title: Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptor.
abstract: BACKGROUND
  Thromboxane A(2) receptor (TXA(2)R) abnormality appears to dominantly disturb platelet function.
  
  
  OBJECTIVE
  To reveal a molecular genetic defect in a patient with TXA(2)R abnormality and investigate the mechanism for the impaired response to TXA(2).
  
  
  METHODS
  The proband (OSP-2, PT) was a 7-year-old Japanese girl, suffering from repeated mucocutaneous bleeding.
  
  
  RESULTS
  U46619 (2.5 and 10 μm)-induced platelet aggregation was remarkably impaired in the proband and her father. Immunoblots showed that TXA(2)R expression levels in their platelets were approximately 50% of controls, and nucleotide sequence analysis revealed that they were heterozygous for a novel mutation, c.167dupG in the TXA(2)R cDNA. Expression studies using Chinese hamster ovary (CHO) cells indicated that the mutation is responsible for the expression defect in TXA(2)R. We then examined α(IIb)β(3) activation by employing an initial velocity analysis and revealed that U46619 failed to induce a sustained α(IIb)β(3) and Rap1B activation in the proband. In addition, platelet secretion as monitored by P-selectin expression was markedly impaired in response to U46619 but not to ADP. The interaction between secreted ADP and P2Y(12) has been shown to play a critical role in the sustained α(IIb)β(3) activation (Kamae et al. J Thromb Haemost 2006; 4: 1379). As expected, small amounts of exogenous ADP (0.5 μm) partially restored the sustained α(IIb)β(3) activation induced by U46619.
  
  
  CONCLUSIONS
  Our present data strongly suggest that the impaired platelet activation in response to U46619 in the heterozygous subject for the TXA(2)R mutation is, at least in part, as a result of the decrease in ADP secretion.
authors.affiliation: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kamae
authors.forename: K
authors.initials: K
authors.lastname: Kiyomizu
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.forename: S
authors.initials: S
authors.lastname: Tadokoro
authors.forename: H
authors.initials: H
authors.lastname: Kashiwagi
authors.forename: S
authors.initials: S
authors.lastname: Honda
authors.forename: Y
authors.initials: Y
authors.lastname: Kanakura
authors.forename: Y
authors.initials: Y
authors.lastname: Tomiyama
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016466:CHO Cells; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006470:Hemorrhage; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010290:Parents; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D043562:Receptors, G-Protein-Coupled; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid