications (Grade 1B).
- For children with femoral artery thrombosis, we suggest surgical intervention when there is a contraindication to thrombolytic therapy and organ or limb death is imminent (Grade 2C). 1.20.4. We suggest for children in who thrombolysis or surgery is not required, conversion to LMWH to complete 5 to 7 days of treatment (Grade 2C).
- For pediatric patients with peripheral arterial catheters in situ, we recommend UFH through the catheter, preferably by continuous infusion (5 U/mL at 1 mL/h) [Grade 1A].
- For children with a peripheral arterial catheter-related TE, we suggest immediate removal of the catheter (Grade 1B). We suggest UFH anticoagulation with or without thrombolysis, or surgical thrombectomy (Grade 2C).
Recommendation: For pediatric patients undergoing MBTS, we suggest intraoperative therapy with UFH followed by either aspirin (1–5 mg/kg/d) or no further antithrombotic therapy compared to prolonged LMWH or VKAs (Grade 2C).
Background: Blalock-Taussig shunts (subclavian to pulmonary artery shunt) are a form of palliative surgery used to enhance pulmonary artery blood flow in patients with severe or progressive cyanosis, usually secondary to pulmonary stenosis. An MBTS, in which a plastic (Gortex; WL Gore; Newark, DE) tube graft is taken from the side of the subclavian artery and is anastomosed to the pulmonary artery, has been used since 1980. Because of the short length and very high flow, acute thrombosis is less common with the MBTS compared to the classical Blalock-Taussig shunt. Nevertheless, thrombotic occlusion of the MBTS remains a problem, with an incidence between 1% and 17%. In a 155-patient study, smaller shunt size (_ 4 mm) was a risk factor for occlusion of the MBTS.233 A retrospective review reported on 146 infants aged _ 60 days who underwent MBTS and were discharged from the hospital alive, 21 died after discharge (14%) and before further planned surgery. 234 Of these 21 infants, 17 (81%) were apparently clinically well before sudden death. Autopsies were obtained in 15 cases and attributed the cause of death to shunt thrombosis in 5 infants (33%) and myocardial infarction in 2 infants (13%). The mortality rate of patients discharged on aspirin (11%) was almost identical to that of patients discharged receiving no anticoagulation (12.3%).234 A retrospective series of 546 MBTS procedures reported an overall early failure rate of 1.4% when heparin was administered intraoperatively and for 48 h postoperatively, in contrast to an early failure rate of 3.4% when heparin was not used (p _ 0.29).235 Overall rates of failure during followfollow- up were 9.1% in heparinized patients vs 13.6% (p _ 0.17) in nonheparinized patients. Administration of aspirin during follow-up after the MBTS procedure nonsignificantly reduced failure from 11 to 6.7%, p _ 0.176. In another, much smaller case study, aspirin was reported to decrease the incidence of stent thrombosis after MBTS.236 No published RCTs are available to guide the antithrombotic medical management of MBTS patients. A current randomized, blinded, placebocontrol trial (Efficacy and Safety of Clopidogrel in Neonates/Infants With Systemic to Pulmonary Artery Shunt Palliation) is currently enrolling patients (ClinicalTrials.gov Identifier: NCT00396877) to evaluate the efficacy of clopidogrel for the reduction of all-cause mortality and shunt-related morbidity in neonates or infants with cyanotic congenital heart disease palliated with a systemic to pulmonary artery shunt.
Recommendation: For patients who underwent the Norwood procedure, we suggest UFH immediately after the procedure, with or without ongoing antiplatelet therapy (Grade 2C).
The Norwood procedure is now commonly performed as the initial surgery for children with hypoplastic left heart, which was previously an almost uniformly fatal condition. Although investigators have reported thrombotic complications following Stage 1 Norwood surgery, the major causes of postoperative death remain surgical and hemodynamic factors.237–243 The potential for thrombosis to increase pulmonary pressures and so restrict the potential for subsequent Fontan surgery is important. There are no specific studies examining the role of anticoagulant prophylaxis although common practice is to use heparin immediately post operatively followed by aspirin, as per Blalock-Taussig shunts. Recently, some centers report using aspirin and clopidogrel as combination therapy for prophylaxis of Blalock-Taussig shunts during Norwood procedures, and continue this until immediately prior to BCPS.139 The safety and efficacy of this therapy are unproven. Recommendations for patients undergoing the Norwood procedure are therefore based on generalization from other major cardiac surgery in infants and children.
Recommendation: In patients who have BCPS, we suggest postoperative UFH (Grade 2C). We suggest this should be followed by no anticoagulation or antiplatelet therapy or anticoagulation with VKAs to achieve a target INR of 2.5 (range, 2.0 to 3.0) to continue until the patient is ready for Fontan surgery (Grade 2C).
Glenn successfully performed the classic cavopulmonary anastomosis in 1957 as palliation for tricuspid atresia. The bidirectional Glenn is now frequently used as an intermediate step in patients with single ventricles prior to definitive Fontan surgery (following Blalock Taussig shunts in hypoplastic right heart, and following stage I Norwood in hypoplastic left hearts). Thrombotic complications following the Glenn shunt are infrequently reported.244–246 No published data support the need for routine thromboprophylaxis. However, once again, the fact that many patients subsequently proceed to Fontan procedures has led to some suggestions that thromboprophylaxis is warranted after a Glenn shunt to reduce the risk of thrombosis in the pulmonary vasculature, hence increasing the likelihood of successful conversion to a full Fontan circuit. Current clinical practices vary, and include no anticoagulation, UFH followed by aspirin, and UFH followed by warfarin therapy. There is no evidence to support a preference for any of these approaches at this time. Thus, recommendations for patients undergoing BCPS are therefore based on generalization from other major vascular procedures in infants and children.
Recommendation: For children after Fontan surgery, we recommend aspirin (1–5 mg/kg/d) or therapeutic UFH followed by VKAs to achieve a target INR of 2.5 (range, 2.0 to 3.0) [Grade 1B]. Remark: The optimal duration of therapy is unknown. Whether patients with fenestrations require more intensive therapy until fenestration closure is unknown.
The Fontan procedure, or a modified version, is the definitive palliative surgical treatment for most congenital univentricular heart lesions. TE remains a major cause of early and late morbidity and mortality. Reported incidences of VTE and stroke ranged from 3 to 16% and 3 to 19%, respectively, in retrospective cohort studies in which thrombosis was the primary outcome, and from 1 to 7% in retrospective studies assessing multiple outcomes.247,248 TE may occur anytime following Fontan procedures but often present months to years later. No predisposing factors have been identified with certainty, although this may be due to inadequate power and the retrospective nature of the studies. Transesophageal echocardiography is more sensitive than transthoracic echocardiography for the diagnosis of intracardiac and central venous thrombosis. 36–38 Despite aggressive therapy, TE following Fontan procedures have a high mortality, and respond to therapy in _ 50% of cases. There is no consensus in the literature, or in routine clinical practice, as to the optimal type or duration of antithrombotic therapy to prevent such events.165,246,249,250 Consequently a wide variety of prophylactic anticoagulant regimes are in use. There are very few studies that compare treatment options (Tables 13). There are a number of recent reviews of thromboprophylaxis following Fontan procedures and there is a large multicenter prospective trial of prophylactic anticoagulation therapy following Fontan procedures, which is nearing completion.247,248 The trial compares aspirin (5 mg/kg/d) to initial UFH followed by warfarin (target INR 2.5; range, 2.0–3.0) and primary prophylaxis, and results are expected in late 2007.
Recommendation: For children having endovascular stents inserted, we suggest administration of UFH perioperatively (Grade 2C).
Endovascular stents are used with increasing frequency in the management of congenital heart lesions including branch pulmonary artery stenosis, pulmonary vein stenosis, coarctation of the aorta, and to treat subsequent surgical stenosis.251 Although stents can be successfully used in infants _ 1 year of age, the small vessel size increases the risk of thrombosis. There are no studies assessing the role of anticoagulation or antiplatelet therapy to avoid stent occlusion in children. Clinicians commonly administer UFH at the time of stent insertion, followed by aspirin therapy. Further studies are required to determine optimal prophylactic anticoagulation after such procedures.
Recommendation: We suggest that pediatric patients with cardiomyopathy receive VKAs to achieve a target INR of 2.5 (range, 2.0 to 3.0) no later than their activation on a cardiac transplant waiting list (Grade 2C).
Underlying values and preferences: Our suggestion for administration of VKAs places a high value on avoiding thrombotic complications, and a relatively low value on avoiding the inconvenience, discomfort and limitations of anticoagulant monitoring in children who are eligible for transplant, which is a potentially curative therapy.
The etiology of cardiomyopathy in children is quite different to that seen in adults. Postviral and idiopathic cardiomyopathies occur in otherwise well children, whereas dilated cardiomyopathy occurs frequently during the end stage of muscular dystrophies. The outcome is frequently poor, and heart transplant, although potentially curative in many cases, is associated with long wait times.252–256 In a cross-sectional study of children awaiting cardiac transplant, 31% were said to have acute PE confirmed by ventilation/perfusion scan or angiography. 257 There are no studies of anticoagulant prophylaxis in pediatric patients. However, based on adult studies, and the apparent risk of PE and stroke in children with cardiomyopathy, primary prophylaxis with warfarin (target INR 2.5; range, 2.0 to 3.0) is often used.258
Recommendation: In children with primary pulmonary hypertension, we suggest anticoagulation with VKAs commencing when other medical therapy is commenced (Grade 2C).
There are relatively little specific data about the role of anticoagulant therapy as primary prophylaxis in children with pulmonary hypertension. However, based on adult data, and the basic pathophysiology of the disease, clinicians commonly administer anticoagulant prophylaxis. The ACCP guidelines for medical management of primary pulmonary hypertension in adults recommend routine anticoagulant prophylaxis with VKAs, although there is variation with respect to the target range recommended. The guidelines acknowledge that some centers use a target INR of 2.0 (range, 1.7–2.5), while others use target INR 2.5 (range, 2.0 –3.0). The ideal time to commence anticoagulant therapy in children is uncertain; however, simultaneous to the commencement of vasodilator or other medical therapy is common.259–261
Recommendation: For children with biological prosthetic heart valves, we recommend that clinicians follow the relevant recommendations from the adult population (see chapter by Salem et al in this supplement*).
Biological prosthetic heart valves may be surgically placed in infants and children with congenital or acquired heart disease when their innate tricuspid and/or pulmonary valve is not surgically repairable. 262 Mechanical valves are preferred for mitral and aortic replacement given the catastrophic consequences of valve failure in these anatomical positions. Patients with biological prosthetic heart valves are usually provided with an antiplatelet agent. Thromboembolic and bleeding events are uncommon with this therapy.263–267 There is no specific evidence describing optimal thromboprophylaxis in children with bioprosthetic heart valves, and as a result, clinicians should follow recommendations for adults in these circumstances (see chapter by Salem et al in this supplement).
Recommendation: For children with mechanical prosthetic heart valves, we recommend that clinicians follow the relevant recommendations from the adult population with respect to the intensity of anticoagulation therapy.
For children with mechanical prosthetic heart valves who have had thrombotic events while receiving therapeutic antithrombotic therapy, or in patients for whom there is a contraindication to full-dose VKAs, we suggest adding aspirin therapy (Grade 2C).
Mechanical prosthetic heart valves may be surgically placed in infants and children with congenital or acquired heart disease when their innate valve is not surgically repairable. Thrombotic complications associated with mechanical prosthetic heart valves are well described in adults. For this reason, clinicians generally use VKAs to prevent complications that include TE, valve thrombosis, and ischemic stroke. In children, optimal strategies for thromboprophylaxis for mechanical heart valves are less clear. Studies in children typically consists of retrospective case series, with many of the studies including small numbers of infants and children, a spectrum of age ranges, with varied valve positions and types. Antithrombotic regimens described to prevent TE complications range from no anticoagulation, to the use of antiplatelet agents, or VKA. The outcome events reported include TE (valve thrombosis and stroke), bleeding, and mortality (Table 14). The incidence of TE in children with mechanical valves is reported as high as 68% per patient-year in children who received aspirin,268 and 27% per patient-year for children who received no drug therapy.268 Bleeding, when reported, was extremely rare.136,267,269–274 When VKAs were prescribed, the incidence of TE was reduced, but there was an increased bleeding incidence.136,263,267,270,271,273–283 There are few prospective studies and no RCTs in children. Recommendations are therefore based on the strong evidence supporting anticoagulant thromboprophylaxis in adults and the available evidence in children.
Recommendation: For neonates and children requiring CC via an artery, we recommend administration of IV UFH prophylaxis (Grade 1A).
We recommend the use of UFH doses of 100 to 150 U/kg as a bolus (Grade 1B). We suggest further doses of UFH rather than no further therapy in prolonged procedures (Grade 2B).
We recommend against the use of aspirin therapy for prophylaxis for CC (Grade 1B).
The femoral artery is the most common access site for cardiac catheterization (CC). The development of thrombus at the puncture site and into the ileofemoral system is one of the serious complications of CC. Signs of femoral thrombosis range from a mild decrease in pulse strength as a result of partial obstruction by a thrombus to severe ischemia and potential loss of limb secondary to a significant interruption of arterial blood flow. Technical difficulty and increased catheter/artery size ratios increase the risk of femoral artery thrombosis. Arterial spasm may initially mimic femoral thrombosis but usually resolves within 4–6 h. Incidence: The incidence of femoral artery thrombosis after CC is approximately 40%,302,303 with younger children (ie, those _ 10 years of age) having an increased incidence compared to older children. 302,303 Arterial complications following CC are six times more likely to occur when balloon angiography or valvotomy is performed. Patient size, patient hemodynamic status, operator technique, larger catheter size and total time of arterial cannulation act together to create the risk for arterial thrombosis.304 Outcomes: Outcomes related to TEs following CC include short-term and long-term consequences. Short-term consequences of CC related thrombosis include threatened limb viability, and the morbidity associated with anticoagulant or thrombolytic therapy. Long-term consequences of femoral artery thrombosis likely reflect the effectiveness of the treatment provided and include leg-length discrepancies, muscle wasting, claudication, and loss of arterial access, which is important for children who require multiple CCs in the future.305 Symptomatic ischemia may occur at times when the child experiences rapid growth, as occurs in the first year of life and during puberty.305 Late complications of femoral artery catheterization can be clinically important. In a study by Taylor et al,306 58 children who were _ 5 years old at the time of catheterization were evaluated 5 to 14 years later using arterial duplex scanning and lower extremity radiographs of bone length. Arterial occlusion was present in 33% of patients. The mean ankle/brachial index in the catheterized limbs was 0.79, and leg growth retardation was present in 8% of children.306 Celermajer et al307 reports _ 30% of previously catheterized children and adolescents present with vascular access problems at subsequent catheterizations due to an occluded vessel, a stenosed vessel, or scar tissue. The practical implications of difficult access include prolonged access time, prolonged total catheter duration, and significant discomfort for patients studied under local anesthesia. Hurwitz et al308 evaluated 48 children in whom recatheterization was performed 6 months to 9 years following the initial CC. Complete occlusion of the femoral artery was present in 4 of 48 patients (8%), with extensive hypogastric collateralization reconstituting the femoral artery approximately 3 to 4 cm below the inguinal ligament.308 Evidence for Prophylaxis: Five prospective trials have examined the value of prophylaxis to prevent femoral artery thrombosis302,303,309–311 (Table 15). Freed et al302 demonstrated that prophylactic anticoagulation therapy with aspirin does not significantly reduce the incidence of femoral artery thrombosis. However, anticoagulation therapy with 100 to 150 U/kg unfractionated heparin (UFH) reduces the incidence from 40 to 8%. Although a more recent small randomized trial has suggested that a 50 U/kg bolus of heparin may be as efficacious as 100 U/kg when given immediately after arterial puncture, this study was underpowered, and a bolus of 50 U/kg cannot not be recommended as optimal prophylaxis at this time.311 Importantly, recent advances in interventional catheterization have resulted in the use of larger catheters and sheaths, which may increase the risk of thrombosis. Further heparin boluses or a constant infusion are frequently used in prolonged procedures (ie, _ 60 min), especially during interventional catheterizations, however, the benefits of this practice are not known.
* Monagle P, Chalmers E, Chan A, deVeber G, Kirkham F, Massicotte P, Michelson A. Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133;887S-968S.