Animal Models of HIT

One of the earliest animal models of HIT used the natural immune process of anti-idiotypic antibody production to invoke expression of HIT-IgG in mice (Blank et al., 1997, 1999). Mice immunized with HIT-IgG developed anti-idiotypic IgG that now recognized PF4-H. Unfortunately, this model has limited use, as the mice did not develop thrombosis, perhaps because murine platelets lack FcyRIIa.

Other investigators (Arepally et al., 2000) developed a murine monoclonal antibody, termed KKO, by immunizing mice with PF4-H. This murine IgG2bK monoclonal antibody mimics HIT-IgG, as it requires both PF4 and heparin to activate human platelets through their FcyRIIa. However, besides lacking FcyRIIa, mouse PF4 is not recognized by HIT-IgG or KKO. To overcome these problems, Reilly and colleagues (2001) produced transgenic mice that express both human FcyRIIa and human PF4. In these animals, addition of KKO caused thrombocyto-penia and death, including thrombosis of the lung vasculature. This murine model has proven useful to address immunological questions related to HIT. First, large macromolecular complexes are a necessary component in the development of HIT (Rauova et al., 2005). Second, a preexisting prothrombotic condition may influence the development of HIT. Mice fed a hypercholesterolemic diet had increased platelet and endothelial-cell activation and were predisposed to HIT to a greater extent than healthy, diet-fed syngeneic control mice (Reilly et al., 2006).

When platelet-activating (anti-CD9) IgG was administered to FcyRIIa trans-genic mice, more severe thrombocytopenia resulted, compared with a previously studied anti-mouse platelet (nonactivating) IgG (Taylor et al., 2000). Severe thrombosis, shock, and death developed in FcyRIIa transgenic mice crossed with FcRy-chain knockout mice. Moreover, splenectomy facilitated anti-CD9-mediated shock in FcyRIIa transgenic mice. The authors concluded that the clearance of antibody-sensitized platelets by phagocytic cells in the spleen may play a protective role in preventing thrombosis.

Unlike mice, primate platelets do possess FcyRIIa. Thus, a primate model for HIT may be feasible, as suggested by a recent report (Ahmad et al., 2000). The animals (Macaca mulatto) used do not express the human Arg-His polymorphism, perhaps explaining why less variability in platelet activation response to HIT-IgG was observed in these in vitro studies. The primate model may have value in evaluating therapeutic agents for HIT (Untch et al., 2002).

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