title: Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus).
abstract: Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n = 6) induced severe thrombocytopenia (< 12 × 10(9)/L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet- and von Willebrand factor-rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n = 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n = 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.
authors.affiliation: Laboratory for Thrombosis Research, Katholieke Universiteit Leuven Campus Kortrijk, Kortrijk, Belgium. hendrik.feys@kuleuven-kortrijk.be
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Feys
authors.forename: Jan
authors.initials: J
authors.lastname: Roodt
authors.forename: Nele
authors.initials: N
authors.lastname: Vandeputte
authors.forename: Inge
authors.initials: I
authors.lastname: Pareyn
authors.forename: Seb
authors.initials: S
authors.lastname: Lamprecht
authors.forename: Walter J
authors.initials: WJ
authors.lastname: van Rensburg
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Anderson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.forename: Vernon J
authors.initials: VJ
authors.lastname: Louw
authors.forename: Philip N
authors.initials: PN
authors.lastname: Badenhorst
authors.forename: Hans
authors.initials: H
authors.lastname: Deckmyn
authors.forename: Karen
authors.initials: K
authors.lastname: Vanhoorelbeke
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010215:Papio; D011697:Purpura, Thrombotic Thrombocytopenic / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D013927:Thrombosis / Q000473:pathology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D051722:ADAM Proteins