Taken together, the above reported findings suggest that numerous, heterogeneous and complex events underlie pregnancy complications in APS patients. However several aspects with regard to the events that break out the aPL activity and precipitate the different clinical manifestations of obstetric APS are still debated and need further investigation. Nevertheless, it is nowadays well established the ability of aPL to directly target both the invading trophoblasts and the maternal decidua/endometrial endothelial cells in the human placenta and, then, to induce a negative effect on placentation not necessarily related to prothrombotic or inflammatory events.

From a practical point of view, the knowledge of the aPL-mediated placental action has allowed important therapeutical implications. In clinical practice, several strategies have been proposed to improve the pregnancy outcome, including combinations of aspirin and unfractionated (UFH) or low molecular weight (LMWH) heparin [47–49]. Treatment with heparin is mainly based on the initial assumption that thrombotic events played the major role in APS pregnancy morbidity [46, 47]. However the evidence of alternative mechanisms of aPL-induced placental damage and the success of treatment with heparin on the pregnancy outcome suggested additional mechanisms of action for the drug [50, 51]. Actually it has been demonstrated the ability of LMWH to prevent the aPLs binding to trophoblast cells and to restore in vitro placental invasiveness and differentiation [49]. Accordingly, heparin has been shown to prevent the binding of β2GPI to negatively charged phospholipids (PL), which in turn prevents the deposition of the anti-β2GPI in tissues. Subsequent studies reported the ability of heparin to block the aPL-mediated inhibition of HEEC angiogenic differentiation [52]. As a whole, these results suggest that heparin, by interfering with the aPL binding, is able to prevent the aPL pathogenic action not only on the fetal side of the placenta (trophoblast cells) but also on the maternal one (HEECs).

In addition, other researchers, in line with the aPL/complement-mediated pathogenic action, demonstrated that the protective effect of heparin in the mouse model is linked to its anticomplement activity [50].

The likelihood of a good pregnancy outcome in women with APS is around 75–80 % under correct management. Unfortunately, a significant proportion of women, about 20–21 %, does not respond to the standard treatment and still suffer from miscarriages and adverse pregnancy events [53, 54]. The role of glucocorticoids remains still worthy of further assessment. The addition of 40–60 mg of prednisolone to aspirin alone or associated to heparin during gestation has shown no clear benefits in APS pregnant women in spite of important side effects, such as preterm delivery because of premature rupture of membranes or preeclampsia [55–57]. By contrast, a recent study by Brahman et al. seems to suggest that the addition of low-dose prednisolone (10 mg) from the time of positive pregnancy test up to 14 weeks of gestation may be effective in increasing live birth rate [58]. The addition of intravenous immunoglobulin (IVIg) has not been shown to be superior to heparin and aspirin in unselected patients, while it seems to be efficacious in obstetric APS patients selected for poor prognosis or autoimmune phenomena [59].

A possible explanation for the high proportion of refractory APS might be that not all the mechanisms underlying aPL-mediated pregnancy complications have been clarified. Novel alternative therapies are urgently needed [60]. Given the evidence that β2GPI and the related autoantibodies play a central role in aPL-mediated obstetric manifestations, new molecules able to interfere with β2GPI expression at the placental level have been recently investigated. This is the case of a synthetic peptide, TIFI, sharing structural similarity with the PL-binding site of β2GPI. Through this similarity, TIFI can compete with the β2GPI PL-binding site and displace the molecule from the cell surface, ultimately inhibiting the aPL reaction with the target tissues [61]. Accordingly, this peptide is able to prevent aPL-mediated thrombosis in vivo and to inhibit the in vitro binding of β2GPI to human endothelial cells, murine monocytes, trophoblast cells, and HEECs [46, 61, 62]. Furthermore, when passively infused in naïve pregnant mice, TIFI prevents the aPL-mediated fetal loss [46]. As a whole, these results show how molecules, possibly disrupting the β2GPI placental expression, can inhibit the binding of β2GPI-dependent aPL and, in turn, the aPL-mediated placental damage. At the same time, these results lead to investigate a further and more specific therapeutical approach able to abrogate the aPL pathogenic effects. Indeed, the observation that mice lacking β2GPI show a compromised early pregnancy suggested that functional β2GPI is necessary for optimal implantation and placental morphogenesis [63]. This has led researchers to conceive novel and promising biological therapies useful for refractory APS patients and based on the use of immunomodulatory drugs [64] or a monoclonal antibody which are able to prevent the aPL-mediated activation of the complement and the procoagulant and pro-abortive effects, without interfering with the expression of the placental β2GPI [65, 66].