Thromboembolic events (TE) are increasingly recognized in children, with a 70% rise in diagnosis in tertiary children’s hospitals since 2001,¹ with an annual cost of over 90 million dollars² for pediatric patients. In Western countries the rate of venous thromboembolism (VTE) appears to be higher than Asian countries; both populations demonstrate a bimodal distribution, with neonates and adolescents at highest risk.^2–7 Deep vein thrombosis (DVT) is more common, with pulmonary embolism (PE) responsible for only 8% of pediatric VTE.⁵ Central venous sinus thrombosis (CVST) is a rare disease that carries high morbidity and mortality, and will be discussed separately.^8–10 Other locations of venous thrombosis are rarely reported.¹¹ Arterial thromboembolism (ATE) is more common in neonates and children with cardiac disorders, likely due to the use of umbilical artery catheters, cardiac catheters, ECMO circuits, and valvular disease; however, it is also reported in older children and adolescents.^12,13

RISK FACTORS

Risk factors for developing VTE assume two primary forms: inherited and acquired. Inherited thrombophilias such as protein C and S deficiencies,¹⁴ antithrombin deficiency,¹⁵ and the presence of lupus anticoagulant¹⁶ are considered high-risk states. Factor V Leiden disease, prothrombin mutation, elevated factor VIII, hyperhomocysteinemia, and others also add to the inherited risk.^17,18 Compared to adults with similar conditions, children present more commonly with unprovoked VTE, cerebral vascular events, and multiple VTEs, but less PE.¹⁹ Healthy children with a single thrombophilic trait rarely present with TE, but the risk increases with multiple traits or with the addition of acquired risk factors.^20,21 Congenital venous anomalies also predispose to VTE.^22,23

Acquired risk factors are numerous. The most consistent risk factor for VTE is central venous catheter (CVC) placement. In neonatal TE, 65% to 90% are catheter related, and 64% of non-neonatal TE is associated with CVCs.^12,24 Oral contraceptives are well known to increase VTE risk,^25–28 with effects persisting up to 3 months after use.²⁹ In a study of VTE in adolescents, 75% of females with VTE were using oral contraceptives, yet they all had one or more additional risk factor³⁰—commonly obesity, which is an independent risk factor.^28,31–33 The new drospirenone-containing contraceptives increase the risk for VTE even further.³⁴ Other commonly cited acquired risk factors are listed in Table 45-1. Among medical conditions, the most concerning risk factor is cancer.³⁵ Both acute leukemia and sarcoma carry high risk of VTE.^14,36,37 Contrary to the high adult VTE rate in brain cancer,³⁸ children with brain tumors have less than 1% incidence of clinically apparent TE.³⁹ Although cancer is an identified high risk feature, the overall rate of VTE in pediatric cancer patients remains low, at 1 to 2 per 1000 patients per year.⁴⁰ In the adolescent population, obesity and infection become important risk factors. Obesity is present in nearly half of adolescents with VTE.⁴¹ Musculoskeletal infections, primarily community acquired methicillin-resistant Staphylococcus aureus osteomyelitis, are associated with DVT development.^42,43 Hospitalized pediatric patients with S. aureus bacteremia, especially with resistant strains, are more likely to develop VTE, increasing mortality.⁴⁴ VTE appears to be quite rare in pediatric trauma, with most reports documenting incidence between 0.06% and 0.18%, with adolescent patient incidence rising to just less than 1%.^45–48 In a study specific to traumatic brain injury (TBI), incidence was also low, at 0.45%, yet charges were nearly $240,000 higher per patient than non-VTE cases.⁴⁹ The highest risk factors for trauma patients include spinal cord injury, major vascular injury, older age, CVC placement, nonaccidental trauma, prolonged length of stay, immobility, poor perfusion, increased need for critical interventions, and operative interventions.^47–52 Prior DVT/PE for any reason increases risk for recurrent disease.⁵³

DIAGNOSIS

Clinical Presentation

The first challenge of diagnosing VTE is clinical suspicion. In many children, VTE is not suspected but is found on routine management of common conditions.⁵⁴ It is impossible to know if a patient has underlying inherited risk factors if they have not had a previous event or thrombophilia evaluation. If a patient presents with signs or symptoms of VTE, a thorough search for predisposing conditions is warranted, including obtaining a thorough family history.

Clinically DVT presents as pain, swelling, and erythema of the involved extremity. The differential diagnosis includes musculoskeletal injury, tumor, infection, arteriovenous malformation, and cystic lesions including Baker’s cyst in the lower extremity.^55–58 In contrast to adults, DVT in children commonly occurs in the upper extremity, correlating strongly with the common locations of CVCs.¹² Very rarely, thrombosis may lead to complete venous occlusion, leading to elevated compartment pressures and limb threatening phlegmasia cerulea dolens, evidenced by edema, pain, and potentially tissue necrosis.⁵⁹ PE provides an even more complicated scenario. Even when well studied in adults, a significant proportion of patients lack some of the characteristic clinical findings of pleuritic chest pain, shortness of breath, tachycardia, tachypnea, hypoxia, and signs or symptoms of DVT.^60,61

Although prediction rules guide evaluation for VTE in adult populations^62,63 and are being studied in trauma and other hospitalized pediatric patients,^50,64–66 no prospectively validated clinical decision rule or diagnostic paradigm exists to direct the evaluation for VTE in pediatric emergency department patients. Although initial retrospective studies suggest they are feasible,^2,53,67 further work remains.

Laboratory Testing

Baseline CBC, electrolytes, PT, PTT, and type and screen should be considered for a patient with VTE requiring treatment. The serum D-dimer test assesses for fibrin breakdown products and is commonly used in adults to rule out VTE in combination with a low-pretest probability.^63,68–70 It should not be relied on as a pediatric screening test, as 40% of pediatric patients with proven VTE have negative assays.^71,72 Once VTE is established, persistently elevated D-dimer levels do predict risk of further events or complications.^73,74 Anti-Xa activity may be used to monitor and adjust anticoagulation with both unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) but is not helpful in initial management.⁷⁵ A thrombophilia workup can proceed after emergency department evaluation.

Imaging

DVT diagnosis is historically based on imaging with ultrasound (US), yet pitfalls remain. US is the most commonly accepted initial imaging modality, based on technical ease, noninvasive nature of the test, lack of radiation exposure, and high sensitivity in the lower extremities.^76,77 US is also effective in the neck and upper extremities; however, sensitivity drops to 37% in the upper extremity due to skeletal structures obscuring the subclavian vein, brachiocephalic vein, and superior vena cava. Other studies for DVT include CT venogram, MR venogram, and conventional venography, and should be considered if US is unable to visualize thrombus and clinical suspicion remains high^78,79 (Fig. 45-1).

Advanced imaging studies remain the mainstay of diagnosis for PE. Use of either ventilation–perfusion (V/Q) lung scans or CT angiogram imaging is appropriate as a first-line investigation. Few studies with V/Q consider the pediatric population; however, very low false negative rates are reported. A negative V/Q or perfusion-only scan rules out PE and exposes the patient to a significantly smaller amount of radiation than CT.^80,81 Scans with perfusion defects should be assumed to be PE, as most pediatric patients lack chronic pulmonary diseases.⁸² V/Q scans in children and adolescents are associated with a low rate of indeterminate studies compared with adults.⁸¹ Therefore, if a patient does not have an underlying pulmonary process, a chest radiograph is void of significant disease, the patient is hemodynamically stable and able to comply, and reliable interpretation is available, a V/Q or perfusion-only nuclear study may be considered as the initial imaging study for PE. If the study is nondiagnostic, further imaging should be obtained, which may provide other useful information⁸³ (Fig. 45-2). MRI has been used to evaluate PE in adults with mixed results.^84–86 MRI has poor sensitivity in children, and cannot be recommended for first-line use.^87,88 Echocardiography, including point of care performed by emergency personnel, may reveal right heart dysfunction consistent with pulmonary embolism.⁸⁹

Treatment

The mainstay of treatment for VTE is anticoagulation to prevent further clot formation, and should be done in conjunction with a pediatric hematologist when possible. Anticoagulation is achieved acutely with UH or LMWH, followed by longer-term anticoagulation with either LMWH or vitamin K antagonists, depending on the clinical scenario. Heparin dosing in children is not well studied, with limited studies in neonates and pediatric oncology patients with CVCs, not showing a mortality benefit.^90,91 Despite the lack of data, heparin remains the acute anticoagulant of choice due to familiarity and lack of alternatives. Recognizing the limitations of the data, the American College of Chest Physicians (ACCP) recommend initial bolus dosing of UFH of 75 to 100 units/kg.⁷⁵ Doses vary with patient age. The LMWHs enoxaparin and dalteparin have been studied in multiple venues and proven safe in treatment of VTE in the pediatric population. Prevention of recurrent VTE is less clear with research both supporting^92,93 and questioning efficacy.⁹⁴ Significant variation in response between age groups compounds dosing difficulties, suggesting that anti-Xa activity monitoring is crucial in management beyond the ED.⁹⁵ Fondaparinux is a synthetic heparin alternative with small studies supporting once-a-day use in the pediatric population.^96,97

Direct oral anticoagulants (DOACs), including factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban, and others, as well as direct thrombin inhibitors (DTIs) such as dabigatran and argatroban, have become commonplace in adult VTE management. Other than argatroban,⁹⁸ these medications lack support for pediatric dosing, safety, and efficacy,^99,100 and are not FDA approved for pediatric use. A common concern for emergency providers using these types of anticoagulants is major hemorrhage and lack of a reversal agent. Reversal mechanisms are not widely available for these agents; however, options include prothrombin complex concentrate (PCC), activated PCC, and recombinant factor VIIa.⁹⁹ Specific reversal agents are under evaluation, such as andexanet, a recombinant factor Xa decoy.¹⁰¹ Studies regarding DOACs are ongoing in the pediatric population.¹⁰²

Thrombolytics are effective in the pediatric population, but not without risk at higher doses. Tissue plasminogen activator (tPA), the most studied thrombolytic for children, can be given continuously for the treatment of arterial thrombosis, extensive or dangerous DVT, or massive PE.^35,103 Major complications associated with tPA therapy occur in 40% of patients receiving high systemic medication at rates of 0.1 to 0.5 mg/kg/h. Predictors of major complications include higher dose, significantly longer duration of tPA therapy, and a greater decline in post-tPA fibrinogen levels.¹⁰⁴ Low-dose continuous infusions (0.03–0.06 mg/kg/h) are effective in treating acute thrombosis in children, with only minor bleeding common at this rate, but life-threatening hemorrhage is rare.¹⁰⁵ Escalating regimens, starting at low dose and increasing if needed, have also reported success.^106–108 The coadministration of heparin is necessary, as tPA does not inhibit clot propagation or alter hypercoagulability.^106,109 Local catheter–directed thrombolysis with or without mechanical thrombectomy has been described.^110,111 The ACCP recommends thrombolysis with tPA only for limb- or life-threatening thrombosis, with systemic treatment preferred to local unless there is significant institutional experience with catheter-directed thrombolysis.⁷⁵ See Table 45-2 for dosing recommendations for anticoagulants and thrombolytic therapy.^{75,96–98,104–107,112–117}