Overview
Definition:
Thrombophilia refers to an increased tendency to develop venous or arterial thrombosis
In pediatrics, inherited or acquired conditions can predispose children to thromboembolic events, necessitating careful consideration for diagnostic testing.
Epidemiology:
The incidence of venous thromboembolism (VTE) in neonates is estimated at 5 per 10,000 neonates, increasing to 0.05 per 1,000 children annually
The prevalence of inherited thrombophilia in children with VTE varies widely, with Factor V Leiden and the prothrombin gene mutation being most common.
Clinical Significance:
Identifying thrombophilia in children is crucial for guiding acute management of thrombosis, determining the duration of anticoagulation, assessing the risk of recurrence, and facilitating family screening to prevent future events
Misguided testing can lead to unnecessary anxiety and cost.
Clinical Presentation
Symptoms:
Presentation varies with site and age
Neonates may present with purpura fulminans, arterial stroke, or abdominal vein thrombosis
Older children and adolescents may experience deep vein thrombosis (DVT) symptoms like limb swelling, pain, erythema, and warmth
Pulmonary embolism (PE) can manifest as dyspnea, chest pain, tachypnea, or cyanosis
Arterial events may include stroke, limb ischemia, or myocardial infarction.
Signs:
Physical findings can include unilateral limb edema, tenderness, venous distension, skin discoloration (cyanosis, pallor), absent pulses in affected limbs, respiratory distress, hypoxia, and neurological deficits
Purpura fulminans is characterized by ecchymotic lesions that progress to necrosis.
Diagnostic Criteria:
No specific diagnostic criteria for thrombophilia itself, but diagnosis of VTE in children often relies on clinical suspicion confirmed by imaging (ultrasound, CT venography, MRI)
Guidelines from organizations like the American Society of Hematology (ASH) and the International Society on Thrombosis and Haemostasis (ISTH) provide recommendations for testing.
Diagnostic Approach
History Taking:
Key history points include a personal or family history of VTE, presence of acquired risk factors (immobility, surgery, trauma, malignancy, central venous catheters, infection, dehydration, certain medications like L-asparaginase or oral contraceptives), congenital heart disease, inflammatory bowel disease, nephrotic syndrome, and genetic predisposition syndromes
Neonatal history of complicated birth or maternal thrombophilia is important.
Physical Examination:
Systematic examination should focus on assessing for signs of VTE in all major venous and arterial beds
This includes thorough inspection and palpation of extremities, auscultation of the chest, neurological assessment, and evaluation of skin integrity
Assess for signs of underlying conditions like malignancy or vasculitis.
Investigations:
Initial investigations for suspected VTE include Doppler ultrasound for DVT, CT pulmonary angiography for PE, and MRI/CT for arterial thrombosis
For thrombophilia testing, a stepwise approach is recommended
Common inherited thrombophilias tested include: Factor V Leiden mutation (PCR), Prothrombin G20210A mutation (PCR), Antithrombin deficiency (functional assay), Protein C deficiency (functional assay), Protein S deficiency (functional assay)
Acquired conditions like Antiphospholipid Syndrome (APS) require specific antibody testing (lupus anticoagulant, anticardiolipin antibodies, anti-beta2 glycoprotein I antibodies).
Differential Diagnosis:
Differentiating VTE from other conditions is crucial
In infants, differential diagnoses for purpura fulminans include sepsis, disseminated intravascular coagulation (DIC), and meningococcemia
For limb swelling, consider cellulitis, trauma, or lymphatic obstruction
For dyspnea, consider pneumonia, asthma exacerbation, or cardiac conditions
For stroke, consider metabolic disorders, infections, or trauma.
When To Test For Thrombophilia
Strong Indications:
Strong indications include: 1
Unprovoked VTE (arterial or venous) in children and adolescents
2
VTE in neonates with significant risk factors or recurrent events
3
Family history of thrombophilia with VTE in a first-degree relative
4
Certain high-risk medical conditions like nephrotic syndrome with VTE, or inflammatory bowel disease with VTE
5
Recurrent VTE despite adequate anticoagulation.
Relative Indications:
Relative indications (testing may be considered based on clinical context) include: 1
Provoked VTE with strong risk factors and recurrence risk assessment
2
Arterial stroke in children with no other identifiable cause
3
Family history of VTE in a more distant relative without personal VTE.
Considerations For Testing:
Testing should be performed when the results will influence management, such as duration of anticoagulation or need for family screening
Consider testing in children with specific genetic predispositions or severe VTE at a young age
Testing should ideally be done after the acute thrombotic event has resolved and ideally when not on anticoagulation or when specific assays allow for it.
When Not To Test For Thrombophilia
Avoid Testing In Low Risk:
Avoid routine testing in: 1
Children with provoked VTE due to transient, reversible risk factors (e.g., short period of immobilization, minor trauma) where anticoagulation is clearly indicated and of limited duration
2
Asymptomatic individuals with a family history of thrombophilia but no personal history of VTE
3
Conditions where VTE is a predictable complication without a primary thrombophilia component (e.g., some cancers where anticoagulation is standard prophylaxis).
Testing Limitations:
Be aware that many inherited thrombophilias are common and may be present in healthy individuals
Testing may lead to unnecessary anxiety and over-treatment
Acquired risk factors for thrombosis are far more common than inherited thrombophilias in the pediatric population
The clinical utility of genetic testing for certain thrombophilias in the absence of VTE is debated.
Impact Of Anticoagulation:
Some thrombophilia tests (e.g., Protein C and S functional assays) can be significantly affected by anticoagulation therapy
It is often best to perform these tests before initiating or after discontinuing anticoagulation, or use specialized assays that are less affected by warfarin
Factor V Leiden and Prothrombin gene mutation testing (PCR) are not affected by anticoagulation.
Management Of Thrombophilia
Acute Management:
Acute management of VTE in children typically involves anticoagulation with unfractionated heparin, low molecular weight heparin (LMWH), or direct oral anticoagulants (DOACs) depending on age and clinical situation
The choice of anticoagulant and duration are guided by the VTE event, risk factors, and patient characteristics.
Long Term Management:
Long-term management strategies depend on the underlying cause of thrombosis, presence of thrombophilia, and recurrence risk
For children with inherited thrombophilia and VTE, extended anticoagulation is often considered
Antiphospholipid syndrome requires long-term anticoagulation, often with aspirin as well.
Family Screening:
Family screening for inherited thrombophilias should be considered if a pathogenic mutation is identified in a child with VTE, especially if it significantly impacts long-term management or recurrence risk
Genetic counseling is recommended.
Key Points
Exam Focus:
Focus on the indications for thrombophilia testing in pediatric VTE, understanding when testing is most beneficial and when it is unnecessary
Differentiate between inherited and acquired thrombophilias
Know the common inherited thrombophilias and their genetic basis
Understand the impact of anticoagulation on test results
Recognize high-risk pediatric conditions associated with VTE.
Clinical Pearls:
Always consider acquired risk factors first, as they are far more common than inherited thrombophilias in children
In neonates, VTE is often multifactorial
Testing for thrombophilia should only be done if it will change management
Discuss the implications of positive results with families and consider genetic counseling.
Common Mistakes:
Common mistakes include ordering broad thrombophilia panels without clear indications, misinterpreting test results in the context of anticoagulation, and over-diagnosing thrombophilia in children with simple, provoked VTE
Failure to consider acquired risk factors is also a frequent error.