Lee S. Benjamin
• 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
ARTERIAL THROMBOEMBOLISM [ATE]
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.
DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
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.41The 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
Frequently Cited Acquired Risk Factors for Thromboembolism
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 high65,66 (Fig. 44-1).
FIGURE 44-1. Diagnostic algorithm for deep vein thrombosis. DVT, deep vein thrombosis; US, ultrasound; CTV, computed tomogram venography; MRV, magnetic resonance venography.
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.69Scans 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
FIGURE 44-2. Diagnostic algorithm for pulmonary embolism. PE, pulmonary embolism; CXR, chest radiograph; V/Q, ventilation–perfusion; CTA, computed tomogram angiography.
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.91Thrombolysis 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.
CENTRAL VENOUS SINUS THROMBOSIS
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.96,97Anemia, 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).
1. Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124(4):1001–1008.
2. van Ommen CH, Heijboer H, Buller HR, Hirasing RA, Heijmans HS, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in the Netherlands. J Pediatr. 2001;139:676–681.
3. Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr. 2004;145(4):563–565.
4. Andrew M, David M, Adams M, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood. 1994;83(5):1251–1257.
5. Jackson BF, Porcher FK, Zapton DT, Losek JD. Cerebral sinovenous thrombosis in children: diagnosis and treatment. Pediatr Emerg Care. 2011;27(9):874–880.
6. Dlamini N, Billinghurst L, Kirkham FJ. Cerebral venous sinus (sinovenous) thrombosis in children. Neurosurg Clin N Am. 2010;21(3):511–527.
7. Friefeld SJ, Westmacott R, Macgregor D, Deveber GA. Predictors of quality of life in pediatric survivors of arterial ischemic stroke and cerebral sinovenous thrombosis. J Child Neurol. 2011;26(9):1186–1192.
8. Kuhle S, Massicotte P, Chan A, et al. Systemic thromboembolism in children. Data from the 1–800-NO-CLOTS Consultation Service. Thromb Haemost. 2004;92(4):722–728.
9. Yager PH, Singhal AB, Nogueira RG. Case records of the Massachusetts General Hospital. Case 31-2012. An 18-year-old man with blurred vision, dysarthria, and ataxia. N Engl J Med. 2012;367(15):1450–1460.
10. Bonduel M, Sciuccati G, Hepner M, et al. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. Acta Haematol. 2006;115(3–4):180–185.
11. Monagle P, Newall F, Barnes C, et al. Arterial thromboembolic disease: a single-centre case series study. J Paediatr Child Health. 2008;44(1–2):28–32.
12. Mackay MT, Wiznitzer M, Benedict SL, et al. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Ann Neurol. 2011;69(1):130–140.
13. Bowen MD, Burak CR, Barron TF. Childhood ischemic stroke in a nonurban population. J Child Neurol. 2005;20(3):194–197.
14. Srinivasan J, Miller SP, Phan TG, Mackay MT. Delayed recognition of initial stroke in children: need for increased awareness. Pediatrics. 2009;124(2):e227–e234.
15. Albisetti M, Schmugge M, Haas R, et al. Arterial thromboembolic complications in critically ill children. J Crit Care. 2005;20(3):296–300.
16. Suzuki A, Kamiya T, Kuwahara N, et al. Coronary arterial lesions of Kawasaki disease: cardiac catheterization findings of 1100 cases. Pediatr Cardiol. 1986;7(1):3–9.
17. Zheng D, Fan D, Liu L. Takayasu arteritis in China: a report of 530 cases. Heart Vessels Suppl. 1992;7:32–36.
18. Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood. 1984;64(6):1297–1300.
19. Egeberg O. An inherited hemorrhagic trait with characteristics resembling both mild hemophilia of type A and Von Willebrand’s disease. Scand J Clin Lab Invest. 1965;17(suppl 84):25–32.
20. Manco-Johnson MJ, Nuss R. Lupus anticoagulant in children with thrombosis. Am J Hematol. 1995;48(4):240–243.
21. Nowak-Gottl U, Dubbers A, Kececioglu D, et al. Factor V Leiden, protein C, and lipoprotein (a) in catheter-related thrombosis in childhood: a prospective study. J Pediatr. 1997;131(4):608–612.
22. Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995;345(8943):152–155.
23. Kosch A, Junker R, Kurnik K, et al. Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study. Thromb Res. 2000;99(6):531–537.
24. Tormene D, Simioni P, Prandoni P, et al. The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study. Blood. 2002;100(7):2403–2405.
25. Brightwell RE, Osman IS. Iliofemoral deep vein thrombosis in childhood; developing a management protocol. Eur J Vasc Endovasc Surg. 2006;31(6):667–678.
26. Bruins B, Masterson M, Drachtman RA, Michaels LA. Deep venous thrombosis in adolescents due to anatomic causes. Pediatr Blood Cancer. 2008;51(1):125–128.
27. Monagle P, Adams M, Mahoney M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res. 2000;47(6):763–766.
28. Manzoli L, De Vito C, Marzuillo C, Boccia A, Villari P. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf. 2012;35(3):191–205.
29. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ. 2011;343:d6423.
30. Jick SS. Risk of venous thromboembolism in oral contraceptive users varies according to progestin type. Evid Based Nurs. 2012;15(3):82–83.
31. Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. National center for Health Statistics. Vital Health Stat. 2010;23:29
32. Krishnamoorthy N, Simpson CD, Townend J, Helms PJ, McLay JS. Adolescent females and hormonal contraception: a retrospective study in primary care. J Adolesc Health. 2008;42(1):97–101.
33. Samková A, Lejhancová K, Hak J, Lukes A. Venous thromboembolism in adolescents. Acta Medica (Hradec Kralove). 2012;55(2):78–82.
34. Monagle P, Chan A, Massicotte P, Chalmers E, Michelson AD. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):645S–687S.
35. Paz-Priel I, Long L, Helman LJ, Mackall CL, Wayne AS. Thromboembolic events in children and young adults with pediatric sarcoma. J Clin Oncol. 2007;25(12):1519–1524.
36. O’Brien SH, Klima J, Termuhlen AM, Kelleher KJ. Venous thromboembolism and adolescent and young adult oncology inpatients in US children’s hospitals, 2001 to 2008. J Pediatr. 2011;159(1):133–137.
37. Marras LC, Geerts WH, Perry JR. The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer. 2000;89(3):640–646.
38. Tabori U, Beni-Adani L, Dvir R, et al. Risk of venous thromboembolism in pediatric patients with brain tumors. Pediatr Blood Cancer. 2004;43(6):633–636.
39. Azu MC, McCormack JE, Scriven RJ, Brebbia JS, Shapiro MJ, Lee TK. Venous thromboembolic events in pediatric trauma patients: is prophylaxis necessary? J Trauma. 2005;59(6):1345–1349.
40. Greenwald LJ, Yost MT, Sponseller PD, Abdullah F, Ziegfeld SM, Ain MC. The role of clinically significant venous thromboembolism and thromboprophylaxis in pediatric patients with pelvic or femoral fractures. J Pediatr Orthop. 2012;32(4):357–361.
41. Hanson SJ, Punzalan RC, Greenup RA, Liu H, Sato TT, Havens PL. Incidence and risk factors for venous thromboembolism in critically ill children after trauma. J Trauma. 2010;68(1):52–56.
42. David M, Andrew M. Venous thromboembolic complications in children. J Pediatr. 1993;123(3):337–346.
43. Vavilala MS, Nathens AB, Jurkovich GJ, Mackenzie E, Rivara FP. Risk factors for venous thromboembolism in pediatric trauma. J Trauma. 2002;52(5):922–927.
44. Mantadakis E, Plessa E, Vouloumanou EK, Michailidis L, Chatzimichael A, Falagas ME. Deep venous thrombosis in children with musculoskeletal infections: the clinical evidence. Int J Infect Dis.2012;16(4):e236–e243.
45. Kuhfahl KJ, Fasano C, Deitch K. Scapular abscess, septic emboli, and deep vein thrombosis in a healthy child due to community-acquired methicillin-resistant Staphylococcus aureus: case report. Pediatr Emerg Care.2009;25(10):677–680.
46. Lee EY, Tse SK, Zurakowski D, et al. Children suspected of having pulmonary embolism: multidetector CT pulmonary angiography-thromboembolic risk factors and implications for appropriate use. Radiology.2012;262(1):242–251.
47. Crary SE, Buchanan GR, Drake CE, Journeycake JM. Venous thrombosis and thromboembolism in children with osteomyelitis. J Pediatr. 2006;149(4):537–541.
48. Balint PV, Sturrock RD. Inflamed retrocalcaneal bursa and Achilles tendonitis in psoriatic arthritis demonstrated by ultrasonography. Ann Rheum Dis. 2000;59(12):931–933.
49. Christenson JT. Popliteal venous aneurysm: a report on three cases presenting with chronic venous insufficiency without embolic events. Phlebology. 2007;22(2):56–59.
50. Langsfeld M, Matteson B, Johnson W, Wascher D, Goodnough J, Weinstein E. Baker’s cysts mimicking the symptoms of deep vein thrombosis: diagnosis with venous duplex scanning. J Vasc Surg.1997;25(4):658–662.
51. Kane D, Balint PV, Gibney R, Bresnihan B, Sturrock RD. Differential diagnosis of calf pain with musculoskeletal ultrasound imaging. Ann Rheum Dis. 2004;63(1):11–14.
52. Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest. 1995;107(1):139–143.
53. Stein PD, Henry JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest. 1997;112(4):974–979.
54. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S–e801S.
55. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patient’s probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost.2000;83(3):416–420.
56. Kline JA, Nelson RD, Jackson RE, Courtney DM. Criteria for the safe use of D-dimer testing in emergency department patients with suspected pulmonary embolism: a multicenter US study. Ann Emerg Med. 2002;39(2):144–152.
57. Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med. 2001;161(1):92–97.
58. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349(13):1227–1235.
59. Rajpurkar M, Warrier I, Chitlur M, et al. Pulmonary embolism-experience at a single children’s hospital. Thromb Res. 2007;119(6):699–703.
60. Biss TT, Brandão LR, Kahr WH, Chan AK, Williams S. Clinical probability score and D-dimer estimation lack utility in the diagnosis of childhood pulmonary embolism. J Thromb Haemost.2009;7(10):1633–1638.
61. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med. 2004;351(11):1081–1088.
62. Palareti G, Legnani C, Cosmi B, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003;108(3):313–318.
63. Pomero F, Dentali F, Borretta V, et al. Accuracy of emergency physician-performed ultrasonography in the diagnosis of deep-vein thrombosis. A systematic review and meta-analysis. Thromb Haemost.2013;109(1):137–145.[CE5]
64. Tay ET, Stone MB, Tsung JW. Emergency ultrasound diagnosis of deep venous thrombosis in the pediatric emergency department: a case series. Pediatr Emerg Care. 2012;28(1):90–95.
65. Male C, Chait P, Ginsberg JS, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic antithrombin replacement in kids with ALL treated with Asparaginase. Thromb Haemost. 2002;87(4):593–598.
66. Qanadli SD, El Hajjam M, Bruckert F, et al. Helical CT phlebography of the superior vena cava: diagnosis and evaluation of venous obstruction. AJR Am J Roentgenol. 1999;172(5):1327–1333.
67. Uderzo C, Faccini P, Rovelli A, et al. Pulmonary thromboembolism in childhood leukemia: 8-years’ experience in a pediatric hematology center. J Clin Oncol. 1995;13(11):2805–2812.
68. Glaser JE, Chamarthy M, Haramati LB, Esses D, Freeman LM. Successful and safe implementation of a trinary interpretation and reporting strategy for V/Q lung scintigraphy. J Nucl Med.2011;52(10):1508–1512.
69. Gelfand MJ, Gruppo RA, Nasser MP. Ventilation-perfusion scintigraphy in children and adolescents is associated with a low rate of indeterminate studies. Clin Nucl Med. 2008;33(9):606–609.
70. Babyn PS, Gahunia HK, Massicotte P. Pulmonary thromboembolism in children. Pediatr Radiol. 2005;35(3):258–274.
71. Tsai KL, Gupta E, Haramati LB. Pulmonary atelectasis: a frequent alternative diagnosis in patients undergoing CT-PA for suspected pulmonary embolism. Emerg Radiol. 2004;10(5):282–286.
72. Kluge A, Luboldt W, Bachmann G. Acute pulmonary embolism to the subsegmental level: diagnostic accuracy of three MRI techniques compared with 16-MDCT. AJR Am J Roentgenol. 2006;187(1):W7–W14.
73. Stein PD, Chenevert TL, Fowler SE, et al. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med.2010;152(7):434–443.
74. Oudkerk M, van Beek EJ, Wielopolski P, et al. Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Lancet.2002;359(9318):1643–1647.
75. Pleszewski B, Chartrand-Lefebvre C, Qanadli SD, et al. Gadolinium-enhanced pulmonary magnetic resonance angiography in the diagnosis of acute pulmonary embolism: a prospective study on 48 patients. Clin Imaging.2006;30(3):166–172.
76. McDonald MM, Hathaway WE, Reeve EB, Leonard BD. Biochemical and functional study of antithrombin III in newborn infants. Thromb Haemost. 1982;47(1):56–58.
77. Andrew M, Marzinotto V, Massicotte P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res. 1994;35(1):78–83.
78. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med.1993;119(9):874–881.
79. Ignjatovic V, Najid S, Newall F, Summerhayes R, Monagle P. Dosing and monitoring of enoxaparin (low molecular weight heparin) therapy in children. Br J Haematol. 2010;149(5):734–738.
80. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest. 2001;119(1 suppl):344S–370S.
81. Gupta AA, Leaker M, Andrew M, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr. 2001;139(5):682–688.
82. Leary SE, Harrod VL, de Alarcon PA, Reiss UM. Low-dose systemic thrombolytic therapy for deep vein thrombosis in pediatric patients. J Pediatr Hematol Oncol. 2010;32(2):97–102.
83. Wang M, Hays T, Balasa V, et al. Low-dose tissue plasminogen activator thrombolysis in children. J Pediatr Hematol Oncol. 2003;25(5):379–386.
84. Manco-Johnson MJ, Grabowski EF, Hellgreen M, et al. Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2002;88(1):157–158.
85. Goldenberg NA, Branchford B, Wang M, et al. Percutaneous mechanical and pharmacomechanical thrombolysis for occlusive deep vein thrombosis of the proximal limb in adolescent subjects: findings from an institution-based prospective inception cohort study of pediatric venous thromboembolism. J Vasc Interv Radiol. 2011;22(2):121–132.
86. Dittrich S, Schlensak C, Kececioglu D. Successful thrombectomy of the superior vena cava thrombosis in a newborn after cardiopulmonary bypass surgery. Interact Cardiovasc Thorac Surg.2003;2(4):692–693.
87. Sur JP, Garg RK, Jolly N. Rheolytic percutaneous thrombectomy for acute pulmonary embolism in a pediatric patient. Catheter Cardiovasc Interv. 2007;70(3):450–453.
88. Raffini L, Cahill AM, Hellinger J, Manno C. A prospective observational study of IVC filters in pediatric patients. Pediatr Blood Cancer. 2008;51(4):517–520.
89. Goldenberg NA, Donadini MP, Kahn SR, et al. Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors. Haematologica. 2010;95(11):1952–1959.
90. Sharathkumar AA, Pipe SW. Post-thrombotic syndrome in children: a single center experience. J Pediatr Hematol Oncol. 2008;30(4):261–266.
91. Lyle CA, Gibson E, Lovejoy AE, Goldenberg NA. Acute prognostic factors for post-thrombotic syndrome in children with limb DVT: a bi-institutional cohort study. Thromb Res. 2013;131(1):37–41.
92. Goldenberg NA, Durham JD, Knapp-Clevenger R, Manco-Johnson MJ. A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of post thrombotic syndrome in children. Blood.2007;110(1):45–53.
93. Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost. 2004;91(4):719–724.
94. Dager WE, White RH. Low-molecular-weight heparin-induced thrombocytopenia in a child. Ann Pharmacother. 2004;38(2):247–250.
95. deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417–423.
96. Matsushige T, Nakaoka M, Kiya K, Takeda T, Kurisu K. Cerebral sinovenous thrombosis after closed head injury. J Trauma. 2009;66(6):1599–1604.
97. Sébire G, Tabarki B, Saunders DE, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128(Pt 3):477–489.
98. Habis A, Hobson WL, Greenberg R. Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia. Pediatr Emerg Care. 2010;26(11):848–851.
99. Ozsvath RR, Casey SO, Lustrin ES, Alberico RA, Hassankhani A, Patel M. Cerebral venography: comparison of CT and MR projection venography. AJR Am J Roentgenol. 1997;169(6):1699–1707.
100. Teksam M, Moharir M, Deveber G, Shroff M. Frequency and topographic distribution of brain lesions in pediatric cerebral venous thrombosis. AJNR Am J Neuroradiol. 2008;29(10):1961–1965.
101. Moharir MD, Shroff M, Stephens D, et al. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann Neurol. 2010;67(5):590–599.
102. Rammos SK, Phillips J, Lin J, Moresco K, Meagher S. Successful rheolytic mechanical thrombectomy of cerebral venous thrombosis in a pediatric patient. J Neurosurg Pediatr. 2013;11(2):140–143.
103. Biousse V, Ameri A, Bousser MG. Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999;53(7):1537–1542.
104. İncecik F, Hergüner MO, Altunbaşak S. Evaluation of sixteen children with pseudotumor cerebri. Turk J Pediatr. 2011;53(1):55–58.
105. Stienen A, Weinzierl M, Ludolph A, Tibussek D, Häusler M. Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension. Eur J Neurol. 2008;15(12):1416–1418.
106. Weesner CL, Cisek JE. Lemierre syndrome: the forgotten disease. Ann Emerg Med. 1993;22(2):256–258.