Chapter 44: Thromboembolic Disease

• The single greatest risk factor for thromboembolic disease in children is an indwelling central venous catheter.

• Disease patterns for pulmonary embolism in children and adolescents are similar to those in adults, yet diagnosis and management is often delayed or inappropriate.

• Arterial thromboembolism 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.

• Anticoagulation is achieved acutely with unfractionated heparin (UH) or low-molecular-weight heparin (LMWH), followed by long-term anticoagulation with either LMWH or warfarin.

Thromboembolic events (TE) are increasingly recognized in children, with a 70% rise in diagnosis in tertiary children's hospitals since 2001.¹ There is a bimodal distribution, with neonates and adolescents at highest risk.^2–7 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.^8,9 Arterial stroke is discussed further in Chapter 57.

Deep vein thrombosis (DVT) is the most common venous thromboembolism (VTE) with pulmonary embolism (PE) responsible for only 8% of pediatric VTE.⁴ Central venous sinus thrombosis (CVST) is a rare disease that is potentially fatal and leads to significant morbidity in survivors.^5–7

ATE leads to higher morbidity and mortality than VTE.^10,11 About 9% to 22% of pediatric patients with ischemic stroke have no identifiable underlying risk factors.^12,13 Initial diagnosis is challenging, with median time to diagnosis of stroke taking over 24 hours in children and 88 hours in neonates, likely due to lack of initial consideration of the diagnosis.¹⁴ Among critically ill children, 96% of ATE is related to catheter usage.¹⁵ Noncatheter-related ATE occur in patients with underlying hematologic risk factors similar to those correlated with VTE and include organ transplantation and vasculitides such as Kawasaki disease and Takayasu arteritis.^16,17 Complications of ATE include death, stroke, limb loss, and dysfunction of the involved distal organs.

Risk Factors

Risk factors for developing VTE assume two primary forms: inherited and acquired. Inherited thrombophilias such as protein C and S deficiencies,¹⁸ antithrombin deficiency,¹⁹ and the presence of lupus anticoagulant²⁰ are considered high-risk states. Factor V Leiden disease, prothrombin mutation, elevated factor VIII, hyperhomocysteinemia, and others also add to the inherited risk.^21,22 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.^23,24 Congenital venous anomalies are also predisposing risk factors for DVT.^25,26

Acquired risk factors are numerous. The most consistent risk factor for new VTE is central venous catheter placement. In neonatal TE, 65% to 90% are catheter related, and 64% of non-neonatal TE is associated with central venous lines.^8,27 Oral contraceptive use is associated with increased risk.^28–30 Fifteen percent of American females aged 15 to 19 use oral contraceptives³¹ compared with 40.5% in Scotland.³² 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 factor.³³ Other commonly cited acquired risk factors are listed in Table 44-1. Among medical conditions, lupus and congenital heart disease are significant risk factors, yet the most concerning risk factor is cancer.³⁴ Both acute leukemia and sarcoma carry high risk of VTE.^18,35,36 Contrary to the high adult VTE rate in brain cancer,³⁷ children with brain tumors have clinically apparent TE incidence of less than 1%.³⁸ VTE appears quite rare in pediatric trauma with only 0.06% incidence in children younger than 17 years of age.^39,40 However, one recent single-site study reported up to 6.2% incidence, with most children having poor perfusion, immobility, and a central line.⁴¹ The highest traumatic risk factors for VTE include spinal cord injury, major vascular injury, older age, central line placement, and operative interventions.^42,43 Musculoskeletal infections, primarily community acquired methicillin-resistant Staphylococcus aureus osteomyelitis, are also associated with DVT development.^44,45 Prior DVT/PE is also a known risk factor for recurrent disease.⁴⁶

Diagnosis

Clinical Presentation

The first challenge of diagnosing DVT/PE is clinical suspicion. In many children, DVT/PE is not suspected, but found on routine management of common conditions.⁴⁷ Furthermore, it is impossible to know if a patient has underlying inherited risk factors for VTE 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 family history of VTE.

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.^48–51 In contrast to adults, DVT in children commonly occurs in the upper extremity, correlating strongly with the common locations of central venous catheters.⁸

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.^52,53 No validated paradigm exists to direct the evaluation for PE in pediatric patients.

Laboratory Testing

Baseline CBC, electrolytes, PT, PTT, and type and screen should be considered for a patient with VTE requiring treatment. Anti-Xa activity is used to monitor and adjust anticoagulation with both unfractionated heparin (UH) and low-molecular-weight heparin (LMWH), but is not helpful in the initial evaluation.⁵⁴ The serum d-dimer test assesses for fibrin breakdown products, and is commonly used in adults to rule out DVT/PE in combination with a low-pretest probability.^55–58 It should not be relied on as a pediatric screening test as 40% of pediatric patients with proven VTE have negative assays.^59,60 Once VTE is established, persistently elevated d-dimer levels do predict risk of further events or complications.^61,62 A thrombophilia workup can proceed after emergency department evaluation.

Imaging

DVT diagnosis is historically based on imaging with either ultrasound (US) or venogram, yet pitfalls remain. US is the most commonly accepted initial imaging modality, based on technical ease and noninvasive nature of the test.^63,64 Sensitivity in the lower extremities is high, therefore US is the typical diagnostic tool. US is also effective in the neck and upper extremities; however, sensitivity drops as low as 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, conventional venography, and echocardiogram, and should be considered if US is unable to visualize thrombus and clinical suspicion remains high^65,66 (Fig. 44-1).

Advanced imaging studies remain the mainstay of diagnosis for PE.⁶⁷ Use of either ventilation–perfusion (V/Q) lung scans or CT imaging may lead to the diagnosis. Few studies with V/Q consider the pediatric population, however very low false-negative rates are reported.⁶⁸ A negative V/Q or perfusion only scan rules out PE and exposes the patient to a significantly smaller amount of radiation than CT.⁶⁹ Scans with perfusion defects should be assumed to be PE as most pediatric patients lack chronic pulmonary diseases.⁷⁰ V/Q scans in children and adolescents are associated with a low rate of indeterminate studies compared with adults;⁶⁹ therefore, if a chest radiograph is void of significant disease, and the patient is hemodynamically stable and able to comply, it is the author's opinion that V/Q, or a perfusion only nuclear study, should be the initial advanced imaging study for PE. If the study is nondiagnostic, further imaging with CT should be obtained, which may provide other useful information.⁷¹ Pulmonary angiography remains an option as well⁶⁷ (Fig. 44-2). MRI has been used to evaluate PE in adults with mixed results.^72,73 MRI has poor sensitivity in children, and cannot be recommended for first-line use.^74,75

Treatment

The mainstay of treatment in DVT/PE 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; however, infants appear to require higher doses per unit body weight than do older children due to physiologically low levels of antithrombin.⁷⁶ The American College of Chest Physicians recently reviewed the antithrombotic literature, and recommend initial bolus dosing of UFH of 75 to 100 units/kg, recognizing limited pediatric data.⁵⁴ Maintenance infusions are suggested as 28 units/kg in children <1 year of age, 20 units/kg in children over 1 year of age,⁷⁷ and 18 units/kg in adolescents.⁷⁸ Initial treatment doses of LMWH vary based on age as well. Enoxaparin, for example, is recommended to be given as 1 mg/kg/dose every 12 hours if older than 2 months, but 1.5 mg/kg/dose every 12 hours if under 2 months.⁵⁴ The difficulty in dosing is compounded by recent studies suggesting even more variation between age groups, suggesting that anti-Xa activity monitoring is crucial in achieving appropriate anticoagulation with enoxaparin.⁷⁹

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 DVT, or massive PE.^34,80 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.⁸¹ 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. Escalating regimens, starting at low dose and increasing if needed, have reported success as well.^82,83 The coadministration of heparin is necessary as tPA does not inhibit clot propagation or alter hypercoagulability.^83,84 Local catheter–directed thrombolysis with mechanical thrombectomy has been described as well.⁸⁵ 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.⁵⁴

Surgical interventions are another treatment modality for TE. Authors report both open thrombectomy and catheter aspiration thrombectomy in the pediatric literature.^86,87 Inferior vena cava filters have also been used successfully in pediatric patients, primarily when contraindications to anticoagulation exist.⁸⁸

Complications

Complications of thromboembolism are common. Mortality directly attributable to VTE has been reported as 2% to 9%.^4,27 As many as 18.5% of patients have recurrent thrombosis, and up to 63% develop post-thrombotic syndrome (PTS), clinically described as chronic extremity swelling and pain likely due to venous insufficiency resulting from DVT-induced valvular damage.^27,89 Risk of developing PTS rises with high levels of d-dimer,⁶¹ delay of more than 48 hours to diagnosis and treatment of DVT, multiple recurrences of DVT,⁹⁰ and the presence of circulating lupus anticoagulant.⁹¹ Thrombolysis may significantly decrease the development of PTS.⁹² A complication of treatment, heparin-induced thrombocytopenia (HIT), is reported primarily in children undergoing anticoagulation with UH, yet there are case reports of children developing HIT while using LMWH as well.^93,94

In summary, DVT and PE are becoming more commonly recognized in the pediatric population. Those at high risk commonly have indwelling central catheters, as well as other inherited or acquired predisposing diseases. Clinicians must have high index of suspicion for these diagnoses, be familiar with the limitations of laboratory and imaging techniques, and must be able to initiate appropriate therapy in conjunction with pediatric hematology.

CVST is a rarely reported form of venous thrombosis that carries significant morbidity and mortality. Approximately 40% occur in the first month of life.⁹⁵ Risk factors include many of the same underlying processes as other VTE, yet significant dehydration, closed head injury, preexisting intracranial pathology, and infectious processes such as otitis media, mastoiditis, and sinusitis play a significant role.^96,97 Anemia, including iron-deficiency anemia, is also a suggested risk factor.⁹⁸ Clinical presentation varies from subacute headache, vomiting, and decreased level of consciousness to ataxia, hemiparesis, focal cranial nerve deficits, seizure, and coma.^95,97 Diagnosis requires high index of suspicion and appropriate neuroimaging. Although the classic “empty delta” sign of sagittal sinus thrombosis can be seen on noncontrast CT, CT venogram or MR venogram is the most appropriate study to evaluate for CVST, although no direct comparisons have been made in the pediatric population.^99,100

Treatment relies on treating the primary insult, such as antibiotics and surgery for mastoiditis, supporting hydration status, managing seizures, and initiating anticoagulation therapy (ACT), even in the setting of minor obstruction-related intracranial hemorrhage (ICH). Although pre-anticoagulation ICH predicts increased risk of major ICH while anticoagulated, patient outcomes were not significantly worse in this population.¹⁰¹ Overall outcomes were improved with ACT, leading the ACCP to recommend anticoagulation in patients with CVST without significant ICH.⁵⁴ Mechanical thrombectomy has also been reported in the management of pediatric CVST.¹⁰²

Survivors are commonly neurologically intact, but many will have significant neurologic deficits. Poor outcome is predicted by seizures in non-neonates and presence of infarcts.⁹⁵ Improved outcomes occur in patients with lateral or sigmoid sinus involvement, yet these locations also increase the likelihood of developing pseudotumor cerebri.^97,103 In two small series of children with initially diagnosed pseudotumor cerebri, 12% to 55% of patients had CVST on follow-up imaging.^104,105 It is unclear if CVST is a cause of pseudotumor cerebri, or if it is a result of primary increased intracranial pressure. Recurrence of VTE in patients with previous CVST is not uncommon, and is frequently systemic.⁹⁵

Other VTE that may be encountered include renal vein, inferior vena cava (IVC), and right atrium thrombosis. The prior presents with flank mass, pain, hematuria, thrombocytopenia, and hypertension. IVC thrombosis may present with bilateral lower extremity swelling, pallor, cyanosis, or pain, and is associated with significant long-term disease. Cardiac thrombus is associated with catheter malfunction and congestive heart failure. All of these processes are most common in ill neonates and infants who have indwelling catheters. In otherwise healthy adolescents however, oropharyngeal infections can lead to Lemierre's disease, thrombophlebitis of the internal jugular vein that carries significant morbidity and mortality.¹⁰⁶ US remains the standard imaging modality for evaluating these pathological processes (see Chapter 96).