In conclusion, our study provides direct evidence that hyperthermia increases mitochondria-derived ROS production in platelets, which in turn, induces platelet apoptosis and GPIbα ectodomain shedding. Hyperthermia induces platelet apoptosis, which in turn impairs platelet function and decreases the numbers of peripheral platelets; an outcome that manifest as increased hemorrhage or thrombocytopenia. Recently, Zhang et al. reported that P2Y12 activation protects platelets from apoptosis [54]. Application of P2Y12 activation in combination with hyperthermic therapy might be a physiologically important option to counter hyperthermia-induced platelets apoptosis.