Identification and characterization of a FLI1-related defect in a pedigree with platelet storage pool deficiency

Introduction FLI1 encodes a member of the ETS family of winged helix-turn-helix transcription factors that plays an essential role in embryogenesis, vascular development, and megakaryopoiesis. Whole gene deletions are associated with Paris-Trousseau Thrombocytopenia and Jacobsen Syndrome, depending of the size of the deletion on chromosome 11q23, whereas single pathogenic alterations in FLI1 causeFLI1 -related defect (MIM #617443), a prevalently autosomal-dominant disorder associated with bleeding tendency due to a platelet function defect and, often, mild thrombocytopenia. Affected subjects display a defective ATP secretion in response to different agonists. Reduced or even absent delta granules and abnormally enlarged and fused alpha granules have been also described. We report on a 16-year-old male (Index patient, IP) presenting with a mild bleeding diathesis (ISTH-BAT score 5) and his parents, who were referred to our Center in Freiburg for evaluation. The father had a history of mild leukopenia and thrombocytopenia. He also experienced occasional epistaxis. No further bleeding complications have occurred in the past. Method Light transmission aggregometry (LTA), flow cytometry, and immunofluorescence microscopy were performed to assess of platelet phenotype. NGS and family genotyping using Sanger sequencing were used for molecular testing. Results IP and his father presented with normal (Mean 174x10 9 /L) and mildly reduced platelet count (117 x10 9 /L), respectively. The mean platelet volume was normal in both subjects. LTA displayed mainly impaired platelet aggregation after stimulation with ADP (4, 10, 20µmol/L) in the IP. A similar, albeit milder defect was found in the father. In the IP, flow cytometry revealed a combined secretion defect with severely reduced platelet exposure of CD62-P (alpha-granule marker) and CD63 (lysosomal and delta-granule marker) after activation with thrombin. Upon staining against the markers of lysosomes and dense granules Lamp 1, Lamp 2, and CD63, immunofluorescence microscopy confirmed a reduction in the number of visible granule structures in both the IP and in the father. By light microscopy, clusters compatible with alpha granule agglomerates were apparent. Genetic analysis identified a heterozygous missense variant in FLI1 (NM_002017.5:c.1033A>G, p.Lys345Glu) in IP and his father. The variant is annotated in dbSNP (rs1064797087) and Clinvar (ID 424636) as pathogenic and has been already reported, in heterozygous status, in one patient. A defective transcriptional activity has been shown for p.Lys345Glu [ 1 ] [ 2 ]. The mother was unaffected. Conclusion A comprehensive diagnostic work-up, including molecular testing, is required to provide patients with rare inherited platelet disorders such as FLI1- related defect with secure diagnosis and appropriate treatment. For instance in perioperative setting, these patients might require prophylactic measures with antifibrinolytics and possibly platelet transfusions. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany