title: Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia.
abstract: Heparin-induced thrombocytopenia (HIT) is characterized by a high incidence of thrombosis, unlike other antibody-mediated causes of thrombocytopenia. We have shown that monocytes complexed with surface-bound platelet factor 4 (PF4) activated by HIT antibodies contribute to the prothrombotic state in vivo, but the mechanism by which this occurs and the relationship to the requirement for platelet activation via fragment crystallizable (Fc)γRIIA is uncertain. Using a microfluidic model and human or murine blood, we confirmed that activation of monocytes contributes to the prothrombotic state in HIT and showed that HIT antibodies bind to monocyte FcγRIIA, which activates spleen tyrosine kinase and leads to the generation of tissue factor (TF) and thrombin. The combination of direct platelet activation by HIT immune complexes through FcγRIIA and transactivation by monocyte-derived thrombin markedly increases Annexin V and factor Xa binding to platelets, consistent with the formation of procoagulant coated platelets. These data provide a model of HIT wherein a combination of direct FcγRIIA-mediated platelet activation and monocyte-derived thrombin contributes to thrombosis in HIT and identifies potential new targets for lessening this risk.
authors.affiliation: School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA;
authors.forename: Valerie
authors.initials: V
authors.lastname: Tutwiler
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA;
authors.forename: Daria
authors.initials: D
authors.lastname: Madeeva
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA;
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Ahn
authors.affiliation: Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia;
authors.forename: Izabella
authors.initials: I
authors.lastname: Andrianova
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA;
authors.forename: Vincent
authors.initials: V
authors.lastname: Hayes
authors.affiliation: Division of Laboratory Medicine, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Douglas B
authors.identifier: http://orcid.org/0000-0001-5986-504X
authors.initials: DB
authors.lastname: Cines
authors.affiliation: Department of Medicine, Thomas Jefferson University, Philadelphia, PA; and.
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Lubica
authors.identifier: http://orcid.org/0000-0003-1990-3077
authors.initials: L
authors.lastname: Rauova
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects* / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D002478:Cells, Cultured; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D051379:Mice; D046210:Microfluidic Analytical Techniques; D009000:Monocytes / Q000276:immunology*; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000150:complications* / Q000276:immunology; D013927:Thrombosis / Q000209:etiology* / Q000276:immunology
chemical_list: D000925:Anticoagulants; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D010978:Platelet Factor 4; D006493:Heparin