A GLANZMANN THROMBASTHENIA-LIKE PHENOTYPE CAUSED BY A DEFECT IN INSIDE-OUT SIGNALING THROUGH THE INTEGRIN ALPHA(IIB)BETA(3)

Activation of the platelet integrin alpha(IIb)beta(3), an essential st ep in platelet aggregation, is regulated by intracellular signal pathw ays (inside-out signaling). In this study, we characterize a 35-year-o ld Japanese female, HM, with a life-long history of mucocutaneous blee ding. HM showed a Glanzmann thrombasthenia-like phenotype with normal expression of alpha(IIb)beta(3), and failure of platelet aggregation i nduced by various agonists. An activation-independent ligand mimic mon oclonal antibody (mAb), OP-G2, and RODS peptides bound normally to the patient's alpha(IIb)beta(3),, while an activating anti-beta(3) mAb, A P5, induced normal aggregation of HM platelets. The nucleotide sequenc e of the entire coding region of the patient's alpha(IIb) and beta(3), including the cytoplasmic domains of each subunit, revealed no abnorm alities. Agonist-induced phosphorylation of platelet pleckstrin and my osin light chain was not impaired. Recently, we proposed that a Na+/Ca 2+ exchanger is involved in inside-out signaling, especially in the ca se of chymotrypsin-induced alpha(IIb)beta(3) activation (Blood 88: 259 4, 1996). However, chymotrypsin-induced platelet aggregation occurred normally in patient HM. Measurement of changes in cytosolic free calci um concentration ([Ca2+](i)) revealed that the plateau level of [Ca2+] (i) after thrombin stimulation was significantly inhibited in patient HM. Our data suggest that patient HM exhibits a Glanzmann thrombasthen ia-like phenotype associated with an abnormality in inside-out signali ng which would otherwise activate alpha(IIb)beta(3).