Why Antiphospholipid Antibody Syndrome Should Be On Your Radar

A two-hit hypothesis may explain thrombosis in APS: aPLs (first hit) increase the risk of thrombotic events that occur in the presence of another thrombophilic condition (second hit). According to this model, the initiating “first hit” injury disrupts the endothelium and the “second hit” potentiates thrombus formation.¹⁴

Antiphospholipid Antibodies

Anti-β2GPI antibodies are considered the most clinically significant of the aPLs since several studies have shown that aPLs are strongly associated with thrombosis.¹⁵

Domain I of β2GPI was shown to be an integral pathogenic component of this protein. The interaction of β2GPI with phospholipids induces major conformational change in this protein, which exposes hidden epitopes within domain I. Anti-β2GPI with specificity to domain I (anti–Dm1) increases susceptibility to thrombosis, and high titers are present in patients who have all three aPLs.¹⁶ Triple antibody positivity has been associated with a high risk of thrombosis and pregnancy morbidity.¹⁷

Otomo et al recently formulated the antiphospholipid score, to quantify the risk of thrombosis/obstetric events in a cohort of patients with various autoimmune diseases.¹⁸ Five clotting assays for LAC and six enzyme-linked immunosorbent assays (ELISA)—IgG/IgM aCL, IgG/IgM β2GPI, and IgG/IgM phosphatidylserine-dependent antiprothrombin (aPS/PT) antibodies—were included. The authors concluded that combining assays may compensate for the lack of standardization of single assays. High aPL scores (≥30) can provide a useful quantitative index for diagnosing APS and may serve as a predictive marker for thrombosis in autoimmune diseases.¹⁸

The Global APS Score (GAPSS) is another scoring system that provides substantial improvement in risk prediction of thrombosis and pregnancy loss. GAPSS is derived from the combination of independent risk for both thrombosis and loss of pregnancy. It combines the patient’s aPL profile, their conventional cardiovascular risk factors, their autoimmune antibody profile, and their use of thromboprophylactic drugs.¹⁷

Mechanisms of Pregnancy Loss

The mechanism of pregnancy loss associated with aPL remains uncertain. Thrombosis of the microvasculature of the placenta and subsequent infarction resulting in placental insufficiency, fetal growth restriction, and ultimately, fetal loss, represents a possible mechanism. Other potential mechanisms include complement activation leading to a defective placentation mediated directly by aPL and the disruption of the annexin A5 (AnxA5), which is a potent vascular and placental anticoagulant protein.¹³ A decrease in AnxA5 has been shown in aPL-treated endothelial cells.^13,19

In a prospective study known as “Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus (PROMISSE),” researchers have examined 250 pregnant patients with SLE and/or aPL and found that LAC is the primary predictor of adverse pregnancy outcome after 12 weeks’ gestation in aPL-associated pregnancies. If the LAC was not present, aCL and anti-β2GPI alone did not predict adverse pregnancy outcome.^20,21