Thrombopoietin promotes hematopoietic recovery and survival after high-dose whole body irradiation

Purpose: The therapeutic potential of thrombopoietin (TPO), the major regul ator of platelet production, was evaluated for hematopoietic recovery and s urvival in mice following; lethal and supralethal total body irradiation (T BI), Methods and Materials: Hematopoietic recovery was studied in C57BL6/J mice after 8 Gy TBI (gamma-rays), Survival experiments were performed with C57BL 6/J and BCBA F-1, mice. Two protocols of TPO administration were evaluated: treatment for 7 consecutive days (7 x 0.3 mu g/mice) beginning 2 h after e xposure, or a single dose (0.3 mu g/mice) administered 2 h after irradiatio n. Results: TPO improved the platelet nadir and accelerated the platelet recon stitution of irradiated mice in comparison to placebo-treated mice. Recover y of neutrophils and erythrocytes was stimulated as well. TPO induced an ac celerated recovery of hematopoietic progenitors and immature multilineage p rogenitors in bone marrow and spleen. In addition, TPO administration induc ed approximately 90% survival of 8 Gy irradiated C57BL6/J mice, a TBI dose which resulted in 100% mortality within 30 days for placebo-treated mice. S ingle TPO administration was as effective as repeated injections for hemato poietic recovery and prevention of mortality. Dose-effect survival experime nts were performed in BCBA F-1, mice and demonstrated that TPO shifted the LD50/30 from approximately 9.5 Gy to 10.5 Gy TBI given as a single dose, an d from 14 Gy to as high as 17 Gy when TBI was given in three equal doses, e ach separated by 24 h, Conclusion: These results demonstrate that the multilineage hematopoietic e ffects of TPO may be advantageously used to protect against lethal bone mar row failure following high dose TBI, (C) 1999 Elsevier Science Inc.