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T. P. Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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castration decreases Thrombocytopoiesis and testosterone restores platelet production in castrated balb c mice evidence that testosterone acts on a bipotential hematopoietic precursor cell
Journal of Laboratory and Clinical Medicine, 1995Co-Authors: Patrick S. Sullivan, C W Jackson, T. P. McdonaldAbstract:BALB/c male mice have higher platelet counts than female mice of the same strain. To test the hypothesis that testosterone influences platelet production, we evaluated indices of both red blood cell and platelet production in intact male BALB/c mice, in male mice 4 weeks after castration, and in castrated mice administered maintenance doses of testosterone as testosterone propionate. As predicted, castration resulted in decreased hematocrit and body weight in BALB/c mice. Body weights and hematocrits returned to noncastrated levels after 2 and 7 days, respectively, of administration of testosterone. Total circulating red blood cell mass and total circulating red blood cell count were both decreased by castration and were returned to control (noncastrated) levels after 2 days of testosterone therapy. Reticulocyte counts were not changed by castration, but they increased above counts of uncastrated and castrated control mice after 3 days of testosterone administration. White blood cell (WBC) numbers were unaffected by castration or testosterone administration. Additionally, platelet count (956 vm 834×10 3 /μl), platelet size (3.87 vs 3.75 μm 3 ), sulfur 35 incorporation into platelets (6.36 vs 4.87×10 -3 %), mean megakaryocyte ploidy (17.43N vs 16.89N), total circulating platelet mass (TCPM) (490 vs 379× 10 8 μm 3 ), and total circulating platelet count (TCPC) (131 vs 103×10 7 ) were significantly (p<0.05) decreased in castrated mice as compared with intact control mice. Administration of daily subcutaneous injections of testosterone (0.5 mg/day) to castrated mice resulted in a return to control (noncastrated) values of mean megakaryocyte ploidy and TCPM (after 2 days of treatment); platelet size, platelet count, and TCPC (after 3 days of treatment); and percentage of 35 S incorporation into platelets (after 5 days of treatment). Thus these data support the conclusion that testosterone has a positive influence on Thrombocytopoiesis. In contrast to late-acting stimulators of erythropoiesis (such as erythropoietin and thyroxine) that cause competitive reduction in platelet production, testosterone in this work increased both red cell and platelet production in male castrates with no effect on WBC number. We speculate that this testosterone induced increase in both erythropoiesis and Thrombocytopoiesis is likely due to the stimulation of bipotential precursor cells that can differentiate along either the erythroid or megakaryocyte differentiation pathways
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Thrombopoietin from human embryonic kidney cells causes increased Thrombocytopoiesis and decreased erythropoiesis in mice
Comparative Haematology International, 1994Co-Authors: P. S. Sullivan, M. S. Freedman, T. P. McdonaldAbstract:Recent studies have shown that large doses of erythropoietin (EPO) administered daily over a 7-day period elevate erythropoiesis and lead to marked thrombocytopenia. Conversely, anaemia was found in mice following stimulation of Thrombocytopoiesis by an acute thrombocytopenic episode. Although erythropoiesis and Thrombocytopoiesis have been studied in mice after treatment with either hypoxia or EPO injection, only the effects of endogenous thrombopoietin (released after an acute episode of thrombocytopenia caused by an injection of antiplatelet serum) on erythropoiesis have been investigated. Therefore, we injected mice with a potent source of thrombopoietin and evaluated both Thrombocytopoiesis and erythropoiesis at 3 and 5 days after treatment. The data show that thrombopoietin elevated Thrombocytopoiesis with a concomitant reduction in erythropoiesis. We found significantly elevated percentage ^35S incorporation into platelets, platelet sizes, and total circulating platelet masses following thrombopoietin injections at both 3 and 5 days; haematocrits, reticulocyte counts, and total circulating red blood cell masses were reduced significantly in these same mice. Compared to controls treated with human serum albumin, megakaryocyte size was increased on day 3, and megakaryocyte numbers were elevated on day 5 in mice treated with thrombopoietin. Thrombopoietin did not change the blood volume of mice, but did cause an increase in splenic weight. However, splenic sequestration of red blood cells was not the cause of anaemia in mice treated with thrombopoietin, since splenectomised mice also showed increased Thrombocytopoiesis with decreased erythropoiesis. These data agree with previous studies showing an inverse relation between erythropoiesis and Thrombocytopoiesis, and are consistent with the hypothesis that the erythrocytic and megakaryocytic cell lines are in competition.
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thyroxine suppresses Thrombocytopoiesis and stimulates erythropoiesis in mice
Experimental Biology and Medicine, 1992Co-Authors: Patrick S. Sullivan, T. P. McdonaldAbstract:: Thyroxine has been shown in vitro to stimulate erythropoiesis by two mechanisms: a direct, beta 2-adrenergic receptor-mediated stimulation of red cell precursors, and an indirect, erythropoietin-mediated mechanism. Clinical reports have suggested that excess thyroxine also exerts depressive effects on Thrombocytopoiesis, but the most sensitive methods of assessing platelet production, i.e., percentage of 35S incorporation into platelets and determination of megakaryocyte size and number, are not appropriate for analysis of platelet production in human patients. The purpose of this study was to use a mouse model to investigate the effects of the hyperthyroid state on erythropoiesis and Thrombocytopoiesis, and to assess in vivo the two mechanisms by which thyroxine has been described to stimulate erythropoiesis in vitro. We found that thyroxine administration significantly depressed platelet production and stimulated erythropoiesis in mice. Both the D- and L-isomers of thyroxine in appropriate doses produced this depression of Thrombocytopoiesis, and the effect was dose dependent for both isomers. Daily administration of thyroxine:increased blood volume; decreased the peripheral platelet count, total circulating platelet count and mass, percentage of 35S incorporation into platelets, and megakaryocyte number and size; and concurrently increased indices of red cell production (packed cell volume, red blood cell count, total circulating red blood cell count and mass, and reticulocyte count). Additionally, propranolol, a nonspecific beta-blocker, partially reversed the suppression of platelet production by L-thyroxine, lending credence to the assertion that the direct, beta 2-adrenergic receptor-mediated stimulation of the erythroid cell line by thyroxine reported to exist in vitro may also be important in vivo.
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Large, chronic doses of erythropoietin cause thrombocytopenia in mice [see comments]
Blood, 1992Co-Authors: T. P. Mcdonald, Re Clift, Mb CottrellAbstract:Abstract Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased Thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO- injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase Thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated Thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease Thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased Thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.
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humoral control of Thrombocytopoiesis
Handbook of experimental pharmacology, 1992Co-Authors: T. P. McdonaldAbstract:It is well established that a Thrombocytopoiesis stimulating factor (TSF or thrombopoietin) is a major controlling factor of megakaryocytopoiesis and thus Thrombocytopoiesis. During the past 30 years there have been intermittent periods of active research on the hormone, with most of the decisive work occurring during the past 15 years. It should be noted that the study has been difficult, largely because of the lack of suitable assays and stable sources of the hormone. Only during the past decade have reliable assays been developed and potent sources identified. Therefore, with these assays and sources, definitive studies on the presence and characterization of the hormone have now been published and will be discussed in this review. In this chapter, a model for megakaryocytopoiesis and its controUing factors, to include the megakaryocyte-colony stimuladng factor (meg-CSF) and thrombopoietin, are presented. Since thrombopoietin is the major controlling factor of in vivo blood platelet production, it will be considered in greater detail than the other factors. Its biology, mode of action, immunology, site of production, purification, and chemical characterization will be reviewed in some detail. Although the effects of thrombopoiedn on megakaryocytopoiesis appear to be similar to those of other humoral factors with their control of specific hematopoietic hneages, there are some aspects of platelet production mechanisms that need additional discussion, e.g., the effects of hypoxia and its ability to interrupt Thrombocytopoiesis and the stimulating effects of erythropoietin and other growth factors on megakaryocytopoiesis and Thrombocytopoiesis. The clinical aspects of thrombopoietin, to include several disease states that are known to be associated with increased or decreased thrombopoietin titers, will be briefly mentioned, along with a brief summary and views of its future in chnical medicine.
Patrick S. Sullivan - One of the best experts on this subject based on the ideXlab platform.
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castration decreases Thrombocytopoiesis and testosterone restores platelet production in castrated balb c mice evidence that testosterone acts on a bipotential hematopoietic precursor cell
Journal of Laboratory and Clinical Medicine, 1995Co-Authors: Patrick S. Sullivan, C W Jackson, T. P. McdonaldAbstract:BALB/c male mice have higher platelet counts than female mice of the same strain. To test the hypothesis that testosterone influences platelet production, we evaluated indices of both red blood cell and platelet production in intact male BALB/c mice, in male mice 4 weeks after castration, and in castrated mice administered maintenance doses of testosterone as testosterone propionate. As predicted, castration resulted in decreased hematocrit and body weight in BALB/c mice. Body weights and hematocrits returned to noncastrated levels after 2 and 7 days, respectively, of administration of testosterone. Total circulating red blood cell mass and total circulating red blood cell count were both decreased by castration and were returned to control (noncastrated) levels after 2 days of testosterone therapy. Reticulocyte counts were not changed by castration, but they increased above counts of uncastrated and castrated control mice after 3 days of testosterone administration. White blood cell (WBC) numbers were unaffected by castration or testosterone administration. Additionally, platelet count (956 vm 834×10 3 /μl), platelet size (3.87 vs 3.75 μm 3 ), sulfur 35 incorporation into platelets (6.36 vs 4.87×10 -3 %), mean megakaryocyte ploidy (17.43N vs 16.89N), total circulating platelet mass (TCPM) (490 vs 379× 10 8 μm 3 ), and total circulating platelet count (TCPC) (131 vs 103×10 7 ) were significantly (p<0.05) decreased in castrated mice as compared with intact control mice. Administration of daily subcutaneous injections of testosterone (0.5 mg/day) to castrated mice resulted in a return to control (noncastrated) values of mean megakaryocyte ploidy and TCPM (after 2 days of treatment); platelet size, platelet count, and TCPC (after 3 days of treatment); and percentage of 35 S incorporation into platelets (after 5 days of treatment). Thus these data support the conclusion that testosterone has a positive influence on Thrombocytopoiesis. In contrast to late-acting stimulators of erythropoiesis (such as erythropoietin and thyroxine) that cause competitive reduction in platelet production, testosterone in this work increased both red cell and platelet production in male castrates with no effect on WBC number. We speculate that this testosterone induced increase in both erythropoiesis and Thrombocytopoiesis is likely due to the stimulation of bipotential precursor cells that can differentiate along either the erythroid or megakaryocyte differentiation pathways
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Megakaryocytic and erythrocytic cell lines share a common precursor cell.
Experimental Hematology, 1993Co-Authors: Ted P. Mcdonald, Patrick S. SullivanAbstract:: Several recent studies show that production of platelets and red blood cells (RBC) are inversely related. For example, it is well established that hypoxia, a stimulator of erythropoiesis, causes thrombocytopenia in laboratory animals. The thrombocytopenia is most likely the result of a reduction in the production of platelets caused by a decrease in the number of colony-forming units-megakaryocyte (CFU-Meg), early precursor megakaryocytes (small acetylcholinesterase-positive cells, SAChE+), and recognizable megakaryocytes in the bone marrow. In all cases, active erythropoiesis was required for the thrombocytopenia. The hypoxia-induced thrombocytopenia was not caused by sequestration of platelets in an enlarged spleen or by expanding blood volumes. We speculate that this thrombocytopenia is caused by competition of a precursor cell of the erythrocytic and megakaryocytic cell lines; that is, marked stimulation of the erythroid cells by erythropoietin (Epo) causes a decrease in the number of immature megakaryocytes, leading to decreased Thrombocytopoiesis. In support of this hypothesis, other recent work shows that thyroxine (a stimulator of erythropoiesis) and Epo (when given in large, chronic doses) elevate erythropoiesis and cause thrombocytopenia. Conversely, both endogenous and exogenous sources of thrombopoietin lead to elevated Thrombocytopoiesis and anemia in mice. It should also be mentioned that megakaryocytes and erythrocytes have several biochemical similarities, and several clinical conditions point to an inverse relationship between RBC and platelet production. These in vivo, biochemical, and clinical data support the hypothesis that megakaryocytes and erythrocytes share a common precursor cell.
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thyroxine suppresses Thrombocytopoiesis and stimulates erythropoiesis in mice
Experimental Biology and Medicine, 1992Co-Authors: Patrick S. Sullivan, T. P. McdonaldAbstract:: Thyroxine has been shown in vitro to stimulate erythropoiesis by two mechanisms: a direct, beta 2-adrenergic receptor-mediated stimulation of red cell precursors, and an indirect, erythropoietin-mediated mechanism. Clinical reports have suggested that excess thyroxine also exerts depressive effects on Thrombocytopoiesis, but the most sensitive methods of assessing platelet production, i.e., percentage of 35S incorporation into platelets and determination of megakaryocyte size and number, are not appropriate for analysis of platelet production in human patients. The purpose of this study was to use a mouse model to investigate the effects of the hyperthyroid state on erythropoiesis and Thrombocytopoiesis, and to assess in vivo the two mechanisms by which thyroxine has been described to stimulate erythropoiesis in vitro. We found that thyroxine administration significantly depressed platelet production and stimulated erythropoiesis in mice. Both the D- and L-isomers of thyroxine in appropriate doses produced this depression of Thrombocytopoiesis, and the effect was dose dependent for both isomers. Daily administration of thyroxine:increased blood volume; decreased the peripheral platelet count, total circulating platelet count and mass, percentage of 35S incorporation into platelets, and megakaryocyte number and size; and concurrently increased indices of red cell production (packed cell volume, red blood cell count, total circulating red blood cell count and mass, and reticulocyte count). Additionally, propranolol, a nonspecific beta-blocker, partially reversed the suppression of platelet production by L-thyroxine, lending credence to the assertion that the direct, beta 2-adrenergic receptor-mediated stimulation of the erythroid cell line by thyroxine reported to exist in vitro may also be important in vivo.
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Acetylsalicylic Acid Stimulates Murine Megakaryocyte Precursor Cells
Experimental Biology and Medicine, 1990Co-Authors: Patrick S. Sullivan, Ted P. McdonaldAbstract:AbstractDepression of platelet function with a single intraperitoneal injection of acetylsalicylic acid was found to produce significant increases in several thrombocytopoietic indicators despite no observed change in platelet counts. There was an increase in the number of megakaryocytic precursor cells (small acetylcholinesterase positive or “SAChE+“ cells), platelet size, and 35S incorporation into platelets. The results are qualitatively comparable to data from previous experiments showing that treatment of mice with a Thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) and rabbit anti-mouse platelet serum will elevate Thrombocytopoiesis. The results presented herein indicate that interruption of platelet function by aspirin results in the production of new platelets, presumably by the action of a feedback system controlling Thrombocytopoiesis.
M S Cairo - One of the best experts on this subject based on the ideXlab platform.
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sequential treatment with rmil 3 or simultaneous treatment with rmil 3 or rhil 11 with thrombopoietin tpo fails to enhance in vivo neonatal rat Thrombocytopoiesis
Experimental Hematology, 1997Co-Authors: G W Fernandez, T Herbst, A Knoppel, M S CairoAbstract:: Multipotent-lineage nondominant growth factors, acting alone or in combination with lineage-dominant cytokines, are known to influence both myelopoiesis and Thrombocytopoiesis. Interleukin (IL)-3 and IL-11 stimulate and expand multilineage progenitor cells and induce Thrombocytopoiesis. These cytokines also act synergistically with various other lineage dominant and lineage-nondominant cytokines in vitro to expand primitive and committed hematopoietic stem cells. In this study we investigated the in vivo effects of IL-3 and IL-11 in combination with the c-mpl ligand, thrombopoietin (rhTPO), on neonatal rat hematopoiesis. Newborn Sprague-Dawley rats (24 36 hours old, weighing 6-8 g) were intraperitoneally injected with rhTPO (10 microg/kg) for 14 days, rmIL-3 (10 microg/kg) for 5 days followed by rhTPO (10 microg/kg) for 9 days, rmIL-3 (10 microg/kg) + rhTPO (10 microg/kg) for 14 days, rhIL-11 (250 microg/kg) + rhTPO (10 microg/kg) for 14 days, or PBS/human serum albumin (HSA) for 14 days. When compared with PBS/HSA, rhTPO at a dosage of 10 microg/kg significantly increased platelet count (10(-9) L) (day 6, 569 +/- 37.1 vs. 1446 +/- 43.8, p < 0.001; day 10, 796 +/- 68.3 vs. 1774 +/- 238.4, p < 0.01; day 14, 850 +/- 64.4 vs. 3441 +/- 98.1 /10(-9) l, p < 0.001) and absolute neutrophil count (ANC) (day 6, 335.2 +/- 59.6 vs. 752 +/- 335.2, p < 0.01; day 12, 664 +/- 54.1 vs. 1520 +/- 158.2, p < 0.01). However, rhTPO has no effect on the circulating hematocrit or red blood cell count. RhTPO-treated animals also displayed higher platelet counts (/10(-9) L) vs. rhIL-11 or rhIL-6 beginning on day 6 (day 6, 1597.6 +/- 134.7 vs. 930.7 +/- 67.3 vs. 863 +/- 19.6, p < 0.01; day 8, 1686 +/- 208.4 vs. 990 +/- 29.4, vs. 977 +/- 34.33, p < 0.05; day 10, 1774 +/- 238.4 vs. 1096 +/- 49.6, vs. 937 +/- 65, p < 0.01; day 14, 2187 +/- 127.5 vs. 1280 +/- 35.8 vs. 951 +/- 50.7 /10(-9) L, p < 0.01). Sequential administration of rmIL-3 followed by rhTPO resulted in no significant increase in platelet counts compared with PBS-HSA/rhTPO. RhTPO + rmIL-3 given simultaneously also had no additive effect on the circulating platelet count compared with rhTPO alone. Similarly, no additive effect on circulating platelet counts was observed with rhIL-11 + rhTPO vs. rhTPO alone. Bone marrow studies showed a significant increase in the number of megakaryocytes per high-power field in all the groups treated with rhTPO vs. control (p < 0.05), but no additive effect was seen in neonatal rats additionally receiving either rmIL-3 or rhIL-11. Colony forming unit (CFU)-Meg colony formation was also significantly increased in all the groups treated with rhTPO vs. control (p < 0.05), with no additive effect observed after the addition of either rmIL-3 or rhIL-11. These data suggest that rhTPO is more effective than rmIL-3 or rhIL-11 in inducing neonatal in vivo Thrombocytopoiesis in rats, and that no additive effect is to be expected when rhTPO is combined sequentially with rhIL-3 or simultaneously with either rmIL-3 or rhIL-11. We hope that these preclinical data will provide insight into the design and future application of these thrombopoietic cytokines, alone or in combination, to prevent or treat thrombocytopenia.
Pierre Piguet - One of the best experts on this subject based on the ideXlab platform.
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stimulation of Thrombocytopoiesis decreases platelet beta2 but not beta1 or beta3 integrins
British Journal of Haematology, 1998Co-Authors: Pierre PiguetAbstract:The expression of CD29, CD61, CD18 and CD11a on platelets was examined by flow cytometry in mice treated with leukaemia inhibitory factor (LIF) or megakaryocyte growth and development factor (PEG-rHuMGDF or mpl-ligand). Treatment for 7–14 d with PEG-rHuMGDF or LIF increased the number of platelets in peripheral blood from 0.9 up to <2.0×106/μl. These treatments decreased the expression of CD11a and CD18, whereas that of CD29 or CD61 was not markedly changed. Study after various doses or times of PEG-rHuMGDF administration indicated that a decrease of CD18 expression occurred when platelet counts started to rise. Platelet RNA content was increased in mice treated with PEG-rHuMGDF but double staining indicated that expression of CD18 was not correlated with RNA content. To evaluate integrin expression as a function of time in circulation, platelets were biotinylated in vivo. In normal or PEG-rHuMGDF-treated mice, the expression of CD29 or CD61 did not change, whereas that of CD18 decreased significantly as a function of time in circulation. These findings indicate, firstly, that stimulation of Thrombocytopoiesis leads to the release of platelets with a low content of β2 integrin and, secondly, that this integrin is also selectively lost while in the circulation.
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Stimulation of Thrombocytopoiesis decreases platelet beta2 but not beta1 or beta3 integrins.
British Journal of Haematology, 1998Co-Authors: Pierre PiguetAbstract:The expression of CD29, CD61, CD18 and CD11a on platelets was examined by flow cytometry in mice treated with leukaemia inhibitory factor (LIF) or megakaryocyte growth and development factor (PEG-rHuMGDF or mpl-ligand). Treatment for 7–14 d with PEG-rHuMGDF or LIF increased the number of platelets in peripheral blood from 0.9 up to
Ted P. Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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Megakaryocytic and erythrocytic cell lines share a common precursor cell.
Experimental Hematology, 1993Co-Authors: Ted P. Mcdonald, Patrick S. SullivanAbstract:: Several recent studies show that production of platelets and red blood cells (RBC) are inversely related. For example, it is well established that hypoxia, a stimulator of erythropoiesis, causes thrombocytopenia in laboratory animals. The thrombocytopenia is most likely the result of a reduction in the production of platelets caused by a decrease in the number of colony-forming units-megakaryocyte (CFU-Meg), early precursor megakaryocytes (small acetylcholinesterase-positive cells, SAChE+), and recognizable megakaryocytes in the bone marrow. In all cases, active erythropoiesis was required for the thrombocytopenia. The hypoxia-induced thrombocytopenia was not caused by sequestration of platelets in an enlarged spleen or by expanding blood volumes. We speculate that this thrombocytopenia is caused by competition of a precursor cell of the erythrocytic and megakaryocytic cell lines; that is, marked stimulation of the erythroid cells by erythropoietin (Epo) causes a decrease in the number of immature megakaryocytes, leading to decreased Thrombocytopoiesis. In support of this hypothesis, other recent work shows that thyroxine (a stimulator of erythropoiesis) and Epo (when given in large, chronic doses) elevate erythropoiesis and cause thrombocytopenia. Conversely, both endogenous and exogenous sources of thrombopoietin lead to elevated Thrombocytopoiesis and anemia in mice. It should also be mentioned that megakaryocytes and erythrocytes have several biochemical similarities, and several clinical conditions point to an inverse relationship between RBC and platelet production. These in vivo, biochemical, and clinical data support the hypothesis that megakaryocytes and erythrocytes share a common precursor cell.
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thrombopoietin from human embryonic kidney cells causes increased Thrombocytopoiesis in sublethally irradiated mice
Radiation Research, 1992Co-Authors: Candace D Carter, Ted P. McdonaldAbstract:: Previous work showed that mice treated with platelet-specific antiserum prior to whole-body irradiation did not suffer the degree or duration of thrombocytopenia as did irradiated control mice. We now report that a partially purified preparation of a Thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) mimics the biological effects of platelet-specific antiserum treatment in hematopoietically suppressed mice. Male C3H mice were exposed to 3.0 or 4.5 Gy of 137Cs gamma radiation and injected with a total dose of 4 units (U) of TSF. Human serum albumin (HSA) and rabbit anti-mouse platelet serum-injected mice, along with unirradiated mice, served as controls. Packed cell volumes (PCV), RBC counts, WBC counts, platelet counts, and percentage 35S incorporation into platelets were measured in mice at various days (7-14) following treatment. The results showed that irradiated mice treated with TSF had increased 35S uptake into platelets and higher platelet counts than HSA-treated controls. Also, PCV, RBC counts, and WBC counts of irradiated mice treated with TSF were significantly higher than values for HSA-treated mice. Additional experiments using 40,000 U/mouse of Interleukin-6 (IL-6), 227 U/mouse of granulocyte macrophage-colony stimulating factor (GM-CSF), or a combination of GM-CSF and IL-6 did not show increased platelet counts or 35S incorporation into platelets on Days 10 and 14 when compared to other mice treated with control substances. These results suggest that the radioprotective effects of platelet antibodies reported previously may be due to the release and action of thrombopoietin. These studies also demonstrate that thrombopoietin therapy will modulate the severe thrombocytopenia that occurs in radiation-induced bone marrow suppression.
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Large, chronic doses of erythropoietin cause thrombocytopenia in mice.
Blood, 1992Co-Authors: Ted P. Mcdonald, Re Clift, Mb CottrellAbstract:Both large, acute doses of erythropoietin (EPO) and short-term hypoxia increase platelet counts in mice, but long-term hypoxia causes thrombocytopenia. Therefore, we tested the hypothesis that EPO injected in large, chronic doses (a total of 80 U of EPO over a 7-day period) might cause thrombocytopenia. EPO caused increased red blood cell (RBC) production, ie, increased hematocrits, RBC counts, mean cell volume (MCV), and reticulocyte counts (from P less than .05 to P less than .0005), and decreased Thrombocytopoiesis, ie, decreased platelet counts, percent 35S incorporation into platelets, and total circulating platelet counts (TCPC) (P less than .0005). Femoral marrow megakaryocyte size was unchanged, but megakaryocyte number was significantly (P less than .005) reduced in mice treated with EPO. EPO- injected mice had increased spleen volumes (P less than .0005), but blood volumes (BV) were unchanged. In EPO-treated, splenectomized mice, RBC production was also increased (P less than .05 to P less than .0005) and platelet counts, TCPC, and percent 35S incorporation into platelets were decreased (P less than .05), but BV was not altered. Therefore, the decrease in platelet counts observed in EPO-treated mice was not due to increased BV or to an enlarged spleen. In other experiments, mice were rendered acutely thrombocytopenic to increase Thrombocytopoiesis, and platelet and RBC production rates were determined. In mice with elevated Thrombocytopoiesis, RBC counts, hematocrits, percent 59Fe RBC incorporation values, and MCV were decreased (P less than .05 to P less than .0005). Because 59Fe RBC incorporation and MCV were not elevated, the decrease in RBC counts and hematocrits does not appear to be due to bleeding. Therefore, we show that large, chronic doses of EPO increase erythropoiesis and decrease Thrombocytopoiesis. Conversely, acute thrombocytopenia causes increased Thrombocytopoiesis and decreased erythropoiesis. These findings support the hypothesis of competition between precursor cells of the erythrocytic and megakaryocytic cell lines (stem-cell competition) as the cause of thrombocytopenia in EPO-treated mice and the cause of anemia in mice whose platelet production rates were increased.
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Thrombopoietin production in mice treated with acetylsalicylic acid.
Experimental Biology and Medicine, 1991Co-Authors: R. Clift, M. Cottrell, Ted P. McdonaldAbstract:: Recent work revealed that mice in which platelet function was inhibited by acetylsalicylic acid (ASA) treatment showed evidence of increased platelet production. It was proposed that poorly functioning platelets gave rise to elevated Thrombocytopoiesis by causing the release and action of thrombopoietin. However, direct evidence is lacking. Therefore, in the work reported here, plasma from mice treated with ASA was injected into normal recipient mice in an attempt to document the existence of the humoral factor. Compared with control mice given normal plasma, the injection of mice with plasma from ASA-treated mice resulted in increased Thrombocytopoiesis, as evidenced by significant increases in the percentage of 35S incorporation into platelets, larger platelet size, and elevated megakaryocyte precursor cells (the small acetylcholinesterase-positive cell). For a positive control, additional mice were treated with plasma from animals made thrombocytopenic by an injection of antiplatelet serum. These mice also showed significant increases in Thrombocytopoiesis. The results support the hypothesis that platelet production in ASA-treated mice is elevated by release and action of thrombopoietin.
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Acetylsalicylic Acid Stimulates Murine Megakaryocyte Precursor Cells
Experimental Biology and Medicine, 1990Co-Authors: Patrick S. Sullivan, Ted P. McdonaldAbstract:AbstractDepression of platelet function with a single intraperitoneal injection of acetylsalicylic acid was found to produce significant increases in several thrombocytopoietic indicators despite no observed change in platelet counts. There was an increase in the number of megakaryocytic precursor cells (small acetylcholinesterase positive or “SAChE+“ cells), platelet size, and 35S incorporation into platelets. The results are qualitatively comparable to data from previous experiments showing that treatment of mice with a Thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) and rabbit anti-mouse platelet serum will elevate Thrombocytopoiesis. The results presented herein indicate that interruption of platelet function by aspirin results in the production of new platelets, presumably by the action of a feedback system controlling Thrombocytopoiesis.