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Pearls and Pitfalls

Observations on Iron, Anemia, and Sickle Cell Trait

Eichner, E. Randy MD, FACSM

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Current Sports Medicine Reports: 1/2 2017 - Volume 16 - Issue 1 - p 2-3
doi: 10.1249/JSR.0000000000000328
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Introduction

I am asked about the role of intravenous iron therapy in athletes with low ferritin values. Also about hematuria in an athlete with sickle cell trait (SCT). And about a recent exertional sickling death in a white boy, a football player, with SCT. Here are some observations.

Intravenous Iron Therapy

Blood fascinates mankind. Mentioned more than 500 times in the Bible, blood permeates our body and our language. We speak of thick blood and thin blood. Of hot blood and cold blood. Of bad blood and blue blood. Of blood feuds and blood brothers. Of drawing first blood and of blood in the water. Bloodletting was practiced by doctors for 2000 yr. And now, we have blood doping, which has killed some athletes. And we confront the age-old problem of “iron-poor tired blood” — of which a modern variant in athletes is “iron-deficient non-anemia” (IDNA), a perennial in sports medicine.

It has long been argued that IDNA saps top athletic performance and contributes to fatigue. But fatigue has many faces, and definitions come hard. Even “mild anemia” is hard to define. For example, the lower limit of normal for hemoglobin (Hb) concentration is not only lower in women than men but also lower in older men than younger men, and lower in African Americans than in whites (1). Also, among endurance athletes, the most common cause of low Hb level varies by gender; in women, it is iron deficiency anemia, but in men it is a condition once known as “sports anemia.” Sports anemia is a false anemia — the red cell mass is normal. Hb level is low because aerobic exercise expands baseline plasma volume and dilutes Hb down. Sports anemia is not a detriment, but a benefit to athletes (5).

For these and other reasons, IDNA is hard to define and study. Yet many studies exist, including a recent meta-analysis of 17 studies of iron therapy for IDNA. Studies included were controlled trials in endurance athletes who got iron therapy or placebo (or no therapy) for IDNA defined as serum ferritin 35 g·L−1 or less and Hb > 12 g·dL−1. Iron therapy greatly improved iron status (raised serum ferritin and serum iron levels) and moderately improved V˙O2max. But iron therapy also moderately improved Hb level, especially among women (2). This suggests, as noted before, that many female athletes with “IDNA” have mild anemia, and that reversing the anemia, not increasing the ferritin, is what improves performance. For example, a female athlete with a normal Hb of 14 g·dL−1 is anemic at 13 g·dL−1 and will feel that her stamina is sapped (7).

Sports medicine physicians are now being asked to give intravenous (IV) iron to female athletes with low ferritin (and mild or no anemia) despite oral iron therapy (which, as I have learned, they may or may not take as directed). Granted, newer formulations of iron for IV use exist (e.g., Ferrlecit, Venofer, Feraheme, Ferinject), are safer than the older iron dextran, and are increasingly used in medicine and sports medicine. But in my opinion, few female athletes with IDNA or mild anemia need IV iron therapy.

In one relevant study, 27 distance runners with IDNA got oral or IV iron (8). Ferritin rose higher after IV iron, but Hb did not change. In one small subset, that with the most women, Hb mass increased on IV iron, and so did aerobic performance. But this subset had the lowest baseline Hb level, so it would be expected to benefit the most from iron, and the same may have occurred on oral iron. This study is inconclusive on IV iron versus oral iron, but it supports prior studies suggesting that if Hb rises on iron, athletic performance improves (7). In a study of 15 elite distance runners with IDNA who got IV iron or placebo, IV iron raised ferritin levels for at least 4 wk, but failed to increase Hb mass or improve V˙O2max or aerobic performance (3).

Finally, in a long-term case study of a female Olympic 1500-m runner, when she got IV iron, her ferritin rose to > 35 to 45 g·L−1, but declined after a few weeks to prior levels of about 20 to 25 g·L−1 and went even lower (<20 g·L−1) at times of peak training volumes. She never had Hb < 12 g·dL−1, and no clear link was seen between IV iron and performance (9). The case for IV iron for IDNA is inconclusive, but I expect its use to increase in sports medicine.

Hematuria in SCT

Recently, a wide receiver in the National Football League missed some time because of gross hematuria, which he seemed to attribute to a hard hit, but team doctors seemed to attribute to SCT. Gross hematuria occurs in less than 5% of persons with SCT. It results from sickling deep in the renal medulla, sometimes with renal papillary necrosis (RPN). About 80% of the time, the bleeding is from the left kidney, because of back pressure from compression of the left renal vein between the aorta and the superior mesenteric artery. Bleeding can be major, with clots, and can wax and wane for weeks. In most cases, with conservative therapy, hematuria stops, and the athlete returns to play. I have covered other therapy elsewhere (6).

Rarely, the hematuria can be major enough to cause iron deficiency anemia, as in an African-American boy, 16 yr of age, who had SCT and developed spontaneous gross hematuria, presumably from RPN, that lasted 3 to 6 wk and led to severe iron deficiency anemia, Hb 5.4 g·dL−1, ferritin 9 g·L−1. He was transfused with 2 U of red blood cells and got months of oral iron therapy; 1 yr later, hematuria had not recurred, and his Hb was normal at 15 g·dL−1 (4).

Exertional Sickling Deaths

The National Collegiate Athletic Association (NCAA) program for SCT has sharply cut the rate of exertional sickling deaths in NCAA Division-1 football conditioning. We had 10 such deaths in the 10 yr immediately before the program began, but only one such death in the 6 yr after the program began, a statistically significant reduction. And in that one death, the university admitted negligence in not heeding the NCAA guidelines. So we are making progress in preventing exertional sickling deaths.

But in the summer of 2016, we had three more exertional sickling deaths in athletes with SCT. One fatal sickling collapse was at an NCAA Division 2 college, on the first day of football conditioning. Two fatal collapses were in high school students. One was an African-American boy, 15 yr of age, who collapsed just after finishing a timed 1.5-mile run in basketball conditioning. He was known to have SCT, and he had struggled in a 1-mile timed run the week before. The other was a white boy, 14 yr of age, whose fatal collapse was on the first day of football conditioning.

The exertional sickling death of a white boy reminds us that SCT is malarial, not racial. Anyone whose heritage is from a malarial part of the world may carry SCT, because it protects from death from malaria. SCT has nothing to do with skin color. If the public better understood this, it would solve some problems.

And the sports medicine community should understand that we still have work to do. We need to keep educating team physicians, coaches, athletic trainers, parents, and young athletes on exertional sickling, and we need to foster greater awareness and get more help from pediatricians and emergency room physicians. Together, we can end these tragic and preventable deaths.

The author declares no conflict of interest and does not have any financial disclosures.

References

1. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood. 2006; 107:1747–50.
2. Burden RJ, Morton K, Richards T, Whyte GP, Pedlar CR. Is iron treatment beneficial in, iron-deficient but non-anaemic (IDNA) endurance athletes? A systematic review and meta-analysis. Br. J. Sports Med. 2015; 49:1389–97.
3. Burden RJ, Pollock N, Whyte CP, et al. Effect of intravenous iron on aerobic capacity and iron metabolism in elite athletes. Med. Sci. Sports Exerc. 2015; 47:1399–407.
4. Chapa-Rodriguez A, Dighe D, Giordano L. Severe anemia in an adolescent male with sickle cell trait: a case report. J. Pediatr. Hematol. 2015; 37:e60–2.
5. Eichner ER. Sports medicine pearls and pitfalls: anemia in athletes. Curr. Sports Med. Rep. 2007; 6:2–3.
6. Eichner ER. Sickle cell considerations in athletes. Clin. Sports Med. 2011; 30:537–49.
7. Eichner ER. Perennial questions: on fatigue, on iron, and on anemia. Curr. Sports Med. Rep. 2012; 11:274–5.
8. Garvican LA, Saunders PU, Cardoso T, et al. Intravenous iron supplementation in distance runners with low or suboptimal ferritin. Med. Sci. Sports Exerc. 2014; 46:376–85.
9. Pedlar CR, Whyte GP, Burden R, Moore B, Horgan G, Pollock N. A case study of an iron-deficient female Olympic 1500-m runner. Int. J. Sports Physiol. Perform. 2013; 8:695–8.
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