Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.
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.
Rauova
Lubica
L
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. lubica@email.chop.edu
Hirsch
Jessica D
JD
Greene
Teshell K
TK
Zhai
Li
L
Hayes
Vincent M
VM
Kowalska
M Anna
MA
Cines
Douglas B
DB
Poncz
Mortimer
M
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
D000925:Anticoagulants; D001323:Autoantibodies; D001324:Autoantigens; D006025:Glycosaminoglycans; D010978:Platelet Factor 4; D006493:Heparin