What is the diagnosis and treatment for Antiphospholipid Syndrome (APS) in children?

Diagnosis and Treatment of Antiphospholipid Syndrome (APS) in Children

Diagnosis

Testing for antiphospholipid antibodies (aPL) should include lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti-β2 glycoprotein-I antibodies (aβ2GPI), with positive results confirmed on two separate occasions at least 12 weeks apart. 1, 2

When to Test for APS in Children

• Test children with unexplained thrombotic events (venous, arterial, or small vessel thrombosis) for aPL 3, 4
• Screen children with immune thrombocytopenia (ITP) who fail to improve after 3-6 months for antiphospholipid antibodies including anticardiolipin antibody (ACA) and lupus anticoagulant (LAC) 1
• Consider testing in children with other autoimmune diseases (particularly systemic lupus erythematosus), thrombocytopenia, hemolytic anemia, chorea, or livedo reticularis 5
• Screen for additional thrombophilic factors including protein C, protein S, antithrombin III, factor V Leiden, and prothrombin gene mutation, especially in children with family history of thrombosis 6

Diagnostic Criteria

• Clinical criteria: Thrombotic events (venous, arterial, or small vessel) or pregnancy morbidity (in adolescents) 2
• Laboratory criteria: Persistent presence of aPL on two occasions ≥12 weeks apart 2
• Moderate titer threshold: ≥40 Units 2
• High titer threshold: ≥80 Units 2
• Triple positivity (positive for LAC, aCL, and aβ2GPI) indicates highest risk for thrombotic events 2

Important Diagnostic Considerations

• Healthy children frequently have transient circulating antiphospholipid antibodies without thrombotic complications, often related to infections 7, 5
• Non-thrombotic manifestations may precede vascular thrombotic events in pediatric APS 3, 8
• Pediatric APS typically presents with large-vessel thrombosis, thrombotic microangiopathy, and rarely obstetric morbidity in adolescents 3
• Consult a pediatric hematologist to eliminate other differential thrombophilic conditions 3

Treatment

Acute Thrombotic Events

For acute thrombosis in children with APS, initiate unfractionated heparin or low-molecular-weight heparin (LMWH) immediately, followed by transition to vitamin K antagonists (warfarin) with target INR 2.0-3.0 for venous thrombosis. 2, 3, 7

• For arterial thrombosis, consider higher intensity anticoagulation with target INR 3.0-4.0 2
• Treatment is the same for primary APS (isolated occurrences) and secondary APS (associated with another autoimmune disease like SLE) 3
• Long-term anticoagulation is required to prevent recurrent thrombotic events after withdrawal of anticoagulation 4

Primary Prevention (Asymptomatic aPL-Positive Children)

For asymptomatic children with positive antiphospholipid antibodies, particularly those with high-risk antibody profiles (triple-positive or high titers), low-dose aspirin (75-100 mg daily) is recommended for primary prevention. 2

• Low-dose aspirin may be considered in children with multiple thrombophilic risk factors and family history of thrombosis, though evidence is limited 6

Catastrophic APS

For catastrophic APS, use aggressive triple therapy: anticoagulation plus intravenous corticosteroid pulse therapy plus plasma exchange. 2, 3

• Consider adding intravenous immunoglobulin for children and adolescents with catastrophic APS 3
• Eculizumab (complement inhibitor) and sirolimus appear promising for catastrophic APS 3, 8

Adjunctive Therapies

• Consider adding hydroxychloroquine to standard therapy for patients with primary APS, as it may decrease complications 2
• Statins may have a role due to anti-inflammatory and immunomodulatory properties 2

Critical Warnings

• Avoid direct oral anticoagulants (DOACs) in triple-positive APS patients due to increased risk of recurrent thrombotic events, especially arterial thrombosis and stroke 2
• If a triple-positive patient is already on a DOAC, transition to warfarin therapy 2
• Avoid medications that adversely affect platelet function in children with thrombocytopenia 1

Special Considerations for Adolescents

• Screen for additional prothrombotic risk factors 3
• Provide counseling regarding contraceptive strategies (avoid estrogen-containing contraceptives due to thrombotic risk) 3
• Address lifestyle recommendations, treatment adherence, and mental health issues associated with this chronic autoimmune thrombophilia 3
• For pregnant adolescents with obstetric APS, use combined therapy with low-dose aspirin (81-100 mg daily) and prophylactic-dose heparin (usually LMWH) 2
• For pregnant adolescents with thrombotic APS, use therapeutic-dose heparin plus low-dose aspirin throughout pregnancy and postpartum 2

Monitoring

• Regular monitoring of anticoagulation therapy is essential 2
• Use anti-Xa monitoring for patients on heparin or LMWH 2
• Patients with high-risk profiles (triple-positive or double-positive with LAC) require more intensive anticoagulation and closer monitoring 2

Refractory Cases

• For patients who fail standard therapy, consider increasing the target INR range 2
• Consider hydroxychloroquine as adjunctive therapy for refractory APS 2
• B cell inhibitors and complement inhibitors are emerging therapies, especially for catastrophic APS 8