Overview of platelet and tumor cell interaction. Platelet activation can occur by many routes, initiated here by tumor-derived adenosine diphosphate (ADP) interaction with platelet P2Y₁₂, which can be blocked by thienopyridines. Endothelial damage exposes subendothelial matrix proteins, allowing von Willebrand factor (vWF) to bind and tether to platelet GPIb. Cyclooxygenase (COX) inhibitors prevent platelet-expressed COX-1 production of TXA₂. Aspirin also inhibits COX-2–mediated endothelial prostacyclin (PGI₂) production and platelet adhesion. Upregulation of GPIIb/IIIa allows platelet-platelet and platelet–tumor cell aggregation. Upregulation of P-selectin from platelet α granules interacts with many ligands on tumor cells (eg, PSGL-1, sialyl-Lewis^x–modified CD24 [sLe^x-modified CD24], CD44 variant [CD44_v], PCLP1). Platelet release of platelet-derived growth factors (eg, platelet-derived growth factor [PDGF], vascular endothelial growth factor [VEGF], epithelial growth factor [EGF], transforming growth factor β [TGFβ], and cytokines) promotes tumor cell immune evasion, migration, epithelial-mesenchymal transition (EMT), invasion, and proliferation. AA, arachidonic acid; cAMP, cyclic adenosine monophosphate; CLEC-2, C-type lectin-like receptor 2; PCLP1, podocalyxin-like protein 1; PDGFR, PDGF receptor; PGI₂, prostacyclin; PSGL-1, P-selectin glycoprotein ligand-1; TPα, thromboxane receptor α; TXA₂, thromboxane A2.