title: N-acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura.
abstract: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic disorder diagnosed by thrombocytopenia and hemolytic anemia, associated with a deficiency in von Willebrand factor (VWF)-cleaving protease ADAMTS13. Current treatment is based on plasma infusion for congenital TTP, or plasma exchange, often in combination with immunosuppressive agents, for acquired TTP. These treatment methods are not always effective; therefore, new treatment methods are highly necessary.N-acetylcysteine (NAC), an FDA-approved anti-mucolytic agent, is a possible new treatment strategy for TTP, as it was demonstrated to reduce disulfide bonds in VWF, thereby decreasing VWF multimers size and hence their prothrombotic potential. We investigated whether NAC, without concurrent plasma exchange and immunosuppressive therapy, is effective in preventing and resolving TTP signs, using well-established murine and baboon models for TTP. In mice, prophylactic administration of NAC was effective in preventing severe TTP signs. This in vivo finding was supported by in vitro data demonstrating the VWF multimer-reducing properties of NAC in solution. Nonetheless, in both mice and baboons, administration of NAC was not effective in resolving preexisting TTP signs; thrombocytopenia, hemolytic anemia, and organ damage could not be reversed, as thrombus resolution was not achieved. Failure to improve clinical outcome occurred even though a reduction in VWF multimers was observed, demonstrating that NAC was efficient in reducing disulfide bonds in circulating VWF multimers. In conclusion, prophylactic administration of NAC, without concurrent plasma exchange, was effective in preventing severe TTP signs in mice, but NAC was not effective in resolving preexistent acute TTP signs in mice and baboons.
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tersteeg
authors.affiliation: Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.|Department of Haematology, National Health Laboratory Service Tertiary Laboratory, Universitas Hospital, Bloemfontein, South Africa.
authors.forename: Jan
authors.initials: J
authors.lastname: Roodt
authors.affiliation: Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Van Rensburg
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dekimpe
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Vandeputte
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Pareyn
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Vandenbulcke
authors.affiliation: Shire, Vienna, Austria; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plaimauer
authors.affiliation: Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
authors.forename: Seb
authors.initials: S
authors.lastname: Lamprecht
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Hans
authors.identifier: 0000-0003-3952-5501
authors.initials: H
authors.lastname: Deckmyn
authors.affiliation: Department of Biochemistry and Department of Medicine, Bloodworks Research Institute, Seattle, WA.
authors.forename: José A
authors.identifier: 0000-0002-2478-1767
authors.initials: JA
authors.lastname: Lopez
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
authors.affiliation: Laboratory for Thrombosis Research, Interdisciplinary Research Facility Life Sciences, Katholieke Universiteit Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
authors.forename: Karen
authors.identifier: 0000-0003-2288-8277
authors.initials: K
authors.lastname: Vanhoorelbeke
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics / Q000378:metabolism; D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010215:Papio; D055503:Protein Multimerization / Q000187:drug effects*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D000071120:ADAMTS13 Protein; D000111:Acetylcysteine