期刊
LUPUS
卷 19, 期 4, 页码 460-469出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/0961203310361485
关键词
annexin A5; annexins; antiphospholipid antibodies; antiphospholipid syndrome; pregnancy losses; thrombosis
类别
资金
- National Institutes of Health/the National Heart Lung and Blood Institute [RO1 HL061331, RC1 HL101031, RO1 HL096944]
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-beta 2glycoprotein 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. Lupus (2010) 19, 460-469.
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