title: Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG).
abstract: T cell depletion with antithymocyte globulins (ATG) can be complicated by thrombopenia and hypercoagulability. The underlying mechanism is still unclear. We found that binding of ATG to platelets caused platelet aggregation, α-granule release, membrane phosphatidylserine exposure and the rapid release of procoagulant platelet microvesicles (MV). Platelet activation and MV release were complement-dependent and required membrane insertion of C5b-8 but not stable lytic pore formation by C5b-9. ATG also activated platelets via binding to the low-affinity Fc gamma receptor FcγRII. However, only complement inhibition but not blockade of FcγRII prevented MV release and subsequent thrombin activation in plasma. In 19 hematopoietic stem cell and kidney transplant patients, ATG treatment resulted in thrombopenia and increased plasma levels of d-dimer and thrombin-antithrombin complexes. Flow cytometric analysis of complement fragments on platelet MV in patient plasma confirmed dose-dependent complement activation by ATG. However, the rapid rise in MV numbers observed in vitro was not seen during ATG treatment. In vitro experiments suggested that this was due to adherence of C3b-tagged MV to red blood cells via complement receptor CR1. These data suggest a clinically relevant link between complement activation and thrombin generation and offer a potential mechanism underlying ATG-induced hypercoagulability.
authors.affiliation: Department of Research, Basel University Hospital, Basel, Switzerland.|Department of Medicine, Basel University Hospital, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Cumpelik
authors.affiliation: Department of Research, Basel University Hospital, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gerossier
authors.affiliation: Department of Medicine, Basel University Hospital, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Hematology, Basel University Hospital, Basel, Switzerland.|Department of Laboratory Medicine, Basel University Hospital, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Tsakiris
authors.affiliation: Department of Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Dickenmann
authors.affiliation: Department of Research, Basel University Hospital, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Sadallah
authors.affiliation: Department of Research, Basel University Hospital, Basel, Switzerland.|Department of Medicine, Basel University Hospital, Basel, Switzerland.
authors.forename: J A
authors.initials: JA
authors.lastname: Schifferli
authors.affiliation: Department of Research, Basel University Hospital, Basel, Switzerland.|Department of Medicine, Basel University Hospital, Basel, Switzerland.|Department of Nephrology, University Medical Center Regensburg, Regensburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Zecher
mesh_terms: D000961:Antilymphocyte Serum / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D055252:Cell-Derived Microparticles / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation; D015539:Platelet Activation / Q000187:drug effects* / Q000276:immunology; D013917:Thrombin / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis; D019851:Thrombophilia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis
chemical_list: D000961:Antilymphocyte Serum; D015415:Biomarkers; D007166:Immunosuppressive Agents; D013917:Thrombin
keywords: Coagulation and hemostasis; complement biology; immunosuppressant; polyclonal preparations: rabbit antithymocyte globulin