Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug
Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug
复制标题
DOI：
10.1182/blood-2009-04-213520
复制
发表时间：
2010-03-18
期刊：
影响因子：
20.3
通讯作者：
Taatjes, Douglas J.
中科院分区：
文献类型：
--
作者：
Rand, Jacob H.;Wu, Xiao-Xuan;Taatjes, Douglas J.
膜联蛋白A5（AnxA 5）是一种有效的抗凝蛋白，它在磷脂双层（PLB）上结晶，阻止它们用于凝血反应。抗磷脂抗体破坏AnxA 5结合，从而加速凝血反应。这种破坏可能导致血栓形成和流产的抗磷脂综合征（APS）。我们研究了抗疟药羟氯喹（HCQ）是否会影响这种促血栓形成机制。用标记的AnxA 5测量AnxA 5与PLB的结合，并用原子力显微镜成像。免疫球蛋白G水平，AnxA 5，血浆凝固时间测定培养的人脐静脉内皮细胞和合体滋养层细胞系。还测定了APS患者血浆的AnxA 5抗凝活性。HCQ逆转了抗磷脂抗体对AnxA 5的作用，并恢复了AnxA 5与PLB的结合，原子力显微镜证实了这一作用。在人脐静脉内皮细胞和合体化滋养层细胞系的表面上测量了抗磷脂诱导的异常的类似逆转，其中HCQ降低了抗磷脂抗体的结合，增加了细胞表面AnxA 5浓度，并延长了血浆凝固至对照水平。此外，HCQ增加了APS患者血浆的AnxA 5抗凝活性。总之，HCQ逆转了PLB和培养细胞以及APS患者血浆中抗磷脂介导的AnxA 5破坏。这些结果支持新的治疗方法，解决特定的APS疾病机制的概念。（血。2010; 115：2292-2299）
Annexin A5 (AnxA5) is a potent anticoagulant protein that crystallizes over phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating coagulation reactions. This disruption may contribute to thrombosis and miscarriages in the antiphospholipid syndrome (APS). We investigated whether the antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic mechanism. Binding of AnxA5 to PLBs was measured with labeled AnxA5 and also imaged with atomic force microscopy. Immunoglobulin G levels, AnxA5, and plasma coagulation times were measured on cultured human umbilical vein endothelial cells and a syncytialized trophoblast cell line. AnxA5 anticoagulant activities of APS patient plasmas were also determined. HCQ reversed the effect of antiphospholipid antibodies on AnxA5 and restored AnxA5 binding to PLBs, an effect corroborated by atomic force microscopy. Similar reversals of antiphospholipid-induced abnormalities were measured on the surfaces of human umbilical vein endothelial cells and syncytialized trophoblast cell lines, wherein HCQ reduced the binding of antiphospholipid antibodies, increased cell-surface AnxA5 concentrations, and prolonged plasma coagulation to control levels. In addition, HCQ increased the AnxA5 anticoagulant activities of APS patient plasmas. In conclusion, HCQ reversed antiphospholipid-mediated disruptions of AnxA5 on PLBs and cultured cells, and in APS patient plasmas. These results support the concept of novel therapeutic approaches that address specific APS disease mechanisms. (Blood. 2010; 115: 2292-2299)