Diagnosing Antiphospholipid Syndrome (APS) in Children
Diagnose pediatric APS using the same laboratory criteria as adults—testing for lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-beta2 glycoprotein I antibodies (aβ2GPI) IgG/IgM—with two consecutive positive tests at least 12 weeks apart, combined with clinical manifestations of thrombosis or non-thrombotic features. 1, 2
Laboratory Testing Approach
First-Line Antibody Panel
Test all three antiphospholipid antibodies simultaneously: 1, 2
Lupus anticoagulant (LA): Use 3-step methodology (screening, mixing, confirmation) with parallel testing using both activated partial thromboplastin time (APTT) and dilute Russell's viper venom time (dRVVT)—omitting either test increases underdiagnosis risk by up to 55% 1
Anticardiolipin antibodies (aCL): Measure IgG and IgM isotypes by ELISA or validated solid phase assays, with positivity defined as values above the 99th percentile of normal controls 1, 2
Anti-beta2 glycoprotein I antibodies (aβ2GPI): Measure IgG and IgM isotypes by solid phase assays, with positivity defined as values above the 99th percentile of normal controls 1, 2
Confirmation Testing
Repeat all positive tests after exactly 12 weeks (minimum) to confirm persistent positivity and exclude transient antibodies, which are common in children following infections 3, 4. This confirmation step is critical because many healthy children have transient circulating antiphospholipid antibodies without thrombotic complications 4, 5.
Clinical Context for Diagnosis
Thrombotic Manifestations in Children
Look for these specific presentations that differ from adults: 6, 7, 8
- Large-vessel thrombosis: Deep venous thrombosis, stroke, and pulmonary embolism are the most common presentations 6, 7
- Thrombotic microangiopathy: More frequent in pediatric APS than adult disease 6
- Recurrent thrombosis: Children have a higher risk of recurrent thromboembolic events compared to adults 7
Non-Thrombotic Manifestations
Non-thrombotic clinical features are frequently seen in pediatric APS and may precede vascular thrombotic events, making early recognition crucial: 6, 8
- Thrombocytopenia (consider APS testing in children with ITP that persists beyond 3-6 months) 3
- Neurological manifestations
- Cardiac valve abnormalities
- Livedo reticularis
Risk Stratification Based on Antibody Profile
High-Risk Profile
Triple positivity (LA + aCL + aβ2GPI) carries the highest thrombotic risk and warrants aggressive management: 1, 2
- Triple-positive children have more severe presentations with frequent recurrences 8
- IgG isotype antibodies are clinically more relevant than IgM 1, 2, 9
- Medium/high titer antibodies (>99th percentile or >40 Units) are most important for diagnosis 1, 2
Moderate-Risk Profile
Double positivity with concordant isotype (both aCL and aβ2GPI of the same isotype) significantly increases diagnostic confidence 1, 2
Lower-Risk Profile
Isolated single antibody positivity, particularly isolated IgM, requires careful clinical correlation and may represent transient antibodies 1, 9
Special Considerations for Pediatric Populations
Age-Related Differences
- Gender distribution: Unlike adult APS with marked female predominance, pediatric APS shows more even gender distribution 7
- Primary vs. Secondary APS: Evaluate for underlying systemic lupus erythematosus (SLE), as secondary APS is common in children 6, 7
When to Test for APS in Children
Consider testing in these specific scenarios: 3, 4
- Any child with unexplained thrombotic event (venous or arterial)
- Immune thrombocytopenia (ITP) persisting beyond 3-6 months without improvement
- Stroke or cerebrovascular events
- Recurrent pregnancy loss in adolescents (rare but possible)
- Children with SLE or other autoimmune diseases
Differential Diagnosis to Exclude
Before confirming APS diagnosis, rule out: 6, 5
- Other inherited thrombophilias (Factor V Leiden, prothrombin mutation, protein C/S deficiency)
- Thrombotic thrombocytopenic purpura (TTP)—distinguished by severely reduced ADAMTS13 activity ≤10% 2
- Transient infection-related antibodies
Critical Pitfalls to Avoid
Do not diagnose APS based on a single positive test—transient antibodies after infections are extremely common in children and do not represent true APS 4, 5. The 12-week confirmation period is mandatory 3, 1.
Do not test during acute illness or immediately post-infection—wait until the child has recovered to avoid false-positive results from transient antibodies 4, 5.
Do not rely on classification criteria alone—the adult APS classification criteria are poorly validated in pediatric populations where pregnancy-related complications are absent 7, 8. Clinical judgment combined with laboratory findings is essential.
Ensure proper LA testing technique—both APTT and dRVVT must be performed in parallel, as using only one method misses up to 55% of cases 1. LA testing may be unreliable during anticoagulation, requiring specialized approaches 1, 2.
Interpret isolated IgM positivity cautiously—particularly isolated IgM aβ2GPI has limited diagnostic value in thrombotic APS, though it may be relevant in obstetric APS in adolescents 9.
Consultation and Referral
Refer all children with suspected or confirmed APS to a pediatric hematologist for comprehensive evaluation, exclusion of other thrombophilic conditions, and management planning 6, 5. The rarity of pediatric APS and complexity of long-term anticoagulation in active children necessitates specialist involvement 4, 7.