title: Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders.
abstract: Prevailing approaches to manage autoimmune thrombotic disorders, such as heparin-induced thrombocytopenia, antiphospholipid syndrome and thrombotic thrombocytopenic purpura, include immunosuppression and systemic anticoagulation, though neither provides optimal outcome for many patients. A different approach is suggested by the concurrence of autoantibodies and their antigenic targets in the absence of clinical disease, such as platelet factor 4 in heparin-induced thrombocytopenia and β(2)-glycoprotein-I (β(2)GPI) in antiphospholipid syndrome. The presence of autoantibodies in the absence of disease suggests that conformational changes or other alterations in endogenous protein autoantigens are required for recognition by pathogenic autoantibodies. In thrombotic thrombocytopenic purpura, the clinical impact of ADAMTS13 deficiency caused by autoantibodies likely depends on the balance between residual antigen, that is, enzyme activity, and demand imposed by local genesis of ultralarge multimers of von Willebrand factor. A corollary of these concepts is that disrupting platelet factor 4 and β(2)GPI conformation (or ultralarge multimer of von Willebrand factor oligomerization or function) might provide a disease-targeted approach to prevent thrombosis without systemic anticoagulation or immunosuppression. Validation of this approach requires a deeper understanding of how seemingly normal host proteins become antigenic or undergo changes that increase antibody avidity, and how they can be altered to retain adaptive functions while shedding epitopes prone to elicit harmful autoimmunity.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4274, USA. dcines@mail.med.upenn.edu
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Sachais
authors.forename: Eline T
authors.initials: ET
authors.lastname: Luning Prak
authors.forename: Don L
authors.initials: DL
authors.lastname: Siegel
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000071120:ADAMTS13 Protein; D000918:Antibody Specificity; D016824:Antigens, Human Platelet / Q000737:chemistry / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000628:therapy*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D001704:Biopolymers; D006493:Heparin / Q000009:adverse effects; D006801:Humans; D007239:Infections / Q000150:complications; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010978:Platelet Factor 4 / Q000737:chemistry / Q000276:immunology; D011487:Protein Conformation; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000139:chemically induced / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D014612:Vaccines / Q000009:adverse effects; D053482:beta 2-Glycoprotein I / Q000737:chemistry / Q000276:immunology; D014841:von Willebrand Factor / Q000737:chemistry / Q000276:immunology
chemical_list: D016824:Antigens, Human Platelet; D001323:Autoantibodies; D001324:Autoantigens; D001704:Biopolymers; D014612:Vaccines; D053482:beta 2-Glycoprotein I; D014841:von Willebrand Factor; D010978:Platelet Factor 4; D006493:Heparin; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human