REDUCTION OF ANNEXIN IN ANTIPHOSPHOLIPID PREGNANCY LOSS

我们最近在抗磷脂抗体综合征中发现了一种导致妊娠丢失的血栓形成机制，即抗磷脂抗体取代滋养细胞阴离子磷脂表面的胎盘抗凝蛋白Annexin-V，并加速该部位的凝血反应。这项赠款的核心假设是：a)Annexin-V通过屏蔽阴离子磷脂(显著加速凝血酶反应)参与凝血反应，在母亲血液和胎盘绒毛交界处的解剖部位发挥血栓调节作用；b)抗磷脂抗体竞争性地取代磷脂表面的Annexin-V，破坏Annexin-V的“盾牌”，从而增加导致血栓的阴离子磷脂的暴露。这一过程会导致母体循环中与胎儿滋养细胞交界处的血栓形成，最终导致妊娠并发症和丢失，并决定其临床疗效。我们的具体目标是：1)确定抗磷脂抗体和辅因子减少滋养细胞顶膜膜联蛋白-V数量并加速凝血反应的机制(S)；2)建立减少膜联蛋白-V与磷脂结合和抑制膜联蛋白-V抗凝活性的实验。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途径，并可能导致诊断和治疗的改进。

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.