Tissue factor

FIGURE 1 Pathogenesis of HIT; a central role for thrombin generation: HIT-IgG antibodies bind to several identical epitopes on the same antigen complex, thus forming immune complexes that become localized to the platelet surface. The IgG immune complexes can cross-link the platelet FcgIIa receptors, resulting in FcgIIa receptor-dependent platelet activation (Kelton et al., 1988). The GP IIb/IIIa complex is not required for platelet activation (Greinacher et al., 1994a). The activated platelets trigger a cascade of events that ultimately lead to activation of the coagulation pathways, resulting in thrombin generation. Activated platelets release their a-granule proteins (Chong et al., 1994), including PF4, leading to formation of more multimolecular PF4-heparin complexes, setting up a vicious cycle of platelet activation, triggering even more platelet activation (Greinacher, 1995). The activated platelets bind fibrinogen, recruit other platelets, and begin to form a primary clot. During shape change, procoagulant, platelet-derived microparticles are released, providing a phospholipid surface for amplifying thrombin generation (Warkentin et al., 1994). The released PF4 also binds to endothelial cell heparan sulfate, forming local antigen complexes to which HIT antibodies bind (Cines et al., 1987; Visentin et al., 1994; Greinacher et al., 1994b). Tissue factor expression on activated endothelial cells and monocytes (Arepally and Mayer, 2001; Pouplard et al., 2001) further enhances thrombin generation. Abbreviations: GP, glycoprotein; HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4.

(e.g., inflammation) is an important unresolved question (Warkentin and Sheppard, 2006).

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