Adp

PIateIet membrane

FIGURE 2 Fcy receptor-mediated signal transduction. PF4-heparin-IgG complexes (1) bind to FcyRIIa, causing receptor clustering (2). The ITAMs on FcyRIIa are phosphorylated by PTKsrc (3). The phosphorylated ITAMs interact with SH domains on p72syk to phosphorylate PLCy2 (4). ADP receptors, activated via ADP and Gi proteins, generate PIP3 via PI 3-kinase (not shown) (5), which helps phosphorylate PLCy2. Activated PLCy2 acts on PIP2 to generate IP3, and DAG from phosphatidylinositol-bisphosphate (6). IP3 mobilizes Ca++ to the intracellular space via Ca++ channels (7) and together with DAG activates downstream PKC signaling pathways (8). Abbreviations: DAG, diacylglycerol; IP3, inositol triphosphate; ITAMs, immunoreceptor tyrosine activation motifs; PF4, platelet factor 4; PKC, protein kinase C; PLCy2, phospholipase Cy2; PIP3, phosphatidylinositol-trisphosphate; PTKĀ®rc, src protein tyrosine kinases.

activation assay, employing radiolabeled serotonin, as an activation endpoint that was sensitive and specific for detecting clinically significant HIT antibodies. This same group later reported that platelet activation by HIT antibodies was platelet FcyRIIa dependent, as it could be completely abrogated by a murine monoclonal anti-FcyRIIa antibody, IV.3 (Kelton et al., 1988). Other workers confirmed the central importance of the platelet Fc receptor in mediating platelet activation in HIT (Adelman et al., 1989; Chong et al., 1989a,b). Subsequently, Amiral and colleagues (1992) reported that the major target antigen for HIT-IgG was PF4 complexed to heparin, a finding quickly confirmed by other workers (Greinacher et al., 1994a; Kelton et al., 1994; Visentin et al., 1994).

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