Model of a “vicious cycle” of cooperation between platelets and tumors. (A) Tumors stimulate TPO production, usually indirectly by their elaboration of IL-6 or other cytokines; (B) bone marrow responds to TPO stimulation by increasing platelet production and release into the circulation; (C) circulating platelets are activated either by direct contact with tumor cells via tumor-activated Fcγ receptors or indirectly through the generation of the potent platelet agonist thrombin in the tumor microenvironment (not shown), and in turn, activated platelets that are attracted to the site of tumor stick to and provide a “protective cloak” for circulating tumor cells, shielding them from immune destruction by natural killer cells (C enlarged); and (D) platelets further facilitate metastasis by augmenting circulating tumor cell extravasation. Platelets can also promote metastatic tumor growth by releasing proangiogenic proteins, including vascular endothelial growth factor (not shown), thereby stimulating tumor angiogenesis. The positive-feedback loop is completed as the platelet-assisted growing tumors secrete more TPO-stimulatory cytokines (D enlarged).