Introduction

Heparin-induced thrombocytopenia (HIT) is a unique immune-mediated disorder. HIT is common, occurring in as many as 5% of certain patient populations. Affected patients can develop a paradoxical thrombotic episode, rather than bleeding, despite having thrombocytopenia. One possible reason for the unique clinical profile is the central role of platelet Fcy receptor (FcyR) IIa in mediating platelet activation in HIT. Indirect evidence suggests a crucial role for platelet activation in the pathogenesis of HIT since thrombocytopenia and the presence of HIT antibodies are strongly associated with thrombosis, whereas formation of antibodies without thrombocytopenia is not (Warkentin et al., 1995). Notwithstanding the role that platelet FcyRs play in platelet activation, leukocyte FcyRs could also contribute to the pathogenesis of HIT.

It has been known for several years that HIT results from a predominant IgG immune response to antigenic determinants involving platelet-bound heparin (Green et al., 1978). Thus, the pathogenesis of HIT resembles a type II immune reaction, i.e., a cytotoxic antibody response (Roitt et al., 1985), and a murine model of HIT supports a T-cell dependent immune response (Suvarna et al., 2005). The typical features of a type II immune response, such as phagocytosis, killer-cell activity, or complement-mediated lysis, do not seem to predominate in HIT. Instead, thrombocytopenia results primarily from FcyRIIa-mediated platelet activation, aggregation, and granule release (Chong et al., 1981) as a result of IgG binding to platelet factor 4-heparin (PF4-H) complexes on the platelet surface. Furthermore, HIT antibodies activate endothelium in vitro by interaction with PF4-heparan sulfate complexes (Cines et al., 1987; Greinacher et al., 1994a; Visentin et al., 1994). However, unlike platelets, human endothelium (with the exception of placental villous endothelial cells and a subset of endothelial cells found in the superficial dermal vascular plexus) does not express any FcyRs, either constitutively or in the setting of immune complex diseases (Sedmak et al., 1991; Gröger et al., 1996). Thus, platelet activation and endothelial activation in HIT probably arise from fundamentally distinct processes. Other effects of HIT include the formation of platelet-leukocyte aggregates, the release of tissue factor (TF) from monocytes, and the FcyRIIIa-dependent phagocytosis or natural killer (NK) cell destruction of antibody-sensitized platelets (Khairy et al., 2001; Pouplard et al., 2001; Gruel et al., 2004).

One of the most important unanswered questions in the pathophysiology of this disorder is an explanation for why only a few patients who develop HIT antibodies become thrombocytopenic. This problem has led investigators to study the role of FcyRIIa in explaining, at least partly, the heterogeneous clinical sequelae among patients with HIT. This chapter will (1) review the structure and function of the platelet FcyRIIa; (2) describe the mechanism of HIT antibody-induced platelet activation by FcyRIIa; and (3) summarize the studies that have attempted to identify the role of FcyRs in modifying the clinical manifestations of HIT.

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