title: Defective platelet responsiveness to thrombin and protease-activated receptors agonists in a novel case of gray platelet syndrome: correlation between the platelet defect and the alpha-granule content in the patient and four relatives.
abstract: BACKGROUND
  We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of alpha-granule secretory proteins, myelofibrosis and splenomegaly.
  
  
  RESULTS
  Platelet function studies showed a marked reduction of aggregation and Ca(2+) mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B(2) (TXB(2)) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or alpha-granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet alpha-granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB(2) production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance.
  
  
  CONCLUSIONS
  Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of alpha-granule content in GPS.
authors.affiliation: Department of Internal Medicine, Haemostasis Research Centre, Agostino Gemelli Hospital, Catholic University School of Medicine, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: De Candia
authors.forename: A
authors.initials: A
authors.lastname: Pecci
authors.forename: G
authors.initials: G
authors.lastname: Ciabattoni
authors.forename: R
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: S
authors.initials: S
authors.lastname: Rutella
authors.forename: Z
authors.initials: Z
authors.lastname: Yao-Wu
authors.forename: I
authors.initials: I
authors.lastname: Lazzareschi
authors.forename: R
authors.initials: R
authors.lastname: Landolfi
authors.forename: S
authors.initials: S
authors.lastname: Coughlin
authors.forename: C L
authors.initials: CL
authors.lastname: Balduini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D020013:Calcium Signaling / Q000187:drug effects; D003029:Coagulants / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000032:analysis; D010375:Pedigree; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects*; D010978:Platelet Factor 4 / Q000032:analysis; D010979:Platelet Function Tests; D010981:Platelet Storage Pool Deficiency / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044463:Receptor, PAR-1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D013917:Thrombin / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000032:analysis; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D003029:Coagulants; D009842:Oligopeptides; D019007:P-Selectin; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D019700:Thrombospondin 1; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; D010978:Platelet Factor 4; D013929:Thromboxane B2; D013917:Thrombin