Articoli di riviste: "Gray platelet syndrome"

1

Wills, E. J. "Gray Platelet Syndrome". Ultrastructural Pathology 13, n. 4 (gennaio 1989): 451–55. http://dx.doi.org/10.3109/01913128909048495.

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Michelson, Alan D. "Gray platelet syndrome". Blood 121, n. 2 (10 gennaio 2013): 250. http://dx.doi.org/10.1182/blood-2012-09-455550.

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Bain, Barbara J., e Manju Bhavnani. "Gray platelet syndrome". American Journal of Hematology 86, n. 12 (28 luglio 2011): 1027. http://dx.doi.org/10.1002/ajh.22055.

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Rosa, Jean-Philippe. "The gray platelet syndrome". Sang thrombose vaisseaux 26, n. 5 (settembre 2014): 240–54. http://dx.doi.org/10.1684/stv.2014.0854.

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Rosa, Jean-Philippe. "The gray platelet syndrome". Hématologie 19, n. 2 (marzo 2013): 123–35. http://dx.doi.org/10.1684/hma.2013.0793.

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Baruch, Dominique, Theo Lindhout, Evelyne Dupuy e Jacques P. Caen. "Thrombin-Induced Platelet Factor Va Formation in Patients with a Gray Platelet Syndrome". Thrombosis and Haemostasis 58, n. 02 (1987): 768–71. http://dx.doi.org/10.1055/s-0038-1645967.

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SummaryThe present study was initiated to establish the functional factor V concentration in platelets of patients with a mild bleeding disorder ascribed to a gray platelet syndrome. This inherited platelet disorder has been characterized by a specific deficiency of alpha-granules and subsequent deficiencies in the alpha-granule proteins. We found that the concentration of plasma factor V was slightly decreased (70% of normal values). In contrast, platelet factor Va formation was severely impaired. Besides a much lower factor V content than in control platelets (10-20% of normal), the dependency of platelet factor Va formation on tlnumbin concentration was altered. Increasing the thrombin concentration 4-lold compared to the concentration that results in maximal factor Va generation from normal platelets did not result in a maximal factor Va formation from gray platelets. When a suspension of washed gray platelets was incubated with a prostacyclin analogue prior to the stimulation with thrombin, a 10-fold lower factor VQ activity was measured. Thus, thrombin-induced factor Va formation in a suspension of gray platelets is the result of a release reaction, followed by the thrombin-catalyzed activation of released factor V. Whereas the kinetics of the former reaction are apparently impaired, the kinetics of the latter one were found to be identical to those observed for normal platelet and plasma factor V activation.

7

Tubman, Venée N., Jason E. Levine, Dean R. Campagna, Rita Monahan-Earley, Ann M. Dvorak, Ellis J. Neufeld e Mark D. Fleming. "X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation". Blood 109, n. 8 (5 gennaio 2007): 3297–99. http://dx.doi.org/10.1182/blood-2006-02-004101.

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AbstractWe identified a family with gray platelet syndrome (GPS) segregating as a sex-linked trait. Affected males had a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of GPS, while obligate carrier females were asymptomatic but had dimorphic platelets on peripheral smear. Associated findings included mild erythrocyte abnormalities in affected males. Linkage analysis revealed a 63 cM region on the X chromosome between markers G10578 and DXS6797, which segregated with the platelet phenotype and included the GATA1 gene. Sequencing of GATA1 revealed a G-to-A mutation at position 759 corresponding to amino acid change Arg216Gln. This mutation was previously described as a cause of X-linked thrombocytopenia with thalassemia (XLTT) but not of gray platelet syndrome. Our findings suggest that XLTT is within a spectrum of disorders constituting the gray platelet syndrome, and we propose that GATA1 is an upstream regulator of the genes required for platelet α-granule biogenesis.

8

Köhler, Michael. "Treatment of Gray Platelet Syndrome". Thrombosis and Haemostasis 60, n. 01 (1988): 123. http://dx.doi.org/10.1055/s-0038-1647649.

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Nurden, Paquita, Martine Jandrot-Perrus, Robert Combrié, Joelle Winckler, Veronique Arocas, Christelle Lecut, Jean-Max Pasquet, Thomas J. Kunicki e Alan T. Nurden. "Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome". Blood 104, n. 1 (1 luglio 2004): 107–14. http://dx.doi.org/10.1182/blood-2003-11-3842.

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Abstract We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and platelets lacking α-granules. Dense granules were normally present. Platelet aggregation with collagen was severely decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative analysis of GPVI using fluorescein isothiocyanate (FITC)–Cvx in flow cytometry showed its virtual absence on the patient's platelets. The GPVI deficiency was confirmed using monoclonal antibodies in Western blotting and in immunogold labeling on frozen thin sections where internal pools of GPVI were confirmed for normal platelets. The Fc receptor γ-chain, constitutively associated with GPVI in normal platelets, was present in subnormal amounts, and the phospholipase Cγ2–dependent activation pathway appeared to function normally. No autoantibodies to GPVI were found in the patient's serum using monoclonal antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in the patient's platelets, pointing to a probable acquired defect in GPVI expression. Our results may provide a molecular explanation for the subgroup of patients with severely deficient collagen-induced platelet aggregation as previously described for GPS in the literature.

10

Rao, A. Koneti, e Deepak A. Rao. "Gray platelet syndrome: immunity goes awry". Blood 136, n. 17 (22 ottobre 2020): 1898–900. http://dx.doi.org/10.1182/blood.2020008196.

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11

Tyagi, Seema, e Renu Saxena. "Gray Platelet Syndrome Presenting As Menorrhagia". International Journal of Hematology 77, n. 2 (febbraio 2003): 201–2. http://dx.doi.org/10.1007/bf02983224.

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Mues, Gabriele, Frank H. Wians e Steven H. Kroft. "EDTA-Induced Pseudo–Gray Platelet Syndrome". Laboratory Medicine 32, n. 7 (1 luglio 2001): 361–64. http://dx.doi.org/10.1309/7vbg-ym6h-am90-vnqt.

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White, James G., e Richard D. Brunning. "Neutrophils in the gray platelet syndrome". Platelets 15, n. 5 (agosto 2004): 333–40. http://dx.doi.org/10.1080/09537100410001714872.

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Berrebi, Alain, Abraham Klepfish, David Varon, Mordechai Shtalrid, Eliakim Vorst, Emanuel Nir e Judith Lahav. "Gray platelet syndrome in the elderly". American Journal of Hematology 28, n. 4 (agosto 1988): 270–72. http://dx.doi.org/10.1002/ajh.2830280411.

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Obydennyi, S. I., I. I. Kireev e M. A. Panteleev. "The electron microscopy contribution to platelet structural pathology investigation". Pediatric Hematology/Oncology and Immunopathology 21, n. 3 (15 ottobre 2022): 142–46. http://dx.doi.org/10.24287/1726-1708-2022-21-3-142-146.

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This article discusses the role of electron microscopy in the diagnosis and study of morphological changes that cause platelet structural abnormalities in a variety of congenital diseases. Morphological abnormalities can be divided into the abnormalities of the platelet cytoskeleton, of alpha and dense granules, and membrane abnormalities. Our paper describes ultrastructural platelet defects in Wiskott–Aldrich syndrome, MYH9-associated syndromes, gray platelet syndrome, Hermansky–Pudlak syndrome, Paris–Trousseau syndrome, Chediak–Higashi syndrome.

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Drouin, Arnaud, Rémi Favier, Jean-Marc Massé, Najet Debili, Alain Schmitt, Carole Elbim, Josette Guichard, Mircea Adam, Marie-Anne Gougerot-Pocidalo e Elisabeth M. Cramer. "Newly recognized cellular abnormalities in the gray platelet syndrome". Blood 98, n. 5 (1 settembre 2001): 1382–91. http://dx.doi.org/10.1182/blood.v98.5.1382.

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The gray platelet syndrome (GPS) is a rare congenital bleeding disorder in which thrombocytopenia is associated with increased platelet size and decreased α-granule content. This report describes 3 new pediatric cases presenting with the classical platelet abnormalities of GPS within one family with normal parents. Examination of blood smears of the 3 patients demonstrated not only gray platelets, but also gray polymorphonuclear neutrophils (PMNs) with decreased or abnormally distributed components of secretory compartments (alkaline phosphatase, CD35, CD11b/CD18). Secondary granules were also decreased in number as assayed by immunoelectron microscopy. These data confirm that the secretory compartments in neutrophils were also deficient in this family. Megakaryocytes (MKs) were cultured from the peripheral blood CD34+ cells of the 3 patients for 14 days, in the presence of thrombopoietin and processed for immunoelectron microscopy. Although von Willebrand factor (vWF) was virtually undetectable in platelets, vWF immunolabeling was conspicuous in cultured maturing MKs, particularly within Golgi saccules, but instead of being packaged in α-granules, it was released into the demarcation membrane system. In contrast, P-selectin followed a more classical pathway. Double-labeling experiments confirmed that vWF was following an intracellular pathway distinct from the one of P-selectin. In these 3 new cases of GPS, the MKs appeared to abnormally process vWF, with secretion into the extracellular space instead of normal α-granule packaging. Furthermore, the secretory compartment of another blood cell line, the neutrophil, was also affected in this family of GPS.

17

Van der Reijden, Bert A., Davide Monteferrario, Nikhita Bolar, Anna Marneth, Konnie Hebeda, Saskia Bergevoet, Hans Veenstra et al. "A Dominant-Negative GFI1B Mutation in Gray Platelet Syndrome". Blood 122, n. 21 (15 novembre 2013): LBA—3—LBA—3. http://dx.doi.org/10.1182/blood.v122.21.lba-3.lba-3.

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Abstract Gray platelet syndrome (GPS) is a hereditary, usually autosomal recessive bleeding disorder caused by defective production of α-granules in platelets. GPS patients show reduced numbers of platelets that are larger and have a typical gray appearance under light microscopy, caused by the lack of α-granules. We describe a large family with an autosomal dominant type of GPS characterized by mild to severe bleeding complications. In addition to large gray platelets, other GPS-associated phenomena like myelofibrosis, thrombocytopenia, and low platelet factor 4 expression were observed in affected individuals. Histopathological examination of a BM biopsy from a patient showed a cellular marrow with increased numbers of megakaryocytes that were pleomorphic in size and shape. Megakaryocytes clustered along BM sinuses and showed dysmorphic stretched features. To determine the disease causing mutation we performed linkage analysis and identified a candidate locus on chromosome 9q34 with a LOD score of 3.9. We considered GFI1B (Growth Factor Independence 1B), located within this region, an excellent candidate gene because of its function as a transcriptional repressor in megakaryocyte development. Sequence analysis identified a nonsense mutation in GFI1B exon 6 (c.859C>T, p.Gln287*) that completely co-segregated with the GPS disease in this family. The mutated transcript predicts a 44 amino acid C-terminally truncated protein, GFI1BTr. The truncation is located within zinc finger 5 of GFI1B, deleting all of its four amino acids that directly interact with DNA. Luciferase gene reporter assays showed that GFI1BTr was unable to repress gene expression. Importantly, GFI1BTr inhibited gene repression mediated by wild type GFI1B, indicating that the mutant interferes with wild type GFI1B in a dominant-negative manner. To validate that GFI1BTr adversely affects normal GFI1B, we expressed the mutant in mouse bone marrow cells followed by induction of megakaryocytic differentiation. Compared to control cells, GFI1BTr-positive megakaryocytes showed dysplastic features including hypolobulation of the nuclei, irregular contours and multiple separate nuclei, that were very similar to those observed in patient cells. This indicates that GFI1BTr causes megakaryocytic abnormalities and that it functions in a dominant-negative manner. GFI1B silencing inhibits the development of human megakaryocyte colonies in vitro. We observed that megakaryocyte colony forming cells were significantly more frequent in patient bone marrow compared to controls. In addition, patient-derived megakaryocyte colonies were significantly larger compared to controls. Immunophenotypic analyses of peripheral blood showed no differences in myeloid and erythroid lineages and the platelet markers GP3B, ITGA2B and ITGB3 among affected an non-affected individuals. However, within the ITGA2B/CD41-positive platelet population, 5 of 6 affected members showed a marked decrease in the platelet surface membrane glycoprotein 1b-α (GP1BA/CD42b), compared to unaffected members. In addition, a strong expression of CD34, which is usually confined to immature hematopoietic progenitors, was detected on platelets from all studied affected individuals. Immunostaining of a BM biopsy from a patient showed the presence of ITGB3/CD61 positive megakaryocytes that intensely expressed CD34. Electron microscopy analysis showed megakaryocytes with few, small, irregularly shaped and centrally located α-granules characterized by an extensive peripheral cytoplasm with irregular proplatelets, largely devoid of cell organelles. To test whether these abnormalities were cell intrinsic, we stimulated CD34+ cells from two patients to differentiate along the megakaryocytic lineage in vitro. Megakaryocytic cells showed dysplastic features reminiscent of those observed in the bone marrow aspirates. In addition, increased CD34 and decreased GP1BA/CD42b expression were observed on megakaryocytes, indicating that GFI1BTr-induced abnormalities are intrinsic to the cell. In summary, we have identified GFI1B as a causative gene in autosomal dominant GPS. GFI1BTr acts in a dominant-negative manner over wild type GFI1B and affects the development of megakaryocytes and platelets, demonstrating a pivotal role of GFI1B in governing normal megakaryopoiesis and platelet production. Disclosures: No relevant conflicts of interest to declare.

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Rensing-Ehl, Anne, Ulrich Pannicke, Stefanie-Yvonne Zimmermann, Myriam Ricarda Lorenz, Benedicte Neven, Ilka Fuchs, Ulrich Salzer et al. "Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome". Blood 126, n. 16 (15 ottobre 2015): 1967–69. http://dx.doi.org/10.1182/blood-2015-06-654145.

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Di Paola, Jorge. "Novel Congenital Platelet Disorders". Blood 128, n. 22 (2 dicembre 2016): SCI—39—SCI—39. http://dx.doi.org/10.1182/blood.v128.22.sci-39.sci-39.

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The processes of megakaryocyte differentiation, proplatelet formation, and the daily release of 1011 platelets into the bloodstream are tightly regulated. Genetic disturbances can lead to a cascade of downstream molecular alterations that markedly affect the function of megakaryocytes and platelets. Therefore, identifying new genes and their function in megakaryocytes and platelets is critical for understanding how these unique cells contribute to health and disease. Over the last decade advances in genomics, specifically next generation sequencing, have allowed for the discovery of several mutations and genetic variants that cause disease or influence associated hematological traits. By performing platelet RNA-Seq we were among the first to identify NBEAL2 as the causative gene for gray platelet syndrome (GPS) and showed that NBEAL2 regulates megakaryocyte development and platelet function.1-3 Mice carrying targeted Nbeal2 null alleles not only replicated the thrombocytopenia and lack of alpha granules observed in humans, but also provided new information about the role of platelets in thromboinflammation, wound healing, myelofibrosis and metastasis dissemination.4-7 More recently, we and others found that germline mutations in ETV6 lead to thrombocytopenia, red cell macrocytosis, and predisposition to lymphoblastic leukemia.8,9ETV6 encodes an ETS family transcriptional repressor, which exerts its activity by binding a consensus sequence in the promoter regions of DNA. Mice with conditional Etv6 knockout in megakaryocytic-erythroid cells are thrombocytopenic indicating the involvement of Etv6 in thrombopoiesis.10 Several of the families recently described have a missense mutation in the central domain of ETV6 (p.P214L). This mutation results in aberrant cellular localization of ETV6, decreased transcriptional repression, and impaired megakaryocyte maturation. The bone marrow of individuals affected by this mutation show hyperplasia of immature megakaryocytes suggesting a differentiation arrest. Deep sequencing of the platelet transcriptome also revealed significant differences in mRNA expression levels between patients with the ETV6 p.P214L mutation and non-affected family members, indicating that ETV6 is critically involved in defining the molecular phenotype and function of platelets. Consistent with this notion, individuals with the ETV6 p.P214L mutation experience bleeding that is disproportionate to their mild thrombocytopenia. We have also used CRISPR/Cas9 technology to generate a mouse colony where the human p.P214L ETV6 mutation was inserted into the conserved site of Etv6. Mice with this mutation (Etv6H.P214L) have reduced platelet counts. In summary, advances in human genetics that led to the discovery of novel congenital platelet disorders coupled with relevant animal models will likely contribute to our understanding of megakaryopoiesis and platelet function. References 1. Kahr WH, Hinckley J, Li L, et al. Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome. Nature genetics. 2011;43(8):738-740. 2. Gunay-Aygun M, Falik-Zaccai TC, Vilboux T, et al. NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet alpha-granules. Nature genetics. 2011;43(8):732-734. 3. Albers CA, Cvejic A, Favier R, et al. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nature genetics. 2011;43(8):735-737. 4. Deppermann C, Cherpokova D, Nurden P, et al. Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice. The Journal of clinical investigation. 2013. 5. Kahr WH, Lo RW, Li L, et al. Abnormal megakaryocyte development and platelet function in Nbeal2(-/-) mice. Blood. 2013;122(19):3349-3358. 6. Guerrero JA, Bennett C, van der Weyden L, et al. Gray platelet syndrome: proinflammatory megakaryocytes and alpha-granule loss cause myelofibrosis and confer metastasis resistance in mice. Blood.2014;124(24):3624-3635. 7. Tomberg K, Khoriaty R, Westrick RJ, et al. Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. PLoS One. 2016;11(3):e0150852. 8. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature Genetics. 2015;47(5):535-538. 9. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nature genetics. 2015;47(2):180-185. 10. Wang LC, Swat W, Fujiwara Y, et al. The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes & development. 1998;12(15):2392-2402. Disclosures Di Paola: CSL BEhring: Consultancy; Biogen: Consultancy.

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MORI, KAZUO, SOZO SUZUKI, KOJI SUGAI, YASUYUKI AKUTSU, MASAAKI ISHIKAWA e HIDEAKI SAKAI. "Morphological changes of platelets during the process of platelet aggregation in gray platelet syndrome." Tohoku Journal of Experimental Medicine 149, n. 4 (1986): 425–36. http://dx.doi.org/10.1620/tjem.149.425.

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Aminkeng, F. "GFI1Bmutation causes autosomal dominant gray platelet syndrome". Clinical Genetics 85, n. 6 (9 aprile 2014): 534–35. http://dx.doi.org/10.1111/cge.12380.

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Di Paola, Jorge, e Jan Johnson. "Thrombocytopenias Due to Gray Platelet Syndrome orTHC2Mutations". Seminars in Thrombosis and Hemostasis 37, n. 06 (settembre 2011): 690–97. http://dx.doi.org/10.1055/s-0031-1291379.

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White, James G., Asish Kumar e Marjorie J. Hogan. "Gray Platelet Syndrome in a Somalian family". Platelets 17, n. 8 (gennaio 2006): 519–27. http://dx.doi.org/10.1080/09537100600758636.

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Monteferrario, Davide, Nikhita A. Bolar, Anna E. Marneth, Konnie M. Hebeda, Saskia M. Bergevoet, Hans Veenstra, Britta A. P. Laros-van Gorkom et al. "A Dominant-NegativeGFI1BMutation in the Gray Platelet Syndrome". New England Journal of Medicine 370, n. 3 (16 gennaio 2014): 245–53. http://dx.doi.org/10.1056/nejmoa1308130.

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Ido, Kentaro, Takahiko Nakane, Nao Tanizawa, Yosuke Makuuchi, Hiroshi Okamura, Shiro Koh, Satoru Nanno et al. "Acquired Gray Platelet Syndrome Associated with Primary Myelofibrosis". Internal Medicine 59, n. 21 (1 novembre 2020): 2751–56. http://dx.doi.org/10.2169/internalmedicine.4912-20.

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McGinnis, Eric, e Kate M. Chipperfield. "Striking emperipolesis in megakaryocytes of gray platelet syndrome". Blood 133, n. 26 (27 giugno 2019): 2809. http://dx.doi.org/10.1182/blood.2019000494.

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Kahr, Walter H. A., e Yigal Dror. "Gray platelet syndrome: macrothrombocytopenia with deficient α-granules". Blood 120, n. 13 (27 settembre 2012): 2543. http://dx.doi.org/10.1182/blood-2012-03-415778.

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Tubman, Venée N., Jason E. Levine, Dean R. Campagna, Mark D. Fleming e Ellis J. Neufeld. "X-Linked Gray Platelet Syndrome Due to a GATA1 Arg216Gln Mutation." Blood 106, n. 11 (16 novembre 2005): 5. http://dx.doi.org/10.1182/blood.v106.11.5.5.

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Abstract (sommario):

Abstract Gray Platelet Syndrome (GPS) is characterized by a variable, mild bleeding diathesis, associated with thrombocytopenia and large, agranular, functionally abnormal platelets. While the disorder has been well-described both biochemically and pathologically, to our knowledge, no genetic mutation has been associated with the disease. Most cases are sporadic, with a few sibships and apparent autosomal kindreds reported. In our investigation, the proband is a healthy 1 year-old female whose father and uncle had recently been diagnosed with GPS. The child had a platelet count of 382 x103 platelets/μl, comprised of a dimorphic population of normal and large, agranular forms. Her CBC and peripheral blood smear were otherwise unremarkable. We subsequently analyzed four generations of this family. In addition to the proband’s father and uncle, several other members had known bleeding tendencies. The symptomatic individuals were invariably males, consistent with a sex-linked pattern of inheritance. Several symptomatic and asymptomatic family members were evaluated by CBC and blood smear. Large, agranular platelets were found in symptomatic males, while obligate carrier females exhibited both normal and abnormal forms. Using a set of fifteen microsatellite markers spanning the X chromosome, a common haplotype was identified in all affected men, their mothers, and their daughters. Aided by the published sequence of the X chromosome, we examined this region for candidate genes. Although the common haplotype between markers GATA144D04 and DXS6797 (Xp11.3-Xq22.3) contains hundreds of genes, only two, GATA1 and WAS, have known associations with thrombocytopenia. PCR amplification and sequencing of a 3′ segment of the GATA-1 promoter and the five coding exons of the GATA-1 gene revealed an G759A missense mutation resulting in an Arg216Gln substitution in exon 4 (NCBI RefSeq: NM_002049) that segregated with the phenotype and was present in all obligate carrier females. This mutation has been previously associated with X-linked thrombocytopenia and beta-thalassemia (XLTT), a syndrome characterized by splenomegaly, thrombocytopenia, and imbalanced globin chain synthesis (Balduini et al, Thromb Haemost. 2004; 91:129). Comparison of the ultrastructural characteristics of the platelets in both disorders and a review of literature on both diseases suggests that XLTT, and the associated mutation in GATA1, could represent one genetic origin for GPS. As carrier females generally display a less severe phenotype than affected males, without thrombocytopenia and with subtle dimorphism on smears, it is possible that this mutation may account for some previously reported “sporadic” cases of GPS.

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Perez-Pujol, Silvia, Lorraine B. Anderson, Michael B. Martinez, LeeAnn Higgins, James G. White, Gary L. Nelsestuen e Nigel S. Key. "Proteomic Analysis of Gray Platelet Syndrome by iTRAQ Labelling and Mass Spectroscopy: A Potential New Diagnostic Strategy for Platelet Disorders." Blood 106, n. 11 (16 novembre 2005): 2161. http://dx.doi.org/10.1182/blood.v106.11.2161.2161.

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Abstract The recent introduction of novel proteomic techniques to evaluate normal human platelet proteins and their modifications following activation may also help to elucidate the causes and improve diagnoses of platelet-related bleeding disorders. Previous studies from this and other laboratories have demonstrated the sensitivity and reliability of this new technique to detect minor changes (+/−20%) in the protein content of platelets. More than 600 proteins shared by normal platelets were identified, and >200 in platelet-derived microparticles (MPs) generated by ionophore or Thrombin Receptor Activating Peptide (TRAP) activation. As a prelude to our ultimate goal of establishing this new technology, we applied the iTRAQ method (multiplexed relative protein quantitation by mass spectrometry) in the study of two unrelated patients with the Gray Platelet Syndrome (GPS). Megakaryocytes of patients with GPS can synthesize alpha-granule proteins and enclose them within membranes. However, the membranes lack structure linked latency, and enclosed proteins leak out of the organelles before platelets are delivered to circulating blood. Thus, GPS platelets contain empty alpha-granule vacuoles instead of alpha-granules. Due to large changes in platelet properties, it was surprising to find that cytoskeletal proteins of GPS were present in similar abundance to normal platelets (i.e. in the range of 0.80–1.20). Receptor proteins showed a similar distribution. As expected, the content of most alpha-granule proteins in the platelets from the 2 GPS patients was markedly reduced, with individual protein abundance ratios of 0.10 to 0.52 compared to normal platelets. However, certain trans-membrane proteins of alpha-granules (such as vesicle-associated proteins and P-selectin) were better preserved in GPS platelets, with ratios in the range of 0.73 to 1.16 compared to normal platelets. These results showed that many structural components (such as cytoskeleton and receptor proteins) are unchanged in GPS platelets. The results support our previous data indicating that detection of a change of as little as 20% may indicate a pathological change in the platelet proteome that may impact normal function. Our results therefore demonstrate that highly sensitive methods, capable of detecting small protein changes, may be needed to fully appreciate pathological disorders. The iTRAQ technique is able to detect low level changes and may be a leading tool that can generate new insights into the molecular pathophysiology and genetic variations of platelet disorders.

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Sims, Matthew C., Louisa Mayer, Janine H. Collins, Tadbir K. Bariana, Karyn Megy, Cecile Lavenu-Bombled, Denis Seyres et al. "Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome". Blood 136, n. 17 (22 ottobre 2020): 1956–67. http://dx.doi.org/10.1182/blood.2019004776.

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Abstract (sommario):

Abstract Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.

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Gootenberg, Joseph E., George R. Buchanan, Christine A. Holtkamp e Catherine S. Casey. "Severe hemorrhage in a patient with gray platelet syndrome". Journal of Pediatrics 109, n. 6 (dicembre 1986): 1017–19. http://dx.doi.org/10.1016/s0022-3476(86)80289-x.

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Nurden, Alan T., e Paquita Nurden. "The gray platelet syndrome: Clinical spectrum of the disease". Blood Reviews 21, n. 1 (gennaio 2007): 21–36. http://dx.doi.org/10.1016/j.blre.2005.12.003.

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33

Bottega, Roberta, Elena Nicchia, Caterina Alfano, Ana C. Glembotsky, Annalisa Pastore, Debora Bertaggia-Calderara, Bettina Bisig et al. "Gray platelet syndrome: Novel mutations of the NBEAL2 gene". American Journal of Hematology 92, n. 2 (17 gennaio 2017): E20—E22. http://dx.doi.org/10.1002/ajh.24610.

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34

Riley, Roger, Asad Khan, Shella Pai, Laura Warmke, Marcus Winkler e William Gunning. "A Case of Chronic Thrombocytopenia in a 17-Year-Old Female". Laboratory Medicine 50, n. 4 (22 giugno 2019): 406–20. http://dx.doi.org/10.1093/labmed/lmz013.

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AbstractStorage pool deficiency (SPD) is a group of rare platelet disorders that result from deficiencies in α-granules, δ-granules, or both. One type of α-SPD is gray platelet syndrome (GPS), caused by mutations in the neurobeachin-like 2 (NBEAL2) gene that results in a bleeding diathesis, thrombocytopenia, splenomegaly, and progressive myelofibrosis. Due to the lack of α-granules, platelets have a gray and degranulated appearance by light microscopy. However, definitive diagnosis of GPS requires confirmation of α-granule deficiency by electron microscopy. Treatment is nonspecific, with the conservative utilization of platelet transfusions being the most important form of therapy. We present a case of a 17-year-old female with a past medical history of thrombocytopenia, first identified at the age of five. Her clinical symptomatology included chronic fatigue, gingival bleeding, bruising, menorrhagia, and leg pain. This report will discuss both the clinical and the pathophysiologic aspects of this rare platelet disorder.

35

Breton-Gorius, J., P. Clezardin, J. Guichard, N. Debili, L. Malaval, W. Vainchenker, EM Cramer e PD Delmas. "Localization of platelet osteonectin at the internal face of the alpha- granule membranes in platelets and megakaryocytes". Blood 79, n. 4 (15 febbraio 1992): 936–41. http://dx.doi.org/10.1182/blood.v79.4.936.936.

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Abstract Osteonectin is a 32-Kd phosphoglycoprotein originally described in bone but also found in platelets. Platelet and bone osteonectin are different both structurally and immunologically. We have previously shown that platelet osteonectin, by binding to thrombospondin, is involved in the secretion-dependent phase of the platelet aggregation process. In this study, we used antiosteonectin antibodies in combination with immunogold labeling to investigate by electron microscopy the fine localization of osteonectin within normal and gray platelets. Using both a polyclonal and monoclonal antibody ON3, osteonectin was specifically located at the internal face of alpha- granule membranes within normal platelets. Osteonectin was not distributed within all alpha-granules, probably because of its low platelet content. In addition, using immunofluorescence, osteonectin could also be detected in immature and mature megakaryocytes with a granular pattern of staining, suggesting that osteonectin is synthesized by megakaryocytes. Using platelets from two patients with gray platelet syndrome, osteonectin was absent within all abnormal small alpha-granules, but was detected in some rare normal-sized alpha- granules. In separate double-label studies, thrombospondin and von Willebrand factor did not colocalize with osteonectin in resting platelets. However, osteonectin was located at the inner face of the alpha-granules, as it is for alpha-granule membrane protein GMP-140 and glycoprotein IIb-IIIa. These results, taken together with the fact that monoclonal antibodies to osteonectin bind only to the surface of activated platelets, suggest that platelet osteonectin is redistributed to the cell surface during fusion of alpha-granule membranes with the plasma membrane.

36

Breton-Gorius, J., P. Clezardin, J. Guichard, N. Debili, L. Malaval, W. Vainchenker, EM Cramer e PD Delmas. "Localization of platelet osteonectin at the internal face of the alpha- granule membranes in platelets and megakaryocytes". Blood 79, n. 4 (15 febbraio 1992): 936–41. http://dx.doi.org/10.1182/blood.v79.4.936.bloodjournal794936.

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Abstract (sommario):

Osteonectin is a 32-Kd phosphoglycoprotein originally described in bone but also found in platelets. Platelet and bone osteonectin are different both structurally and immunologically. We have previously shown that platelet osteonectin, by binding to thrombospondin, is involved in the secretion-dependent phase of the platelet aggregation process. In this study, we used antiosteonectin antibodies in combination with immunogold labeling to investigate by electron microscopy the fine localization of osteonectin within normal and gray platelets. Using both a polyclonal and monoclonal antibody ON3, osteonectin was specifically located at the internal face of alpha- granule membranes within normal platelets. Osteonectin was not distributed within all alpha-granules, probably because of its low platelet content. In addition, using immunofluorescence, osteonectin could also be detected in immature and mature megakaryocytes with a granular pattern of staining, suggesting that osteonectin is synthesized by megakaryocytes. Using platelets from two patients with gray platelet syndrome, osteonectin was absent within all abnormal small alpha-granules, but was detected in some rare normal-sized alpha- granules. In separate double-label studies, thrombospondin and von Willebrand factor did not colocalize with osteonectin in resting platelets. However, osteonectin was located at the inner face of the alpha-granules, as it is for alpha-granule membrane protein GMP-140 and glycoprotein IIb-IIIa. These results, taken together with the fact that monoclonal antibodies to osteonectin bind only to the surface of activated platelets, suggest that platelet osteonectin is redistributed to the cell surface during fusion of alpha-granule membranes with the plasma membrane.

37

Aarts, Cathelijn E. M., Kate Downes, Arie J. Hoogendijk, Evelien G. G. Sprenkeler, Roel P. Gazendam, Rémi Favier, Marie Favier et al. "Neutrophil specific granule and NETosis defects in gray platelet syndrome". Blood Advances 5, n. 2 (25 gennaio 2021): 549–64. http://dx.doi.org/10.1182/bloodadvances.2020002442.

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Abstract Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of α-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD34+ hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.

38

Larocca, Luigi M., Paula G. Heller, Gianmarco Podda, Nuria Pujol-Moix, Ana C. Glembotsky, Alessandro Pecci, Maria Adele Alberelli et al. "Megakaryocytic emperipolesis and platelet function abnormalities in five patients with gray platelet syndrome". Platelets 26, n. 8 (25 marzo 2015): 751–57. http://dx.doi.org/10.3109/09537104.2014.994093.

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39

K�hler, M., P. Hellstern, E. Morgenstern, C. Mueller-Eckhardt, R. Berberich, R. J. Meiser, P. Scheffler e E. Wenzel. "Gray platelet syndrome: Selective ?-granule deficiency and thrombocytopenia due to increased platelet turnover". Blut 50, n. 6 (giugno 1985): 331–40. http://dx.doi.org/10.1007/bf00320926.

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40

Gunay-Aygun, Meral, Yifat Zivony-Elboum, Fatma Gumruk, Dan Geiger, Mualla Cetin, Morad Khayat, Robert Kleta et al. "Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p". Blood 116, n. 23 (2 dicembre 2010): 4990–5001. http://dx.doi.org/10.1182/blood-2010-05-286534.

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Abstract Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B12 as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.

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Kasthuri, Raj S., Lorraine B. Anderson, LeeAnn Higgins, Jorge Di Paola, Georges E. Rivard, Catherine P. M. Hayward e Nigel S. Key. "Proteomics in the Study of Qualitative Platelet Defects: Validation of the Approach in the Gray Platelet Syndrome and Quebec Platelet Disorder." Blood 110, n. 11 (16 novembre 2007): 3900. http://dx.doi.org/10.1182/blood.v110.11.3900.3900.

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Abstract Qualitative platelet defects are a heterogeneous group of disorders characterized by abnormal platelet function. Currently available laboratory assays lack sensitivity and specificity for detecting Storage Pool and Platelet Secretion defects. The Gray Platelet Syndrome (GPS) is an autosomal recessive disorder characterized by a decrease or absence of alpha granule contents. The Quebec Platelet Disorder (QPD) results from proteolysis of alpha granule proteins due to increased amounts of platelet urokinase. A decrease or deficiency of multimerin is characteristic. Proteomics is a rapidly developing field with great promise in the study of pathophysiology and biomarker development. Recent advances have made measurement of relative protein abundance in multiple samples feasible. We used one such approach, “isotope Tagging for Relative and Absolute Quantitation” (iTRAQ) to characterize the platelet proteome of healthy volunteers and patients with GPS and QPD. iTRAQ allows analysis of up to 4 different samples simultaneously, and differences in protein abundance as low as 20% are reliably detected. The platelet proteomes of 4 healthy volunteers were analyzed. Platelet proteome analysis of study patients was as follows; 2 GPS patients compared to 2 controls; 2 heterozygous GPS patients compared to a homozygote and a control; and 3 QPD patients compared to a control. For comparison, platelet proteins were grouped by location into 3 groups - receptor, alpha granule and cytoskeletal proteins. The results are shown in the figure. Protein abundance in healthy volunteers was very consistent, with inter-individual variability ≤ 20%. Distribution of receptor and cytoskeletal proteins in GPS patients mirrored the controls, but alpha granule proteins were significantly decreased as expected. Comparison of homozygous to heterozygous GPS platelets showed this to be true only in the homozygotes, again, as expected (figure inset). Variable decreases in alpha granule proteins were observed in QPD patients but this was less profound. Multimerin was detected in QPD patients, but at levels significantly lower than controls. While urokinase was not detected in QPD platelets in this study, it was detected in a parallel study evaluating platelet releasates. The iTRAQ technique was reproducible and yielded consistent results, but currently is a relatively expensive and time-consuming approach. In summary, our results suggest that the platelet proteome is tightly regulated and very stable in healthy individuals. A significant decrease in alpha granule proteins was noted in patients with GPS but this was less remarkable in the QPD group, probably because peptides resulting from urokinase-mediated proteolysis are still labeled and quantified. Figure Figure

42

Pfueller, Sharron L., Margaret A. Howard, James G. White, Chandrasekhara Menon e Elizabeth W. Berry. "Shortening of Bleeding Time by 1-Deamino-8-Arginine Vasopressin (DDAVP) in the Absence of Platelet von Willebrand Factor in Gray Platelet Syndrome". Thrombosis and Haemostasis 58, n. 04 (1987): 1060–63. http://dx.doi.org/10.1055/s-0038-1646056.

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SummaryThe Gray platelet syndrome is a rare disorder characterised by the absence of platelet a-granules and their contents. We describe a new patient and the effects of infusions of l-deainino-8-aiginine vasopressin (DDAVP). The patient had a prolonged skin bleeding time and his platelets had reduced numbers of a-granules, increased vacuolation and reduced retention on glass beads. Flatelet von Willebrand factor antigen (vWf:Ag) was undetectable and levels of platelet fibrinogen, p-thioniboglobulin, platelet factor 4 and thrombospondin were reduced. All tests of plasma coagulation factors were normal, including Factor VIII (F. VIII: C), vWf: Ag, ristocetin cofactor (R: CoF) and botrocetin cofactor. Platelet ATP, ADP, platelet albumin, surface membrane glycoproteins and 14C-serotonin uptake were also normal. Infusions of DDAVP increased plasma F.VIII:C, vWf:Ag and R.CoF and sliuitened the bleeding time un two occasions. This suggests that DDAVP shortens the bleeding time by releasing vWf: Ag and/or other proteins from cellular storage sites other than the platelet.

43

Cramer, EM, W. Vainchenker, G. Vinci, J. Guichard e J. Breton-Gorius. "Gray platelet syndrome: immunoelectron microscopic localization of fibrinogen and von Willebrand factor in platelets and megakaryocytes". Blood 66, n. 6 (1 dicembre 1985): 1309–16. http://dx.doi.org/10.1182/blood.v66.6.1309.1309.

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Abstract An immunogold method was used for investigating the subcellular localization of von Willebrand factor (vWF) and fibrinogen (Fg) in platelets and cultured megakaryocytes from normal subjects and from three patients with the gray platelet syndrome (GPS), a rare congenital disorder characterized by the absence of alpha-granules. In normal platelets at rest, vWF was detected exclusively in alpha-granules, with a characteristic distribution: gold particles were localized at one pole of each labeled granule, outlining the inner face of its membrane. vWF was distributed similarly in the alpha-granules of megakaryocytes at day 12 of culture, where it was also found in small vesicles near the Golgi complex. In contrast, Fg was observed in the whole matrix of all platelet alpha-granules but not in the nucleoids. In platelets from three patients with GPS, vWF and Fg were distributed homogeneously in the rare normal alpha-granules, which could be recognized by their size, and also in small granules identified as abnormal alpha-granules, which were similar in size to the small, possibly immature granules present in normal megakaryocytes. In addition, in some unstimulated platelets, Fg labeling was associated with dense material in the lumen of the surface-connected canalicular system (SCCS). At day 12 of culture, megakaryocytes from the patients with GPS contained some small alpha-granules labeled for Fg and vWF identical to those found in mature platelets. The majority of alpha-granules of normal size appeared partially or completely empty. Thus, we conclude that vWF is distributed differently from Fg in normal alpha-granules, and that unstimulated platelets from patients with GPS contain Fg and vWF in a population of small granules identifiable as abnormal alpha-granules only by immunoelectron microscopy. In addition, the presence of Fg in the SCCS of gray platelets suggests a spontaneous release of the alpha- granule content.

44

Cramer, EM, W. Vainchenker, G. Vinci, J. Guichard e J. Breton-Gorius. "Gray platelet syndrome: immunoelectron microscopic localization of fibrinogen and von Willebrand factor in platelets and megakaryocytes". Blood 66, n. 6 (1 dicembre 1985): 1309–16. http://dx.doi.org/10.1182/blood.v66.6.1309.bloodjournal6661309.

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Abstract (sommario):

An immunogold method was used for investigating the subcellular localization of von Willebrand factor (vWF) and fibrinogen (Fg) in platelets and cultured megakaryocytes from normal subjects and from three patients with the gray platelet syndrome (GPS), a rare congenital disorder characterized by the absence of alpha-granules. In normal platelets at rest, vWF was detected exclusively in alpha-granules, with a characteristic distribution: gold particles were localized at one pole of each labeled granule, outlining the inner face of its membrane. vWF was distributed similarly in the alpha-granules of megakaryocytes at day 12 of culture, where it was also found in small vesicles near the Golgi complex. In contrast, Fg was observed in the whole matrix of all platelet alpha-granules but not in the nucleoids. In platelets from three patients with GPS, vWF and Fg were distributed homogeneously in the rare normal alpha-granules, which could be recognized by their size, and also in small granules identified as abnormal alpha-granules, which were similar in size to the small, possibly immature granules present in normal megakaryocytes. In addition, in some unstimulated platelets, Fg labeling was associated with dense material in the lumen of the surface-connected canalicular system (SCCS). At day 12 of culture, megakaryocytes from the patients with GPS contained some small alpha-granules labeled for Fg and vWF identical to those found in mature platelets. The majority of alpha-granules of normal size appeared partially or completely empty. Thus, we conclude that vWF is distributed differently from Fg in normal alpha-granules, and that unstimulated platelets from patients with GPS contain Fg and vWF in a population of small granules identifiable as abnormal alpha-granules only by immunoelectron microscopy. In addition, the presence of Fg in the SCCS of gray platelets suggests a spontaneous release of the alpha- granule content.

45

Yoo, Jaeeun, Yonggoo Kim e Kyungja Han. "Pseudo gray platelet syndrome: the first case report in Korea". Blood Research 50, n. 2 (2015): 117. http://dx.doi.org/10.5045/br.2015.50.2.117.

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46

Deppermann, Carsten, Paquita Nurden, Alan T. Nurden, Bernhard Nieswandt e David Stegner. "TheNbeal2−/−mouse as a model for the gray platelet syndrome". Rare Diseases 1, n. 1 (gennaio 2013): e26561. http://dx.doi.org/10.4161/rdis.26561.

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47

Pluthero, Fred G., Jorge Di Paola, Manuel D. Carcao e Walter H. A. Kahr. "NBEAL2 mutations and bleeding in patients with gray platelet syndrome". Platelets 29, n. 6 (5 giugno 2018): 632–35. http://dx.doi.org/10.1080/09537104.2018.1478405.

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48

Berger, G., JM Masse e EM Cramer. "Alpha-granule membrane mirrors the platelet plasma membrane and contains the glycoproteins Ib, IX, and V". Blood 87, n. 4 (15 febbraio 1996): 1385–95. http://dx.doi.org/10.1182/blood.v87.4.1385.bloodjournal8741385.

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We have recently shown that several components from the platelet plasma membrane were also present at different rates in the alpha-granule membrane. This is the case for the glycoprotein (GP) IIb-IIIa (CD41), CD36, CD9, PECAM1, and Rap1b, while the GPIB-IX-V complex was considered to escape the rule. In this investigation, we studied the subcellular localization of GPIb, GPIX, and GPV in the resting platelets of normal subjects, patients with Bernard-Soulier syndrome, patients with Gray platelet syndrome, and human cultured megakaryocytes. Ultra-thin sections of the cells were labeled with antibodies directed against glycocalicin, GPIb, GPIX, and GPV. We have shown that a significant and reproducible labeling for the three GPs was associated with the alpha-granule membrane, accounting for approximately 10% of the total labeling. Furthermore, GPIb labeling appears Willebrand factor (vWF). After thrombin activation, vWF remained close to the limiting membrane of the open canalicular system (OCS), suggesting an early association of both receptor and ligand. Plasma membrane and alpha-granule labeling was virtually absent from the Bernard-Soulier platelets (characterized by a GPIb deficiency), thus proving the specificity of the reaction. In Gray platelets (storage granule deficiency syndrome), the small residual alpha- granules were also occasionally labeled for GPIb, GPIX, and GPIX. Cultured megakaryocytes that displayed the classical GPIb distribution, eg, demarcation and plasma membranes, exhibited also a discrete labeling associated to the alpha-granules. In conclusion, this study shows that, evenly for these three GPs, the alpha-granule membrane mirrors the plasma membrane composition. This might occur through an endocytotic process affecting each plasma membrane protein to a different extent and could have a physiologic relevance in further presentation of a receptor bound to its alpha-granule ligand to the platelet surface.

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Boulaftali, Yacine, Frédéric Adam, Laurence Venisse, Véronique Ollivier, Benjamin Richard, Sabrina Taieb, Denis Monard et al. "Anticoagulant and antithrombotic properties of platelet protease nexin-1". Blood 115, n. 1 (7 gennaio 2010): 97–106. http://dx.doi.org/10.1182/blood-2009-04-217240.

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AbstractProtease nexin–1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma but is expressed by platelets. Here, we studied platelet PN-1 in resting and activated conditions and its function in thrombosis. Studies on human platelets from healthy donors and from patients with a Gray platelet syndrome demonstrate that PN-1 is present both at the platelet surface and in α-granules. The role of PN-1 was investigated in vitro using human platelets incubated with a blocking antibody and using platelets from PN-1–deficient mice. Both approaches indicate that platelet PN-1 is active on thrombin and urokinase-type plasminogen activator. Blockade and deficiency of platelet PN-1 result in accelerated and increased tissue factor-induced thrombin generation as indicated by calibrated automated thrombography. Moreover, platelets from PN-1–deficient mice respond to subthreshold doses of thrombin, as assessed by P-selectin expression and platelet aggregation. Thrombus formation, induced ex vivo by collagen in blood flow conditions and in vivo by FeCl3-induced injury, is significantly increased in PN-1–deficient mice, demonstrating the antithrombotic properties of platelet PN-1. Platelet PN-1 is thus a key player in the thrombotic process, whose negative regulatory role has been, up to now, markedly underestimated.

50

Wang, Yuhuan, Ronghua Meng, Vincent Hayes, Rudy Fuentes, Xiang Yu, Charles S. Abrams, Harry F. G. Heijnen, Gerd A. Blobel, Michael S. Marks e Mortimer Poncz. "Pleiotropic platelet defects in mice with disrupted FOG1-NuRD interaction". Blood 118, n. 23 (1 dicembre 2011): 6183–91. http://dx.doi.org/10.1182/blood-2011-06-363580.

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Abstract Understanding platelet biology has been aided by studies of mice with mutations in key megakaryocytic transcription factors. We have shown that point mutations in the GATA1 cofactor FOG1 that disrupt binding to the nucleosome remodeling and deacetylase (NuRD) complex have erythroid and megakaryocyte lineages defects. Mice that are homozygous for a FOG1 point mutation (ki/ki), which ablates FOG1-NuRD interactions, have platelets that display a gray platelet syndrome (GPS)–like macrothrombocytopenia. These platelets have few α-granules and an increased number of lysosomal-like vacuoles on electron microscopy, reminiscent of the platelet in patients with GATA1-related X-linked GPS. Here we further characterized the platelet defect in ki/ki mice. We found markedly deficient levels of P-selectin protein limited to megakaryocytes and platelets. Other α-granule proteins were expressed at normal levels and were appropriately localized to α-granule–like structures. Treatment of ki/ki platelets with thrombin failed to stimulate Akt phosphorylation, resulting in poor granule secretion and platelet aggregation. These studies show that disruption of the GATA1/FOG1/NuRD transcriptional system results in a complex, pleiotropic platelet defect beyond GPS-like macrothrombocytopenia and suggest that this transcriptional complex regulates not only megakaryopoiesis but also α-granule generation and signaling pathways required for granule secretion.

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