Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Lupus. 2010 Apr;19(4):460-9. doi: 10.1177/0961203310361485.
Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-beta2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal 'patches' over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays.
膜联蛋白 A5（AnxA5）与磷脂双层结合，形成二维晶体，阻止凝血酶反应中磷脂的可用性。抗磷脂（aPL）抗体导致 AnxA5 的有序结晶出现间隙，暴露出磷脂，从而加速血液凝固反应。在人工磷脂双层和包括内皮细胞、胎盘滋养层和血小板在内的细胞膜上，已经证实了 aPL 抗体介导的 AnxA5 结晶破坏。最近，我们报道了羟氯喹，一种合成的抗疟药物，通过两种机制逆转这种抗体介导的过程：（1）抑制 aPL IgG-β2 糖蛋白 I 复合物的形成；和（2）通过促进在免疫复合物破坏 AnxA5 结晶的区域上形成 AnxA5 晶体“补丁”的第二层。在另一个转化应用中，我们开发了一种机制测定法，该测定法报告了具有 aPL 抗体的血浆中对 AnxA5 抗凝活性的抗性。AnxA5 抗性可能确定了 aPL 综合征患者的一个亚组，对这些患者而言，这是妊娠丢失和血栓形成的一种机制。阐明 aPL 介导的血栓形成和妊娠并发症机制可能为使用靶向治疗和机制测定法来解决这种疾病开辟新的途径。
