title: Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents thrombotic thrombocytopenic purpura in murine models.
abstract: ADAMTS13 metalloprotease cleaves von Willebrand factor (VWF), thereby inhibiting platelet aggregation and arterial thrombosis. An inability to cleave ultralarge VWF resulting from hereditary or acquired deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). Plasma exchange is the most effective initial therapy for TTP to date. Here, we report characterization of transgenic mice expressing recombinant human ADAMTS13 (rADAMTS13) in platelets and its efficacy in inhibiting arterial thrombosis and preventing hereditary and acquired antibody-mediated TTP in murine models. Western blotting and fluorescent resonance energy transfer assay detect full-length rADAMTS13 protein and its proteolytic activity, respectively, in transgenic (Adamts13(-/-)Plt(A13)), but not in wild-type and Adamts13(-/-), platelets. The expressed rADAMTS13 is released on stimulation with thrombin and collagen, but less with 2MesADP. Platelet-delivered rADAMTS13 is able to inhibit arterial thrombosis after vascular injury and prevent the onset and progression of Shigatoxin-2 or recombinant murine VWF-induced TTP syndrome in mice despite a lack of plasma ADAMTS13 activity resulting from the ADAMTS13 gene deletion or the antibody-mediated inhibition of plasma ADAMTS13 activity. These findings provide a proof of concept that platelet-delivered ADAMTS13 may be explored as a novel treatment of arterial thrombotic disorders, including hereditary and acquired TTP, in the presence of anti-ADAMTS13 autoantibodies.
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA;
authors: Brandy
authors: B
authors: Pickens
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA;
authors: Yingying
authors: Y
authors: Mao
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA;
authors: Dengju
authors: D
authors: Li
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA;
authors: Don L
authors: DL
authors: Siegel
authors: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors: Mortimer
authors: M
authors: Poncz
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA;
authors: Douglas B
authors: DB
authors: Cines
authors: Department of Pathology and Department of Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA; Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL.
authors: X Long
authors: http://orcid.org/0000-0003-1680-5295
authors: XL
authors: Zheng
mesh_terms: D051722:ADAM Proteins / Q000008:administration & dosage / Q000378:metabolism*; D000071120:ADAMTS13 Protein; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013927:Thrombosis / Q000150:complications*; D014162:Transfection
chemical_list: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human