A world-first study has revealed how space travel can cause lower red blood cell counts, known as space anemia. Analysis of 14 astronauts showed their bodies destroyed 54 percent more red blood cells in space than they normally would on Earth, according to a study published in Nature Medicine.
“Space anemia has consistently been reported when astronauts returned to Earth since the first space missions, but we didn’t know why,” said lead author Dr. Guy Trudel, a rehabilitation physician and researcher at The Ottawa Hospital and professor at the University of Ottawa. “Our study shows that upon arriving in space, more red blood cells are destroyed, and this continues for the entire duration of the astronaut’s mission.”
Before this study, space anemia was thought to be a quick adaptation to fluids shifting into the astronaut’s upper body when they first arrived in space. Astronauts lose 10 percent of the liquid in their blood vessels this way. It was thought astronauts rapidly destroyed 10 percent of their red blood cells to restore the balance, and that red blood cell control was back to normal after 10 days in space.
Instead, Dr. Trudel’s team found that the red blood cell destruction was a primary effect of being in space, not just caused by fluid shifts. They demonstrated this by directly measuring red blood cell destruction in 14 astronauts during their six-month space missions.
On Earth, our bodies create and destroy 2 million red blood cells every second. The researchers found that astronauts were destroying 54 percent more red blood cells during the six months they were in space, or 3 million every second. These results were the same for both female and male astronauts.
Dr. Trudel’s team made this discovery thanks to techniques and methods they developed to accurately measure red blood cell destruction. These methods were then adapted to collect samples aboard the International Space Station. At Dr. Trudel’s lab at the University of Ottawa, they were able to precisely measure the tiny amounts of carbon monoxide in the breath samples from astronauts. One molecule of carbon monoxide is produced every time one molecule of heme, the deep-red pigment in red blood cells, is destroyed.
While the team didn’t measure red blood cell production directly, they assume the astronauts generated extra red blood cells to compensate for the cells they destroyed. Otherwise, the astronauts would end up with severe anemia, and would have had major health problems in space.
“Thankfully, having fewer red blood cells in space isn’t a problem when your body is weightless,” said Dr. Trudel. “But when landing on Earth and potentially on other planets or moons, anemia affecting your energy, endurance, and strength can threaten mission objectives. The effects of anemia are only felt once you land, and must deal with gravity again.”
In this study, five out of 13 astronauts were clinically anemic when they landed—one of the 14 astronauts did not have blood drawn on landing. The researchers saw that space-related anemia was reversible, with red blood cells levels progressively returning to normal three to four months after returning to Earth.
Interestingly, the team repeated the same measurements one year after astronauts returned to Earth, and found that red blood cell destruction was still 30 percent above preflight levels. These results suggest that structural changes may have happened to the astronaut while they were in space that changed red blood cell control for up to a year after long-duration space missions.
The discovery that space travel increases red blood cell destruction has several implications. First, it supports screening astronauts or space tourists for existing blood or health conditions that are affected by anemia. Second, a recent study by Dr. Trudel’s team found that the longer the space mission, the worse the anemia, which could impact long missions to the Moon and Mars. Third, increased red blood cell production will require an adapted diet for astronauts. And finally, it’s unclear how long the body can maintain this higher rate of destruction and production of red blood cells.
These findings could also be applied to life on Earth. As a rehabilitation physician, most of Dr. Trudel’s patients are anemic after being very ill for a long time with limited mobility, and anemia hinders their ability to exercise and recover. Bedrest has been shown to cause anemia, but how it does this is unknown. Dr. Trudel thinks the mechanism may be like space anemia. His team will investigate this hypothesis during future bedrest studies done on Earth.
“If we can find out exactly what’s causing this anemia, then there is a potential to treat it or prevent it, both for astronauts and for patients here on Earth,” said Dr. Trudel.
These are the first published results from MARROW, a made-in-Ottawa experiment looking at bone marrow health and blood production in space. The project is funded by the Canadian Space Agency and led by Dr. Trudel.
“This is the best description we have of red blood cell control in space and after return to Earth,” said Dr. Trudel. “These findings are spectacular, considering these measurements had never been made before and we had no idea if we were going to find anything. We were surprised and rewarded for our curiosity.”
The idea that spaceflight might lead to anemia was first detailed in the 1960s after six Gemini astronauts displayed reduced red blood cell (RBC) mass after returning from space.1 Lower hemoglobin (Hb) concentrations (Hb) were reported in 10 astronauts after 9-to-14-day missions in the 1980s and 1990s.
It was estimated that the astronauts lost roughly 1 % of their Hb per day in space.2-4 However, 31 astronauts had normal Hb during 180-day missions onboard the International Space Station (ISS), seemingly contradicting the hypothesis that space flight leads to anemia. This paradox raised the hypothesis that the human erythropoietic system adapted to the effects of space.5, 6
The study of anemia during and after spaceflight is complicated by the diagnostic criteria for anemia that are based on Hb concentration, a quantity affected by both changes in plasma volume and changes in RBC mass.7 Exposure to space causes an almost immediate central and cephalad redistribution of an estimated two liters of blood.8, 9 This blood volume redistribution rapidly reduces plasma volume by 10%.1, 8, 10, 11 The shift in plasma volume is reversed upon return to Earth, where it must return to a distribution that can overcome the pull of the Earthʼs gravity.10-12
The life of a human RBC begins in the bone marrow. Stimulated by the hormone erythropoietin (EPO), progenitor stem cells develop into RBCs before being released into the blood stream. This process takes approximately 7 days.13 Assuming that erythropoiesis in space progressively reaches a “space normal” state, it follows that any change caused by return to Earth will take at least 7 days before impacting the postflight RBC mass.
These initial 7 days after landing during which plasma volume increases, but before enhanced erythropoiesis increases RBC mass, can be used to quantify RBC decrements in space. During this window, hemodilution lowers the Hb level to a nadir, effectively unmasking RBC decrements when compared to preflight Hb. From this nadir on, enhanced erythropoiesis progressively corrects the RBC decrements.
Does space anemia exist? The National Aeronautics and Space Administrationʼs Lyndon B. Johnson Space Center (NASA JSC) has recorded hematological data since the inception of their human spaceflight program. In addition, the Longitudinal Study of Astronaut Health (LSAH) recruited three controls for each astronaut and conducted long-term follow up even after the astronauts and controls retired. These contain data from 711 mission-astronauts with 1962 [Hb] measurements and 721 mission-astronauts with 17 336 [Hb] measurements respectively.14 Analyses of these two datasets offered a first comprehensive view of space anemia and its dose-response relationship with exposure to space.
Exposure to space had a dose-response relationship with the incidence of space anemia and the severity of both acute and chronic Hb decrements. While reductions in RBC mass have been measured experimentally after the hemoconcentration and hemodilution cycle of a space mission is completed3, 4 the dependency of space anemia on the duration of exposure to space and the permanent effects are discoveries.
Multiple hypotheses have been put forth to explain space anemia: ineffective erythrocyte production or egress from the bone marrow,3, 15, 16 low EPO levels or sensitivity,3, 4 abnormally-shaped erythrocytes,17 sequestration in the spleen,3, 15 and shortened lifespan.4, 18-20 Our epidemiologic data measured a mean Hb reduction of 0.74% per day after missions averaging 5.4 days, and of 0.43% per day after missions averaging 11.5 days.
On Earth, an erythrocyte lifespan of 120 days predicts that 1/120 (0.83%) of young erythrocytes enter the blood and the same number of senescent erythrocytes are destroyed daily. The daily Hb reduction rates in space are within the range expected if no new erythrocytes entered the blood stream or if erythrocytes were peripherally destroyed.13 They are not compatible with a hormone-mediated mechanism that would take up to 7 days to manifest. Whether the space and earthly erythrokinetics share the same modulation of erythrocyte production, hemolysis, and lifespan is an open question.
Astronauts returning from short and medium duration missions had most of their erythrocytes produced on Earth whereas astronauts returning from missions longer than 120 days had all their circulating erythrocytes produced in space. Therefore, the 10.9% Hb reduction we reported in astronauts returning from missions averaging 145 days may represent the completed human erythrocytic adaptation; the new “space normal”.
The 10.9% Hb reduction matched with the 10% plasma volume loss previously measured in space,1, 8, 10, 11 suggesting that Hb regulation in space replicates earthly Hb levels. This would explain the paradox that astronauts are not anemic while on a long duration mission in space but present low nadir Hb, while undergoing reverse plasma volume shift after landing.5 In other words, the RBCs decrement in space is masked by a corresponding plasma volume loss. The Hb reductions only become apparent upon return to Earth. Using the Hb preflight and the nadir Hb postflight we provided a quantitative measure of the importance of the Hb decrement, its recovery and its dependency on the duration of spaceflight.
Returning astronauts presented a lifelong lower Hb proportional to the time they spent away from Earthʼs surface. Whether this feature of space anemia involves permanent, structural changes in bone marrow, spleen function, or erythropoietic control remains to be determined.21 Changes in attributes of erythrocytes produced in space should disappear 120 days after landing, the average lifespan of erythrocytes.
The larger effects of spaceflight on Hb in female astronauts may be related to many women harboring borderline low iron levels.22 Suppressed expression of hepcidin by EPO as shown in the mouse liver may increase levels of circulating iron after landing.23 Serious iron deficiency was unlikely in this entire cohort of closely-monitored astronauts that contained a minority of woman.24
Unexpectedly, astronauts proved resistant to the age-related decline in Hb. Male and female astronauts showed Hb accrual over 20 years of data collection contrasting with the age-decline Hb in controls. This may be related to selection, extensive physical training, and active lifestyles during and after an active career as an astronaut.
This finding is unrelated to spaceflight, since a group of 19 astronauts never assigned a mission also accrued Hb longitudinally (Figure 3). The age-related Hb increase of astronauts may mitigate the negative effects of exposure to space, but a male astronaut would need 15 terrestrial years to overcome every 1 year spent in space, with 21 years for female astronauts.
These novel findings are clinically relevant for longer space exploration missions, space tourism and also for bedridden patients. A reduced post-landing Hb is a risk for future astronauts and missions. Unlike astronauts landing on Earth, where ground personnel are on hand to relieve weakness, dizziness, limited endurance, and work output, landing on extraterrestrial worlds will require astronauts to initiate precise tasks on their own.
The magnitude of the Hb reductions can be expected to depend on the gravity at the destination. Anemia, possibly taking up to 60 days to fully resolve, may interfere with the mission. The current epidemiologic data demonstrated a vigorous erythropoietic response to low Hb after a mean 145 days in space, which is reassuring. Erythropoietic response to low Hb is paramount for astronaut health and safety. An insufficient response may be life threatening and necessitate planning for onboard artificial blood products and remotely guided intervention for moon, planetary, or asteroid landings.
Whether the same erythropoietic response is present during flight is unknown. Terrestrial space flight and high-altitude experiments measured rapid increases in EPO levels that normalized upon landing.24-26 Landing from space activates baroreflexes, produces a reverse fluid shift and hemodilution; these stimuli enhance EPO secretion to assist with the recovery from space anemia.27
Space tourists should consider medical conditions such as anemia, angina, peripheral hypoperfusion, and orthostatic hypotension. Space anemia is not only of interest to flight physicians but also to clinicians working with immobilized patients. Human models of prolonged bedrest featured similar hematologic and plasma volume changes as those seen in space.20, 21, 28
Limitations of the study include the various egress and landing protocols over five decades which constitute potential confounding factors. These heterogeneous protocols potentially altered the landing day Hb data. However, the main new findings and conclusions of the study are based on the time and depth of nadir Hb; days after the effects of egress/landing interventions have dissipated.
The data groupings into short, medium, and long duration missions motivated by data analysis imperatives isolated the effect of space flight across vessels, eras, and space programs (eg, Skylab, Space Shuttle, ISS). Physiological insight would be gained by replicating a similar epidemiological approach to databases that include iron, reticulocytes, B12, blood or plasma volumes and others despite potential limitations related to the lower collected frequency than Hb with respect to flight, unavailability for earlier missions and analytical technology changes over decades.
The site of Hb measure (JSC Medical Clinic) and the technology to measure Hb (single-beam photometer at a wavelength of 525 nm on lysed erythrocytes) were unchanged over the study period ensuring consistency across time. The epidemiological data will benefit future experimental investigations on the contribution of changes in blood volumes, red cell mass, erythropoiesis rate and red cell life span to space anemia.
This epidemiological analysis of five decades of human space data overcame limitations of small sample sizes of past experimental studies. We characterized space anemia, its dose-response relationship with exposure to space as well as longitudinal effects. Whether acute space anemia will turn into chronic anemia depends critically on the duration of exposure to space.
More information: Trudel, G et al, Hemolysis contributes to anemia during long-duration space flight. Nat Med (2022). doi.org/10.1038/s41591-021-01637-7