Single administration of thrombopoietin to lethally irradiated mice prevents infectious and thrombotic events leading to mortality

Objective. A sufficiently high dose of thrombopoietin to overcome initial c -mpl-mediated clearance stimulates hematopoietic reconstitution following m yelosuppressive treatment, We studied the efficacy of thrombopoietin on sur vival after supralethal total body irradiation (9 Gy) of C57BL6/J mire and the occurrence of infectious and thrombotic complications in comparison wit h a bone marrow graft or prophylactic antibiotic treatment, Methods and Results. Administration of 0.3 mug thrombopoietin, 2 hours afte r irradiation, protected 62% of the mice as opposed to no survival in place bo controls, A graft with a supraoptimal number of syngeneic bone marrow ce lls (10(6) cells) fully prevented mortality, whereas antibiotic treatment w as ineffective. Blood cell recovery was observed in the thrombopoietin-trea ted mice but not in the placebo or antibiotic-treated group, Bone marrow an d spleen cellularity as well as colony-forming unit granulocyte-macrophage and burst-forming unit erythroid were considerably increased in thrombopoie tin-treated mice relative to controls. Histologic examination at day II rev ealed numerous petechiae and vascular obstructions within the brain microva sculature of placebo-treated mice, which was correlated with hypercoagulati on and hypofibrinolysis. Thrombopoietin treatment prevented coagulation/fib rinolysis disorder and vascular thrombosis, High fibrinogen levels were rel ated to bacterial infections in 67% of placebo-treated mice and predicted m ortality, whereas the majority of the thrombopoietin-treated mice did not s how high fibrinogen levels and endotoxin was not detectable in plasma. Conclusion. We conclude that thrombopoietin administration prevents mortali ty in mice subjected to 9-Gy total body irradiation both by interfering in the cascade leading to thrombotic complications and by amelioration of neut rophil and platelet recovery and thus protects against infections and hemor rhages. (C) 2001 International Society for Experimental Hematology. Publish ed by Elsevier Science Inc.