Single administration of thrombopoietin to lethally irradiated mice prevents infectious and thrombotic events leading to mortality.
A sufficiently high dose of thrombopoietin to overcome initial c-mpl-mediated clearance stimulates hematopoietic reconstitution following myelosuppressive treatment. We studied the efficacy of thrombopoietin on survival after supralethal total body irradiation (9 Gy) of C57BL6/J mice and the occurrence of infectious and thrombotic complications in comparison with a bone marrow graft or prophylactic antibiotic treatment. Administration of 0.3 microg thrombopoietin, 2 hours after irradiation, protected 62% of the mice as opposed to no survival in placebo controls. A graft with a supraoptimal number of syngeneic bone marrow cells (10(6) cells) fully prevented mortality, whereas antibiotic treatment was ineffective. Blood cell recovery was observed in the thrombopoietin-treated mice but not in the placebo or antibiotic-treated group. Bone marrow and spleen cellularity as well as colony-forming unit granulocyte-macrophage and burst-forming unit erythroid were considerably increased in thrombopoietin-treated mice relative to controls. Histologic examination at day 11 revealed numerous petechiae and vascular obstructions within the brain microvasculature of placebo-treated mice, which was correlated with hypercoagulation and hypofibrinolysis. Thrombopoietin treatment prevented coagulation/fibrinolysis disorder and vascular thrombosis. High fibrinogen levels were related to bacterial infections in 67% of placebo-treated mice and predicted mortality, whereas the majority of the thrombopoietin-treated mice did not show high fibrinogen levels and endotoxin was not detectable in plasma. We conclude that thrombopoietin administration prevents mortality in mice subjected to 9-Gy total body irradiation both by interfering in the cascade leading to thrombotic complications and by amelioration of neutrophil and platelet recovery and thus protects against infections and hemorrhages.
Mouthon
M A
MA
Institut de Protection et de Sûreté Nucléaire, IPSN, Fontenay-aux-Roses Cedex, France. marc-andre.mouthon@ipsn.fr
Gaugler
M H
MH
Van der Meeren
A
A
Vandamme
M
M
Gourmelon
P
P
Wagemaker
G
G
D000818:Animals; D001424:Bacterial Infections / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers; D001778:Blood Coagulation Disorders / Q000209:etiology; D001853:Bone Marrow / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000150:complications / Q000209:etiology; D004198:Disease Susceptibility; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000209:etiology / Q000517:prevention & control; D005340:Fibrinogen / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D005342:Fibrinolysis / Q000187:drug effects; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils; D015539:Platelet Activation / Q000187:drug effects; D010976:Platelet Count; D012333:RNA, Messenger / Q000096:biosynthesis; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013926:Thrombopoietin / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D014916:Whole-Body Irradiation / Q000009:adverse effects
D015415:Biomarkers; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005340:Fibrinogen; D013926:Thrombopoietin