title: PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI.
abstract: Heparin-induced thrombocytopenia (HIT) is a potentially devastating form of drug-induced thrombocytopenia that occurs in patients receiving heparin for prevention or treatment of thrombosis. Patients with HIT develop autoantibodies to the platelet factor 4 (PF4)/heparin complex, which is termed the HIT Ab complex. Despite a decrease in the platelet count, the most feared complication of HIT is thrombosis. The mechanism of thrombosis in HIT remains poorly understood. We investigated the effects of the HIT Ab complex on tissue factor (TF) expression and release of TF-positive microparticles in peripheral blood mononuclear cells and monocytes. To model these effects ex vivo, we used a murine mAb specific for the PF4/heparin complex (KKO), as well as plasma from patients with HIT. We found that the HIT Ab complex induced TF expression in monocytes and the release of TF-positive microparticles. Further, we found that induction of TF is mediated via engagement of the FcγRI receptor and activation of the MEK1-ERK1/2 signaling pathway. Our data suggest that monocyte TF may contribute to the development of thrombosis in patients with HIT.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. raj_kasthuri@med.unc.edu
authors.forename: Raj S
authors.initials: RS
authors.lastname: Kasthuri
authors.forename: Sam L
authors.initials: SL
authors.lastname: Glover
authors.forename: William
authors.initials: W
authors.lastname: Jonas
authors.forename: Troy
authors.initials: T
authors.lastname: McEachron
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Gowthami M
authors.initials: GM
authors.lastname: Arepally
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010978:Platelet Factor 4 / Q000097:blood / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000276:immunology*; D013925:Thromboplastin / Q000096:biosynthesis / Q000276:immunology; D013927:Thrombosis / Q000188:drug therapy / Q000276:immunology
chemical_list: D000925:Anticoagulants; D001323:Autoantibodies; C489017:FCGR1A protein, human; D017452:Receptors, IgG; D010978:Platelet Factor 4; D006493:Heparin; D013925:Thromboplastin; D048049:Extracellular Signal-Regulated MAP Kinases