期刊
BLOOD
卷 124, 期 4, 页码 611-622出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-02-554980
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资金
- National Institutes of Health, National Heart, Lung and Blood Institute [P01 HL087203, R01 HL095084]
- Lupus Research Institute
Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-beta 2-glycoprotein-1 autoantibodies (anti-beta 2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-beta 2GP1autoantibody/beta 2GP1complex in vivo were studied using a laser-induced thrombosis model of APS in a live mouse and human anti-beta 2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled beta 2GP1 and anti-beta 2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-beta 2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, monitored by intercellular adhesion molecule-1 expression. When eptifibatide was infused to block platelet thrombus formation, enhanced fibrin generation and endothelial cell activation were eliminated. Thus, the anti-beta 2GP1 autoantibody/beta 2GP1 complex binds to the thrombus, enhancing platelet activation, and platelet secretion leads to enhanced endothelium activation and fibrin generation. These results lead to a paradigm shift away from the concept that binding of the anti-beta 2GP1 autoantibody/beta 2GP1 complex activates both endothelial cells and platelets toward one in which activation of platelets in response to anti-beta 2GP1 autoantibody/beta 2GP1 complex binding leads to subsequent enhanced endothelium activation and fibrin generation.
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