Thrombopoietin increases platelet sensitivity to alpha-thrombin via activation of the ERK2-cPLA(2) pathway

Thrombopoietin (TPO) regulates stem cell proliferation and maturation of me gakaryocytes by activating the c-Mpl-receptor, a member of the hematopoieti c cytokine family. As human platelets possess c-Mpl-receptors and supraphys iological concentrations of TPO trigger platelet aggregation and secretion, we searched for the signalling pathways through which the c-Mpl-receptor m ight activate platelets. A physiological concentration of TPO (20 ng/mL) di d not trigger platelet functions. but increased their sensitivity to alpha- thrombin resulting in a 4-fold faster dense granule secretion. The effect o f TPO was abolished by indomethacin and caused by synergism with signal gen eration by alpha-thrombin at the level of the cytosolic phospholipase A(2) (cPLA(2)) pathway resulting in more arachidonate release, cPLA(2), phosphor ylation and thromboxane A(2) formation. A similar synergism was seen at the level of extracellular signal-regulated kinase 2 (ERK2 or p42-MAPK). These data suggest, that TPO increases the sensitivity of platelets to alpha-thr ombin by enhancing cPLA(2) activation via the ERK2-cPLA(2) pathway.