Evidence for heterogeneity of the obstetric antiphospholipid syndrome: thrombosis can be critical for antiphospholipid-induced pregnancy loss
Evidence for heterogeneity of the obstetric antiphospholipid syndrome: thrombosis can be critical for antiphospholipid-induced pregnancy loss
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DOI：
10.1111/j.1538-7836.2011.04475.x
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发表时间：
2011-10-01
影响因子：
10.4
通讯作者：
Martin, T.
中科院分区：
文献类型：
--
作者：
Poindron, V.;Berat, R.;Martin, T.
背景：在抗磷脂综合征期间，抗磷脂抗体与血栓形成和反复妊娠丢失有关。一些实验结果表明，纯化的抗磷脂抗体直接导致炎症导致的妊娠丢失，或导致滋养层界面膜联蛋白A5屏障的破坏。我们以前发现，被动转移CIC15，一种与心磷脂和膜联蛋白A5结合的单克隆抗磷脂抗体，可以诱导妊娠小鼠的胎儿吸收。目的：探讨CIC15致妊娠流产的机制。方法/结果：我们发现CIC15通过一种可能与促凝血活性有关的新机制导致胎儿丧失。时间进程与之前描述的模型不同，组织学分析显示，胎盘没有任何炎症迹象，但显示出一些血栓事件的迹象。尽管有这些不同之处，CIC15和“炎症性”模型有一些相似之处：缺乏对FcγRI/III的依赖，以及肝素在防止胎儿丢失方面的有效性。然而，后一种观察在这里主要归因于抗凝而不是补体抑制，因为磺达帕丁钠和水飞蓟素显示出相似的疗效。在体外，CIC15可增强心磷脂诱导的凝血酶生成。最后，使用表面敏感方法的组合，我们表明，尽管CIC15结合了心磷脂-膜联蛋白A5的复合体，但它不能破坏膜联蛋白A5的二维有序阵列。结论：这种人类单抗通过一种涉及血栓形成的新机制导致妊娠丢失。这一机制增加了产科抗磷脂综合征的异质性。
Background: Antiphospholipid antibodies are associated with thrombosis and repeated pregnancy losses during the antiphospholipid syndrome. Several experimental findings indicate that purified antiphospholipid antibodies are directly responsible for inflammation-induced pregnancy losses, or for disruption of the annexin A5 shield at the trophoblastic interface. We previously showed that passive transfer of CIC15, a monoclonal antiphospholipid antibody binding to cardiolipin and annexin A5 that was isolated from a patient with primary antiphospholipid syndrome, induces fetal resorption in pregnant mice. Objectives: To investigate the mechanisms of CIC15-induced pregnancy loss. Methods/results: We show that CIC15 induces fetal loss through a new mechanism that is probably related to procoagulant activity. The time course is different from those of previously described models, and histologic analysis shows that the placentas are devoid of any sign of inflammation but display some signs of thrombotic events. Despite these differences, the CIC15 and 'inflammatory' models share some similarities: lack of Fc gamma RI/III dependency, and the efficacy of heparin in preventing fetal losses. However, this latter observation is here mostly attributable to anticoagulation rather than complement inhibition, because fondapar-inux sodium and hirudin show similar efficiency. In vitro, CIC15 enhances cardiolipin-induced thrombin generation. Finally, using a combination of surface-sensitive methods, we show that, although it binds complexes of cardiolipin-annexin A5, CIC15 is not able to disrupt the two-dimensional ordered arrays of annexin A5. Conclusions: This human monoclonal antibody is responsible for pregnancy loss through a new mechanism involving thrombosis. This mechanism adds to the heterogeneity of the obstetric antiphospholipid syndrome.