title: Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.
abstract: Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation.
authors: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. lubica@email.chop.edu
authors: Lubica
authors: L
authors: Rauova
authors: Jessica D
authors: JD
authors: Hirsch
authors: Teshell K
authors: TK
authors: Greene
authors: Li
authors: L
authors: Zhai
authors: Vincent M
authors: VM
authors: Hayes
authors: M Anna
authors: MA
authors: Kowalska
authors: Douglas B
authors: DB
authors: Cines
authors: Mortimer
authors: M
authors: Poncz
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D006025:Glycosaminoglycans / Q000276:immunology / Q000378:metabolism; D006493:Heparin / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D010978:Platelet Factor 4 / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013921:Thrombocytopenia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D001323:Autoantibodies; D001324:Autoantigens; D006025:Glycosaminoglycans; D010978:Platelet Factor 4; D006493:Heparin