Immune Vascular Injury And Monocyte Activation In Hitassociated Thrombosis

The studies described above support the notion that platelet activation and/or an inflammatory milieu contribute to EC dysfunction, predisposing to HIT-associated thrombosis. This view of HIT as an inflammatory disorder has gained additional experimental support by recent findings that monocytes are activated as well. HIT plasma or IgG stimulates monocytes to elaborate tissue factor-dependent procoagulant activity in monocytes (Pouplard et al., 2001). This procoagulant effect required small amounts of heparin to activate the monocytes in whole blood, but appeared to be heparin-independent when isolated mononuclear cells were studied, presumably by exposure of cell-associated proteoglycans (Pouplard et al., 2001). Heparin-independent upregulation of monocyte tissue factor activity by HIT antibodies was confirmed using human and murine antibodies (Arepally et al., 2001). Maximal tissue factor expression was detected at 4-6 h, suggesting that synthesis rather than de-encryption was primarily responsible for increased nr activated platelets platelet Fc receptor nr

HITT antibody activated platelets

HITT antibody

adp resting endothelial cell activated endothelial cell

FIGURE 3 (See color insert) Model of HIT antibody interactions with endothelial cells. (1) HIT antibodies bind to antigen (multimolecular PF4/heparin complexes) localized to platelets. (2) Platelet activation occurs after Fc receptor binding, leading to platelet granule release. (3) Released PF4 binds to platelets and endothelial cell HS displacing AT from endothelial cells. (4) Antigenic complexes on endothelial cells bind HIT antibodies. (5) HIT antibody binding to endothelial cells leads to endothelial cell activation and further platelet activation. Abbreviations: ADP, adenosine diphosphate; AT, antithrombin; HIT, heparin-induced thrombocytopenia; HS, heparan sulfate; PF4, platelet factor 4.

adp resting endothelial cell activated endothelial cell

FIGURE 3 (See color insert) Model of HIT antibody interactions with endothelial cells. (1) HIT antibodies bind to antigen (multimolecular PF4/heparin complexes) localized to platelets. (2) Platelet activation occurs after Fc receptor binding, leading to platelet granule release. (3) Released PF4 binds to platelets and endothelial cell HS displacing AT from endothelial cells. (4) Antigenic complexes on endothelial cells bind HIT antibodies. (5) HIT antibody binding to endothelial cells leads to endothelial cell activation and further platelet activation. Abbreviations: ADP, adenosine diphosphate; AT, antithrombin; HIT, heparin-induced thrombocytopenia; HS, heparan sulfate; PF4, platelet factor 4.

procoagulant activity. Monocyte surface proteoglycans likely also bind PF4 to form antigenic complexes and following activation, macrophages express increasing hypersulfated surface GAGs (Ghiselli et al., 1998). The development of monoclonal antibodies against PF4 and PF4/heparin (Arepally et al., 2000) and murine models (Reilly et al., 2001; Suvarna et al., 2005) should help to delineate the contribution of monocyte activation to the immune pathogenesis of thrombocyto-penia and thrombosis in HIT.

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