*3.2.3 Inflammation, complement activation, and disruption of annexin shield*

A well-known fingerprint of APS placenta histology is inflammation. In addition to increased release of cytokines such as IL-1β as described above, aPLs effect complement activation. Girardi et al. [59] had shown that aPLs increased complement

deposition on the trophoblast surface in vitro. While, murine models of APS demonstrate a crucial role of the complement system in determining pregnancy morbidity [59–61], on the other hand, the placenta of women with APS showed deposition of C4d and C3b [62]. Moreover, data from the PROMISSE study in pregnant SLE and/or APS or aPL positive patients, showed that detection of increased Bb and sC5b-9 levels early in pregnancy was predictive of adverse pregnancy outcome, confirming complement activation as a contributor to pregnancy failure [63]. Complement activation stimulates neutrophils to release tumor necrosis factor-alfa (TNF-α); pregnant mice lacking TNF-α are protected from pregnancy loss induced by injections of aPLs [64].

Last, but not least, aPLs disrupt the binding of annexin V, an anticoagulant protein that crystallizes over phospholipid bilayers blocking their availability for coagulation reactions. This disruption additionally contributes to both thrombosis and miscarriages in the APS [65, 66].

Overall, the pathogenetic mechanisms by which aPLs cause obstetric complications are complex and include both inflammatory and non-inflammatory mechanisms, which are not mutually exclusive and may coincide in time. This could reflect the different characteristics of fetal complications. Adequate invasion of the trophoblast into the maternal decidua remains crucial for a normal-evolving pregnancy. Inadequate invasion of the maternal spiral arteries by the extravillous cytotrophoblast and severe inflammation of the placenta, together with reduced hormone secretion leading to early miscarriages are thought to be the major pathogenic mechanisms of early pregnancy loss in APS patients. While, a lack of transformation of the maternal spiral arteries together with activation of the complement and of the coagulation cascade are responsible for late pregnancy loss and preeclampsia.
