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Andra T.: What Causes Antiphospholipid Syndrome? – Four Steps, not One Cause

AI Generated

Nov 8, 2026, 17:48

Andra T.: What Causes Antiphospholipid Syndrome? – Four Steps, not One Cause

Andra T., Intelligence Liaison Officer at JMED MCM CBRN, shared a post on LinkedIn:

“What causes antiphospholipid syndrome? Four steps, not one cause.

The name misleads.

The antibodies that matter in APS do not target a phospholipid.

They target β2-glycoprotein I, a plasma protein that circulates closed and circular – over 99% of it.

Bound to an anionic surface it opens, exposing a cryptic epitope in domain I (Gly40–Arg43).

Antibodies to that epitope are the pathogenic subset. β2GPI-dependent lupus anticoagulant carried an odds ratio of 42.3 for past thrombosis; lupus anticoagulant that did not depend on β2GPI, 1.6.

So what starts it?

Genes load it. The first genome-wide study in primary APS (482 patients) found two significant signals: a regulatory variant in HLA class II near HLA-DRA, and STAT4. Odds ratios under 2. Susceptibility, not inheritance.
A trigger breaks tolerance. Mice immunised with H. influenzae, N. gonorrhoeae or tetanus toxoid – all carrying β2GPI-like sequences – made pathogenic anti-β2GPI antibodies and lost pregnancies. The gut commensal Roseburia intestinalis carries mimotopes of both the T-cell and the domain I B-cell epitope, and patient T-cell clones cross-react with it.
One antibody subset persists. Anti-domain I IgG: thrombosis OR 3.5 cross-sectionally, adjusted HR 3.90 over 43 months of follow-up.
A second hit fires it. The part we under-teach. Asymptomatic carriers clot at roughly 1 event per 100 patient-years, and single positivity sits at background population risk. Of 500 catastrophic APS episodes, 65% had an identifiable precipitant, most often infection (49%). The antibodies had usually been present for years.

And the damage is not only clot. Patient IgG activates PI3K–AKT–mTORC in endothelium – 70% vs 11% graft survival at 144 months on sirolimus. In mice, C5a and neutrophils are required for antibody-driven fetal loss; F(ab)′2 fragments cause none.

Still unsettled: whether infection-induced antibodies, post-COVID included, ever become the persistent pathogenic type.”

Andra T.