title: A Glanzmann thrombasthenia-like phenotype caused by a defect in inside-out signaling through the integrin alpha(IIb)beta3.
abstract: Activation of the platelet integrin alpha(IIb)beta3, 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 alpha(IIb)beta3, 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 alpha(IIb)beta3, while an activating anti-beta3 mAb, AP5, induced normal aggregation of HM platelets. The nucleotide sequence of the entire coding region of the patient's alphaIIb and beta3, 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 alpha(IIb)beta3 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 alpha(IIb)beta3.
authors.affiliation: Second Department of Internal Medicine, Osaka University Medical School, Suita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: M
authors.initials: M
authors.lastname: Shiraga
authors.forename: S
authors.initials: S
authors.lastname: Kinoshita
authors.forename: H
authors.initials: H
authors.lastname: Ambo
authors.forename: Y
authors.initials: Y
authors.lastname: Kurata
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: T J
authors.initials: TJ
authors.lastname: Kunicki
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002918:Chymotrypsin / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006474:Hemorrhagic Disorders / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013915:Thrombasthenia; D013917:Thrombin / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D018076:DNA, Complementary; D018994:Myosin Light Chains; D009842:Oligopeptides; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019831:Sodium-Calcium Exchanger; C039077:platelet protein P47; D005340:Fibrinogen; C046617:arginyl-glycyl-aspartyl-serine; D002918:Chymotrypsin; D013917:Thrombin