Navigating the Diagnostic and Clinical Spectrum of Thrombocytopenia and Thrombocytopathy: Lessons from a Case Series

BACKGROUND: Despite major advances in platelet function testing and molecular genetic diagnostics, the evaluation of inherited thrombocytopenia and thrombocytopathy remains challenging. Overlapping clinical phenotypes, variants of uncertain significance (VUS), and structural variants detectable only by complementary copy-number variant (CNV) analysis or array comparative genomic hybridization (CGH) frequently impede diagnostic classification.

METHODS: We report seven pediatric patients from five unrelated families, structured into two diagnostic parts. Part 1 addresses inherited platelet disorders evaluated using a standardized diagnostic algorithm including complete blood count, light transmission aggregometry (LTA), flow cytometry (FC)-based platelet phenotyping, and targeted next-generation sequencing (NGS) including CNV analysis. Part 2 focuses on disorders involving the von Willebrand factor (VWF) axis, assessed by the VWF antigen (VWF:Ag), VWF collagen binding activity (VWF:CBA), VWF multimer analysis, ADAMTS13 activity and antigen, LTA, and molecular genetic testing.

RESULTS: Three diagnostically relevant constellations were identified. In Part 1, one patient with a classical Hermansky-Pudlak syndrome phenotype required CNV analysis to detect compound heterozygous pathogenic variants. Two siblings fulfilled diagnostic criteria for Glanzmann thrombasthenia based on LTA, FC, and genetic testing. A third patient showed a Glanzmann-like phenotype in LTA and FC but carried a homozygous VUS in ITGA2B combined with a heterozygous ANKRD26 nonsense mutation. In Part 2, three additional patients demonstrated rare VWF-mediated mechanisms of thrombocytopenia due to ADAMTS13 deficiency or von Willebrand disease type 2B.

CONCLUSIONS: This case series highlights the diagnostic complexity of pediatric platelet disorders and emphasizes the importance of a multimodal approach integrating functional platelet assays, NGS including CNV analysis, and careful clinical correlation.