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Thrombosis

Carboxyl Terminus of ADAMTS13 Directly Inhibits Platelet Aggregation and Ultra Large von Willebrand Factor String Formation Under Flow in a Free-Thiol–Dependent Manner

Jialing Bao, Juan Xiao, Yingying Mao, X. Long Zheng
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https://doi.org/10.1161/ATVBAHA.113.302547
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.302547
Originally published December 19, 2013
Jialing Bao
From the Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia (J.B., J.X., Y.M., X.L.Z.); The University of Pennsylvania Perelman School of Medicine, Philadelphia (J.X., X.L.Z.); and the Department of Obstetrics and Gynecology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China (J.X., X.L.Z.).
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Juan Xiao
From the Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia (J.B., J.X., Y.M., X.L.Z.); The University of Pennsylvania Perelman School of Medicine, Philadelphia (J.X., X.L.Z.); and the Department of Obstetrics and Gynecology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China (J.X., X.L.Z.).
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Yingying Mao
From the Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia (J.B., J.X., Y.M., X.L.Z.); The University of Pennsylvania Perelman School of Medicine, Philadelphia (J.X., X.L.Z.); and the Department of Obstetrics and Gynecology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China (J.X., X.L.Z.).
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X. Long Zheng
From the Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia (J.B., J.X., Y.M., X.L.Z.); The University of Pennsylvania Perelman School of Medicine, Philadelphia (J.X., X.L.Z.); and the Department of Obstetrics and Gynecology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China (J.X., X.L.Z.).
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Abstract

Objective—ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, 13) cleaves von Willebrand factor (VWF), thereby inhibiting thrombus formation. Proteolytic cleavage relies on the amino-terminal (MDTCS) domains, but the role of the more distal carboxyl-terminal domains of ADAMTS13 is not fully understood. A previous study demonstrated the presence of multiple surface-exposed free sulfhydryls on ADAMTS13 that seemed to interact with those on VWF under shear. Here, we determined the physiological relevance of such an interaction in antithrombotic responses under flow.

Approach and Results—A microfluidic assay demonstrated that a carboxyl-terminal fragment of ADAMTS13, comprising either 2 to 8 thrombospondin type 1 (TSP1) repeats and CUB domains (T2C) or 5 to 8 Thrombospondin type 1 (TSP1) repeats and CUB domains (T5C), directly inhibited platelet adhesion/aggregation on a collagen surface under arterial shear. In addition, an intravital microscopic imaging analysis showed that the carboxyl-terminal fragment of ADAMTS13 (T2C or T5C) was capable of inhibiting the formation and elongation of platelet-decorated ultra large (UL) VWF strings and the adhesion of platelets/leukocytes on endothelium in mesenteric venules after oxidative injury. The inhibitory activity of T2C and T5C on platelet aggregation and ULVWF string formation were dependent on the presence of their surface free thiols; pretreatment of T2C and T5C or full-length ADAMTS13 with N-ethylmaleimide that reacts with free sulfhydryls abolished or significantly reduced its antithrombotic activity.

Conclusions—Our results demonstrate for the first time that the carboxyl terminus of ADAMTS13 has direct antithrombotic activity in a free-thiol–dependent manner. The free thiols in the carboxyl-terminal domains of ADAMTS13 may also contribute to the overall antithrombotic function of ADAMTS13 under pathophysiological conditions.

  • Received September 17, 2013.
  • Accepted December 4, 2013.
  • © 2013 American Heart Association, Inc.
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    Carboxyl Terminus of ADAMTS13 Directly Inhibits Platelet Aggregation and Ultra Large von Willebrand Factor String Formation Under Flow in a Free-Thiol–Dependent Manner
    Jialing Bao, Juan Xiao, Yingying Mao and X. Long Zheng
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.302547, originally published December 19, 2013
    https://doi.org/10.1161/ATVBAHA.113.302547

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    Carboxyl Terminus of ADAMTS13 Directly Inhibits Platelet Aggregation and Ultra Large von Willebrand Factor String Formation Under Flow in a Free-Thiol–Dependent Manner
    Jialing Bao, Juan Xiao, Yingying Mao and X. Long Zheng
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.302547, originally published December 19, 2013
    https://doi.org/10.1161/ATVBAHA.113.302547
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