REDUCTION OF ANNEXIN IN ANTIPHOSPHOLIPID PREGNANCY LOSS

点击翻译按钮获取中文摘要

We recently discovered a thrombogenic mechanism for pregnancy loss in the antiphospholipid antibody syndrome that antiphospholipid antibodies displace the placental anticoagulant protein, annexin-V, from the anionic phospholipid surfaces of trophoblasts and accelerate coagulation reactions at that site. The core hypotheses of this grant are: a) Annexin-V serves a thromboregulatory role at the anatomic site where maternal blood and placental villi interface by shielding anionic phospholipids (which markedly accelerate coagulation enzyme reactions) from participation in coagulation reactions and; b) antiphospholipid antibodies competitively displace annexin-V from that phospholipid surface, disrupting the annexin-V "shield", thereby increasing the exposure of the thrombogenic anionic phospholipid. This process leads to thrombosis in the maternal circulation at the sites of interface with fetal trophoblasts and to ultimately to pregnancy complications and losses and determine their clinical efficacy. Our specific aims are: 1) To determine the mechanism(s) by which antiphospholipid antibodies and cofactors reduce the quantity of annexin-V on trophoblast apical membrane and accelerate coagulation reactions and 2) To develop tests for the reduction of annexin-V binding to phospholipids and the inhibition of annexin-V anticoagulant activity. This innovative project opens a new path toward elucidating the mechanism of pregnancy loss in the antiphospholipid syndrome and is likely to lead to improved diagnosis and treatment.