Antiphospholipid antibodies as cause of pregnancy loss

Abstract

Antiphospholipid antibodies detected by lupus anticoagulant, anticardiolipin or anti-beta2 glycoprotein I assays were associated with fetal loss. Rather than being diagnostic tools only, antiphospholipid antibodies are thought to be pathogenic. The strongest demonstration of their pathogenic role lies in the ability to induce fetal resorptions--the experimental equivalents of the human fetal losses--when passively infused in pregnant naive animals. However, still debated is how the antibodies might induce the obstetrical manifestations. Thrombotic events at the placental levels might be related to endothelial cell activation, inhibition of protein C/S system and fibrinolysis as well as to Annexin V displacement. However, the thrombophilic state apparently cannot explain all the miscarriages and a direct antibody-mediated damage on the trophoblast has been suggested. During differentiation to syncytium, trophoblasts express cell membrane anionic phospholipids that can bind beta2 glycoprotein I, the main cationic phospholipid binding protein recognized by the antiphospholipid antibodies. Adhered beta2-glycoprotein I might be recognized by the antibodies that, once bound, strongly interfere with in vitro trophoblast cell maturation so resulting in a defective placentation. These mechanisms have been suggested to play a role in early fetal loss, while thrombotic events would be responsible for miscarriages late in the pregnancy.

Disturbances in placental immunology: ready for therapeutic interventions?

“…The production of trophoblast-specific proteins (human chorionic gonadotropin) and adhesion molecules (α1 and α5 integrins, as well as E and VE cadherins) was also reduced [18,19]. Certain antibodies, such as those against annexin V, were also shown to induce trophoblast apoptosis [3]. These effects have recently been confirmed by the use of placental explant cultures, where it was shown that aPL antibodies increased placental apoptosis, decreased villous trophoblast proliferation and reduced extra villous trophoblast invasion through matrigel [20].…”

“…Although these antibodies have been shown to bind to a wide variety of membrane phospholipids (e.g. cardiolipin and phosphatidyl serine), they do not appear to bind directly to phospholipid but rather to phospholipid-binding proteins or to phospholipid/phospholipid-binding protein complexes [3,15]. One of these proteins is beta 2 glycoprotein (β2GPI), which is localised on extravillous cytotrophoblast and syncytiotrophoblast [15,16].…”

“…Antiphospholipid syndrome and recurrent fetal loss High titres of antiphospholipid (aPL) antibodies occur in 30-40% of patients with a history of recurrent miscarriage [2,3]. Although these antibodies have been shown to bind to a wide variety of membrane phospholipids (e.g.…”

“…It is possible, therefore, that the function of aPL antibodies may be to disrupt the function of β2GPI. Although such antibodies have been implicated in coagulation and thrombosis, a number of studies indicated that antiphospholipid antibodies can affect trophoblast behaviour in vitro [2,3]. These effects include inhibition of trophoblast proliferation and the diminished invasion of maternal spiral arteries [17].…”

“…Recurrent fetal loss, also termed recurrent spontaneous abortion (RSA) or recurrent miscarriage, is defined by the loss of three or more consecutive pregnancies of non-viable fetuses [2,3]. This may occur before 12 weeks of pregnancy (early loss) or post 12 weeks of gestation (late loss).…”