Date of Award
Doctor of Philosophy
Comparative and Experimental Medicine
Ted P. McDonald
James Brace, Roger Carroll, Donita Frazier, Erby Wilkinson
The inverse relationship between erythropoiesis and thrombocytopoiesis observed in mice held in hypoxia has given rise to an hypothesis of hematopoietic stem-cell competition a strong hormonal call for the production of red blood cells results in increased erythropoiesis at the expense of platelet production. In this work, the relevant literature concerning this hypothesis is reviewed, and 5 experimental and clinical studies designed to test the hypothesis are detailed In experiments with thyroxine, mice made iatrogenically hyperthyroid by administration of exogenous L-thyroxine were found to have increased production of red blood cells, with a concurrent suppression of platelet production Since the stimulatory effect of thyroxine on erythropoiesis is partly mediated by a Β2 adrenergic mechanism, propranolol, an inhibitor, was administered concurrently with thyroxine in other experiments, the results showed a decrease in the level of suppression of thrombocytopoiesis. Testosterone, a hormone which stimulates production of red blood cells by promoting proliferation of early hematopoietic stem cells, produced increases in red blood cell and platelet production of castrated mice, with no effect on white blood cell numbers, the results of these experiments suggest that testosterone acts to increase populations of bipotential hematopoietic stem cells, which are capable of producing both red blood cells and platelets. Further, administration of thrombopoietin to mice resulted in increased thrombocytopoiesis, with a concomitant decrease in red blood cell production. In these experiments, a positive correlation of thrombopoietin dose and mean megakaryocyte ploidy was documented, and an inverse relationship between thrombopoietin dose and packed cell volume was reported In the clinical models of this work, hypothyroid dogs were found to be anemic with increased platelet counts and decreased platelet size, whereas hyperthyroid cats had an increased mean platelet volume when compared to euthyroid cats. Additionally, greyhound dogs, which have an erythrocytosis secondary to a defective hemoglobin function, showed a relative thrombocytopenia when compared to non-greyhound control dogs. In summary, the results of these studies indicate that the erythrocytic and megakaryocytic cell lines share a common, bipotential stem cell. Selective stimulation of red cell or platelet production occurs at the expense of the sister cell line
Sullivan, Patrick Sean, "Experimental and Clinical Models of Hematopoietic Stem-Cell Competition. " PhD diss., University of Tennessee, 1994.