Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; and Johnson Space Center, Houston, TX
Submitted for publication December 1995.
Accepted for publication May 1996.
Address for correspondence: Clarence P. Alfrey, Baylor College of Medicine, Baylor Plaza, Houston, TX 77030.
Space flight results in a rapid change in total blood volume, plasma volume, and red blood cell mass because the space to contain blood is decreased. The plasma volume and total blood volume decreases during the first hours in space and remain at a decreased level for the remainder of the flight. During the first several hours following return to earth, plasma volume and total blood volume increase to preflight levels. During the first few days in space recently produced red blood cells disappear from the blood resulting in a decrease in red blood cell mass of 10-15%. Red cells 12 d old or older survive normally and production of new cells continues at near preflight levels. After the first few days in space, the red cell mass is stable at the decreased level. Following return to earth the hemoglobin and red blood cell mass concentrations decrease reflecting the increase in plasma volume. The erythropoietin levels increase responding to “postflight anemia”; red cell production increases, and the red cell mass is restored to preflight levels after several weeks.
This paper concerns the regulation of red blood cell volume in microgravity and elsewhere. Dr. Udden, Ms. Driscoll, and Dr. Huntoon have participated with me in these studies on SLS 1 and SLS 2(1,2). These experiments were based on observations, made in the same laboratories first by Dr. Phil Johnson in the early Gemini missions (2,9). One of the most consistent physiologic observations out of the space program(3) is that the red blood cell mass is regularly decreased in space flight. An event previously observed but not understood was the magnitude of change that occurred in the first few days in space. Dr. Frey noted the occurrence of orthostatic hypertension in the early astronauts very soon after return from what we would now identify as missions of short duration.
What I am going to tell you about today is that the world is really“round.” The “flat world” as far as red cells are concerned says that they live 100-120 d and that there is no physiologic mechanism by which their survival is shortened. There are pathologic processes in which red cell survival is shortened; hemolytic anemias and blood loss, for example, cause the length of time a cell circulates in the blood to be decreased. A second piece of contemporary scientific dogma is also erroneous, contemporary theory holds that the size of the red blood cell mass is controlled through erythropoietin by regulating the rate of division of primitive red blood cell precursors (4) and/or by decreasing apoptosis (cell death) (7) of these precursors. Six days are required to make a red cell, and there is no control mechanism with regard to either increasing or decreasing the number of red cells that are released from bone marrow once the progenitor cell is committed.
Observations from SLS 1 and SLS 2 (1,12) showed that the plasma volume decreased within 22 h after launch and the magnitude of decrease in six astronauts ranged between 15 and 25%. There is likely some increase in the volume of plasma during the remaining period of the flight. The volume of plasma in the first hours postlanding is significantly higher than it was inflight. This is important with regard to those studies that are attempting to equate the blood volume on return to the symptoms of orthostatic hypotension since the plasma volume is increasing from the moment the astronauts reenter the 1G environment and by 6 d the plasma volume is up to preflight levels. Because plasma volume increases prior to the reconstitution of the red blood cell mass, anemia in space flight results.
We were surprised both in SLS 1 and SLS 2 that the changes in hematocrit that were observed inflight were relatively small. Since the plasma volume rapidly decreased by up to 25% we expected an equivalent increase in hematocrit because we thought the fastest the red blood cell mass could decrease was 1% per day, which is the rate of change that would occur if the release of new red blood cells into the blood halted. The reason that the hematocrit did not increase is two-fold: the red blood cell mass decreased a lot quicker than we thought possible, and the size of the circulating red cells decreased. The reason that the size of the cells decreased was that young cells, which are larger than old cells, were selectively removed from the blood. The hemoglobin and red cell count (which do not change with cell age) go up; the hematocrit goes up but only very slightly.
Postflight the hemoglobin concentration decreased as the plasma volume increased. The red blood cell mass was down about 12% for SLS 1 and down 14% for SLS 2; three astronauts were studied on each mission and in both cases the change was statistically significant. The red blood cell mass is a highly reproducible measurement. The variance that we noticed on multiple studies of astronauts both pre- and longtime distance from the flight period was about 1%.
Before SLS 1 I thought that a decrease in production of red cells occurred inflight as a consequence of having too many red cells. If no red blood cells were made for 10 d and red blood cells survived normally (based on the original dictum that red cells live 100 d) then only 1% can disappear a day. Careful inspection of data from all shuttle missions show that even as early as 8 d the red blood cell mass was decreased by 10% a rate faster than expected.
In SLS 1 after 22 h of weightlessness, astronauts injected radiolabeled iron intravenously and then sampled their own blood to determine the rate that the radiolabeled iron disappeared from circulation. From the rate of removal and the serum iron concentration, the amount of iron being removed from the plasma could be calculated and the number of new red blood cells being made determined. We found that the number of new red blood cells being made inflight was very similar to the number made preflight on earth. This was a big surprise to us because we expected the rate of production to be decreased. On reflection, I recalled that it takes 6 d to make a red cell and all of the red cells that are making hemoglobin 22 h inflight were conceived 4 d earlier, i.e, before launch. We first thought that new red cells must be captured on their way out of the bone marrow in order that they not appear in the blood. We did find that there was a decrease in the fraction of the radiolabeled cells that appeared in the blood. Actually the decrease was only 30%, and as noted above to decrease the red blood cell mass by 10% in 10 d no cells could have been made.
We thought our failure to demonstrate a decrease in production in SLS-1 was because we had performed the ferrokinetic studies too early inflight, so we rescheduled our ferrokinetic experiment of SLS 2 to be performed 72 h into space flight, we thought by then the number of red cell precursors would be suppressed because erythropoietin was decreased. We were surprised again when we found that new red cells continued to be made and released into the blood. The bone marrow was still incorporating iron into newly produced red cells at the same rate that it has been incorporated preflight. Ninety percent of the radioiron that the astronauts injected in themselves after they were weightless for 72 h appeared in circulating red blood cells 6 or 7 d later. So not only were they making the red blood cells, but those cells got out of the bone marrow and they circulated.
The life span of red cells using radioactive chromium has been done by Dr. Phil Johnson and others (2,9) many times in astronauts in space. Samples were obtained before flight and after return. In every circumstance the survival of the radiolabeled red cells was determined to be normal. Our quandary was if all red cells live 100 d and a normal number of red cells are being made, how can the red blood cell mass go down 10% in 10 d or less?
The amount of radiolabel that remained on red blood cells when the astronauts returned was the same as expected if they had not flown. There was, however, a change; that is the radioactivity per milliliter of red cells increased over that expected. This increase occurred because there was a decrease in the number of unlabeled cells in the blood. Where do unlabeled cells come from? Unlabeled cells were those cells released into the blood in the 12 d before launch or during flight, since radiolabeling of the cells that were used for determination of survival was done about 2 wk before the flight. During space flight the plasma volume decreases within 1 d; we believe that the red blood cell mass as shown by that increase in specific activity of radiolabeled cells decreases over the first 4 d. Newly produced cells were selectively destroyed in the first 4-5 d; for this reason there was not as much increase in the hemoglobin and hematocrit as we had expected. From these studies we understand better why the red blood cell mass goes down in flight and why it increases after return to earth. A decrease in erythropoietin levels inflight support our contention that there is too much blood and postflight an increase in erythropoietin associated with the anemia of space flight indicates that the optimal volume of red cells is greater at 1G than in microgravity.
The mean total blood volume on return from space flight was 700 ml less than it had been on earth as estimated from the last measured plasma volume in flight and the red blood cell mass that they had on return. Following return there is a rapid increase in the plasma volume; this supports the thesis that the plasma volume in space is less than optimal for a 1G environment. The decrease in the hematocrit and hemoglobin following the increase in plasma volume causes an increase in serum erythropoietin and a gradual increase of red blood cell mass. Up-regulation of the size of the red blood cell mass is a much slower process than “downsizing.” Classical theory(4,7) states that the increase in erythropoietin causes an increase in the number of cells committed to becoming red cell precursors, increases survival of some of these committed precursors, and results in more red cells being released into the blood six or more days later.
A newly formed red blood cell is not finished. When a new red cell comes out of the bone marrow, it is relatively large, it also has some particles in it that have to be removed, Howell-Jolly bodies, and some other particulate materials. As a part of a new red cell's life, it has a physical interaction with a reticuloendothelial cell so that this remodeling can occur. We propose that in the circumstance in which erythropoietin levels are low that when this interaction occurs the reticuloendothelial cells phagocytize the young red cells. Therefore, as a consequence of a decrease in erythropoietin in space flight, there is a resultant catabolism of young cells.
In summary, in space the red blood cell mass decreased at a rate faster than could result from total cessation of the release of red cells from the bone marrow. The rate of formation of new cells from the bone marrow was normal. Survival of cells labeled 12-19 d before flight was normal, and the fraction of unlabeled red cells in the blood decreased. Those unlabeled cells had to be cells that were less than 12-19 d old. These studies indicate that shortly after launch in a circumstance in which the red blood cell mass is greater than optimal, the mass decreased by hemolysis of newly produced red cells.
Question. I really enjoy hearing this, it's most exciting and its clearly one very astonishing thing that has come from the space research. I just wonder that it is so astonishing, however, I am sure in your mind you've gone over the technical aspects of the sampling and so forth, and are there any artifacts that could conceivably account for this postrelease destruction hemolysis of red cells that would not be necessarily a physiologic response but would be just a technical thing that could account for some of these results?
Answer. Well, I do not think so. There are very good studies in another circumstance in which people have too many red cells; this results from descent from altitude of people who are long-time residents at 17,000 ft. in Peru. They have 25% more red cells than residents at sea level. When they come down to sea level, studies showed that the red blood cell mass decreased 10% in the first 10 d at sea level, and in addition ferrokinetics studies showed exactly the same thing that we did; that is, it took several days before there is a suppression of new cell production in the bone marrow(6,8,10,11). Observations of transfusion of normal persons (blood doping) is also instructive(5). If an anemic person is given a transfusion of 200 ml of red cells the red blood cell mass and hematocrit increases 3-4%. If a normal persons receives a similar transfusion, only half of the expected increase in red blood cell mass occurs consistent with the thesis that physiologic processes act to decrease the red blood cell mass. These observations in addition to our own indicate that there is an active decrease in red blood cell mass that occurs when there are too many red blood cells. I think what is most surprising is that the young cell is selectively destroyed.
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