title: Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase.
abstract: Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders.
authors: II. Medizinische Klinik und Poliklinik, Universitätsklinikum Eppendorf, Hamburg, Germany. langer@uke.de
authors: Florian
authors: F
authors: Langer
authors: Brigitte
authors: B
authors: Spath
authors: Cornelia
authors: C
authors: Fischer
authors: Moritz
authors: M
authors: Stolz
authors: Francis A
authors: FA
authors: Ayuk
authors: Nicolaus
authors: N
authors: Kröger
authors: Carsten
authors: C
authors: Bokemeyer
authors: Wolfram
authors: W
authors: Ruf
mesh_terms: D000961:Antilymphocyte Serum / Q000494:pharmacology*; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D003182:Complement C5 / Q000378:metabolism / Q000502:physiology*; D004220:Disulfides / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000378:metabolism / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000961:Antilymphocyte Serum; D003182:Complement C5; D004220:Disulfides; D013925:Thromboplastin; D019704:Protein Disulfide-Isomerases