What is the role of Antiphospholipid Syndrome (APLS) screening in patients with a history of recurrent miscarriages or blood clots?

Role of Antiphospholipid Syndrome (APLS) Screening

APLS screening should be performed in patients with recurrent pregnancy loss (≥3 miscarriages before 10 weeks gestation), unexplained thrombotic events (especially in young adults <50 years), cryptogenic stroke/TIA, or a history of venous thromboembolism, as these populations have the highest yield for diagnosis and benefit most from targeted anticoagulation therapy. 1, 2, 3

When to Screen: High-Yield Clinical Scenarios

Obstetric Indications

• Screen women with ≥3 early pregnancy losses (before 10 weeks gestation), as this threshold triggers strong treatment recommendations and represents the most common obstetric manifestation of APLS 2, 3
• Screen for one or more unexplained late pregnancy losses (≥10 weeks), premature births before 34 weeks due to eclampsia/preeclampsia, or placental insufficiency 2
• Testing should occur at multiple time points including after conception, as pregnancy itself can trigger or unmask APLS in previously seronegative patients 4

Thrombotic Indications

• Screen patients with cryptogenic stroke or TIA, particularly those under 50 years of age, as the association between antiphospholipid antibodies and stroke is strongest in younger adults 1
• Screen patients with unexplained venous thromboembolism, arterial thrombosis, or recurrent thrombotic events in multiple vascular beds 1, 3
• Consider screening in patients with a history of thrombosis plus rheumatological disease, as approximately 13% of APLS patients present with stroke as their initial manifestation 1

When NOT to Screen

• Do not systematically screen older populations (>50 years) with multiple vascular risk factors, as there is no evidence supporting routine testing in this group and the prevalence of incidental positive antibodies increases with age without clear clinical significance 1
• Do not screen asymptomatic patients with only 1-2 miscarriages without other risk factors, as they do not meet treatment thresholds 2

Laboratory Testing Requirements

Diagnostic Criteria

Diagnosis requires BOTH persistent laboratory positivity AND clinical criteria to be met 2, 5

Laboratory Panel

• Test for lupus anticoagulant (LAC), which conveys the greatest risk for adverse pregnancy outcomes (RR 12.15) and is the most clinically significant antibody 2, 5
• Test for anticardiolipin antibodies (IgG and IgM isotypes) using standardized ELISA 5, 6
• Test for anti-β2-glycoprotein I antibodies (IgG and IgM isotypes) using standardized ELISA 5, 6
• Repeat testing after 12 weeks to confirm persistence, as transient positivity does not meet diagnostic criteria and does not warrant treatment 2, 5

Non-Criteria Antibodies

• Consider testing for anti-phosphatidylserine/prothrombin antibodies (aPS/PT IgG/IgM), which can identify up to 60.9% of seronegative APLS patients who would otherwise remain untreated 7
• Consider anti-β2GPI Domain 1 IgG testing, as it appears to be a significant risk factor for pregnancy morbidity 7
• IgA isotypes of anticardiolipin and anti-β2GPI may help identify additional at-risk patients, though these are not part of standard diagnostic criteria 7

Clinical Implications of Positive Screening

Full APLS Syndrome (Laboratory + Clinical Criteria Met)

• For obstetric APLS: Initiate prophylactic or intermediate-dose LMWH plus low-dose aspirin (75-100 mg daily) throughout pregnancy and for at least 6 weeks postpartum 2, 3
• For thrombotic APLS: Use therapeutic-dose LMWH (or 75% of therapeutic dose) plus low-dose aspirin throughout pregnancy and postpartum 2, 3
• For stroke/TIA with full APLS syndrome: Anticoagulation with warfarin targeting INR 2-3 is reasonable over higher intensity anticoagulation (INR >3) to balance bleeding risk against thrombosis risk 1

Isolated Positive Antibodies Without Full Syndrome

• For cryptogenic stroke/TIA with positive antibodies but not meeting full APLS criteria: Use antiplatelet therapy alone (aspirin), as the WARSS/APASS trial showed no benefit of warfarin over aspirin in this population 1
• For asymptomatic pregnant patients with positive antibodies but no clinical criteria: Use only prophylactic aspirin 81-100 mg daily for preeclampsia prophylaxis; do NOT use anticoagulation 2

Critical Pitfalls to Avoid

Testing Errors

• Do not test during acute thrombosis while on anticoagulation, as lupus anticoagulant testing becomes difficult to interpret in anticoagulated patients, though most patients will already be anticoagulated before testing is considered 6
• Avoid single-time-point testing; persistence over 12 weeks is mandatory for diagnosis 2, 5

Treatment Errors

• Never use rivaroxaban in patients with triple-positive antibodies (lupus anticoagulant, anticardiolipin, and anti-β2GPI), as it is associated with excess thrombotic events compared to warfarin 1
• Do not use direct oral anticoagulants (DOACs) in pregnancy, as they are contraindicated due to safety concerns 2
• Avoid vitamin K antagonists in the first trimester (teratogenic) and from week 36 onwards (fetal intracranial bleeding risk) 2

Overtreatment Risks

• Do not anticoagulate patients with only two miscarriages without confirmed APLS or thrombophilia, as this represents overtreatment without evidence of benefit 2
• Recognize that approximately 40.7% of stroke patients may have detectable antiphospholipid antibodies, but these antibodies had no significant effect on stroke recurrence risk in the WARSS/APASS study, emphasizing the importance of full syndrome criteria before escalating to anticoagulation 1