title: Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy.
abstract: This study addressed the contribution of ADAMTS13 deficiency to complement activation in thrombotic thrombocytopenic purpura (TTP). Renal tissue and blood samples were available from 12 TTP patients. C3 and C5b-9 deposition were demonstrated in the renal cortex of two TTP patients, by immunofluorescence and immunohistochemistry, respectively. C3 was also demonstrated in the glomeruli of Shiga toxin-2-treated Adamts13(-/-) mice (n = 6 of 7), but less in mice that were not Shiga toxin-2 treated (n = 1 of 8, p < 0.05) or wild-type mice (n = 0 of 7). TTP patient plasma (n = 9) contained significantly higher levels of complement-coated endothelial microparticles than control plasma (n = 13), as detected by flow cytometry. Exposure of histamine-stimulated primary glomerular endothelial cells to platelet-rich plasma from patients, or patient platelet-poor plasma combined with normal platelets, in a perfusion system, under shear, induced C3 deposition on von Willebrand factor-platelet strings (on both von Willebrand factor and platelets) and on endothelial cells. Complement activation occurred via the alternative pathway. No C3 was detected when cells were exposed to TTP plasma that was preincubated with EDTA or heat-inactivated, or to control plasma. In the perfusion system, patient plasma induced more release of C3- and C9-coated endothelial microparticles compared with control plasma. The results indicate that the microvascular process induced by ADAMTS13 deficiency triggers complement activation on platelets and the endothelium, which may contribute to formation of thrombotic microangiopathy.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Tati
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Kristoffersson
authors.forename: Anne-Lie
authors.initials: AL
authors.lastname: Ståhl
authors.forename: Johan
authors.initials: J
authors.lastname: Rebetz
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Christoph
authors.initials: C
authors.lastname: Licht
authors.forename: David
authors.initials: D
authors.lastname: Motto
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000276:immunology; D000071120:ADAMTS13 Protein; D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008666:Metalloendopeptidases / Q000172:deficiency / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D057049:Thrombotic Microangiopathies / Q000276:immunology* / Q000378:metabolism*
chemical_list: D051722:ADAM Proteins; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human