A Glanzmann Thrombasthenia-like Phenotype Caused by a Defect in Inside-Out Signaling through the Integrin α_IIbβ₃

Summary

Activation of the platelet integrin α_IIbβ₃, an essential step in platelet aggregation, is regulated by intracellular signal pathways (inside-out signaling). In this study, we characterize a 35-year-old Japanese female, HM, with a life-long history of mucocutaneous bleeding. HM showed a Glanzmann thrombasthenia-like phenotype with normal expression of α_IIbβ₃, and failure of platelet aggregation induced by various agonists. An activation-independent ligand mimic monoclonal antibody (mAb), OP-G2, and RGDS peptides bound normally to the patient‘s α_IIbβ₃„ while an activating anti-β₃ mAb, AP5, induced normal aggregation of HM platelets. The nucleotide sequence of the entire coding region of the patient‘s α_IIb and β₃, including the cytoplasmic domains of each subunit, revealed no abnormalities. Agonist-induced phosphorylation of platelet pleckstrin and myosin light chain was not impaired. Recently, we proposed that a Na⁺/Ca²⁺ exchanger is involved in inside-out signaling, especially in the case of chymotrypsin-induced α_IIbβ₃ activation (Blood 88: 2594, 1996). However, chymotrypsin-induced platelet aggregation occurred normally in patient HM. Measurement of changes in cytosolic free calcium 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 thrombasthenia-like phenotype associated with an abnormality in inside-out signaling which would otherwise activate α_IIbβ₃.

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