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Keywords:

  • anticoagulation;
  • childhood;
  • paediatric thrombosis;
  • thrombophilia;
  • thrombosis (venous)

Summary

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

Pulmonary embolism (PE) is rare in childhood but evidence suggests it is under-recognised. Children diagnosed with PE at a large tertiary centre over an 8-year period were retrospectively reviewed. Fifty-six children with radiologically proven PE were identified, 31 males and 25 females, median age 12 years. Eighty-four per cent had symptoms of PE. Risk factors for thromboembolism were present in 54 patients (96·4%); most commonly immobility (58·9%), central venous line (35·7%) and recent surgery (28·6%). Investigation revealed a thrombophilic abnormality in 14/40 patients (35%). Concurrent deep vein thrombosis was confirmed in 31 patients (55·4%), predominantly lower limb. D dimer was elevated at presentation in 26/30 patients (86·7%). Eight patients underwent systemic thrombolysis. An inferior vena cava filter was placed in five patients. Therapy was complicated by major haemorrhage in 12 patients (21·4%). The majority (82·1%) had complete or partial resolution of PE following a median of 3 months anticoagulation. Seven patients had a recurrent thromboembolic event and 12 patients died (mortality 21·4%); five due to thromboembolism (8·9%) and two due to haemorrhage. Risk factors for PE in children are distinct from adults and morbidity and mortality is significant. Multicentre prospective studies are required to determine optimal treatment and long-term outcome of childhood PE.

Pulmonary embolism (PE) is not an uncommon occurrence in adulthood but is a rare event in children. Paediatric registry data has reported the annual incidence of childhood PE as 0·86 per 10 000 hospital admissions (Andrew et al, 1994) and 0·14–0·9 per 100 000 children (Van Ommen et al, 2001; Stein et al, 2004). PE is characteristically seen in children with serious underlying medical disorders and its incidence is likely to rise with the increasingly successful treatment of previously fatal conditions, such as congenital cardiac malformations, prematurity and malignancy. There is also an association with the use of central venous catheters (Massicotte et al, 1998) that are often relied upon for the administration of drugs, parenteral nutrition and chemotherapy.

The masking of symptoms by those of underlying disease states, accompanied by a low index of suspicion in the physician, has resulted in under-diagnosis of PE in the paediatric setting as evidenced by the incidence of up to 4·2% seen in autopsy studies (Buck et al, 1981). Failure to diagnose and treat PE promptly can have serious consequences. Mortality rates of PE in childhood are reported to be around 10% (Andrew et al, 1994; Van Ommen et al, 2001). Morbidity in the form of symptomatic thromboembolic pulmonary hypertension is seen in 3·8% of adults at 2 years (Pengo et al, 2004). The long-term implications of PE in childhood are currently unknown.

Due to the small numbers of evaluable patients, approaches to diagnostic imaging and treatment in childhood PE have mostly been extrapolated from the results of adult studies. The duration of anticoagulant therapy and the role of thrombolytic agents are not well defined (Van Ommen & Peters, 2006).

This retrospective study is the largest descriptive cohort of children presenting to a single centre with PE. In describing the clinical features, this study will lead to a better understanding of childhood PE in terms of presenting features, diagnosis, management and outcome.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

Identification of cases and collection of clinical data

Ethical approval for the study was obtained from the Research Ethics Board at The Hospital for Sick Children, Toronto, Canada. Children with radiologically proven PE were identified from radiology department records, by combination of a previously studied cohort (Babyn et al, 2005) and patients identified by searching for the term ‘pulmonary embolism’ in electronic reports of relevant diagnostic investigations [ventilation-perfusion (V/Q) scan, spiral CT pulmonary angiography (CTPA) and conventional pulmonary angiography]. Imaging criteria for PE within this institution have been described previously (Babyn et al, 2005). Charts were reviewed for demographic data, details of presenting symptoms and risk factors for venous thromboembolism (VTE). Time from presentation with symptoms to diagnosis, D dimer level at presentation and imaging used to confirm the diagnosis were recorded. Treatment modality and duration, in addition to complications of anticoagulant therapy, were also recorded. Outcome in terms of survival, resolution of PE and recurrent thrombotic events were evaluated.

Thrombophilia screening and D dimer measurement

All patients undergoing thrombophilia screening were tested for levels of functional antithrombin, functional protein C, protein S antigen, factor VIII, factor IX, factor XI, lipoprotein (a) and homocysteine. Platelet-poor plasma was investigated for the presence of a lupus anticoagulant using partial thromboplastin time (PTT) as a screening test and dilute Russell’s viper venom time (DRVVT) with platelet neutralisation as a confirmatory test. Serum was tested for the presence of anticardiolipin antibodies. Genetic analysis for factor V Leiden (F5 R506Q) mutation and the prothrombin gene mutation (F2 G20210A) was undertaken. Testing was performed at the end of treatment in the majority of cases. If testing occurred at an earlier time-point, abnormal values were repeated following cessation of anticoagulant therapy. D dimer was measured by quantitative assay at the time of presentation with PE; Turbiquant® D-dimer (Dade Behring, Deerfield, IL, USA), September 1999–July 2003; D-dimer PLUS (Dade Behring), July 2003–December 2005; HemosILTM D dimer HS (Instrumentation Laboratory, Richmond Hill, ON, Canada), December 2005–January 2007.

Definition of major haemorrhage

Major haemorrhage was defined as bleeding requiring immediate transfusion of red blood cells, resulting in a fall in haemoglobin concentration of ≥20 g/l within the first 24 h, or sufficient to require cessation of anticoagulant therapy for a period of 24 h or longer. All intracranial and retroperitoneal bleeding events were deemed to be significant. Minor bleeding events, such as bleeding from intravenous sites, surgical wounds and mucous membranes, or small amounts of blood in urine or stool were not recorded.

Definition of complete/partial resolution of PE and recurrence

Patients underwent repeat imaging studies, using the imaging technique that had confirmed the initial diagnosis, at the end of treatment. In some cases, such as those who received systemic thrombolysis, imaging was repeated sooner. Response to anticoagulant and thrombolytic therapy was defined as: complete, imaging studies returned to normal; partial, reduction in the amount of thrombus seen but without complete resolution; no response, appearances on imaging unchanged. Diagnosis of recurrent PE was based on comparison with prior imaging and required new vessel involvement.

Results

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

Demographic details of children presenting with PE

Fifty-six children were studied, presenting consecutively over an 8-year period from 16th September 1999 to 15th January 2007. Median follow-up time was 56·2 months (range: 5–93 months). There were 31 males (55·4%) and 25 females (44·6%), with a median age of 12 years (range: 1 d–17 years). Two peaks in age at presentation were seen, less than 1 year of age and in adolescence. Summary data are shown in Table I and are discussed in the following text.

Table I.   Summary of outcome data for 56 children with PE according to age and underlying diagnosis.
 Number of patientsMedian age, years (range)Major haemorrhage on anticoagulant therapy (%)Partial/complete resolution of PE on repeat imaging (%)Recurrent thrombotic event (%) Mortality (%)
Age
 <1 year90·3 (01–0·5)3 (33·3)6/8 (75)1 (11·1)5 (55·6)
 ≥1 year4714 (1–17)9 (19·1)40/42 (95·2)6 (12·8)7 (14·9)
Underlying diagnosis
 Congenital heart disease153 (0–17)7 (46·7)12/14 (85·7)3 (20)7 (46·7)
 Malignancy1012·5 (2–16)0 (0)8/9 (88·9)1 (10)3 (30)
 Neither3114 (0–17)5 (16·1)26/27 (96·3)3 (9·7)2 (6·5)

Clinical features at time of presentation with PE

Eighty-four per cent of patients had symptoms or signs of PE. The most frequent symptoms were shortness of breath (57·1%) and pleuritic chest pain (32·1%). Twenty-four patients (42·9%) were hypoxemic and four (7·1%) presented with acute cardiovascular collapse. Additional signs included persistent unexplained tachycardia and fever. Sixteen patients (28·6%) had symptoms of deep vein thrombosis (DVT) at presentation. Nine asymptomatic patients were diagnosed with PE during investigation of DVT or due to computerised tomography (CT) of the chest performed for other reasons, such as staging of malignancy. Forty-one patients (73·2%) were inpatients at the time of onset of symptoms, the remaining patients presented to the emergency department. Diagnosis was made at a median of 1 d after onset of symptoms (range: 0–19 d).

Risk factors for VTE in children presenting with PE

Underlying diagnosis.  The commonest underlying diagnosis was congenital heart disease in 15 patients (26·8%). Seven of these patients were less than 1 year of age. Ten patients (17·9%) had malignancy, including two patients with acute lymphoblastic leukaemia. Advanced or recurrent disease was documented in four of these patients at the time of presentation with PE. Four patients (7·1%) had nephrotic syndrome and two had Wegener granulomatosis. Additional diagnoses included venous malformation of the lower limb (2), systemic lupus erythematosis (1), ulcerative colitis (1), thrombotic thrombocytopenic purpura (1), Varicella-Zoster virus infection (1), septic arthritis of the hip (1) and severe haemophilia A with allo-immune inhibitor (Carcao et al, 2003) (1). Seven patients (12·5%) had no significant underlying diagnosis.

Thrombotic risk factors.  Identified risk factors for VTE at the time of presentation with PE are shown in Fig 1A. The most frequent risk factors were immobility (defined as bed rest, except for access to the bathroom, for ≥3 consecutive days in the 4 weeks prior to PE diagnosis) in 58·9% of patients (55·4% of non-neonates), presence of a central venous catheter in 35·7% and recent surgery (defined as surgical procedure requiring general anaesthesia in the 4 weeks prior to PE diagnosis) in 28·6%. Forty-two (75·0%) had two or more risk factors for VTE at presentation (Fig 1B). Two patients (3·6%) had no identified clinical or laboratory risk factor.

image

Figure 1.  Risk factors for VTE at presentation with PE by individual risk factor (A) and number of risk factors (B). DVT, deep vein thrombosis; OCP, oral contraceptive pill; VTE, venous thromboembolism; *Other risk factors refer to venous malformation of the lower limb (two patients), trauma, ulcerative colitis and thrombotic thrombocytopenic purpura.

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Thrombophilia screening.  Forty patients underwent testing for inherited and acquired thrombophilia (median age: 13 years). Persistent thrombophilic abnormalities were identified in 13 patients, with transient protein S deficiency following Varicella-Zoster virus infection in one (Table II). Four cases had positive Ig G anticardiolipin antibodies (titre of >15) on at least two occasions with at least 3 months between tests. Of these individuals, one had a persistent lupus anticoagulant, detected by DRVVT with platelet neutralisation test, on three occasions. Of the nine patients less than 1 year of age, three underwent thrombophilia screening with normal results.

Table II.   Demographics, personal history, family history of VTE and recurrence data in 14 children presenting with PE found to have a thrombophilic abnormality.
SexAge, yearsClinical scenarioThrombophilic abnormalityThrombophilia test results, age-adjusted normal rangePersonal history of VTEFamily history of VTERecurrent thrombotic event
  1. VTE, venous thromboembolism; OCP, oral contraceptive pill; DVT, deep vein thrombosis; SLE, systemic lupus erythematosis; Ig, immunoglobulin; PE, pulmonary embolism; M, male; F, female; Y, yes; N, no.

M16IdiopathicAntithrombin deficiency0·64, 0·53, 0·64 IU/ml (0·90–1·30 IU/ml)NYN
F17OCPAntithrombin deficiency0·49, 0·52, 0·65 IU/ml (0·90–1·30 IU/ml)NNN
F14IdiopathicProtein S deficiency0·38, 0·39 IU/ml (0·52–0·92 IU/ml)NYN
M 6Varicella-Zoster virus infectionTransient protein S deficiency0·21 IU/ml (0·41–1·14 IU/ml)NYN
F13OCP, overweightF2 G20210A mutationHeterozygousNYN
M15Complicated appendicectomyF2 G20210A mutationHeterozygousNNN
F16OCPF5 R506Q mutationHeterozygousNNN
F12End stage renal failureElevated factor VIII level2·73, 4·70 IU/ml (0·56–1·20 IU/ml)NNLine-related DVT
M14Ulcerative colitisElevated lipoprotein(a) level1·43 μmol/l (<1·28 μmol/l)NNN
F12Cerebral palsy, post-op scoliosis repairElevated lipoprotein(a) level1·82, 1·42 μmol/l (<1·28 μmol/l)NNN
M14SLEAnticardiolipin antibodiesIgG titre 36, 41, 22 (<10)NNN
M17PneumoniaAnticardiolipin antibodiesIgG titre 31, 23 (<10)NNDVT + PE
M14Wegener granulomatosisAnticardiolipin antibodiesIgG titre 20, 28, 17 (<10)Previous trauma-related DVTNN
Lupus anticoagulantPositive on 3 occasions
M16Previous autoimmune haemolytic anaemia and immune thrombocytopeniaAnticardiolipin antibodiesIgG titre 28, 26 (<10)NNN

Co-existing deep vein thrombosis in children with PE

Concurrent DVT was identified in 31 of 43 patients investigated (72·1%), 15 of whom had no symptoms or signs of DVT. Thirteen patients did not undergo lower limb Doppler ultrasonography to rule out DVT. The sites of venous thrombi identified are shown in Fig 2. The majority were lower limb (19 patients), with thrombosis of the iliofemoral veins in 14 patients, extending to the distal inferior vena cava (IVC) in five. Two had isolated calf vein thrombosis, both of whom had venous malformations of the lower limb. Of the seven patients with intra-abdominal thrombus, five had renal vein thrombus extending into the IVC, one had unilateral portal vein thrombus without extension and one had IVC thrombus alone. Six patients had thrombosis of the upper limb or neck vessels; internal jugular vein in three, subclavian/axillary vein in two and brachiocephalic vein in one. Extension of thrombus into the superior vena cava (SVC) occurred in four patients with thrombosis of the upper venous system, with one having additional thrombus in the right atrium.

image

Figure 2.  Frequency and site of co-existing DVT at time of presentation with PE. IVC, inferior vena cava.

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Central venous catheter (CVC)-related thrombosis occurred in 12 patients (21·4%). Six had thrombus in the upper limb/neck, five in the lower limb and one in the portal vein. CVC had been in situ for a median of 11 d prior to detection of thrombus (range: 1–450 d). Nine patients (16·1%) had intra-cardiac thrombus.

Imaging modality used to diagnose childhood PE

The most common imaging modalities used in the diagnosis of PE were V/Q scanning and CTPA in 37·5% and 23·2% of patients, respectively. A combination of both modalities was utilised in 12·5% of patients. Alternative imaging techniques were cardiac angiography (19·6%), conventional pulmonary angiography (3·6%) and transoesophageal/transthoracic echocardiography (3·6%). Bilateral PE was demonstrated in 29 patients (51·8%) and unilateral in 27 patients (48·2%). Patients with bilateral PE were more likely to have co-existing DVT (21/24 patients who underwent imaging to rule out DVT; 87·5%) than patients with unilateral PE (10/19; 53·0%).

D dimer measurement at presentation with PE

D dimer was measured at presentation in 30 patients and was elevated in 26 (86·7%), exceeding five times the upper limit of the normal range in 23 patients (76·7%). Of the four patients with a normal D dimer level, three had underlying malignancy, one was therapeutically anticoagulated for upper limb DVT and one had had symptoms of PE for 4 d.

Management of children with PE

Fifty-five of 56 patients (98·2%) were anticoagulated. Thirty-six patients (64·3%) received intravenous unfractionated heparin initially (target range: 0·35–0·70 IU/ml anti-factor Xa activity). Further anticoagulant treatment consisted of low molecular weight heparin in 57·1% (target range: 0·5–1·0 IU/ml anti-factor Xa activity), warfarin in 8·9% [target International Normalised Ratio (INR): 2·5, range: 2·0–3·0] and low molecular weight heparin followed by warfarin in 30·4%.

Duration of anticoagulant therapy.  For the 36 patients receiving a defined period of anticoagulation, anticoagulant therapy was continued for a median of 3 months (range: 14 d–30 months). Therapeutic anticoagulation was restarted at times of relapse of underlying disease in three patients with nephrotic syndrome and one with ulcerative colitis. Anticoagulation was continued indefinitely in 10 patients (17·9%). Nine patients died during a course of anticoagulant therapy.

Systemic thrombolysis.  Eight patients (14·3%) received thrombolysis with recombinant tissue plasminogen activator (rtPA; Alteplase), six for cardiorespiratory distress, one for left coronary artery thrombus and one for bilateral renal vein thrombus. Four patients had underlying congenital heart disease. Alteplase was administered systemically in courses with a median dose of 0·5 mg/kg/h (range: 0·3–0·67 mg/kg/h) for a median duration of 6 h (range: 2–12 h). While receiving Alteplase, all patients also received intravenous infusion of standard heparin at 10 U/kg/h. Three patients received one course of thrombolysis, two patients received two courses and one received five courses. Thrombolysis was complicated by major haemorrhage in four patients (Table III), none fatal. One patient had complete resolution of thrombus, four had partial resolution and three showed no response at completion of thrombolytic therapy. Of the four patients receiving two or more courses of thrombolytic therapy, none showed improvement in response with subsequent courses. One patient with partial resolution and two with no response died due to thromboembolism.

Table III.   Major haemorrhage in children anticoagulated for PE.
Age, yearsClinical scenarioNature of haemorrhageAnticoagulant therapy at time of haemorrhage, doseCoagulation test resultsOutcome
  1. Normal ranges are as follows unless stated in table: Platelet count, 150–400 × 109/l; INR, 0·8–1·2; PTT, 28–40 s; Fibrinogen, 1·6–4·0 g/l.

  2. INR, International Normalized Ratio; PTT, partial thromboplastin time; UFH, unfractionated heparin by intravenous infusion; rtPA, recombinant tissue plasminogen activator (Alteplase).

8Severe combined immunodeficiencyIntracranialEnoxaparin, 1·3 mg/kg 12 hourlyPlatelet count 431 × 109/l; INR 1·1; PTT 35·7 s; anti-factor Xa activity 0·91 IU/mlDied due to haemorrhage
0·5Congenital heart diseaseIntracranialEnoxaparin, 1·2 mg/kg 12 hourlyPlatelet count 290 × 109/l; INR 1·2; PTT 127 s; fibrinogen 4·1 g/l; anti- factor Xa activity 0·45 IU/ml Survived
17Congenital heart diseasePulmonaryUFH, 20 U/kg/hPlatelet count 60 × 109/l; INR 1·3; PTT 85·6 s; fibrinogen 5·3 g/l; anti-factor Xa activity 0·46 IU/mlDied due to haemorrhage
14Wegener granulomatosisPulmonaryUFH, 17 U/kg/hPlatelet count 490 × 109/l; INR 1·1; PTT 83·7 s; fibrinogen 3·4 g/l; anti- factor Xa activity 1·1 IU/mlSurvived
8Wegener granulomatosisGastrointestinalUFH, 17 U/kg/hPlatelet count 131 × 109/l; INR 1·1; PTT 36·1 s; fibrinogen 2·2 g/l; anti-factor Xa activity 0·47 IU/mlSurvived
3Congenital heart diseaseGastrointestinalrtPA (1st course), 0·3 mg/kg/hPlatelet count 103 × 109/l; INR 1·9; PTT >212 s; fibrinogen 2·5 g/lDied due to recurrent PE
5Congenital heart diseaseGastrointestinal and intra-thoracicrtPA (2nd course), 0·6 mg/kg/hPlatelet count 86 × 109/l; INR 1·4; PTT 212 s; fibrinogen 1·3 g/lSurvived
0·055Congenital heart diseaseGastrointestinal and pulmonaryUFH, 25 U/kg/hPlatelet count 54 × 109/l; INR 1·7; PTT 137 s; fibrinogen 2·4 g/l; anti-factor Xa activity 0·34 IU/mlSurvived
13Septic arthritisRetroperitonealUFH, 25 U/kg/hPlatelet count 90 × 109/l; INR 1·4; PTT 104 s; fibrinogen 4·8 g/l; anti-factor Xa activity 0·43 IU/mlSurvived
0·003Patent ductus arteriosus aneurysmRetroperitonealrtPA (2nd course), 0·5 mg/kg/hPlatelet count 188 × 109/l; INR 1·2; PTT 63·6 s (25–53 s); fibrinogen 2·2 g/lSurvived
17Congenital heart diseaseHaematuria, groin haematoma and epistaxisrtPA (2nd course), 0·5 mg/kg/hPlatelet count 134 × 109/l; INR 2·9; PTT 67·8 s; fibrinogen 1·42 g/lSurvived
12End stage renal failureAbdominal wall haematomaWarfarin, 0·05 mg/kg/dPlatelet count 232 × 109/l; INR 3·1; PTT 44 s; fibrinogen 3·2 g/lSurvived

IVC filters.  Seven patients (12·5%) had an IVC filter placed at a median of 2 d after diagnosis of PE (range: 0–17 d). Indications were haemorrhage whilst on anticoagulant therapy in three, contraindication to anticoagulation in two (one with recent head trauma and one with rectal bleeding) and recurrent embolism despite therapeutic anticoagulation in two. Five patients had proximal lower limb thrombus and two had distal lower limb thrombus within a venous malformation. All were Gunther Tulip filters, placed below the level of the renal veins in six patients and at the level of the renal veins in one. Six filters were removed at a median of 15 d (range: 4–90 d). No IVC filter was complicated by proximal extension of thrombus or recurrent embolism although one filter was unable to be removed due to adherent thrombus. All patients were anticoagulated prior to or at the time of filter removal without bleeding complications.

Surgical thrombectomy.  Two patients underwent surgical thrombectomy, both of whom had congenital heart disease. The indication was severe cardiorespiratory distress in both with a contraindication to thrombolysis (intracranial haemorrhage) in one. One patient had complete resolution of thrombus, the other partial resolution.

Complications of anticoagulant therapy.  Anticoagulant therapy was complicated by major haemorrhage (as defined in ‘Patients and methods’) in 12 of 55 anticoagulated patients (21·8%) and was fatal in two patients (3·6%) with intracranial and pulmonary haemorrhage (Table III). One patient was over-anticoagulated at the time of haemorrhage (anti-factor Xa activity 1·1 IU/ml while receiving intravenous unfractionated heparin) and an additional two patients had laboratory evidence of coagulopathy while receiving Alteplase (Table III). Patients who did not die from bleeding were re-anticoagulated after a period of withholding anticoagulant therapy without further complication.

Outcome

Resolution of radiological abnormalities.  Fifty patients underwent repeat imaging, 39 (78%) with complete resolution of PE and seven (14%) with partial resolution. Complete resolution was demonstrated in 70·4% and 69·0% of patients presenting with unilateral and bilateral PE, respectively. Four patients, all with bilateral PE at presentation, showed early progression of thrombus. Of the six patients who did not undergo repeat imaging, three survived, two died due to haemorrhagic complications of anticoagulant therapy and one died due to unrelated causes. Repeat imaging was performed at the end of anticoagulant therapy in 23/50 patients, the remainder prior to the end of, or during long term, anticoagulant therapy.

Early progression.  Of four patients with early progression of thrombus, two were infants with congenital heart disease and intra-cardiac thrombus. One was therapeutically anticoagulated at the time of clot progression with intravenous unfractionated heparin and the other was receiving rtPA. Both died due to progressive thrombus. One further patient with underlying malignancy, had clot progression despite thrombolysis and also died due to progressive thrombus. The final patient was not anticoagulated at the time of progression, having an IVC filter in place for pulmonary haemorrhage. This patient survived and was subsequently found to have persistent positivity for anticardiolipin antibodies.

Recurrent thrombotic events.  Seven patients (12·5%) had a recurrent venous thromboembolic event during follow-up, one with isolated PE, two with DVT and PE, two with PE in association with recurrent thrombus within a Fontan circuit and two with isolated DVT. Underlying diagnoses included congenital heart disease in three patients and one patient each with nephrotic syndrome and stage IV neuroblastoma. Recurrence occurred at a median of 9 months (range: 8–55 months) after the initial event. Four patients were therapeutically anticoagulated at the time of recurrence, two were subtherapeutic on warfarin and one had ceased anticoagulant therapy 5 months prior. One of the anticoagulated patients had persistent positivity for anticardiolipin antibodies and the patient who had ceased anticoagulation had a persistently elevated factor VIII level (Table II). Recurrent PE was fatal in two patients, both of whom were therapeutically anticoagulated at the time of recurrence. In children greater than 1 year of age who underwent thrombophilia screening, recurrence rates were 2/13 (15·4%) in those with a thrombophilic abnormality and 1/24 (4·2%) in those without.

Mortality data.  Twelve patients (21·4%) died during the study period. Seven of these patients had congenital heart disease and three had malignancy. Five deaths were due to thromboembolism (8·9%), three as a result of early progression and two due to recurrence. Two patients (3·6%) died due to haemorrhage (Table III). Five patients died from unrelated causes: two due to malignancy; two due to infection and one with progressive respiratory failure.

Discussion

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

Fifty-six children with pulmonary embolism have been reported in this cohort, equivalent to an incidence of 5·7/10 000 admissions to the Hospital for Sick Children during this 8-year time period and 4·6/100 000 within the catchment population. These rates are significantly higher than those quoted from registry data (Andrew et al, 1994; Van Ommen et al, 2001; Stein et al, 2004) and may be more accurate due to comprehensive reporting. Alternatively, they could reflect the biased population of a tertiary centre.

Risk factors for childhood PE

Acquired risk factors have been shown to play an important role in provoking venous thromboembolic events in childhood. A CVC is the most consistent factor contributing to the occurrence of thrombotic events in childhood, present in 32·8–63·6% of children with thrombosis (Andrew et al, 1994; Van Ommen et al, 2001) and as many as 94% of neonates with thrombosis (Van Ommen et al, 2001). In a study of 244 children with CVC-related venous thrombosis, 16% were found to have symptomatic PE (Massicotte et al, 1998). Most of the subjects were not investigated for PE and the incidence may therefore have been underestimated. The association between CVC-related thrombosis and PE has been further strengthened by a screening study in children receiving parenteral nutrition (Dollery et al, 1994) and an autopsy study of children admitted to an intensive care unit (Derish et al, 1995). Twenty patients in our cohort (35·7%) had a CVC in situ at the time of their PE diagnosis and 12 patients (21·4%) had CVC-related DVT with 50% of these located in the upper venous system.

Immobility, recent surgery and congenital heart disease are further risk factors for thromboembolic disease in children, as shown in previous studies (Andrew et al, 1994; Stein et al, 2004; Rajpurkar et al, 2007) and confirmed by our current study. The presence of malignancy contributes to the occurrence of thrombotic events in a number of ways, including increased thrombin generation due to the malignancy, the use of CVCs for the administration of chemotherapy and blood products, and particular chemotherapeutic agents, such as asparaginase (Lee, 2002). In a study of 452 children treated for haematological malignancy in a single centre, 2·9% developed symptomatic PE (Uderzo et al, 1995). Children with PE represented 0·4% (3/750) of the total number of children treated for haematological malignancy and 0·6% (7/1106) of children treated for solid tumours at our institution during the study period.

Nephrotic syndrome in children has been shown to induce a hypercoagulable state with elevated plasma levels of factor VIII, fibrinogen and lipoprotein (a), a reduction in antithrombin level and hyperaggregability of platelets (Hoyer et al, 1986). The use of V/Q scanning to screen asymptomatic children with nephrotic syndrome has demonstrated changes consistent with PE in 27·9–40% (Hoyer et al, 1986; Huang et al, 2000). Four patients in our cohort had nephrotic syndrome, making it a significant, albeit less common, risk factor.

Thrombus occurring in association with lower limb venous malformation can result in PE. Embolism can be from proximal DVT but can also occur with isolated calf vein thrombosis due to the presence of abnormal communications between the superficial and deep venous systems (Huiras et al, 2005). This occurred in two patients in our cohort, highlighting the importance of identifying and treating distal thrombi in patients with venous malformations.

In contrast to the adult population, symptomatic PE following trauma in paediatric patients is uncommon, occurring in only two in a study of 28 692 unselected trauma patients. Both of these children had spinal cord injuries with associated paraplegia (McBride et al, 1994). This low incidence was supported by our results, identifying only one patient with PE following trauma, in this case a severe head injury. This patient had a CVC-related lower limb DVT.

According to our data, a higher level of suspicion for PE should be entertained in children with congenital heart disease, nephrotic syndrome and in those with malignancy, particularly that which is metastatic or advanced. Idiopathic PE is rare in childhood, the majority of children having multiple risk factors for thromboembolic disease at presentation.

The age distribution of children presenting with PE reflects that of all thromboembolic events in childhood, with a peak in infancy and a later peak in adolescence (Andrew et al, 1994). The probable reason for the fall in incidence occurring after 16 years of age is the transition of care to adult centres.

The clinical features of PE occurring in adolescence have previously been described in a cohort of 18 patients between the ages of 12 and 21 years presenting to a single centre (Bernstein et al, 1986). This study described a predominance of female patients, in three quarters of whom PE complicated elective abortion or the use of an oral contraceptive pill (OCP), although these patients were all 19 years of age or older. Our series showed a more equal sex distribution within the adolescent age group, 54·8% female, and a variety of underlying diagnoses reflecting the overall characteristics of the cohort. Four events were related to the use of an OCP. The major point of note related to the adolescents within our cohort is the identification of an inherited or acquired thrombophilic abnormality in 52% of those tested. All but one of the patients found to have a thrombophilic abnormality were between the ages of 12 and 17 years.

Some guidelines have advised against the screening of children with unselected thrombotic events for inherited thrombophilia (Walker et al, 2001) due to the low yield of positive results, thrombophilia being detected in only 8·8% (Andrew et al, 1994). However, with a thrombophilic abnormality demonstrated in 52% of adolescents tested and 35% overall, these guidelines should perhaps be revised in the setting of PE, particularly in adolescence. In contrast, thrombophilia testing could be deferred in children presenting with PE in the setting of CVC-related DVT as only one of 12 such patients in this cohort had a thrombophilic abnormality (persistently elevated factor VIII level) and this patient was also a teenager. In this cohort, the finding of heterozygosity for the F5 R506Q mutation at a rate no higher than that in the general population (2·5% of those undergoing genetic analysis) supports recent literature suggesting a relatively low risk of PE in these patients compared to those with F2 G20210A mutation (Martinelli et al, 2007).

Clinical and radiological diagnosis of childhood PE

Clinical prediction rules, such as the Well’s clinical probability score, have been validated in adults presenting with symptoms of PE and provide a useful measure of pre-test probability (Wells et al, 1998). The combination of a negative D dimer and low clinical probability score can safely rule out PE, negating the need for diagnostic imaging (Wells et al, 2000). No such clinical probability score has been validated in a paediatric cohort. A negative quantitative D dimer was not able to rule out PE in 4/30 children tested and quantitative D dimer was negative in 36% and 40% of children with PE in two recently reported studies (Rajpurkar et al, 2007; Strouse et al, 2007), a demonstration of the poor negative predictive value of quantitative D dimer assays. With highly sensitive D dimer testing kits, the frequency of underlying illness in children with PE would probably lead to high numbers of false-positive results. Coupled with the masking of symptoms and signs by that of the underlying diagnosis, the role of clinical probability scores and D dimer measurement remains unknown and requires prospective study in children with suspected PE. D dimer measurement at cessation of anticoagulant therapy as a means of predicting recurrence was not utilised in this patient cohort, although has shown potential value in adults with VTE (Kuruvilla et al, 2003).

The predominant diagnostic imaging modalities were V/Q scanning and CTPA. These are standard modalities for the diagnosis of PE in adults although there are no published studies of the sensitivity and specificity of these techniques for PE diagnosis in childhood. It was noted that seven of the nine infants were diagnosed by modalities other than V/Q and CTPA, namely echocardiography and cardiac angiography. In infants, V/Q scanning is limited by the subject’s inability to comply with the aerosol inhalation required for the ventilation phase of the study and CTPA by the poor sensitivity and specificity in detecting peripheral emboli due to the presence of small calibre vessels (Babyn et al, 2005). Due to the lack of ability to utilise conventional imaging modalities and a historically low level of clinical suspicion, one can speculate that PE may be under diagnosed in this age group. Further study is required in order to substantiate this claim and to develop a better imaging strategy for diagnosing PE in children of all ages.

Diagnosis was made at a median of 1 d from onset of symptoms. This is in contrast to the delay in diagnosis reported in a previous cohort of children with PE when average time to diagnosis was 7 d (Rajpurkar et al, 2007). The reason for this difference may reflect that the majority of patients reported in this cohort were inpatients at the time of onset of symptoms.

Systemic thrombolysis for childhood PE

Thrombolysis is an established treatment for adults with PE associated with haemodynamic instability (Buller et al, 2004). The role of thrombolytic therapy in haemodynamically stable adults with PE is less well defined but may reduce fatality and the need for escalation of treatment without increasing the rate of significant bleeding events (Konstantinides et al, 2002). No clear guidelines exist for the use of thrombolytic therapy in children with PE. Response to thrombolysis was poor in our cohort, with only 1/8 patients achieving complete resolution of thrombus and almost a half failing to respond. Systemic thrombolysis was complicated by major bleeding in 50%. This major bleeding rate is comparable with previous rates quoted at 37% (Gupta et al, 2001) but much greater than the rate of 5% reported in patients undergoing systemic thrombolysis for VTE in the same institution (Traivaree et al, 2007). The indication for thrombolysis was most frequently cardiorespiratory distress or collapse, suggesting a poor risk group who were thrombolysed and this may account for the poor response and the higher rate of major bleeding. If systemic thrombolysis is considered as therapy for childhood PE it should be limited to one course since response to subsequent courses is poor and bleeding risk high.

IVC filters for childhood PE

An IVC filter successfully prevented clinically significant progression in the 12·5% of patients in whom they were inserted. Long-term use of permanent IVC filters resulted in a reduction in PE in adults with lower limb DVT but an increase in recurrent DVT at 8 years follow-up, with no significant difference in overall mortality [The Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) Study Group, 2005]. Short-term use of temporary filters has also been associated with a reduction in embolic events with fewer complications (Kai et al, 2006). However, early complications, such as filter dislocation and filter thrombosis, can occur and use is only advised in select patient groups (Miyahara et al, 2006). For all filters in this series, patients were commenced on anticoagulant therapy as soon as it was safe and filters were removed in a timely manner. The use of temporary filters was effective in prevention of recurrent embolic events and was uncomplicated in all but one patient.

Treatment duration of childhood PE

Median treatment duration in this cohort was 3 months, shorter than that recommended by current guidelines unless PE has occurred in the presence of a transient, reversible risk factor (Buller et al, 2004). Eighty-two per cent of patients achieved a complete or partial resolution on repeat imaging studies and the recurrence rate was low in patients who discontinued anticoagulation, suggesting that duration of anticoagulation was adequate.

Complications and outcome of treatment in childhood PE

Major haemorrhage occurred frequently, in 21·4% of patients. Haemorrhage occurred early in treatment, and most often while receiving thrombolytic therapy and/or intravenous unfractionated heparin. The majority of these patients had underlying congenital heart disease, 25% had had recent surgery (within the previous 14 d) and >50% had coagulopathy in addition to the effects of anticoagulant therapy. Only one patient had laboratory evidence to suggest supra-therapeutic anticoagulation at the time of haemorrhage (Table III).

Overall mortality was high: 21·4% of patients died during the follow-up period. Death due to thromboembolism occurred in 8·9%, consistent with previously reported mortality rates of around 10% (Andrew et al, 1994; Van Ommen et al, 2001). The predominance of congenital heart disease and malignancy as underlying diagnoses in those patients who died reflect a poor prognosis group. Excluding these underlying diagnoses, the outcome from PE, in terms of resolution of thrombus and overall survival, was good. The number of deaths due to thromboembolism (8·9%) exceeded that of haemorrhagic complications (3·6%), supporting the role of anticoagulant therapy for PE in childhood.

Recurrence of childhood PE

Recurrent VTE occurred in 12·5% of the patients reported in this study. This outlines the importance of identifying patients in whom recurrence is more likely to occur and considering long-term anticoagulation on the basis of the individual’s risk-benefit profile. Those with persisting risk factors, such as malignancy, and those with intermittent risk factors, such as relapsing-remitting nephrotic syndrome or inflammatory bowel disease, are likely to require long-term anticoagulation or at least prophylaxis at times of relapse of their underlying disease. The presence of antiphospholipid antibodies in children with lupus has been linked to a VTE recurrence rate of 31% (Levy et al, 2003) and it was noted that one of our patients with recurrence had persistently positive anticardiolipin antibodies although they did not fit the criteria for lupus. In addition, a further patient had an elevated factor VIII level, also shown to increase risk of recurrent thrombotic events (Goldenberg et al, 2004). These individual features should be taken into account when deciding on an appropriate duration of anticoagulant therapy. Five of the seven patients with recurrence had recurrent PE, resulting in death in two patients, supporting data from adult studies showing that patients with PE as a first event have a higher risk of recurrent PE and death when compared to patients with unselected VTE (Douketis et al, 1998).

Conclusions

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

This report describes a consecutive cohort of children presenting with PE and is the largest reported in the literature to date. Limitations of the study include the retrospective nature of the data collection, the small numbers of patients and the reduction in generalisability due to reporting from a single institution. A further limitation is the assumption that radiology records were complete and all children who had a PE within the defined period of time were included in the study population. Although providing information regarding the clinical characteristics of paediatric patients with PE, numerous areas where knowledge is lacking have been identified: imaging strategies for diagnosis; optimal duration of anticoagulant therapy; the role of thrombolysis; and long term consequences of PE in childhood, including pulmonary and cardiac compromise, all of which require evaluation by multicentre prospective studies (Table IV).

Table IV.   (A) Summary of key points; (B) Summary guidance on management.
(A)
 Idiopathic PE in childhood is rare: 96% of children have at least one identifiable risk factor
 Children with distal vein thrombosis and venous malformations are at risk for PE
 D-dimers are elevated at presentation in the majority (87%) of children with PE
 Thrombophilia is not uncommon in children presenting with PE, particularly in adolescent and non CVC-related PE
 Mortality rate is significant (8·9%) in children with PE
 Recurrence following childhood PE is of concern (12·5% recurrence rate)
 Children presenting with PE as a first thrombotic event have a higher risk of PE as a second event, as described in the adult literature
(B)
 Anticoagulation is effective therapy for childhood PE resulting in complete or partial resolution in 82%
 Haemorrhagic complications are frequent in children anticoagulated for PE (21%): attention to the correction of co-existent coagulopathy is essential
 Long-term anticoagulation is warranted when there is no acute, reversible or transient risk factor
 For children with a history of PE in the context of risk factors, prompt re-initiation of anticoagulation with return of risk factors is recommended

Acknowledgements

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

The authors thank Dr Paul S. Babyn for the contribution of cases to this series. Tina T. Biss acknowledges Baxter Bioscience Canada for sponsoring her fellowship post at The Hospital for Sick Children.

Conflict of interest disclosure

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References

The authors declare no competing financial interests.

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  3. Patients and methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. Conflict of interest disclosure
  9. References
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