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- W2589709739 abstract "Abstract Abstract 536 HIT is an iatrogenic, prothrombotic, immune-mediated disorder associated with antibodies directed against platelet factor 4 (PF4) and heparin complexes. Once these pathogenic anti-PF4/heparin antibodies develop, they recognize and bind to antigenic complexes formed on cell surfaces composed of PF4 released from platelets bound to cell membrane glycosaminoglycans (GAGs). Unlike platelets, which have only chondroitin sulfate on their surface, endothelial cells express mainly heparan sulfate resulting in a very high capacity to form PF4/GAG complexes and become targets for HIT antibodies. In fact, activation of endothelial cells by HIT antibodies was recognized almost 25 years ago (Cines et. al., 1987). We now show direct interaction of the HIT-like monoclonal antibody KKO with perithrombus endothelial cells, which propagates thrombosis following laser induced cremaster vessel injury in a passive immunization murine model of HIT. PF4 released from activated platelets at the site of laser injury binds rapidly and predominantly to the adjacent endothelium and is recognized by KKO in both transgenic mice expressing only human PF4 (hPF4+) and mice expressing hPF4 and human FcgRIIA on platelets (hPF4+/FcgRIIA+). These studies show that HIT-like antigenic complexes are present within thrombi prior to antibody exposure, predominantly localized to endothelial cells, which is consistent with their surface GAGs having higher affinity for PF4 than platelets. These endothelial cell surface PF4/GAG complexes, and with it KKO binding, are dissociated by high concentrations of intravenous heparin. Infusion of KKO in hPF4+/FcgRIIA+ mice but not in control mice, reinitiates growth of previously stable thrombi at sites of laser injury, leading to a significant increase in vascular occlusion (24/33 injuries, 73%, compared to 0/30 in control mice; P<0.0001). Clot extension is followed by dissemination of endothelial activation, demarcated by binding of annexin V and Factor Xa, and extension of the endothelial surface that binds KKO. Based on these studies, we propose a model of feed-forward rolling recruitment to explain how the endothelial lining contributes to the prothrombotic state in HIT: PF4 released from activated platelets at a site of injury or disease binds to the surface of perithrombus endothelial cells, which then binds HIT antibodies followed by endothelial cell activation. These activated endothelial cells then bind and activate additional platelets, leading to the next round of PF4 release, more extensive endothelial cell activation and platelet recruitment into thrombi. Disclosures: No relevant conflicts of interest to declare." @default.
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- W2589709739 date "2011-11-18" @default.
- W2589709739 modified "2023-10-01" @default.
- W2589709739 title "“Rolling Recruitment” of Endothelial Cell (EC) Activation in the Prothrombotic Nature of Heparin-Induced Thrombocytopenia (HIT)" @default.
- W2589709739 doi "https://doi.org/10.1182/blood.v118.21.536.536" @default.
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