title: Megakaryocytic emperipolesis and platelet function abnormalities in five patients with gray platelet syndrome.
abstract: The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic α-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2-3) and extensive emperipolesis, with many (36-65%) MKs containing 2-4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease.
authors: a Department of Pathology , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Rome , Italy .
authors: Luigi M
authors: LM
authors: Larocca
authors: b Department of Hematology Research , Instituto de Investigaciones Médicas Alfredo Lanari, University of Buenos Aires, CONICET , Buenos Aires , Argentina .
authors: Paula G
authors: PG
authors: Heller
authors: c Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Scienze della Salute , Università degli Studi di Milano , Milano , Italy .
authors: Gianmarco
authors: G
authors: Podda
authors: d Hemostasis and Thrombosis Unit, Department of Medicine , Institut de Recerca Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain .
authors: Nuria
authors: N
authors: Pujol-Moix
authors: b Department of Hematology Research , Instituto de Investigaciones Médicas Alfredo Lanari, University of Buenos Aires, CONICET , Buenos Aires , Argentina .
authors: Ana C
authors: AC
authors: Glembotsky
authors: e Department of Internal Medicine , IRCCS Policlinico San Matteo Foundation, University of Pavia , Pava , Italy , and.
authors: Alessandro
authors: A
authors: Pecci
authors: f Department of Internal Medicine , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Roma , Italy.
authors: Maria Adele
authors: MA
authors: Alberelli
authors: e Department of Internal Medicine , IRCCS Policlinico San Matteo Foundation, University of Pavia , Pava , Italy , and.
authors: Carlo L
authors: CL
authors: Balduini
authors: f Department of Internal Medicine , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Roma , Italy.
authors: Raffaele
authors: R
authors: Landolfi
authors: c Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Scienze della Salute , Università degli Studi di Milano , Milano , Italy .
authors: Marco
authors: M
authors: Cattaneo
authors: f Department of Internal Medicine , Policlinico A. Gemelli, Università Cattolica del Sacro Cuore , Roma , Italy.
authors: Erica
authors: E
authors: De Candia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D001798:Blood Proteins / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000473:pathology; D057687:Emperipolesis; D005355:Fibrosis; D015870:Gene Expression; D055652:Gray Platelet Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D015539:Platelet Activation; D010974:Platelet Aggregation; D010979:Platelet Function Tests; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001798:Blood Proteins; C561485:NBEAL2 protein, human; D044463:Receptor, PAR-1; D000255:Adenosine Triphosphate
keywords: Emperipolesis; PAR1 receptor; gray platelet syndrome; megakaryocytes; platelet disorder