Characterization of a novel disease entity due to GPIIb/IIIa mutations

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We identified and characterized the juxtamembrane domain mutations of the GPIIb/IIIa receptor as a novel etiology of congenital macrothrombocytopenia. Because this domain is important for the inactive conformation the receptor, GPIIb/IIIa become constitutively activated by the mutation without ligand binding. The surface expression of platelet GPIIb/IIIa is decreased. There is spontaneous binding of PAC1 antibody, which recognizes active conformation of GPIIb/IIIa, to resting platelets without P-selectin expression. Large and decreased platelets were produced from the mutant GPIIb/IIIa-transduced megakaryocytes. This condition is the third most common cause of congenital macrothrombocytopenia in Japan.