FcyIIaRMediated Platelet Activation

Murine monoclonal IgG1 anti-CD9 were among the first studied for their platelet-activating properties. Subsequently, it was determined that monoclonal antibodies to GPIIb/IIIa, ^-microglobulin, GPIV (CD36), and other selected antigens can activate platelets (Rubinstein et al., 1995). In each instance, platelet activation occurs by a consistent mechanism: first, the variable region of the antibody binds to its cognate antigen; then the Fc portion of the antibody interacts with platelet FcyRIIa. Evidence for FcyRIIa dependency includes the inhibition of platelet activation by the murine monoclonal anti-FcyRIIa antibody (IV.3). However, some platelet GPs (e.g., GPIb) do not support activation by monoclonal antibodies; others support activation despite their usual sequestered location within platelets (e.g., GPIa*), and still other GPs (e.g., GPIIb/IIIa) support activation by only certain monoclonal antibodies (Horsewood et al., 1991). These observations suggest that specific factors such as target protein membrane mobility and localization of the epitope, which permit formation of multimolecular GP antigen-IgG-FcyRIIa complexes, are crucial for FcyRIIa-mediated platelet activation. The IgG can interact with either FcyRIIa on the same platelet (intraplatelet activation) or with FcyIIaRs located on other platelets in close proximity (interplatelet activation) (Anderson et al., 1991; Horsewood et al., 1991).

Complexed human IgG is also a potent stimulator of platelet activation. Karas and coworkers (1982) showed that trimeric human IgG and larger immune complexes had significant affinity for platelet FcyRIIa. King et al. (1990) showed that a minimum of trimeric IgG molecules are necessary for platelet activation. Heat-aggregated IgG also is a potent agonist for platelet activation (Warkentin et al., 1994; Warkentin and Sheppard, 1999), as are streptokinase-anti-antistrepto-kinase complexes (Lebrazi et al., 1995) and PF4-H immune complexes (Greinacher et al., 1994a).

HIT-IgG causes the generation of thromboxane A2 and associated platelet granule release (Chong et al., 1981). Indeed, several different "activation assays" have been developed that detect HIT antibodies by their ability to cause resting platelets to aggregate (Greinacher et al., 1991), effect granule release (Sheridan et al., 1986), or generate platelet-derived microparticles (Warkentin et al., 1994) (see Chapter 10).

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