期刊
THROMBOSIS RESEARCH
卷 121, 期 2, 页码 183-191出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2007.03.019
关键词
antithrombotic; fibrinogen gamma chain C-terminus; platelet; clumping factor A; fibrinogen binding protein
We previously reported that the fibrinogen-binding segment (residues 221-550) of Staphylococcus aureus clumping factor A (ClfA), which binds to fibrinogen gamma chain C-terminus, exerted inhibitory effects on platelet aggregation and fibrin clot formation in vitro. Here, we further demonstrated the effectiveness of using ClfA(221-550) to inhibit platelet-rich thrombus formation in vivo. Platelet-rich thrombi were formed in the mesenteric venules of fluorescein-loaded mice by filtered tight illumination. It grew rapidly and ultimately resulted in the cessation of blood flow due to vessel occlusion. Given by intravenous bolus injection, ClfA(221-550) delayed occlusive thrombi formation in a dose-dependent manner: 2-, 3- and 4.5-fold prolongations of vessel occlusion time were attained with 0.69, 6.9 and 34.5 mg/kg of ClfA(221-550), respectively. Reduced fibrin clot formation at the late phase with plasmas, which were prepared from ClfA(221-550)-treated mice, was also dose-dependent. The suppression of fibrin formation ex vivo coincided with the delay of occlusive thrombus formation in vivo, suggesting that the antithrombotic effect of ClfA(221-550) may result from the blockade of fibrinogen gamma chain C-terminal functions, in mediating platelet aggregation and fibrin clot formation. Administration of ClfA(221-550) also lengthened the tail bleeding of mice; however, significant effect was achieved only with a higher dosage, namely 34.5 mg/kg. These results together showed that blockade of fibrinogen gamma chain C-terminus with ClfA(221-550) preferentially affected platelet-rich thrombus formation rather than normal haemostasis, thus providing a rationale for selecting fibrinogen gamma chain C-terminus as a new target for thrombotic intervention. (c) 2007 Elsevier Ltd. All rights reserved.
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