Acute pediatric potentially thrombogenic craniocervical infections: A consecutive series of Lemierre and Lemierre-like syndrome cases

Article Outline

• Summary
• 1. Introduction
• 2. Case reports
  • 2.1. Case 1
  • 2.2. Case 2
  • 2.3. Case 3
  • 2.4. Case 4
  • 2.5. Case 5
  • 2.6. Case 6
• 3. Discussion
• 4. Conclusion
• References
• Copyright

Summary 

Background: Major venous thrombophlebitis and/or thrombosis in association with acute head and neck infection is a serious but uncommon event. The action of specific bacterial toxins causes the thrombophlebitis, which has the propensity of systemic complications and local circulatory effects. Lemierre's syndrome (LS) is a specific entity within this group, often caused by the anaerobe Fusobacterium necrophorum (FN). Objective: Review of six consecutive pediatric cases and a critical revision of diagnostic categories. Setup: Tertiary referral center. Study design: Case series of pediatric craniocervical infections complicated by internal jugular vein thrombophlebitis (IJVT). Demographics, record of anti-thrombosis management, imaging, and antimicrobial management, duration of admission, clinical picture and sequelae were retrospectively collected. Results: Six cases (three girls and three boys; age range from 7 to 16 years old) were identified over a period of 3 years. One case was a certain LS; four were probable LS cases and one possible diagnosis. Six children had IJVT diagnosed on imaging, which also demonstrated embolic seeding to the knee on one occasion and to the ankle in another. Anti-thrombosis management as outpatients was instituted for 3 months in five out of the six. None had permanent sequelae except one (unilateral high tone sensory hearing loss). In four cases, the duration of admission was 10 days or less, whereas the other two cases stayed for 2 and 5 weeks, respectively. Conclusions: Thrombogenic head and neck infections may occur in children more readily than currently believed. Failure to detect the characteristic anaerobe and the low index of suspicion of IJVT may contribute to missing cases. Modern imaging modalities represent a window of opportunity to detect the key pathogenic process to arguably the most morbid event, namely the IJVT. By incorporating their findings from the outset, the disease is categorized and its devastating complications prevented.

Keywords: Thromboembolic, Lemierre's, Internal jugular vein, Thrombosis, Fusobacterium necrophorum

Back to Article Outline

1. Introduction 

In 1936, Andre Lemierre (1875–1965), a bacteriologist at the Claude Bernard hospital in Paris, presented an address in London entitled “On certain septicemias due to anaerobic organisms” [1]. In it he described 20 cases of anaerobic thrombophlebitis of the internal jugular vein (IJV) giving rise to septic emboli to distant areas. In his original article, he mainly addressed Bacillus funduliformis, now known as Fusobacterium necrophorum (FN), as the causative agent. The bacterium whose name literally means, “spindle shaped rod bringing death”, is an anaerobic Gram-negative rod that is a commensal in the oral cavity, gastrointestinal and urinary tract. To date, the trigger that leads to the organism penetrating the mucosa is unknown, but reduced host defenses by viral and other bacterial infection plays a role [2]. Some patients are thought to be more vulnerable to LS, i.e., those who have had a preceding infection with the Epstein Barr virus [3] and those with immunoglobulin A deficiency [4]. But it is notable that, Lemierre maintained that other Gram-negative infective agents have the potential for producing the classic syndrome [1].

We report six consecutive, previously healthy pediatric cases (7–16 years of age) of acute craniocervical infections seen over a 3-year period. These cases had features of LS in various permutations, on occasions qualifying for the classical description and in others raising dilemmas regarding diagnosis and management.

Back to Article Outline

2. Case reports 

All the following cases are of previously healthy, fully immunized children and are summarized in Table 1.

Table 1. Summary of case reports

Abbreviations: IJV, internal jugular vein; CT, computerised tomography; MRI, magnetic resonance imaging; MRV, magnetic resonance venography; SNHL, sensory neural hearing loss; US, ultra sound; Bil, bilateral; FN, Fusobacterium necrophorum; EBV, Ebstein Barr virus; F, female; M, male; Strep A, Streptococcus group A; SS, sigmoid sinus; Lt, left; Rt, right.

2.1. Case 1 

This case was reported elsewhere [5]. An 8-year-old girl was referred to our Pediatric Emergency Department (PED) by her pediatrician. He was treating her for symptoms suggesting viral gastroenteritis. Over the previous 3 days, she had become more irritable and had developed headache and right-sided otorrhea. On examination, she was febrile (38.5°C), had right eye deviation and was refusing to weight bear on her right leg. Otoscopy showed right-sided otorrhea. Cranial nerve examination revealed bilateral abducens nerve palsy. Complete blood count (CBC) showed neutrophilia of 18×10⁹L⁻¹. A computerised tomography (CT) scan of the head unveiled bilateral mastoiditis with a small gas collection in the right internal jugular foramen (Fig. 1). Magnetic resonance imaging (MRI) with magnetic resonance venography (MRV) confirmed mastoiditis with thrombosis of the left sigmoid and transverse sinus and IJV (Fig. 2). The chest radiograph was normal. A left cortical mastoidectomy with drainage of the sigmoid peri-sinus abscess was performed. Cloxacillin, ceftazidime and low-molecular-weight heparin, enoxaparin sodium (LMWH) were initiated. She required a mastoid exploration on the right side 1 day later. Cultures from the left mastoid grew FN confirming LS as the diagnosis. MRI of the right ankle demonstrated distant fibula osteomyelitis with adjacent soft tissue abscess (Fig. 3). Unremitting symptoms of left mastoiditis led to revision of the left mastoidectomy. She made a gradual recovery until discharge 5 weeks post admission. At follow-up 2 weeks after discharge, right-sided severe to profound sensory hearing loss (SHL) was discovered. This gradually, and almost completely, recovered over the next 3 months.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 1. 

  (CT) scan of the head unveiled bilateral mastoiditis with a small gas collection in the right internal jugular foramen.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 2. 

  An oblique view of the 2D time of flight magnetic resonance venogram demonstrating the absent left internal jugular vein, sigmoid sinus and anterior third of the left transverse sinus, due to occlusion by venous thrombosis.

• 
  • View Large Image
  • Download to PowerPoint

• Fig. 3. 

  MRI of the right ankle demonstrated distant fibula osteomyelitis with adjacent soft tissue abscess.

2.2. Case 2 

A 7-year-old boy, presented to our PED with a 3-day history of fever, sore throat, painful neck swelling and right knee pain of similar duration. On examination he was found to be afebrile. A tender mass was palpated on the left side of his neck, measuring 5cm×3cm levels II–III. On examination of his right knee, there was a tender erythematous mass in the posterolateral popliteal area measuring 4cm×3cm. Blood cultures were sterile. A CT scan of his head and neck reportedly showed left parapharyngeal space cellulitis with ipsilateral internal jugular thrombosis. The chest radiograph was normal. A MRI of his right femur demonstrated a collection along the posterior aspect of the thigh and subcutaneous edema. A subsequent Doppler ultra sound (US) of his right leg showed no deep vein thrombosis. He was initially treated with clindamycin along with LMWH. By day 7 his neck and knee swelling improved slowly and he was discharged home on oral penicillin V. On the advice of the thrombosis team, he was anticoagulated with warfarin for 4 weeks. US of his neck 4 weeks after discharge found no residual thrombus and the warfarin was discontinued. On the last review, 2 months after initial presentation, he was fit and well with no sequelae.

2.3. Case 3 

A 16-year-old female presented with “hot potato speech”, throat pain, left otalgia, left jaw pain, trismus and dehydration. Of note, was a positive monospot test 1 week earlier. On examination she was normotensive, but febrile (39.1°C) and tachycardic (120 beats/min). A left peritonsillar abscess, bilateral cervical lymphadenopathy and a tender swollen left side of face and neck were documented. Serology for EBV confirmed recent infection. Marked leuckocytosis (20×10⁹L⁻¹) and mildly elevated liver function tests were returned. US of the neck showed a subacute left distal IJV thrombus but CT scan with contrast suggested bilateral involvement. The chest radiograph was normal. MRI with MRV of the head and neck confirmed the left IJV thrombus and the right IJV. The brain was normal with no venous haemorrhage or infarct. The left peritonsillar abscess was drained and clindamycin and dexamethosone were started. Blood cultures grew FN and metronidazole was added. She was anticoagulated with LMWH and improved very slowly by day 7 after which she was discharged from hospital. Follow-up by the thrombosis and Otolaryngology teams over the next 3 months showed no clinical relapse. An US of the neck showed normal jugular venous flow and the LMWH was stopped.

2.4. Case 4 

An 11-year-old boy was admitted with a 3-day history of increasing right-sided neck pain and limitation in head movement laterally, more so to the right, right otalgia and a sore throat. On examination he was febrile (38.5°C) and had marked trismus. A CBC showed neutrophilic leuckocytosis (33×10⁹L⁻¹). CT of his head and neck demonstrated lack of flow in the right IJV with thrombus formation, level with the second cervical vertebra and a phlegmon in the right parapharyngeal space but no abscess. The chest X-ray was clear. US of the neck confirmed no blood flow in the right IJV below the angle of the jaw. The blood cultures were negative for both aerobic and anaerobic growth, although the anaerobic vial was sent 4h after he was started on penicillin and clindamycin. He was anticoagulated with LMWH. Recovery ensued slowly and by day 3 symptoms were resolving. He was discharged home on day 7 on amoxicillin–clavunanate potassium for 10 days and warfarin. Follow-up by the thrombosis team with US over the following 3 months confirmed clinical resolution of the thrombus and his warfarin was stopped.

2.5. Case 5 

A 12-year-old boy presented to the PED with a 1-week history of sore throat, increasing dysphagia and left-sided neck pain. On examination he was found to be febrile (temperature of 38.5°C), with marked trismus. Tender left-sided cervical swelling and torticollis were noted. Oral examination showed no peritonsillar abscess. CBC showed marked neutrophilia (25×10⁹L⁻¹). Blood cultures were positive for Streptococcus group A. CT scan with contrast showed left-sided IJV thrombosis and suggested a left-sided parapharyngeal collection. The lungs were clear on CT. He was started on penicillin and underwent surgical exploration of his neck. This was negative for pus, but he made a good postoperative recovery. His treatment continued with clindamycin and LMWH. His symptoms slowly resolved by the tenth day of admission and he was well enough to be discharged on amoxicillin and LMWH. Follow-up by the thrombosis team with US over the following 3 months confirmed clinical resolution of the thrombus and his LMWH was stopped.

2.6. Case 6 

A 14-year-old girl was referred to the pediatric otolaryngology service. She presented with a 1-week history of an untreated sore throat and a 1-day history of left-sided neck tenderness and swelling. On examination she was toxic with pyrexia of 38.5°C. She had marked trismus and limitation of neck movement. Oral examination showed tonsillitis but no evidence of a peritonsillar or a parapharyngeal abscess. Nasopharyngoscopy was normal. CBC showed neutrophilic leuckocytosis (28×10⁹L⁻¹) and a monospot test was positive. Doppler US confirmed a deep-seated, left-sided neck abscess, measuring 4cm×3cm with the IJV being reported as patent. The CT of the neck however showed no venous flow between C1 and 4, possibly due to a thrombus or compression due to mass effect. The child underwent incision and drainage of the neck abscess with 20mL of foul smelling pus being drained. Culture grew FN. She was started on clindamycin and metronidazole and LMWH. She improved very slowly over the next 5 days and a follow-up MRV showed normal IJV venous flow so LMWH was stopped. She continued to make a good recovery and was discharged home on 10 days of clindamycin and metronidazole. Follow-up by the Otolaryngology team 6 weeks later confirmed resolution of all symptoms and signs.

Back to Article Outline

3. Discussion 

When Andre Lemierre first described his syndrome, it was barely into the antibiotic era. He had no access to advanced imaging modalities, such as CT and MRI. One can surmise that he established the diagnosis from history, physical examination, simple laboratory studies (CBC, blood culture, chest X-ray), intraoperative and postmortem findings. In Lemierre's seminal paper [1], he wrote: “The appearance and repetition several days after the onset of a sore-throat (and particularly of a tonsillar abscess) of severe pyrexial attacks with an initial rigor, or still more certainly the occurrence of pulmonary infarcts and arthritic manifestations, constitute a syndrome so characteristic that mistake is almost impossible”. He continued, “To anyone instructed as to the nature of these septicemias it becomes relatively easy to make a diagnosis on the simple clinical findings”.

At the time, the distant embolic events secondary to venous thrombophlebitis, coupled with a positive blood culture of FN made the diagnosis unmistakable. In this day and age, one can reach the diagnosis on the basis of these diagnostic pillars:

However, each one, especially with regards to pediatric patients presents certain challenges, in addition to primarily being aware of the condition itself.

Taking each of these three points in turn.

Firstly, the microbiological diagnosis. Although FN is the most common causative bacteria of the condition (81% of LS cases), it is seldom the only culprit, as one third of cases have polymicrobial bacteremia (various streptococci and Gram-negative anaerobes) [1], [10]. Identifying FN can be very difficult, as the anaerobic bacterium can be fickle and elusive to culture. Also, anaerobic blood cultures are not requested routinely in pediatric practice. In addition, the yield of the pathogen is directly proportional to the amount of blood analyzed. In a recent study, sensitivity of a low volume culture (1-mL) was 33% when compared to 72% of a standard pediatric volume culture (3-mL) [11]. Therefore, if the volume of blood obtained is suboptimal, it is advisable to send the whole sample for anaerobic analysis. In our series, FN was only grown three times. No growth was cultured in another two cases while one grew Streptococcus group A.

Secondly the thrombophlebitis. This is the catalyst of much of the morbidity and mortality of the disease. We argue that suspicious and highly suggestive imaging findings in our cases provided an earlier warning to the potential diagnosis in the absence of the classic clinical picture. The observation of an absent or severely decreased flow in a major vein, against the backdrop of local severe clinical infection with potential hypercoagulability state due to sepsis and dehydration (Virchow's triad) in our opinion cannot be ignored. This is especially important when there is no current accepted gold standard imaging modality for the diagnosis of venous thrombosis.

A search of the English literature on the subject was conducted (Medline for articles published the years 1966–2005. The MeSH words utilised were thrombosis, venous, internal jugular vein, diagnostic, and imaging). We found no level I or II evidence in favour of a particular modality. This was reflected by a local debate in our radiology department. Several imaging techniques were mentioned in context and the following is a summary of the relevant points.

Jugular venography is highly specific for recognition of IJVT, but is an invasive procedure carrying the risk of dislodging the thrombus [13]. Other opinions maintain that US provides the most accurate information of diagnosing IJVT [14]. However, it provides poor imaging beneath the clavicle and above the mandible, it can miss a fresh thrombus with low echogenicity [15] and is operator dependent.

When the diagnosis is delayed, the thrombus often becomes organized and its full extent delineated along with the soft tissue. In this instance, CT can be helpful but clearly involves exposure to radiation [16]. More recently, MRI has been used successfully to identify thrombi not detected on CT. It can also distinguish between localized abscess formation in the neck and IJVT, thus potentially avoiding unnecessary surgery [18], [19]. MRI may show abnormal signal from the sigmoid sinus and IJV and high signal intensity on T1 and T2 weighted images. Gadolinium enhancement of MR images may also show a “delta sign” comparable to that seen on CT scanning [18]. MR venography (MRV) is quite sensitive to blood flow and distinguishes thrombosis from slow flow. It has several advantages; it is a rapid non-invasive technique, does not require the use of intravenous contrast agent, does not use ionizing radiation and it can even help detect thrombosis of the superior sagittal and cavernous sinuses [18], [19]. Finally MRI with digital subtraction angiography has gained importance as a relatively low risk procedure. This again has the advantage of being a non-invasive technique with no exposure to radiation [20].

In our case series, all the patients had diminished or absent flow in their regional large veins by at least one imaging modality. The importance of imaging cannot be over emphasized. Even in the absence of the other two “pillars”, it may herald an ominous process and merits to be basis for intervention. This depends largely whether the signs are suggestive of an already formed thrombus or an impending one. One can consider the modern imaging as a window of opportunity that may detect the pathogenesis of thrombotic events in the making.

Lastly, the embolic and arthritic manifestations. Sinave et al. reviewed 38 adult cases of Lemierre's syndrome reported between 1974 and 1989 [12]. Almost all patients (97%) had evidence of septic pulmonary emboli and about a third (32%) had metastatic infections. Metastatic infections included septic arthritis, paravertebral abscess, skin infection, thigh abscess, periorbital cellulitis, meningitis, and osteomyelitis. All patients were treated with at least one antibiotic known to have good anti-anaerobic activity, and in this series, only 2 of 36 patients died. In comparison, none of our pediatric patients had pulmonary symptoms, despite two presenting with distant emboli. These thrombi would have had to pass the body's natural filter, the lungs, before resting as distant septic emboli in the knee and ankle, respectively. In both of these children, normal chest radiographs and CT chest were obtained. These modalities cannot detect subtle pulmonary microemboli and neither isotope ventilation perfusion scans (VQ) nor the more invasive pulmonary angiography were employed. Even so, a ventilation perfusion match is not helpful in ruling out pulmonary embolism with small perfusion defects [21].

Septic emboli in the lungs may produce the characteristic radiographic appearance of multiple peripheral round and wedge shaped opacities that rapidly progress to cavitations [21]. However in others, initial radiography may be clear (patients such as in our case series) or show non-specific patchy consolidation suggestive of bronchopneumonia. CT of the chest often reveals diagnostic information with characteristic appearances of septic infarcts, i.e., predominantly peripheral nodules showing cavitation. With administration of contrast, the lesions often show peripheral enhancement with central areas of reduced attenuation. The so-called “feeding vessel” sign is also characteristic of septic pulmonary embolism [21]. The search for a pulmonary or septic manifestation should not delay the treatment of the patient with antibiotics and anticoagulation, once the thrombophlebitis has been diagnosed.

The estimated incidence of symptomatic venous thrombosis (VTE) in children shows it to be significantly less (5.3/10000 hospital admissions) [22], [23], [24], [25], [26], [27] than that in adults (2.5–5% of hospital admissions) [28], [29], [30], [31]. Several mechanisms likely contribute to the protective effect of age for VTE. These include a reduced capacity to generate thrombin [32], [33], increased capacity of a2 macroglobulin to inhibit thrombin [34], and enhanced antithrombotic potential by the vessel wall [35], [36]. On a pre-emptive basis, one could argue for aggressive treatment with anticoagulants earlier on in the course of the disease. For secondary VTE such as LS, anticoagulant therapy should be continued for at least 3 months using oral anticoagulants to achieve a target INR of 2.5, range 2.0–3.0; or alternatively LMWH to maintain an anti-FXa level of 0.5–1.0UmL⁻¹ [37]. In the presence of ongoing risk factors, such as active nephrotic syndrome, or a lupus anticoagulant, anticoagulant therapy should continue until the risk factor has resolved [37]. The optimal intensity of therapy, therapeutic or prophylactic remains controversial.

The incidence of LS has not changed though the ages, although it is reported incidence remains low, 0.6–2.3 cases per million per year [8], there has been suggestions of a recent increase in incidence attributed to the reduction in antibiotic prescribing for sore throats by family physicians [7]. There has also been more reporting in the literature which coincided with the advent of modern imaging techniques. These modalities (CT, MRI and US), thus, introduced the opportunity to detect the disease process unfolding.

Back to Article Outline

4. Conclusion 

Making a diagnosis of LS with septic thrombosis requires awareness of the disease, vigilance and multidisciplinary management. Our re-reading of our own efforts in managing this case series, in addition to observing the shift in the world literature to dependence on modern imaging indicates a new window of opportunity to diagnose the disease. This is vital as the morbidity and mortality of the disease depends upon the stage of thrombus genesis and its potential septic embolic manifestations. The Lemierre-like spectrum should not be observed until it becomes a Lemierre.

Back to Article Outline

References 

1. Lemierre A. On certain septicemias due to anaerobic organisms. Lancet. 1936;1:701–703
   • View In Article
   • MEDLINE
2. Hagelskjaer Kristensen L, Prag J. Human necrobacillosis, with emphasis on Lemierre's syndrome. Clin. Infect. Dis. 2000;31:524–532
   • View In Article
   • MEDLINE
   • CrossRef
3. Johns MM, Hogikyan ND. Arch. Otolarnygol. 2000;126(12):
   • View In Article
4. Roberto M, et al. Scand. J. Infect. Dis. 2004;36(6–7):523–524
   • View In Article
   • MEDLINE
   • CrossRef
5. Masterson T, El-Hakim H, Magnus K, Robinson J. A case of the otogenic variant of Lemierre's syndrome with atypical sequelae and a review of pediatric literature. Int. J. Pediatr. Otorhinolaryngol. 2005;69(1):117–122
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (328 KB)
   • CrossRef
6. Aliyu SH, Marriott RK, Curran MD, Parmar S, Bentley N, Brown NM, et al. Real-time PCR investigation into the importance of Fusobacterium necrophorum as a cause of acute pharyngitis in general practice. J. Med. Microbiol. 2004;53(10):1029–1035
   • View In Article
   • MEDLINE
   • CrossRef
7. Hagelskjaer LH, Ping J, Malczynski J, Kristensen JH. Incidence and clinical epidemiology of necrobacillosis, including Lemierre's syndrome, in Denmark 1990–1995. Eur. J. Clin. Microbiol. Infect. Dis. 1998;17:561–565
   • View In Article
   • MEDLINE
   • CrossRef
8. Alvarez A, Schreiber JR. Lemierre's syndrome in adolescent children: anaerobic sepsis with internal jugular vein thrombophlebitis following pharyngitis. Pediatrics. 1995;96:354–359
   • View In Article
   • MEDLINE
9. Issaman DJ, Karasic RB, Reynolds EA, et al. Effect on number of blood cultures and volume on detection of bacteremia in children. J. Pediatr. 1996;128:190–195
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (517 KB)
   • CrossRef
10. Sinave CP, Hardy GJ, Fardy PW. The Lemierre syndrome: suppurative thrombophlebitis of the internal jugular vein secondary to oropharyngeal infection. Medicine (Baltimore). 1989;68:85–94
    • View In Article
    • MEDLINE
11. Tovi F, Hirsch M. Computed tomographic diagnosis of septic lateral sinus thrombosis. Ann. Otol. Rhinol. Laryngol. 1991;100(1):79–81
    • View In Article
    • MEDLINE
12. Albertyn LE, Alcock MK. Diagnosis of internal jugular vein thrombosis. Radiology. 1987;162(2):505–508
    • View In Article
    • MEDLINE
13. Nitschmann E, Berry L, Bridge S, Hatton MW, Richardson M, Monagle P, et al. Morphological and biochemical features affecting the antithrombotic properties of the aorta in adult rabbits and rabbit pups. Thromb. Haemost. 1998;79:1034–1040
    • View In Article
    • MEDLINE
14. Irwing RM, Jones NS, Hall-Craggs MA, Kendall B. CT and MR imaging in lateral sinus thrombosis. J. Laryngol. Otol. 1991;105(8):693–695
    • View In Article
    • MEDLINE
15. Daniels DL, Czervionke LF, Hendrix LE, et al. Gradient recalled echo MR imaging of superior sagittal sinus occlusion. Neuroradiology. 1989;31(2):134–136
    • View In Article
    • MEDLINE
    • CrossRef
16. Daniels DL, Czervionke LF, Bonnerille JF, et al. MR of the cavernous sinus: valve of spin echo and gradient recalled echo images. Am. J. Roentgenol. 1988;151(5):1009–1014
    • View In Article
17. Wagner ML, Singleton EB, Egan ME. Digital subtraction angiography in children. Am. J. Roentgenol. 1983;140(1):127–133
    • View In Article
18. Hull RD, Hirsh J, Carter CJ, Jay RM, Dodd PE, Ockelford PA, et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann. Intern. Med. 1983;98(6):891–899
    • View In Article
    • MEDLINE
19. Screaton NJ, Ravenel JG, Lehner PJ, et al. Lemierre's syndrome: forgotten but not extinct—report on four cases. Radiology. 1999;213:369–374
    • View In Article
    • MEDLINE
20. Castaman G, Rodeghiero F, Dini E. Thrombotic complications during l-asparaginase treatment for acute lymphocytic leukemia. Haematologica. 1990;75:567–569
    • View In Article
    • MEDLINE
21. Wise RC, Todd JK. Spontaneous, lower-extremity venous thrombosis in children. Am. J. Dis. Child. 1973;126:766–769
    • View In Article
    • MEDLINE
22. Bernstein D, Coupey S, Schonberg SK. Pulmonary embolism in adolescents. Am. J. Dis. Child. 1986;140:667–671
    • View In Article
    • MEDLINE
23. Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al Venous thromboembolic complications (VTE) in children: first analyses of the CanadianRegistry of VTE. Blood. 1994;83:1251–1257
    • View In Article
    • MEDLINE
24. Monagle P, Adams M, Mahoney M, Ali K, Barnard D, Massicotte MP, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr. Res. 2000;47:763–766
    • View In Article
    • MEDLINE
    • CrossRef
25. Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children. Analysis of the Canadian Registry of Venous Thromboembolic Complications. J. Pediatr. 1998;133:770–776
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (139 KB)
    • CrossRef
26. Andrew M, Massicotte MP, deVeber G, Leaker M, David M, Brown A, et al. 1-800.-NO-CLOTS. A quaternary care solution to a new tertiary care disease: childhood thrombophilia. Thromb. Haemost. 1997;77(Suppl.):727
    • View In Article
27. Coon WW, Willis PW, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation. 1973;48:839–846
    • View In Article
    • MEDLINE
28. Gjores J. The incidence of venous thrombosis and its sequelae in certain districts in Sweden. Acta Chir. Scand. 1956;206:1–10
    • View In Article
29. Carter C, Gent M. The epidemiology of venous thrombosis. In:  Colman R,  Hirsh J,  Marder V,  Salzman E editor. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia: JB Lippincott Co.; 1982;p. 805–819
    • View In Article
30. Andrew M, Schmidt B, Mitchell L, Paes B, Ofosu F. Thrombin generation in newborn plasma is critically dependent on the concentration of prothrombin. Thromb. Haemost. 1990;63:27–30
    • View In Article
    • MEDLINE
31. Andrew M, Mitchell L, Vegh P, Ofosu F. Thrombin regulation in children differs from adults in the absence and presence of heparin. Thromb. Haemost. 1994;72:836–842
    • View In Article
    • MEDLINE
32. Ling X, Delorme M, Berry L, Ofosu F, Mitchell L, Paes B, et al. alpha 2-Macroglobulin remains as important as antithrombin III for thrombin regulation in cord plasma in the presence of endothelial cell surfaces. Pediatr. Res. 1995;37:373–378
    • View In Article
    • MEDLINE
    • CrossRef
33. Xu L, Delorme M, Berry L, Brooker L, Mitchell L, Andrew M. Thrombin generation in newborn and adult plasma in the presence of an endothelial surface. Thromb. Haemost. 1991;65:1230
    • View In Article
34. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest. 2001;119:344S–370S
    • View In Article
    • MEDLINE
    • CrossRef