Extramedullary hematopoiesis

Although generalizations regarding the hematological effects of fuel oils on humans cannot be made, the effect of kerosene on the first two steps of the heme synthetic pathway has been studied in an animal model. Both hepatic -aminolevulinic acid ( -ALA) dehydratase and -ALA synthetase activities were decreased in female rats after intraperitoneal injection of kerosene, while heme oxygenase was unaffected (Rao and Pandya 1980). Since -ALA synthetase is the rate-limiting enzyme of the heme biosynthesis pathway, hepatic heme biosynthesis may be inhibited by kerosene. It is conceivable that this may be related to the extramedullary hematopoiesis reported in other studies (NTP/NIH 1986) however, there are no direct data to support this. 

Hematopoietic development of blood cells begins mainly in the spleen and liver of the fetus during early pregnancy. By the seventh month, however, the marrow of a fetus becomes the primary site of blood cell formation [1]. During childhood, the marrow of the central axial skeleton such as the pelvis, spinal cord, and ribs, and of the extremities, such as the wrist and ankle, provides the key site of hematopoiesis. Hematopoiesis at the periphery (also known as extramedullary hematopoiesis) slowly decreases with age. Chronic administration of hematopoietic growth factors can reverse this decline. Severe hemolytic anemia and hematopoietic malignancies can also reverse the process. 

In the NTP-sponsored intermediate-duration oral study using Fischer 344 rats and B6C3F, mice, dose-related leukopenia and lymphopenia were observed for both male and female Fischer 344 rats at 200 and 600 mg/kg/day killed on day 60, and at all doses in female rats killed on day 120 (NTP 1986). Decreased leukocytes were observed in male and female rats exposed for 60 days to 200 and 600 mg/kg/day benzene. Lymphoid depletion in the B-cell of the spleen was observed in animals exposed to 200 mg/kg/day (3 of 5 males, 4 of 5 females) and 600 mg/kg/day (5 of 5 males, 5 of 5 females) benzene for 60 days and in animals that received 600 mg/kg/day (10 of 10 males, 10 of 10 females) benzene for 120 days. At 600 mg/kg/day benzene exposure, increased extramedullary hematopoiesis was observed in the spleen of 4 of 5 male and 3 of 5 female rats. Dose-related leukopenia and lymphopenia were observed for both male and female mice exposed for 120 days, but not for 60 days. Leukocytes and lymphocytes were significantly decreased in male mice exposed for 120 days to 50, 100, 200, 400, and 600 mg/kg/day benzene. At 120 days of exposure, leukocytes significantly were decreased in female mice at 600 mg/kg/day and lymphocytes at 400 and 600 mg/kg/day. Histological examination revealed no adverse effects in mandibular lymph node or the thymus for either rats or mice (Huff et al. 1989 NTP 1986). Rats exposed to benzene at 50 and 100 mg/kg/day for 6 months had significant leukopenia (Wolf et al. 1956). 

L Massive intrahepatic extramedullary hematopoiesis in myelofibrosis. Abdom. Imag. 2000 25 184—186... 

Intrahepatic cholestasis caused by mechanical obstruction is also common, but is rarely associated with jaundice or with visibly dilated ducts on imaging studies, although it may be associated with increased direct bilirubin. Jaundice typically occurs only with lesions that are very large, or are located near the porta hepatis, where they may obstruct both hepatic ducts. Common causes of intrahepatic obstruction include (1) tumors (particularly metastases), (2) granulomatous diseases (such as sarcoidosis and tuberculosis), and (3) infiltrative processes (such as lymphoma, leukemia, and extramedullary hematopoiesis). 

M (87% increase in relative spleen weight on day 1, extramedullary hematopoiesis)... 

Splenic lesions reported in inhalation studies in mice and rats have included sinusoidal congestion, an increase in extramedullary hematopoiesis and hemosiderin-laden macrophages invading the red... 

First, it has been pointed out that the XC/MlP-receptor-deficient mice are reminiscent of cattle (and humans) deficient in leukocyte adhesion molecules. These animals do not react to normal pathogens with an innate immune response because the PMNs cannot locomote. Leukocytosis and myeloid expansion of the marrow and extramedullary hematopoiesis are observed. Presumably, lack of basal clearance of environmental flora by chemokine-driven leukocyte trafficking results in enhanced levels of growth factors that stimulate myelopoiesis, such as colony-stimulating factors. Lack of clearance may also contribute to the development of acquired immune responses such as the development of antibodies. 

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