Under normal conditions, nucleated red blood cells are found only in the circulating blood of the fetus and the newborn infant. Beyond that period the presence of nucleated red blood cells in the peripheral blood indicates disorder in the blood-producing mechanism. Because nucleated red blood cells are immature cells, they do not enter the blood normally. No totally satisfactory explanation is available of the precise mechanism that maintains a "barrier" that normally prevents primitive cells of the marrow from reaching the peripheral circulation. Evidence suggests at least two mechanisms: one chemical, primarily influenced by anoxia; the other physical, dependent at least in part on the syncytial arrangement of primitive cells. The violation of this "barrier" and the escape of nucleated red blood cells signal the presence of a stimulus that is allowing the release of these cells, before they have passed through the intermediate reticulocyte stage, to become adult red
Schwartz SO, Stansbury F. SIGNIFICANCE OF NUCLEATED RED BLOOD CELLS IN PERIPHERAL BLOODANALYSIS OF 1,496 CASES. JAMA. 1954;154(16):1339–1340. doi:10.1001/jama.1954.02940500019007
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