Venous Thromboembolism and Thrombophilia

Introduction

Venous thromboembolism is a rare event in the paediatric population, being mostly seen in hospitalised and critically unwell children. VTE is especially rare in pre-pubertal children. The most common acquired risk factors for paediatric VTE are:

• Central venous access devices (>90% neonatal VTE, >50% paediatric)
• Critical illness/sepsis/dehydration
• Prolonged immobility
• Malignancy and chemotherapy
• Cardiac disease
• Major burns/trauma
• Obesity
• Medications (e.g. oestrogen-containing oral contraceptive pills)

In contrast to the adult population, these acquired risk factors play a much larger role than inherited risk factors (I.e. ‘thrombophilias’), and testing children for inherited risk factors remains highly controversial as positive results do not tend to influence management. Even in the presence of a relative risk increase due to a thrombophilia, the negligible baseline risk (0.07 – 0.14 per 10,000 children, or 58 per 10,000 hospitalised children) means the absolute risk of thrombosis remains incredibly low.

In the absence of a confirmed thromboembolic event, routine testing of children prior to 18 years of age is NOT recommended even in the presence of a known affected first degree relative, as a positive result does not change management (i.e. primary thromboprophylaxis is not indicated).

The most common inherited thrombophilias in the population

Factor V Leiden

• Most common, although variable prevalence by population
•  Most frequent in populations of European descent (1-9% rate of heterozygosity), rare in people of African and Asian descent

Prothrombin gene mutation 20210A

• Second most common
• Frequency of ~2% in populations of European descent

Antithrombin deficiency

• Extremely rare – estimated prevalence 0.02%
•  Infants may show developmentally normal reduction in levels until >6/12 of age

Protein C deficiency

• Estimated prevalence of heterozygosity ~2%
•  Homozygous/compound heterozygous state presents as purpura fulminans in neonatal life
• Interpretation may be complex – children may show developmentally normal reduction in levels until as late as adolescence

Protein S deficiency

• Rare – estimated prevalence 0.03% - 0.13%
• Infants may show developmentally normal reduction in levels until >6/12 of age
• Homozygosity also presents as purpura fulminans in neonatal life.

With the exception of homozygosity for protein C or S deficiency, Haematology Clinic review is not required for children who have had a positive test result for thrombophilia unless they have a personal history of thrombosis. 

Pre-referral investigations

•  In a child of any age with a confirmed thrombosis or thromboembolic event, urgent telephone consultation with the Clinical Haematologist on call is mandatory. No thrombophilia investigations are required prior to referral and such investigations will be ordered by the Haematology team if deemed appropriate.
• In a child of any age with a family history of VTE or confirmed thrombophilia, routine thrombophilia testing is NOT recommended before adulthood except in the following circumstance:
  • testing may be considered in pubertal girls with a family history of VTE or confirmed thrombophilia if it will help inform contraceptive choices
  • testing may be considered in children with a positive family history who also have significant personal medical risk factors (e.g. cardiac disease, cancer, planned major surgery) in whom medical management may be modified – in such cases, testing should be first discussed with the Clinical Haematologist on call.

Pre-referral management

• If a child has a confirmed thrombosis or thromboembolic event, management should be to immediately refer to Perth Children’s Hospital
• If testing has been performed and a child has tested positive for a thrombophilia but has no personal history of thrombosis, no Haematology Clinic referral is required even in the event of a positive result; routine advice for such children is to follow usual conservative measures such as good hydration, avoidance of immobility, avoidance of smoking and maintenance of a healthy weight. In addition, adolescent girls are advised to avoid oestrogen-containing contraceptive pills unless the benefit greatly outweighs the risk.
• Education should be provided on the signs and symptoms of thromboembolism.

When to refer

Referral to PCH Haematology is appropriate if:

• There is a confirmed personal history of acute thrombosis in a child of any age
• A child with a previously diagnosed thrombosis (even if ascribed to common acquired triggers such as a central venous access device) has experienced a second thrombosis of any type.

How to refer

• Routine non-urgent referrals from a GP or a Consultant should go to the Central Referral Service
• Routine non-urgent referrals from a nurse practitioner, non-medical referrers or private hospitals go to the PCH Referral Office
• Urgent referrals (less than seven days) are made via the PCH Referral Office.

Essential information to include in your referral

• For acute confirmed thrombosis, telephoning the on call Clinical Haematologist about the referral is mandatory.
• Relevant information to provide includes:
  • Demographics (age, sex, height/weight if known)
  • Presentation, clinical status and location of thromboembolism
  • Family history (if known)
  • Medication history.

Useful resources

1. Van Ommen C, Nowak-Gottl U. Inherited thrombophilia in paediatric venous thromboembolic disease: Why and who to test. Front Pediatr 2017;5:50 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348488/
2. Raffini L. Thrombophilia testing in children and adolescents. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. 

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