Recreational MAHA

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  • Introduction:
    • There are now available in the literature reports of a total of some 13 cases in which hemoglobinuria occurred in young men during runs.
  • Study:
    • Hemoglobinemia was observed in 5 of 11 young athletes who ran 2.6 to 2.8 miles, in 5 of 11 athletes who ran 4.5 to 5.1 miles, and in 18 of 22 men who ran 26.2 miles.
    • The occurrence of intravascular hemolysis appeared to be unrelated to the age, body build, or standing position of the runners, or to the number of years or state of their training.
    • Hemoglobinemia and hemoglobinuria disappeared in a few hours after the end of the run.
    • Quantitative studies revealed normal erythrocyte fragility after the marathon runs.
  • Discussion:
    • Hemoglobinuria following exercise occurs only when the plasma hemoglobin is increased considerably; an amount of exercise just short of that required to produce hemoglobinuria in subjects with march hemoglobinuria does nevertheless result in a definite elevation of the plasma hemoglobin.
    • Hemoglobinuria is therefore a secondary manifestation of intravascular hemolysis occurs only in instances with the higher concentrations of plasma hemoglobin.
    • There are not available sufficient statistical data to demonstrate to what extent exercises other than running lead to physiological intravascular hemolysis.
    • However, there are reports indicating that very strenuous marching may lead to hemoglobinemia and hemoglobinuria in normal individuals.
    • The mechanism of the intravascular hemolysis of exercise is obscure.
    • In the present study, there appeared to be no correlation between body build or standing posture and the occurrence of intravascular hemolysis during runs.
    • Hemoglobinemia sometimes accompanied by hemoglobinuria occurs in man with sufficient frequency after strenuous runs to be considered physiological under these conditions. This intravascular hemolysis after  strenuous runs is comparable in its apparently benign nature to the albuminuria of exercise. The importance of differentiating this condition from pathological states leading to the passage of red urine is obvious.
  • Introduction:
    • March hemoglobinuria has been defined as “a condition in which physical exertion gives rise to the passage of a red urine containing hemoglobin in solution.”
    • Up to this time there had been only 40 cases reported in the literature, mainly German.
  • Study:
    • Five cases of march hemoglobinuria syndrome.
    • Presented with:
      • Painful, swollen muscle groups.
      • Dark, coffee-colored urine; the dark-colored urine appeared 24 to 48 hours after exercise.
      • History of excessive, strenuous exercise within a short period of time. 
      • Absent red cells in urine (in 4 of 5).
    • Five cases fell into three categories:
      • Fraternity initiation hazing,
      • Competition between two students for fun to see who had the most endurance.
      • Individual attempt to get into better condition by too strenuous and concentrated physical exercise.
    • Treatment in all these cases consisted of bed rest if the patient desired it, administration of aspirin for the alleviation of muscular soreness, and the prohibition of additional exercises.
  • Discussion:
    • In the past, the syndrome has almost always been associated with exercises performed in the erect posture, such as marching or running.
    • The mechanism of hemoglobinuria is still unknown, but it is generally considered that there is blood destruction intravascularly, i. e., that all the hemoglobin from red blood cell destruction appears in the plasma, giving rise to hemoglobinemia.
    • We believe that in our cases there was a breakdown of the muscle fibers due to the extreme and excessive exercise, so that the myo-hemoglobin was released into the blood plasma and then excreted through the kidneys, causing the dark-colored urine, which gave the diagnosis of march hemoglobinuria. We believe that this syndrome should be called “exercise myohemoglobinuria.”
  • Introduction:
    • The occurrence of hemoglobinuria after strenuous exercise, especially walking and running, has long been recognized.
    • Since Fleischer (1881) first described ‘Marsch Hamoglobinurie’ in a young soldier, some 80 cases, mainly young male subjects, have been reported.
  • Study:
    • Three athletes were identified with passage of dark red urine after exercise.
    • Each case showed a raised plasma hemoglobin level, a reduced plasma haptoglobin level and hemoglobin in the urine.
    • Myoglobinuria was excluded by spectroscopic and electrophoretic examination of the plasma and by spectroscopy and chemical testing of the pigmented urine.
    • The following were normal in resting and post-exercise states:
      • Peripheral smear
      • Osmotic fragility
    • 2 cases involved runners:
      • Hemoglobinuria occurred only after runs on hard roadways even although the distance covered was only about one mile.
      • Running under such conditions caused marked engorgement of the veins of the feet and a feeling of ‘burning’ in the soles.
      • Both runners could run more than five miles on a cinder or grass track without evidence of hemoglobinuria.
      • Case 1, a powerful runner, had a heavy and rather stamping stride.
    • The third case involved a hockey player who trained on a hard floor, suggesting “the intravascular haemolysis might well be related to a mechanical effect on the blood within the vessels of the soles of the feet.”
    • The hemoglobinuric episodes ceased in all three patients after remedial measures were applied. For example, case 1 altered his style of running and took to wearing running shoes with additional resilient insoles. Since adopting these measures two seasons ago, he has had no recurrence of the hemoglobinuria even though his present training schedule includes running an average of 70 miles each week under cross-country conditions.
  • Discussion:
    • The presenting, and sometimes the only, complaint in exertional hemoglobinuria is the passage of red urine.
    • Anemia is rare and if present is usually mild. 
    • Morphological evidence of red cell damage is not a feature but Watson and Fischer noted poikilocytes and occasional ‘four-leaf clover’ cells in the peripheral blood of their patient after exercise.
    • This form of paroxysmal hemoglobinuria is clinically recognized by its characteristic relation to physical exertion in the upright posture, usually walking or running, each ‘paroxysm’ usually lasting only a few hours after  cessation of the causal exertion. 
    • Previously postulated mechanisms:
      • Primary blood disease
      • Underlying defect of the red cell stroma
      • Local red cell destruction in:
        • The spleen
        • The veins of muscles
        • The renal vessels
      • Abnormally fragile red cells released by splenic contraction during exercise
      • The hemolysis was later regarded as ‘physiological’ and analogous to the albuminuria of exercise.
    • Authors conclude that mechanical trauma in soles of feet causes pre-haemolytic red cell damage.
  • Introduction:
    • The attacks of hemoglobinuria are characteristically brought on by exercise in the erect posture, such as walking or running, whereas equal or more strenuous exertion in other positions is without effect.
    • The cause of the acute hemolytic episodes responsible for the hemoglobinuria is not fully understood, and many theories fail to explain satisfactorily why the hemoglobinuria on exertion is so dependent on posture.
    • Recently, Davidson (1964) has presented evidence that haemolysis may result from traumatic damage to red blood-cells in the soles of the feet.
  • Case study:
    • Man aged 20, attended hospital complaining of repeated episodes of passing blackish-red colored urine. 
    • A steeplechaser of county championship standard accustomed to running an average of 50-70 miles per week.
    • Passing dark urine after exercise 1-3 times a week.
    • Detailed inquiry revealed that on almost every occasion discoloration of the urine occurred after running on built-up roads, and seldom followed running across country.
    • Discoloration of the urine occurred immediately after running and persisted for 2-3 hours after the exercise.
    • A sample of urine passed before exercise was completely normal, whereas that immediately after exercise was blackish-red and showed a positive reaction to guaiac, but contained only an occasional red blood-cell; spectroscopic examination confirmed the presence of oxyhemoglobin.
    • The plasma before exercise did not contain any excess hemoglobin nor any methemalbumin, but after exercise the concentration of hemoglobin rose and methemalbumin appeared.
    • Urine immediately after exercise was blackish-red; it contained protein, and spectroscopic examination  confirmed the presence of hemoglobin. The centrifuged deposit showed only an occasional red and white blood-cell.
    • Patient instructed to wear 1/2 in. thick sorbo-rubber insoles, which led to a notable reduction in the number of attacks of hemoglobinuria.
  • Discussion:
    • It is currently believed that the renal threshold for hemoglobin excretion depends on the extent to which hemoglobin in the plasma is bound to haptoglobin, and that hemoglobinuria only occurs after the plasma haptoglobins are saturated.
    • The hemoglobin-binding capacity of the haptoglobins varies inversely with their concentration, and when the haptoglobins become saturated any excess hemoglobin then circulates freely in the plasma.
    • Free hemoglobin, by virtue of its smaller molecular size, can pass through the glomerular membrane and is therefore excreted in the urine.
    • March hemoglobinuria:
      • Anaemia is uncommon.
      • Few symptoms occur other than red discoloration of the urine during an attack.
      • No increased fragility of the red blood cells has been found.
      • The feature that distinguishes march hemoglobinuria from other varieties of intravascular haemolysis with recurrent hemoglobinuria is the occurrence of symptoms during exercise in the erect posture; for example, walking and running-whereas simply standing still or strenuous exercise in other positions is without effect.
      • It has been postulated that during exercise local damage to red cells may arise from vascular stasis in the spleen, muscles, or kidneys, or that sequestrated abnormally fragile red cells are released from the spleen during exercise. But none of these theories are entirely satisfactory.
      • An alternative site of damage to red blood-cells may be in the soles of the feet.
  • Introduction:
    • Hemoglobinuria is occasionally noted in healthy young adults after marching, running, or walking but not after other equally strenuous forms of exercise such as cycling or swimming.
  • Case study:
    • A 26-year-old slaughterman presented with a 3-month history of passing red urine on many occasions, following karate exercise.
    • An experiment was arranged to see whether his karate exercises were responsible. He was subjected to karate exercises consisted of two 15-minute periods of hand-strengthening exercises.
    • During the first period he chopped the ulnar borders of his hands alternately against the seat of a wooden stool at the rate of 120-140 beats per minute as hard as possible. In the second period he punched his clenched fists against a piece of blanket spread on a concrete floor at the same rate. The first set of exercises were performed 
      in a sitting position, the second set was performed in a squatting position.
    • Urine passed 1 hour after commencing exercise was bright red, positive for Hb. 
    • 2 hours after exercise, his urine still contained hemoglobin.
    • His plasma 1 hour after starting exercise also contained hemoglobin and this persisted for 4 h.
    • His plasma-haptoglobin was 120 mg. per 100 ml. before exercise, but was less than 20 mg. per 100 ml. 4 hours later.
    • The mechanical and osmotic fragility and autohemolysis were normal
    • No fragmented red blood cells were seen in blood smears.
    • The second part of the test was performed 1 month later. In this, the patient carried out a similar exercise session, but on this occasion a piece of sponge rubber 4 in. thick was used to cushion the blows. No hemoglobin appeared in either his urine or his plasma, and his serum-haptoglobin levels were unchanged from the pre-exercise level of 120 mg. per 100 ml.
  • Discussion:
    • The hemoglobinuria which occurs after marching, running, or walking has been termed ” march hemoglobinuria.
    • It has been shown to be due to mechanical damage to erythrocytes in the soles of the feet, and can be prevented by the use of foam-rubber insoles or by walking on soft surfaces.
    • In the present case, hemoglobinuria developed after exercise involving considerable trauma to the hands only, and was prevented by the use of sponge rubber. It must be assumed that there was release of hemoglobin from erythrocytes damaged intravascularly by blows to the hands.
    • The factors which predispose to the development of march hemoglobinuria are not known, but may be related
      to:
      • The amount of haptoglobin available for combination with hemoglobin. 
      • The degree of haemolysis which can rapidly deplete the available haptoglobin.
      • The concentration of free hemoglobin in the plasma.
      • The area of body surface exposed to trauma (smaller the exposed body-surface area and the greater the traumatizing force, the more likely it is that hemoglobinuria will ensue).
    • It is of interest that several previous studies of march hemoglobinuria emphasized that hemoglobinuria only
      happened in the erect position, associated in some with a lordosis. There can be no doubt in the present case as to the cause of the hemoglobinuria, and it would thus seem that posture is not related to the causation of march hemoglobinuria.
    • In view of the findings in this case, it would seem that the term “march hemoglobinuria” is a misnomer, and
      that the condition should be more properly referred to as “traumatic hemoglobinuria “.
  • Introduction:
    • Hemoglobinuria and myoglobinuria are common manifestations of clinical disorders associated with hemolysis
      and rhabdomyolysis.
    •  Traumatic destruction of erythrocytes has occurred:
      • After placement of prosthetic heart valves
      • With prolonged foot trauma and karate exercises
    • In the case of pigmenturia described here both pigments appeared simultaneously in the urine of a young man after he played the conga drum, but they were only individually recognized by sensitive and specific methods. Furthermore, hemoglobinuria or myoglobinuria, or both, is an occupational hazard of the percussionist and may be associated with pigment nephropathy.
  • Case:
    • A 20-year-old man presented to the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, with a history of pigmenturia temporally associated with playing the conga drum. 
    • Over the previous year about 25 similar episodes had occurred that were associated with drumming sessions of great physical and emotional intensity. 
    • Otherwise, he was in excellent health.
    • To establish the authenticity of the pigmenturia in a controlled setting, the patient was admitted to the Clinical
      Research Center of the Hospital of the University of Pennsylvania, where a series of drumming sessions were organized. 
    • Several types of drums, including conga and bongo drums, were employed by the patient and his colleagues.
    • A significant fall in haptoglobin levels was noticed in the serum of the patient during these concerts, but the
      creatine phosphokinase level was only modestly elevated.
    • The SGOT, hemoglobin, and hematocrit values and the reticulocyte count were unchanged.
    • Associates of the patient, playing various drums, were invited as controls for the concert of Day 2. Marked elevation of the plasma hemoglobin was observed in two of three drummers.
    • Hb and Mb were detected in the urine (much more Hb than Mb). 
  • Discussion:
    • The predominant heme protein in the urine was hemoglobin.
    • The rise in the plasma hemoglobin levels of two of three drummers after the concert and the progressive fall
      in the serum haptoglobin level of the patient during the week was consistent with the identification of hemoglobin as a major component of the pigmented urine.
    • Intravascular hemolysis associated with erythrocyte trauma is a well-described clinical entity.
    • The successful prevention of erythrocyte hemolysis by putting foam inserts in the shoes of long-distance runners with hemoglobinuria supports the premise of direct erythrocyte fragmentation, through trauma, to the capillary bed of the plantar surface.
    • Our patient (and one of his associates) had a similar syndrome, intravascular hemolysis associated with hand
      trauma.
    • Hemoglobinuria may ensue if the haptoglobin falls to low levels, and unbound serum hemoglobin is cleared by
      the kidney.
  • Introduction:
    • Runner’s hemoglobinuria” was well described in 1943, and padded insoles were shown to reduce “runner’s hemolysis” in 1964.
    • In this era of modern shoes, recent American studies have deemphasized runner’s hemolysis-they have concluded marathon runners have clinically insignificant hemolysis and have characterized “runner’s anemia” as a “functional pseudoanemia”.
  • Study:
    • Male subject began jogging at 30 years of age. From age 37 to 40, he gradually increased his mileage from 12 to 15 to 45 miles per week.
    • He wore first-rate, modern running shoes and changed them every 2 months.
    • One third of his mileage was on city streets; two thirds was on tracks and grass. 
    • During certain marathons:
      • First voided urine sample was brown.
      • The haptoglobin level fell to zero.
      • The plasma hemoglobin level was 8 mg/dl.
      • Three days later, with no running but with daily bicycle exercise, the haptoglobin level had risen to 72 mg/dl, suggesting it was the footstrike that destroyed the red cells.
      • Urinalyses: no red ceils were seen, but the sample was weakly positive for hemosiderin.
  • Discussion:
    • Mild hemolysis, modified by mileage, weight, gait, shoes, and terrain, may be common in today’s distance runners.
    • Individual runners and swimmers with exercise induced hemolysis may have intrinsically abnormal red cells, but most subjects with runner’s hemolysis probably have normal red cells.
    • Runner’s hemolysis can be reduced by reducing mileage but, at high mileage, not necessarily by changing shoes. 
    • Runner’s hemolysis probably involves destruction of small numbers of the oldest red cells during most of the
      runs.
    • Runner’s hemolysis may drain iron stores.
  • Introduction:
    • Several authors have suggested that intravascular hemolysis may be an important factor contributing
      to the depressed iron status in runners.
    • Although it is certain that hemolysis can occur with prolonged bouts of running, the causes of this hemolytic
      response have not been clearly identified.
    • It has been theorized that hemolysis could be caused by mechanical trauma to red cells circulating through the sole of the foot during the footstrike phase of the running gait.
    • If trauma to red cells at footstrike is a principal cause of hemolysis during running, a higher level of foot impact
      force would be expected to cause a greater hemolytic response.
  • Study:
    • Fourteen adult male runners had been running between 35 and 45 miles per week for the 4 months prior to the
      study. Subjects could be described as trained, yet nonelite distance runners.
    • All runners completed a graded treadmill run to exhaustion. During the same visit to the laboratory, foot impact force during running was quantified using foot sole force transducers.
    • Prior to the force measurement, subjects ran for 5 min at 215 m min1 at either +6% or -6% grade.
    • Impact forces were greater in the downhill trial than in the uphill trial in all subjects.
    • Plasma Hb concentration increased significantly from pre- to immediate post-treatment with both exercise
      trials but was relatively unchanged in the control trial. The rise in plasma Hb was significantly greater in the
      downhill treatment than in the uphill treatment. These results demonstrate that a substantial rise in plasma Hb occurred with exercise and that the downhill running treatment resulted in a significantly greater rise in this parameter.
    • Significant changes in haptoglobin concentration between pre- and 1-h post-treatment for both the uphill and downhill running trials.

  • Discussion:
    • The study was designed to observe the effects of two different levels of foot impact force on the hemolytic response to prolonged running in trained male distance runners by monitoring the responses of serum haptoglobin and plasma Hb to controlled bouts of uphill and downhill running on a treadmill.
    • The results of this study indicate that hemolysis did occur with prolonged bouts of submaximal treadmill running and, more importantly, that significantly more hemolysis occurred with downhill running than uphill running.
    • Since foot impact force was greater with the downhill treatment, these findings provide strong support for the theory that mechanical trauma to red cells at footstrike is a major cause of hemolysis during running.
    • We estimated that on average approximately 0.85 ml of red blood cells were hemolyzed in the downhill run and 0.42 ml of red blood cells were hemolyzed in the uphill run.
  • Introduction:
    • Candombe is a drum-based musical form of Uruguay.
    • Involves groups of 60 or more drummers go drumming with their hands and marching for periods of 2 to 4 h.
    • During the main carnival event, called “las llamadas,” which takes place in summer, over 40 groups march drumming for hours. After drumming, some individuals reported passing rust urine (RU). 
  • Cases:
    • 45 volunteer drummers were recruited.
    • Samples from 45 individuals were obtained after drumming session (four women and 41 men).
    • Previous episodes of RU after drumming were reported by 19 (42%) of 45. 
    • Significant changes were demonstrated  pre- and post drumming for:
      • Serum:
        • Creatinine
        • Phosphorus
        • Uric acid
        • Total and indirect bilirubin
        • LDH
        • CK MB
        • Lactic acid
      • Urine:
        • RU in nine (20%)
        • Microhematuria and/or proteinuria in 20 (44%)
        • Hemoglobin in urine was present in all of the patients with RU but only in two of 20 of the non RU group.
        • Myoglobin in urine was present only in one of the nine individuals with RU.
    • When comparing RU with non-RU group:
      • Values for total bilirubin, indirect bilirubin, LDH, and CPK MB were significantly higher.
      • Haptoglobin levels were <25.5 mg/dl in seven of nine individuals with RU, whereas only one individual from the 16 with NU showed haptoglobin <25.5 mg/dl.
  • Discussion:
    • Candombe drumming is growing as a cultural expression in Uruguay, and hand drumming is very common all over the world. Seventy percent of individuals had urinary anomalies after drumming, with RU present in 20% of the cases. RU is related to extracorpuscular hemolysis as a result of the multiple manual traumas.
    • There is similarity between this phenomenon and other conditions that are associated with microvascular injury, such as exercise-induced hemoglobinuria.
    • Prevalence of running-related hematuria is approximately 20 to 25%. Macroscopic hematuria was found mainly in long-distance runners (>10 km) and seems usually to be asymptomatic. It is usually most pronounced in the first urine void after exercise, normalizes often within 72 h after running, and seems to be independent of the
      exercise intensity.
    • The pathogenesis of running-related hematuria is complex. There is a wide body of literature reporting red cell hemolysis as occurring after various forms of exercise. Trauma associated with footstrike is thought to be the
      major cause of hemolysis after running.
    • It needs to be addressed whether repetitive episodes of RU may produce chronic tubular interstitial damage.
    • A public information campaign in Uruguay encourages the drummers to increase hydration and to avoid the  use of toxic substances. We think that the use of a strong glove for drumming can be beneficial to diminish the incidence of RU after drumming.
  • Introduction:
    • Sports anaemia:
      • Typically a transitory condition
      • Less than 8% develop frank anemia (hemoglobin concentration below 140 g/L in males and 120 g/L in females).
      • Mechanisms may include:
        • Increased plasma volume (hemodilution)
        • Increased body temperature
        • Acidosis
        • Gastrointestinal bleeding
        • Increased production of catecholamines
        • Acute and chronic inflammation
        • Compression and damage of RBC in the capillaries within the contracting muscles
        • Intravascular haemolysis
    • Intravascular haemolysis:
      • Implicated in the injury and breakdown of RBC during exercise, especially in long-distance running
      • The most common form of exercise-induced intravascular haemolysis is conventionally known as foot-strike hemolysis, whereby the repeated and forceful impact of the feet with the ground is thought to cause direct injury to the erythrocytes within the capillaries.
      • Although a single haemolytic episode is unlikely to cause iron loss of clinical significance, repeated episodes during hard and continuous training may determine a cumulative effect that might contribute substantially to the pathogenesis of sports anaemia.
  • Study:
    • Eighteen healthy, trained, Caucasian male athletes engaged in specific endurance training for 3 to 10 years.
    • The athletes ran a 60 km ultramarathon.
    • All 18 athletes completed the ultramarathon successfully and without clinically meaningful symptoms.
    • No statistically significant variations were observed in the post-exercise values of:
      • Hemoglobin
      • RBC count
      • Hematocrit
    • The values of MCV and haptoglobin were significantly decreased (haptoglobin was approximately 50% lower after the end of the ultramarathon). 
  • Discussion:
    • We have also shown that a significant and acute post-exercise decrease of serum haptoglobin occurred, reflecting a certain degree of haemolysis during the long distance run.
    • However, the concentration of cell-free hemoglobin always remained below 0.5 g/L (considering the formation of free hemoglobin-haptoglobin complexes), thereby indicating that the degree of RBC injury might be considered very modest or even clinically negligible.
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