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Despite the widespread use of corticosteroids, intravenous immunoglobulin (IVIG) and thrombopoietin receptor agonists (TPO-RAs), 30\u201350% of patients exhibit incomplete, unstable or transient platelet responses, underscoring a persistent unmet need for mechanism-informed therapeutic strategies. Current management paradigms remain largely focused on platelet count restoration rather than direct modulation of pathogenic platelet\u2013immune crosstalk. Accumulating pre-clinical evidence, supported by limited clinical observations, implicates platelet glycoprotein VI (GPVI), a collagen receptor and immunothrombotic signalling hub, as a mechanistically relevant contributor to platelet hyperactivation, inflammatory amplification and aberrant platelet\u2013leucocyte interactions in ITP. Experimental models indicate that GPVI-dependent signalling pathways can promote thromboinflammatory responses, facilitate immune cell engagement and influence platelet clearance dynamics, positioning GPVI as a plausible, albeit incompletely validated, therapeutic target. Emerging pre-clinical studies suggest that selective modulation of GPVI signalling may attenuate pathogenic platelet activation while preserving essential haemostatic function, thereby improving platelet survival and functional competence. This review integrates current insights into GPVI biology within the broader immunopathological landscape of ITP and evaluates innovative therapeutic concepts, including GPVI-targeted inhibitors deployed through nanocarrier systems, autologous platelet-mediated delivery and hydrogel-based protective platforms designed to enhance targeting precision and durability. We further discuss the rationale for combination strategies with established therapies and the potential utility of GPVI-linked biomarkers and platelet functional profiling to guide patient stratification. By reframing platelets as active immunoregulatory effectors rather than passive autoimmune targets, this review advances a mechanistic framework for next-generation, precision-oriented intervention in ITP. Although clinical validation remains limited, GPVI-centred strategies represent a rational and testable avenue for moving beyond symptomatic platelet augmentation towards disease-modifying immunothrombotic modulation.<\/jats:p>","DOI":"10.1017\/erm.2026.10047","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T10:25:36Z","timestamp":1776075936000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":8,"title":["When GPVI Goes Rogue: Pathogenesis and Therapeutic Horizons in ITP"],"prefix":"10.1017","volume":"28","author":[{"given":"Jalal","family":"Naghinezhad","sequence":"first","affiliation":[{"name":"Mazandaran University of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Mohajerian","sequence":"additional","affiliation":[{"name":"Ahvaz Jundishapur University of Medical 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