We wished to test whether thrombopoietin (TPO) is entirely regulated by receptor binding or if other factors may play a role in the mechanism of TPO regulation. Therefore, we analyzed the TPO serum levels in 43 patients with reactive (secondary) thrombocytosis and in 37 with myeloproliferative thrombocytosis. Thrombocytosis was defined as a platelet level greater than 440 x 10(9)/l. Forty-two patients (98%) with reactive thrombocytosis had high concentrations of IL-6 correlating with elevated C-reactive protein levels. Twenty-three patients (53%) in this group had TPO serum concentrations of more than 300 pg/ml (normal: below 300 pg/ml). Only nine patients (24%) with myeloproliferative thrombocytosis had TPO serum levels above normal range, whereas 28 patients (76%) had normal levels of TPO. No correlation between the TPO serum levels and the concentrations of IL-6 or EPO was established. The other investigated thrombopoietic cytokines (IL-3, IL-11, GM-CSF) were unmeasurable; therefore, a correlation could not be assessed. We conclude that TPO concentrations are not strictly inversely related to platelet count. TPO serum levels are elevated especially in a considerable percentage of patients with reactive thrombocytosis, arguing for the existence of additional mechanisms of TPO regulation.