Definition

Anemia is defined as a reduction of red blood cells below the normal range, with the normal range differing for men and women. Hemoglobin and hematocrit are commonly used to identify the red blood cell concentration in the blood. Mild anemia can be asymptomatic, although compared with more sedentary persons, athletes generally notice it much earlier because of its effects on their performance. It is important to identify the underlying cause of the anemia, which can be due to decreased red cell production or increased red cell destruction.

Hemoglobin is the oxygen-carrying protein in red blood cells. Normal hemoglobin (hemoglobin A) consists of two alpha chains and two beta chains. Inherited disorders of hemoglobin are referred to as hemoglobinopathies or thalassemia . A number of hemoglobinopathies have been identified that result from mutations in the alpha or beta chains and have varying degrees of anemia and symptoms. The most common hemoglobin mutation in the United States is hemoglobin S, which causes sickle cell disease in persons with two copies of the mutated gene. Thalassemia refers to decreased production of normal alpha or beta chains and can be clinically silent or markedly symptomatic. Thalassemias are referred to as alpha or beta, depending on which chain is affected. Thalassemias increase in clinical severity as the number of genes affected increases; generally, persons with one or two mutations are asymptomatic, a condition referred to as “thalassemia minor.”

It also appears that some athletes have anemia that is caused by mechanisms not seen in nonathletes, including dilutional “pseudoanemia” and exercise-related intravascular hemolysis. Pseudoanemia refers to a temporary condition that occurs as a result of training-related plasma volume expansion. The degree of volume expansion relates to the duration and intensity of exercise and can result in a dilutional drop in the hemoglobin concentration. Intravascular hemolysis is also common in athletes. Initially referred to as “march hemoglobinuria” or “foot-strike hemoglobinuria,” the mechanism for hemolysis was thought to be induced by mechanical damage to red cells with each foot strike. However, recent observations suggest that the effects of contracting muscles on red cells may contribute to hemolysis and the development of anemia in athletes.

Epidemiology

Anemia is a condition commonly experienced by persons in the United States. Rates are highest in children and adult women, largely because of iron deficiency. The most recent National Health and Nutrition Examination Surveys (1999-2002) estimate that 3.6% of children and 6.9% of women in the United States are anemic, with the highest rates among menstruating women. Iron deficiency is the most common cause of anemia in the United States and is the most common nutritional deficiency worldwide.

Hemoglobin S is the most common inherited blood disorder in the United States. It is estimated that 1 in 12 African Americans carries one copy of the mutated gene, a condition referred to as “sickle cell trait.” The thalassemias are also common and are considered the most prevalent genetic mutation worldwide. Incidence varies geographically; alpha thalassemia is frequent in southeast Asia and western Africa, whereas beta thalassemia is more common in the Mediterranean region of Europe.

Pathophysiology

As previously stated, anemia is caused by either decreased production or increased destruction of red blood cells. Red blood cell production problems ( Table 19-1 ) can be due to a vitamin or mineral deficiency, inflammation, erythropoietin deficiency, or a primary bone marrow disorder. Iron deficiency is the most common cause and is most often the result of blood loss. Menstruation or chronic gastrointestinal blood loss will lead to iron deficiency if oral intake is not able to balance iron loss. Other avenues for iron loss in athletes are hemolysis leading to hemoglobinuria and increased sweat production. Another potential cause of iron deficiency in athletes is celiac disease, which results in iron malabsorption and can occur even in the absence of the gastrointestinal symptoms that are suggestive of celiac disease.

Iron deficiency occurs in three stages. Stage I, also known as prelatent iron deficiency, is associated with an isolated decrease in serum ferritin. At this stage, stainable iron is not present in the bone marrow, but hemoglobin levels remain normal. Stage II is latent iron deficiency; at this stage the ferritin drops further, serum iron and transferrin saturation decrease, and total iron-binding capacity rises. As in stage I, hemoglobin levels remain normal during stage II, although the mean corpuscular volume (MCV) of the red cells may start to decrease. However, in stage III, with progressive depletion of iron stores, an overt microcytic and hypochromic iron-deficiency anemia develops.

Inflammatory conditions have long been known to lead to decreased red cell production, but only recently has the pathophysiology been understood fully. Hepcidin, a protein produced by the liver in response to infection or inflammation, inhibits iron absorption and release from storage sites for use by developing red blood cell precursors. Although data are lacking in athletes, it is plausible that chronic inflammation from training results in elevated hepcidin levels, which contributes to disordered iron metabolism and resultant anemia.

Erythropoietin is an important hormone that promotes red blood cell production. It is produced by the kidney but is also manufactured as a pharmaceutical agent for use in persons with kidney failure and some primary bone marrow disorders. Deficiency in an athlete would be unusual unless significant renal insufficiency was also present. Similarly, primary bone marrow disorders such as leukemia or multiple myeloma often cause significant anemia, but these disorders are rare in athletes.

Hemoglobin S in red blood cells protects against malaria and has been shown to reduce mortality from the disease compared with hemoglobin A. Sickle cell trait has long been believed to be a benign condition, but evidence is increasing that carriers have an increased number of adverse events. Exertional sickling, which was first reported in military recruits more than 25 years ago, has been associated with sudden death during exercise. Causes of sudden death include metabolic acidosis, rhabdomyolysis, renal failure, and cardiac arrhythmia. Risk for adverse events is increased by conditions that can promote sickling of red blood cells, including intense exercise, particularly at a high altitude or in extreme heat. In a recent review of National Collegiate Athletic Association athletes who died suddenly, it was determined that the relative risk for sudden death is 37 times higher for an athlete with sickle cell trait.

Compared with athletes who have sickle cell trait, athletes with thalassemia have a much lower risk for sudden death. Athletes with either alpha or beta thalassemia minor often have a very mild anemia due to decreased hemoglobin A production. Athletes with more significant disease will have significant anemia and may also have splenomegaly and skeletal abnormalities, which would likely preclude participation in competitive athletics.

Diagnosis

The diagnostic approach to the athlete with anemia is aimed at isolating the exact etiology in order to determine the appropriate therapy. A complete blood cell count (CBC) can be a useful guide to the initial evaluation. Significant abnormalities of white blood cells and platelets signal an occult, potentially serious bone marrow disorder that requires referral to a hematologist. However, an isolated anemia is much more common, and the workup can be guided by the CBC and reticulocyte count. Reticulocytes are immature red blood cells and are produced in higher numbers in the presence of bleeding or hemolysis. A high reticulocyte level indicates an appropriate bone marrow response to anemia and is not indicative of a bone marrow problem. Conversely, a low reticulocyte count is suggestive of anemia resulting from decreased red blood cell production ( Fig. 19-1 ).

An approach to the patient with anemia, based on reticulocyte count at presentation. MCV, Mean corpuscular volume.

For disorders associated with decreased red blood cell production, evaluation of the size of red blood cells is pivotal in determining etiology. Microcytosis (mean corpuscular volume [MCV] <80 fL) is most commonly associated with iron deficiency and thalassemia. Macrocytosis (MCV >95 fL) may indicate deficiencies of either vitamin B ₁₂ or folic acid, as well as various endocrine or primary bone marrow disorders. Normocytic anemias (MCV 80-95 fL) can be induced by inflammation, bone marrow disorders, and early vitamin or mineral deficiency.

Iron deficiency is generally evaluated using a series of tests, including hemoglobin, hematocrit, MCV, serum iron, total iron-binding capacity, transferrin saturation, and serum ferritin. Although a bone marrow biopsy with Prussian blue staining for iron is generally regarded as the gold standard for diagnosing iron deficiency, serum ferritin is an excellent surrogate marker for iron stores in most patients. A serum ferritin level less than 10 to 15 ng/mL is nearly always suggestive of iron deficiency. However, higher ferritin values also may be suggestive of occult iron deficiency because a number of underlying inflammatory or malignant conditions can stimulate a threefold elevation in serum ferritin.

A diagnosis of thalassemia minor can often be made from evaluation of a CBC and family history. Thalassemia minor generally presents with severe microcytosis (MCV <70 fL) and mild or borderline anemia. Iron studies typically do not reveal iron deficiency, although some persons may have combined abnormalities. Hemoglobin electrophoresis is used to diagnose beta thalassemia, but results are normal in persons with alpha thalassemia, which is diagnosed by genetic testing.

For normocytic or macrocytic anemias, further testing should include assessment of vitamin B ₁₂ , folate, and thyroid-stimulating hormone levels. Because of their larger size, a significant increase in reticulocytes can cause an increase in the MCV. Any athlete with an MCV greater than 110 fL should be referred to a hematologist.

Treatment

An adequate understanding of the various causes of anemia and related laboratory data is pivotal for adequate treatment of anemia in athletes (see Table 19-1 ). Athletes with iron deficiency anemia commonly present with the gradual onset of fatigue and decreased performance or exercise tolerance. A detailed history, including queries about gastrointestinal or urinary bleeding, menstruation, and nutritional practices, should be obtained. Characteristic laboratory findings include a microcytic, hypochromic anemia; decreased serum ferritin, iron, and transferrin saturation levels; and elevated total iron-binding capacity. Additional testing to determine the etiology of iron deficiency (e.g., evaluation of the gastrointestinal tract) may be advised if necessary.

The replacement of iron in nonanemic, iron-deficient athletes is controversial (this issue is discussed in ). One reasonable approach would be to first ensure that the athlete’s diet includes sufficient amounts of iron in the form of iron-rich foods such as lean meats, poultry, fish, grains, and vegetables. Dietary sources of heme iron have a higher bioavailability than do foods containing non-heme iron, and coingestion of foods containing ascorbic acid may enhance intestinal iron absorption. If dietary changes fail to improve the athlete’s iron status, a therapeutic trial of oral iron supplementation may be useful.

Athletes with documented iron deficiency anemia should be treated with iron replacement therapy, typically with oral ferrous sulfate. Gastrointestinal adverse effects such as nausea or constipation may be dose limiting. Within 2 to 3 weeks, an increase in reticulocytes and MCV should be noted. Improvement in hemoglobin and ferritin levels may take several weeks. A minimum of 6 to 12 months of therapy is usually required, although some athletes may need more extended treatment depending on the underlying cause and severity of the anemia. Athletes who fail to respond to oral iron supplements or have intolerable adverse effects with medication should be referred to a hematologist for consideration of alternative forms of iron replacement therapy.

The approach to athletes with sickle cell trait is controversial. The literature in this area largely consists of case reports or series; no prospective studies in athletes are available to guide assessment of risk-reduction strategies. The National Athletic Trainers’ Association has issued a consensus statement on sickle cell trait and the athlete. Additionally, this Association has published guidelines for preventing sudden death in college and secondary school athletes that focus on risk reduction, gradual acclimatization to conditioning activities, and medical supervision. Because heat exposure, exercise intensity, and hydration are believed to be important risk factors, recommendations for future research have focused on these elements.

Return-to-Play Guidelines

Anemia generally does not preclude athletic participation. Athletes typically notice a decrement in athletic performance before they present with a severe anemia. For athletes with additional hematologic abnormalities, such as leukopenia or thrombocytopenia, referral to a hematologist is suggested before the athlete returns to full activity. For athletes with sickle cell trait, education and risk reduction are important components of safe participation in all athletics. Following these guidelines while closely monitoring the athlete for signs of difficulty should permit full participation.