Williams Hematology



Etiology and Pathogenesis

March Hemoglobinuria

Sports Anemia

Space Anemia
Clinical and Laboratory Features
Differential Diagnosis
Therapy, Course, and Prognosis
Chapter References

Strenuous activities may cause traumatic damage to red cells, with subsequent hemolysis and hemoglobinuria or metabolic changes leading to an expanded plasma volume and dilution anemia. In astronauts, the effect of microgravity leads to changes in blood volume, with relative erythrocytosis when in space and mild anemia after reentry to Earth’s gravitational field.

Individuals involved in strenuous physical activities and astronauts following spaceflights are frequently found to be mildly anemic.1,2 and 3 The causes are complex and controversial but appear to involve hemolysis and blood loss as well as induced alterations in plasma volume and red cell mass. In marchers and runners, traumatic hemolysis may cause hemoglobinuria and anemia, while in athletes and astronauts, a change in blood volume appears to be the major cause.
The first clue to the pathogenesis of hemoglobinuria and anemia in individuals participating in long marches was provided in 1861 by an army physician who studied a young German soldier who had complained of passing dark urine following strenuous field marches.4 He found that the urine contained hemoglobin and that the condition clearly differed from the well-described paroxysmal hemoglobinuria due to cold. During the next 80 years, many additional cases of hemoglobinuria following long-distance running were reported,5,6 but it was not until 1964 that Davidson provided a logical explanation.7 He noticed that two track runners who complained of dark urine after games had a particularly forceful stamping gait, and he proposed that red cells were destroyed in the soles of the feet during running. After some ingenious preparatory studies the runners were encouraged to change their stride and especially to wear soft linings in their shoes, and the hemoglobinuria disappeared. The beneficial effect of better footwear has been noticed in many subsequent studies of athletes,8 but even with well-designed, padded insoles there is still some traumatic disruption of red cells by pressure on the soles during running and walking.9 Similar traumatic red cell destruction with hemoglobinuria has been reported after beating the head against a wall,10 hand-strengthening exercises in a practitioner of karate,11 and playing the conga drums.12
The effects of intravascular hemolysis on hemoglobin concentration in athletes may be augmented by gastrointestinal blood loss, which occurs in about 20 percent of long-distance runners during strenuous races13,14 and by occasional traumatic renal blood loss.15 These effects, however, should be easily compensated for by healthy individuals and would not be expected to cause a measurable anemia.16 Furthermore, hemoglobinuria and gastrointestinal blood loss have only been observed in runners, not in swimmers or bicyclists, and those endurance athletes also have a reduction in hemoglobin concentration.17 It is also unlikely that the associated loss of iron would result in an iron-deficiency state. Nevertheless, the serum ferritin has been found to be decreased in many studies of athletes in training.18,19 and 20 The cause is obscure but may indicate a greater than anticipated loss of iron in sweat21 or even the rapid turnover of iron-containing compounds active in muscular oxidative metabolism.22 It could also be caused by a shift of iron from tissues to the red cell mass if, despite the slight anemia, there is an increase in the size of the red cell mass. That this may actually be the case is suggested by measurements of the red cell and plasma volumes in athletes in active training.23 It appears that elite runners have an increase in both plasma volume and red cell mass,24,25 and 26 but the gain in plasma volume always exceeds the gain in red cell mass. The results should in theory be of considerable benefit, since the circulatory advantage of an increased red cell mass and blood volume are augmented by an increase in blood fluidity.27
Astronauts are moderately anemic when tested several days after reentry. The cause of this anemia has been related to the redistribution of blood volume that occurs during weightlessness.28 At blast-off, there is acute redistribution of blood from the extremities to the torso, resulting in an acute hypervolemia in the upper part of the body. This induces a diuretic response, which reduces the plasma volume and local hypervolemia but results in an increase in the hematocrit. This causes a reduction in the erythropoietin level and the rate of red cell production. After 8 to 10 days in space, the red cell mass is reduced by 10 to 15 percent, and the astronaut will continue the flight with a normal hematocrit but a reduced red cell mass. At reentry into a normal gravitational field, the plasma and blood volumes are restored rapidly to normal, but the hematocrit, now reflecting the low red cell mass, decreases until an increase in the rate of red cell production restores both hematocrit and red cell mass to normal.
The relatively rapid changes in the size of the red cell mass in space and after reentry have been difficult to explain, since erythrokinetic studies have failed to show dramatic changes in iron turnover or erythropoietin titers.29 The absence of overt hemolysis of red cells labeled by 51Cr before the spaceflight has led to the hypothesis that newly created red cells depend on erythropoietin for their survival and will be selectively destroyed during spaceflight.30 However, the lack of marked changes in erythropoietin levels during and after space-flight fail to explain both the traditional and the new explanation for the acute changes in red cell mass.
In march hemoglobinuria and sports anemia, traumatic hemolysis and blood loss play a role in the mild reduction in the hemoglobin concentration; the anemia is usually associated with a slight increase in reticulocyte count and occasionally the presence of echinocytes.31 Immediately after a period of physical exertion, the urine may contain hemoglobin, hemoglobin casts, and hemosiderin. Serum iron and iron-binding capacity are usually normal, but the ferritin may be lower than before the physical exertion. In space anemias, the only finding is a moderate lowering of hemoglobin and hematocrit for a few weeks after reentry.
The history is, of course, of primary importance and leaves little to the imagination. Nevertheless, a reduction in hemoglobin in any young, healthy individual should be investigated further if not easily explained by the history.
The widespread use by athletes of erythropoietin to augment hemoglobin concentration and in turn oxygen transport to muscles has been difficult to diagnose. However, a high hematocrit in a competing athlete should raise suspicion of such misuse, since intense training would tend to lower the hematocrit.
No treatment is necessary, but if hemolysis is severe enough to cause hemoglobinuria, good footwear and a reduction in physical activities may be recommended.

Londemann R: Low hematocrits during basic training: athlete’s anemia. N Engl J Med 299:1191, 1978.

Eichner ER: The anemias of athletes. Phys Sports Med 14:122, 1986.

Leach CS, Johnson PC: Influence of spaceflight on erythrokinetics in man. Science 225:216, 1984.

Fleischer R: Uber eine neue Form von Hämoglobinurie beim Menschen. Berlin Klin Wochenschr 18:691, 1881.

Gilligan DR, Blumgart HL: March hemoglobinuria: studies of the clinical characteristics, blood metabolism and mechanisms with observations on three new cases and review of literature. Medicine (Baltimore) 20:314, 1941.

Gilligan DR, Altschule MD, Katersky EM: Psychologic intravascular hemolysis of exercise: hemoglobinemia and hemoglobinuria following cross-country runs. J Clin Invest 22:859, 1943.

Davidson RJL: Exertional hemoglobinuria: a report on three cases with studies on the haemolytic mechanism. J Clin Pathol 17:536, 1964.

Buckle RM: Exertional (march) hemoglobinuria: reduction of haemolytic episodes by use of sorbo-rubber insoles in shoes. Lancet 1:1136, 1965.

Eichner ER: Runner’s macrocytosis: a clue to footstrike hemolysis. Runner’s anemia as a benefit versus runner’s hemolysis as a detriment. Am J Med 78:321, 1985.

Ensor CW, Barnett JOW: Paroxysmal hemoglobinuria of traumatic origin. Med-Chir Trans 86:165, 1903.

Streeton JA: Traumatic haemoglobinuria caused by karate exercises. Lancet 2:191, 1967.

Furie B, Penn AS: Pigmenturia from conga drumming: hemoglobinuria and myoglobinuria. Ann Intern Med 80:727, 1974.

Buckman MT: Gastrointestinal bleeding in long distance runners. Ann Intern Med 101:127, 1984.

Mechrefe A, Wexler B, Feller E: Sports anemia and gastrointestinal bleeding in endurance athletes. Med Health 80:216, 1997.

Abarbanel J, Benet AE, Lask D, Kimche D: Sports hematuria. J Urol 143:887, 1990.

Hallberg L, Magnusson B: The etiology of “sports anemia.” Acta Med Scand 216:145, 1984.

Clement DB, Asmundson RC, Medhurst CW: Hemoglobin values: comparative study of the 1976 Canadian Olympic Team. Can Med Assoc J 117:614, 1977.

Magnuson B, Hallberg L, Rossander L, Swolin B: Iron metabolism and “sports anemia”: I and II. Acta Med Scand 216:149, 1984.

Newhouse J, Clement D: Iron status in athletes: an update. Sports Med 5:337,1988.

Roberts D, Smith DJ: Training at moderate altitude: iron status of elite male swimmers. J Lab Clin Med 120:387, 1992.

Pauley P, Jordal R, Strandberg Pedersen N: Dermal excretion of iron in intensely training athletes. Clin Chem Acta 127:19, 1983.

Holloszy J, Coyle EF: Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol 56:831, 1984.

Fellmann N: Hormonal and plasma volume alterations following endurance exercise. Sports Med 13:37, 1992.

Brotherhood J, Brogovic B, Pugh LGC: Haematological status of middle- and long-distance runners. Clin Sci Mol Med 48:139, 1975.

Dressendorfer RH, Wade CE, Amsterdam EA: Development of pseudoanemia in marathon runners during a 20-day road race. JAMA 246:1215, 1981.

Schmidt W, Maasen N, Trost R, Boening D: Training-induced effects on blood volume, erythrocyte turnover, and hemoglobin oxygen properties. Eur J Appl Physiol 57:490, 1988.

Thorling EB, Erslev AJ: The “tissue” tension of oxygen and its relation to hematocrit and erythropoiesis. Blood 31:332, 1968.

Udden MM, Driscoll TB, Pickett MH, Leach-Huntoon CS, Alfrey CP: Decreased production of red blood cells in human subjects exposed to microgravity. J Lab Clin Med 125:442, 1995.

Alfrey CP, Udden MM, Leach-Huntoon C, Driscoll T, Pickett MH: Control of the red blood cell mass in spaceflight. J Appl Physiol 81:98, 1996.

Alfrey CP, Rice L, Udden MM, Driscoll TB: Neocytosis: physiological down-regulator of red-cell mass. Lancet 349:1389, 1997.

Selby GB, Frame DC, Eichner LK, Eichner ER: Athlete’s echinocytes: new cause of exertional hemolysis? Blood 70(suppl):56a, 1987.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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