PO026 | AUTOSOMAL DOMINANT ITGA2B AND ITGB3 VARIANTS EXPAND THE PHENOTYPIC SPECTRUM OF ΑIIBΒ3-RELATED PLATELET DISORDERS

S. Ferrari, D. Regazzo, L. Onorati, A. Galbiati, L. Spiezia, A. Bertomoro, P. Simioni | Department of Medicine, University of Padova, Italy

Background and Aims. Autosomal dominant thrombocytopenias caused by heterozygous ITGA2B and ITGB3 pathogenic variants are increasingly recognized as a distinct entity from classical Glanzmann thrombasthenia (GT). These disorders typically present with mild thrombocytopenia, variable platelet function defects, and heterogeneous bleeding severity. However, given their rarity, they remain poorly defined from a clinical, biochemical, and genetic perspective. We aim to describe the clinical, laboratory, and molecular features of two previously unreported heterozygous variants in ITGA2B and ITGB3 genes identified in two unrelated families with autosomal dominant inheritance.
Methods. Affected individuals underwent standardized bleeding assessment using ISTH Bleeding Assessment Tool (BAT), platelet count followed by aggregation studies, performed on platelet-rich plasma using the Born method (Chronolog). Flow cytometric analysis of αIIbβ3 expression was conducted assessing CD41a expression and PAC-1 binding following ADP stimulation. Genetic analysis was performed in the proband using targeted next-generation sequencing. Identified variants were validated and tested for segregation in available family members by Sanger sequencing. Variant pathogenicity was assessed according to ACMG criteria. Reference transcripts were NM_000419.5 (ITGA2B) and NM_000212.3 (ITGB3). Structural impact was evaluated by in silico modelling.
Results. Among Family 1 carriers (5/7 individuals), the heterozygous ITGA2B p.Gly549Asp (c.1646G>A) (Class 4) variant co-segregated with mild thrombocytopenia and mucocutaneous bleeding. The proband showed mildly reduced platelet count (~96×10⁹/L), anisocytosis, and occasional macrothrombocytes. BAT scores ranged from 1 to 7 among the carriers. Platelet aggregation was partially impaired, and above normal range in response to ADP, collagen, and epinephrine, while ristocetin-induced aggregation was preserved (Table 1). Flow cytometry revealed reduced CD41a expression and impaired PAC-1 activation after ADP stimulation. In silico structural modelling suggested destabilization of the extracellular αIIb domain (Table 1). In Family 2, the heterozygous ITGB3 p.Arg662His (c.1985G>A)(Class 4) variant, affecting the same residue as the Sra alloantigen, previously associated with neonatal alloimmune thrombocytopenia, was identified in the proband, his sister, and father (3/4 individuals). The proband exhibited mild thrombocytopenia (~100×10⁹/L), a BAT score of 1, normal platelet aggregation, and normal αIIbβ3 surface expression, consistent with a very mild or subclinical phenotype with variable expressivity.
Conclusions. These findings expand the spectrum of αIIbβ3-related autosomal dominant platelet disorders and highlight significant gene- and variant-specific phenotypic variability. Recognition of these often subtle and heterogeneous presentations is essential for accurate molecular diagnosis and appropriate genetic counselling. The contrasting phenotypes observed between the two families further suggest a continuum of disease severity ranging from functional impairment to near-normal platelet function despite thrombocytopenia depending on a variant-specific effect on αIIbβ3 expression and activation. These observations also underscore the importance of including ITGA2B and ITGB3 in diagnostic workflows for inherited thrombocytopenias, particularly in cases with mild or atypical phenotypes that may be misdiagnosed as other platelet disorders.