REDUCTION OF ANNEXIN IN ANTIPHOSPHOLIPID PREGNANCY LOSS

我们最近发现了抗磷脂抗体综合征导致妊娠丢失的血栓形成机制，即抗磷脂抗体从滋养层的阴离子磷脂表面置换胎盘抗凝蛋白膜联蛋白-V，并加速该部位的凝血反应。这项资助的核心假设是：a）Annexin-V通过屏蔽阴离子磷脂，在母体血液和胎盘绒毛界面的解剖部位起血栓调节作用（其显著加速凝固酶反应）参与凝固反应; B）抗磷脂抗体从磷脂表面竞争性置换膜联蛋白-V，破坏膜联蛋白-V“屏蔽”，从而增加血栓形成阴离子磷脂的暴露。该过程导致在与胎儿滋养层接触的部位处的母体循环中的血栓形成，并最终导致妊娠并发症和损失，并确定其临床疗效。我们的具体目标是：1）确定抗磷脂抗体和辅因子减少滋养层顶膜上膜联蛋白-V的量并加速凝血反应的机制; 2）开发降低膜联蛋白-V与磷脂结合和抑制膜联蛋白-V抗凝活性的试验。这一创新项目为阐明抗磷脂综合征中妊娠丢失的机制开辟了一条新的道路，并有可能改善诊断和治疗。

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.