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Daily levels of urinary colony-stimulating factor (CSF) were measured in two patients with cyclic neutropenia. The CSF levels increased during the neutropenic period concomitant with the maximum peripheral monocytosis. Simultaneous erythropoietin (ESF) levels were measured in one of these patients. ESF also increased in the neutropenic period antecedent to the periodic reticulocytosis. These studies are compatible with a negative feedback system regulating both granulocytopoiesis and erythropoiesis. Whether the cyclic fluctuations of these substances are causally related to the cyclic marrow proliferation is uncertain.

The relationship between erythropoietin excretion and change in hematocrit has been determined in normal and polycythemic subjects. Erythropoietin was measured by a method involving the assay of urinary concentrates in polycythemic protein-depleted mice. Basal erythropoietin excretion in normal subjects ranged from 2.8 to 7.5 Standard B units per day. Studies in subjects made anemic by bleeding demonstrated an inverse relationship between hematocrit and the log of erythropoietin excretion. Patients with hypoxia-induced erythrocytosis had increased levels of urinary erythropoietin when their hematocrit was reduced to normal levels by phlebotomy. Three patients whose erythrocytosis was associated with tumors had an erythropoietin excretion which remained constant over a wide range in hematocrit. In polycythemia vera, erythropoietin output was absent or markedly decreased at high hematocrit levels, but measurable erythropoietin appeared in the urine when the hematocrit was reduced to normal or anemic levels by bleeding.

Studies of marrow regulation were carried out in two families with recessively expressed erythrocytosis. The erythrocytosis in the affected individuals was associated with increased erythropoietin (ESF) production. However, hormone production was uninfluenced by alterations in the O2carrying capacity of the blood when the hematocrit was lowered acutely by phlebotomy. Hemoglobin and red cell function (p50; 2, 3-diphosphoglycerate) in the affected, as well as the unaffected, family members were normal. Renal arteriography revealed no mass lesions and no anatomic abnormalities of the renal macro- or microvasculature. Antisera capable of neutralizing the biological activity of normal human ESF completely inhibited the erythropoietic activity in the serum and urine of those studied. Since increased production of ESF occurred in the absence of recognizable physiologic requirements and since the normal reciprocal relationship between O2delivery and hormone production was absent, the most likely explanation for this clinical constellation is a cellular defect in the regulation of production of ESF or of its precursor substances.

Detailed ferrokinetic measurements have been obtained to characterize red blood cell production in patients with chronic renal failure. Although the rate of red blood cell production is slow, it can improve by means of dialysis therapy, but this improvement may be delayed and possibly prevented by relative or inappropriate hypertransfusion.