Pathophysiology of Antiphospholipid Syndrome in Recurrent Pregnancy Loss
Antiphospholipid antibodies cause recurrent pregnancy loss through a "two-hit" mechanism involving direct placental damage, thrombosis, and complement-mediated inflammation, leading to placental insufficiency and fetal loss. 1, 2
Core Pathophysiological Mechanisms
The pathogenesis of APS-related pregnancy loss operates through multiple interconnected pathways:
Primary Antibody-Mediated Damage
Antiphospholipid antibodies target phospholipid-binding proteins (primarily β2-glycoprotein I) on trophoblast and endothelial cell surfaces, initiating cellular activation and dysfunction 1, 3
The "two-hit" model explains disease manifestation: first, aPL antibodies bind to target cells; second, a triggering event (pregnancy itself, infection, or inflammation) amplifies the pathogenic response, culminating in thrombosis and placental damage 2
Direct trophoblast invasion is impaired by aPL antibodies, preventing adequate placental implantation and development in early pregnancy 2, 3
Thrombotic and Vascular Mechanisms
Inhibition of prostacyclin formation reduces vasodilation and increases platelet aggregation at the maternal-fetal interface 1
Protein C activation is blocked, eliminating a critical natural anticoagulant pathway and promoting microthrombosis in placental vessels 1, 3
Platelet activation is enhanced through direct antibody effects, creating a prothrombotic state in uteroplacental circulation 1, 4
Endothelium-derived relaxing factor (nitric oxide) production is limited, further compromising placental blood flow 1
Fibrinolysis is inhibited, allowing microthrombi to persist in placental vessels and progressively compromise fetal perfusion 1, 3
Inflammatory and Complement Pathways
Complement cascade activation (particularly C3 and C5) occurs at the maternal-fetal interface, causing direct tissue damage and amplifying inflammation 4, 5
Endothelial cell activation releases pro-inflammatory cytokines and adhesion molecules, recruiting inflammatory cells to the placenta 3, 4
Tissue factor expression increases on endothelial and trophoblast cells, initiating the coagulation cascade locally within placental vessels 4
Clinical Consequences of Pathophysiology
Early Pregnancy Loss (Before 10 Weeks)
Inadequate trophoblast invasion and placental development leads to early embryonic demise, manifesting as recurrent first-trimester losses 2, 5
Three or more consecutive losses before 10 weeks is the diagnostic threshold for obstetric APS in this category 6
Late Pregnancy Complications (After 10 Weeks)
Placental insufficiency from progressive microthrombosis causes fetal growth restriction, with odds ratio of 4.7 for IUGR in high-risk aPL profiles 7
Preeclampsia develops due to abnormal placentation and endothelial dysfunction, with odds ratio of 2.3 in high-risk aPL patients 7
Premature delivery before 34 weeks occurs secondary to severe preeclampsia, eclampsia, or placental insufficiency 6, 5
Unexplained fetal death at or after 10 weeks results from acute placental thrombosis or chronic placental failure 6
Risk Stratification Based on Antibody Profile
Highest Risk Profile (Triple-Positive)
Lupus anticoagulant (LAC) positivity is the strongest independent predictor, with relative risk of 12.15 for adverse pregnancy outcomes 6, 8
Triple-positive patients (LAC + anticardiolipin + anti-β2GPI) carry the highest risk for both thrombotic events and pregnancy complications 7, 1, 4
Double-positive with LAC represents the second-highest risk category, requiring aggressive management 1
Moderate Risk Profile
Moderate-to-high antibody titers (≥40 units or ≥99th percentile) for anticardiolipin or anti-β2GPI antibodies indicate significant risk 7, 6
High-risk titers are defined as ≥80 units by the 2023 ACR/EULAR criteria 1
Lower Risk Profile
Isolated anticardiolipin or anti-β2GPI at low-medium titers carry lower risk and may not meet diagnostic criteria for treatment 8
Single positive tests or transient positivity do not indicate true APS and should not trigger treatment 6
Management Based on Pathophysiology
Standard Treatment for Obstetric APS
Low-dose aspirin (81-100 mg daily) starting before 16 weeks inhibits platelet aggregation and reduces thromboxane production at the placental interface 1, 6, 8
Prophylactic-dose LMWH throughout pregnancy (enoxaparin 40 mg daily or dalteparin 5000 units daily) prevents microthrombosis in placental vessels 1, 6, 8
Combined aspirin plus LMWH is strongly recommended for all patients meeting obstetric APS criteria, as this addresses both platelet and coagulation pathways 7, 1, 6
Adjunctive Therapies Targeting Inflammation
Hydroxychloroquine (200-400 mg daily) may be added as it has anti-inflammatory and immunomodulatory properties that may decrease pregnancy complications 1, 6, 8
Hydroxychloroquine is conditionally recommended for primary APS or refractory obstetric APS with pregnancy loss despite standard therapy 1, 8
Treatment for Thrombotic APS in Pregnancy
Therapeutic-dose LMWH plus low-dose aspirin is required throughout pregnancy and for 6-12 weeks postpartum in women with prior thrombotic events 1, 6, 8
Postpartum anticoagulation for at least 6 weeks is critical as thrombotic risk persists after delivery 6, 8
Critical Diagnostic Requirements
Laboratory Confirmation
Persistent antibody positivity on two occasions at least 12 weeks apart is mandatory to exclude transient antibodies, which are common and do not indicate true APS 6, 8
Testing must include all three antibodies: lupus anticoagulant, anticardiolipin (IgG/IgM), and anti-β2GPI (IgG/IgM) 1, 6
Moderate-to-high titers are required: ≥40 units (or ≥99th percentile) for aCL and anti-β2GPI 7, 6
Two positive LAC tests using different detection methods are necessary for confirmation 6
Clinical Criteria
One of three specific pregnancy complications must be present: three or more consecutive losses before 10 weeks, one or more unexplained fetal deaths at or after 10 weeks, or one or more premature births before 34 weeks due to preeclampsia/eclampsia/placental insufficiency 6
Other causes must be excluded before attributing pregnancy loss to APS 6
Common Pitfalls to Avoid
Never diagnose APS based on a single positive test - transient antibodies are common after infections and do not indicate disease 6
Do not use combined estrogen-progestin contraceptives in aPL-positive women due to synergistic thrombotic risk 6
Avoid direct oral anticoagulants (DOACs) in triple-positive APS - they are associated with excess thrombotic events compared to warfarin 1, 6
Low-titer antibodies that do not meet diagnostic criteria should not trigger full APS treatment protocols 8