Intrahepatic Platelets Orchestrate Microenvironmental Remodelling and Cellular Crosstalk in Liver Fibrosis.

Platelets are increasingly recognized as active regulators of liver fibrosis, yet the relationship between systemic thrombocytopenia and intrahepatic platelet behaviour remains poorly understood. In selected etiological and stage-specific contexts, systemic thrombocytopenia may coexist with intrahepatic platelet enrichment and activation, making circulating platelet counts insufficient to reflect local fibrotic activity. This review synthesizes current evidence to define platelet dynamics along the circulation-spleen-liver axis and their multicellular crosstalk within the fibrotic microenvironment, aiming to clarify how platelets integrate into a self-reinforcing fibrogenic network and identify potential therapeutic strategies beyond correcting systemic thrombocytopenia. Systemic thrombocytopenia and intrahepatic platelet enrichment are not mutually exclusive; this paradox renders circulating platelet counts a poor surrogate for intrahepatic fibrotic activity. In the liver, platelets integrate thrombotic, inflammatory, angiogenic, and regenerative signals via mediator release (TGF-β1, PDGF-BB, CXCL4) and interactions with hepatocytes, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs). Platelet-hepatocyte crosstalk exerts opposing effects: injury amplification versus regeneration promotion. Platelet-KC interactions are pro-inflammatory and pro-fibrotic, yet include CLEC4F-mediated phagocytosis that limits excessive platelet accumulation. LSEC capillarization creates a pro-thrombotic niche, where platelet adhesion activates NF-κB, provides P-selectin docking for leukocytes, and drives microthrombosis. Platelet-HSC communication is directly pro-fibrotic via coordinated TGF-β1 and PDGF-BB signalling, reinforced by bidirectional loops. Therapeutically, correction of peripheral thrombocytopenia should be distinguished from investigational strategies aimed at modulating pathogenic intrahepatic platelet activity.