title: A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13.
abstract: Deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a VWF-cleaving protease, is the key factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy. It is well established that ADAMTS13 deficiency results in elevated plasma levels of ultra-large VWF multimers (ULVWF), which are prone to induce platelet aggregation; however, the actual trigger of TTP development remains uncertain. Here we describe a new animal model in which some TTP-like symptoms can be triggered in ADAMTS13 knockout mice by challenge with 2000 units/kg body weight of recombinant human VWF containing ULVWF multimers. Animals rapidly showed clinical symptoms and developed severe thrombocytopenia. Schistocytosis, a decrease in hematocrit, and elevated serum lactate dehydrogenase levels were observed. The heart was identified as the most sensitive target organ with rapid onset of extensive platelet aggregation in the ventricles and myocardial necrosis. Prophylactic administration of 200 units/kg recombinant human ADAMTS13 protected ADAMTS13 knockout mice from developing TTP. Therapeutic administration of 320 units/kg rhADAMTS13 reduced the incidence and severity of TTP findings in a treatment interval-dependent manner. We therefore consider this newly established mouse model of thrombotic microangiopathy highly predictive for investigating the efficacy of new treatments for TTP.
authors.affiliation: Department of Preclinical Pharmacology & Toxicology, Baxter Innovations GmbH, Industriestrasse 67, Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schiviz
authors.forename: Kuno
authors.initials: K
authors.lastname: Wuersch
authors.forename: Christina
authors.initials: C
authors.lastname: Piskernik
authors.forename: Barbara
authors.initials: B
authors.lastname: Dietrich
authors.forename: Werner
authors.initials: W
authors.lastname: Hoellriegl
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Rottensteiner
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Muchitsch
mesh_terms: D051722:ADAM Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D000071120:ADAMTS13 Protein; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006400:Hematocrit; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D051722:ADAM Proteins; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human