DOWNSIZING OF THE RED CELL MASS IN CIRCUMSTANCES OF AN EXCESS
OF RED BLOOD CELLS

Clarence P. Alfrey and Lawrence Rice^*
Section of Hernatology - Oncology, Baylor College of Medicine, Houston, Texas, USA

AUGMENTATION OF ERYTHROPOIESIS

Anemia or hypoxia causes the oxygen content of blood perfusing the kidneys to have a decrease in oxygen content which results in augmentation of erythropoietin production relative to baseline values. The increase in blood leveís of erythropoietin causes an increase in the number of progenitor celis committed to become erythrocytes, an increase in the number of divisions of primitive red cell precursors and a decrease in the rate of apoptosis of colony forming units erythroid (CFU-E). The rate of maturation of committed red cells (as manifest by hemoglobín synthesis) is litúe changed and the effects to increase reticulocytes or augment the number of circulating red cells is not observed for one week or more. When the increase in erythropoiesis causes the red cell mass to increase, then serum ferritin decreases reflecting a transfer of the ¡ron in stores to hemoglobin in circulating red cells. The decrease in serum ferñtin is therefore observed when pernicious anemia is treated with B12 injections, astronauts return from spaceflight with a decreased red cell mass, persons go to high altitude or normal persons receive erythropoietin injections.

As noted above, augmentation of red blood cell mass cannot be appreciated for at least a week following an increase in serum erythropoietin, reflecting the time required for transit of an individual cell through the process of maturation including heme synthesis. This period has been defined by observing the time required for intravenotisly injected radioiron to appear in circulatíng red blood cells.

DOWNSIZING OF THE RED CELL MASS

A decrease in erythropoietin concentration results in a decrease in the number of committed red cells, decreased rate of division of primítive cells or increase in the rate of apoptosis, but cannot ínfluence the number of circulating red cells for a week or more because those cells already in the pipeline would be expected to mature. After one week of persisting erythropoietin suppression, the rate of change in red cells would be expected to be less than one percent per day reflecting the survival of normal red cells.

Observations of Merino (Merino, 1950) and others (Pace et al., 1956) on long time residents of high altitude who go to sea level indicate that their hemoglobin levels decrease by ten percent or more during the first week. A rate which is more than can be explained by the mechanisms described above. Astronauts who enter microgravity have a decrease in red cell mass as a consequence of a decrease in blood contained in capacitance blood vessels and thus "relative plethora." A decrease of twelve to fifteen percent oceurs in less than ten days (Alfrey et al., 1996). In both high altitude dwellers going to sea level (Rice et al., 200 1) and astronauts entering n*rogravity (Alfrey et al., 1996; Udden et al., 1995) the decrease in red cell mass follows a decrease in erythropoietin concentration in blood.

Merino (Merino 1950) found that fóllowing descent to sea level of high altitude residents that serum indirect bilirubin and fecal urobilinogen increased consistent with an increased rate of destruction of red cells. Huff (Huff 195 1) perfórmed ferrokinetic studies on high altitude residents at sea level. He found erythropoiesis as reflected by uptake of intravenously injected radioiron remained at baseline levels for one week and then decreased to low levels consistent with a decrease in new red cell production. We made similar observations in astronauts who were injected with radioiron after twenty four (Udden et al, 1995) or seventy two hours (Alfrey et al., 1996) in spaceflight. In both instances red cell production continued for one week at the same rate as had been observed on earth one month earlier. Thus in neither case could the decrease in red cell mass be attributed to change in production of red cells.

RED CELL SURVIVAL

The life span of circulating red cells was measured in each of six astronauts befóre and during spaceflight (Alfrey et al., 1996; Udden et al., 1995) . The survival of red cells labeled with chromium twelve days before launch was the same inflight as preflight. In the fust four to six days of weightlessness there was selective loss of red cells which had been in the circulation for twelve days or less (¡ron labeled red cells) on launch day. The selective destruction of young red cells accounts for the decrease in red cell mass during spaceflight and has been termed neocytolysis (Alfrey et al., 1997).

The mechanisms through which selective destruction of red cells occurs has not been defined although it is well known that red cells recently released from bone marrow are captured in the spleen where DNA particles (Howell Jolly bodies) are removed and the membrane remodeled. In a circumstance in which the erythropoietin leve¡ is below a threshold value, destruction of the captured red cells might occur. Trial (Trial et al., 2001) has shown that splenic endothelial cells have erythropoietin receptors and that the porosity of an endothelial membrane is increased when erythropoietin levels fall.

ROLE OF ADAPTATION

Neocytolysis effects rapid adaptation to a new environment in which fewer red cells are required. Once the neocytolysis has occurred, the red cell mass may be near optimal to the new environment and erythropoietin production would be expected to return to near baseline levels. This was observed during the second week of spaceflight (Udden et al., 1995). This process may not be desirable for the long time resident at high altitude that makes a short visit to lower altitude causing rapid deadaptation to his place of residence. Similarly neocytolysis may limit the duration of improved performance by athletes who train at high altitude.

SIGNIFICANCE OF NEOCYTOLYSIS

In a previous study of renal failure (Rice et al., 1999), we showed that decrease in erythropoietin levels were associated with neocytolysis. In addition, neocytolysis likely explains why subcutaneous adnínistration of erythropoietin which avoids subthreshold nadirs is more efficient than intravenous administration. Thus, the implications of neocytolysis extend broadly beyond altitude and spaceflight adaptation. The pathophysiologic implications should extend to neonatal horneostasis, "b1ood?doping" by endurance athletes, hemolytic anemias and polycythernic disorders.


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