Podoplanin-positive extracellular vesicles in ovarian cancer: linking thrombosis, platelet crosstalk, and cancer stemness - a narrative review.

Ovarian cancer remains a leading cause of gynecologic cancer death worldwide, largely due to late diagnosis, frequent recurrence, and metastatic tendencies. Thrombosis is a common and life-threatening complication in these patients, contributing to poor prognosis and therapy resistance. Emerging evidence highlights a mechanistic link between tumor-derived extracellular vesicles and thrombotic events - particularly podoplanin-positive small extracellular vesicles (PDPN⁺ sEVs). Secreted by PDPN-expressing ovarian tumor cells, these vesicles act as biologically active messengers that circulate systemically. A central mechanism involves the binding of PDPN⁺ sEVs to C-type lectin-like receptor 2 (CLEC-2) on platelets, inducing platelet activation, aggregation, and the release of pro-inflammatory mediators. This interaction creates a hypercoagulable and pro-inflammatory microenvironment. Beyond coagulation, PDPN⁺ sEVs promote cancer aggressiveness by enhancing cancer stem cell plasticity, driving epithelial-to-mesenchymal transition, and facilitating immune evasion - hallmarks of metastasis and chemoresistance. This dual activity establishes a thromboinflammatory tumor niche that accelerates disease progression while undermining treatment efficacy. The ability of PDPN⁺ sEVs to circulate in ascitic fluid and peripheral blood positions them as promising candidates for liquid biopsy-based diagnostics. Furthermore, targeting the PDPN-CLEC‑2 axis or disrupting sEV biogenesis offers a novel therapeutic strategy to curb both thrombosis and metastatic spread. In conclusion, PDPN⁺ sEVs represent a critical molecular link between coagulation and cancer progression, offering valuable diagnostic, prognostic, and therapeutic potential for improving outcomes in ovarian cancer.