<p>Thrombocytopenia is a defining and prognostically relevant feature of dengue virus infection, yet its mechanistic basis remains incompletely resolved. Classical models have emphasized immune-mediated platelet destruction or transient bone marrow suppression as independent causes of platelet loss. Increasing evidence, however, suggests that these explanations fail to capture the depth, persistence, and severity-dependent amplification of thrombocytopenia, which appears to arise from a coordinated failure of immune-haematopoietic homeostasis driven by viral perturbation of host immune and metabolic networks. To define this framework, a meta-analysis of two independent whole-blood transcriptomic datasets (GSE18090 and GSE51808), integrating patient-derived gene expression signatures with systematic synthesis of 37 mechanistic studies was performed. Across cohorts, dengue infection was characterized by robust activation of innate antiviral and interferon driven programs alongside reproducible repression of megakaryocyte and platelet biogenesis pathways. These transcriptional changes were not restricted to terminal platelet genes but extended to mitochondrial translation, ribosomal assembly, and cytoskeletal regulators essential for effective megakaryocyte maturation. Network integration revealed that dengue viral proteins, particularly non-structural protein 1 (NS1), act as upstream immune perturbators that couple innate immune sensing to endothelial disruption, metabolic reprogramming and accelerated platelet clearance. Together, these findings reposition dengue-associated thrombocytopenia as an emergent systems-level immunopathology rather than a singular consequence of platelet destruction. The integrated immune haematopoietic network framework explains severity dependent platelet loss through convergent defects in platelet production, functional integrity, and survival, and provides platelet homeostasis during dengue infection.</p> Graphical Abstract <p></p>