PO03 | Enlarged platelets with reduced GP IB/IX can indicate disorders other than Bernard-Soulier syndrome
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background and Aims: Evaluation of platelet morphology is a cornerstone of the diagnostic work-up of patients with suspected inherited platelet disorders (IPD). We have established an immunofluorescence microscopy-based method on the peripheral blood smear in combination with light-microscopy as a screening-tool for IPD. The technique has been validated for 9 disorders displaying typical changes of platelet structure. As a quality-control of this approach, we regularly perform a blinded investigation of subjects, who had previously undergone genetic testing. Methods: Blood smears were stained using 13 primary antibodies against different platelet structures (alpha and dense granule, surface glycoproteins, cytoskeletal components) and 2 fluorescence-labelled secondary antibodies. Exclusively based on the morphologic evaluation, we formulated a possible diagnosis. After uncovering patients’ information, we compared the anticipated defect with molecular outcome. Results: Over the last 12 months, we enrolled to this study 30 subjects. Based on the finding of platelet macrocytosis and reduced expression of the surface platelet glycoprotein (GP) Ib/IX, we predicted a diagnosis of Bernard Soulier syndrome (BSS) in 4 individuals. After unblinding molecular results, we could confirm the suspicion only in one case, in whom a pathogenic heterozygous deletion in GP1BB gene (c.236_244del [p.Pro79_Leu81del]) consistent with dominant-inherited BSS was found. In two subjects belonging to the same pedigree, a novel homozygous variant in the gene encoding for UDP-N-acetylglucosamine 2-epimerase (GNE): c.1516G>A [p.Gly506Ser] was found. In one individual, we found two novel variants in compound heterozygosis in the gene encoding for uridine diphosphate (UDP)-galactose-4-epimerase (GALE): c.382G>A [p.Val128Met] and c.590T>C [p.Ile197Thr]. All the three patients suffered from severe thrombocytopenia. In the patient with GALE mutations, a syndromic picture including mental retardation, mitral valve prolapse and hip malformation was also apparent. Conclusions: Platelet macrocytosis with reduced expression of GPIb/IX can indicate inherited thrombocytopenias due mutations in GALE or GNE. These two genes play a role at different levels of platelet production and clearance. In both disorders, the reduced externalization of GPIb/IX is a consequence of impaired protein glycosylation. Immunofluorescence microscopy on the peripheral blood smear and genetic testing complement each other.
Authors: Harimadhavan, Monisha, Ram, Bharath, G, Karthick R, Shetty, Devi Prasad, Prabhu, Shilpa, S, Nataraj K, Nayak, Akshatha, Damodar, Sharat, Zanon, Ezio, Castaman, Giancarlo, Federici, Augusto Bramante, Mancuso, Maria Elisa, Pasut, Gianfranco, Tosetto, Alberto, Rocino, Angiola, Santoro, Rita Carlotta, Barcellona, Doris, Tripodi, Armando, Di Castelnuovo, Augusto, Persichillo, Mariarosaria, Candura, Fabio, Marchesini, Emanuela, Forni, Gian Luca, Gringeri, Alessandro, Gentilini, Ilaria, Tricoli, Mirko, Najjar, Osama, Teofili, Luciana
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4412476834