Hematology
Thomas H. Trojian
Diana L. Heiman
Blood has a central focus in athletics. Its oxygen and nutrient carrying properties make it a matter of concern for many coaches and athletes. Athletes with anemia may present with signs and symptoms only during strenuous exercise (1). Athletes will present with subtle findings, such as fatigue while sprinting. It is important to identify anemia because improvements can be seen in the athletic performance after its correction.
Anemia is a common finding in athletes, as well as in the general population. The signs and symptoms are multiple. Most often, the cause of the anemia is benign, but thorough evaluation is needed to rule out other more serious causes. Evaluations for poor dietary intake, as well as blood or nutrient loss through various sources, such as the gastrointestinal (GI) and genitourinary (GU) systems, and sweat, will provide the cause of anemia in most cases. When the anemia does not follow as per standard evaluation, then abnormal hemoglobin and hemoglobin electrophoresis should be considered.
Variations of the normal alpha and beta unit are not uncommon and can be found in at least 8% of African-American athletes (2). Controversy exists about the true risks of variations, such as sickle cell trait, and exercise. Some concerns are minor but others are very serious, including sudden death. This chapter will review all of these concerns.
On the other end of the continuum is erythrocythemia. This is most often caused by some form of manipulation of blood levels through altered living conditions or some form of blood doping. Athletes are often on the forefront of medical experimentation in the area of hemoglobin (Hgb) boosting. This was emphasized by the alleged use of darbepoetin (a drug not yet available for general use, similar to erythropoietin [EPO]) during the 2002 Winter Olympics in the hope that it would be undetectable in testing.
Pseudoanemia (Sports Anemia)
In 1970, Yoshimura coined the phrase “sports anemia” (3). This is actually a false anemia secondary to plasma expansion from exercise. The red blood cell (RBC) mass is actually normal to slightly increased, but there is a plasma expansion, such as in pregnancy, which causes a lower hematocrit level (4). Therefore, this is actually a dilutional pseudoanemia.
The decreased hematocrit values found are explained by the repeated relative hemoconcentration that occurs from dehydration, loss of plasma in sweat, and increased osmotic pressure in the muscles from lactic acid and other byproducts. After exercise, a plasma expansion occurs. Even a single bout of exercise can cause a 10% change in plasma volume and a hematocrit drop of 3.8% (5). This subsequent overshoot from the post-workout plasma volume expansion will cause a dilutional pseudoanemia. This type of anemia is found in endurance athletes. Therefore, its occurrence should not be high on the differential diagnosis in nonendurance sports such as American Football. The hemoglobin levels can be 1.0 to 1.5 g/dL below normal levels. It is important to evaluate for iron-deficiency anemia, as both can be present. Sports anemia should be considered a diagnosis of exclusion.
Pseudoanemia is not pathological but an adaptive response to endurance training (6). Therefore, supplementation with iron or other vitamins is not necessary. Normalization of the Hgb can be seen after 5 days from cessation of exercise. There is no need for an alteration in training. Dilutional pseudoanemia is functionally beneficial to the endurance athlete. It should not be corrected.
Microcytic Anemia
Iron Deficiency
Iron-deficiency anemia is the most common form of true anemia seen in athletes. It can be seen in any athlete but is most often seen in menstruating female athletes. In menstruating female athletes, the rate is as high as 20%, and it is approximately 6% in postmenopausal women. The rate is 4% in male athletes (7). The incidence of anemia in the athletic population is no different than in the general population (8). Many studies have examined the incidence of iron deficiency in athletes as compared to controls and have given varying results. There are some studies that show significant differences (9) and others that show no difference when compared to appropriately matched controls (10). Studies looking at endurance athletes showed this population to be at increased risk for iron deficiency (11). These studies used serum ferritin, which looks at body iron stores and overestimates anemia. A recent study does not show any difference in the prevalence of the disease in athletes compared to nonathletes (12). The rate of anemia may not be different in athletes, but the effects can be detrimental. Therefore, it is important to identify and correct this problem.
An increased rate of iron deficiency in athletes may be controversial. However, when compared to the general population, there is an increase in nonanemic iron deficiency. The ferritin level is predictive of iron stores. Increased rates of low ferritin levels have been seen in endurance athletes. The significance of a low ferritin on performance is uncertain, as iron replacement has not been shown to change performance outcomes (13). In endurance athletes, pseudoanemia (dilutional anemia) can coexist with a low ferritin level, and an iron-deficiency anemia with a dilutional pseudoanemia must be considered. A trial of iron levels with a follow-up reticulocyte count and hemoglobin level would be appropriate to rule out iron-deficiency anemia (see Table 19.1).
TABLE 19.1 Signs and Symptoms of Iron-Deficiency Anemia | ||||
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In athletes, as in nonathletes, the cause of iron deficiency is either from iron loss or insufficient intake. Iron losses are either from GI or GU sources or, questionably, sweat. GI is the most significant cause, and GI bleed can be a sign of a more serious illness. Appropriate tests should be done for any athlete with frank hematochezia.
Many athletes will develop microscopic GI bleeding while performing endurance sports. The exact mechanism is unknown, but many causes have been touted (14). The ones of note are non-steroidal anti-inflammatory agents (NSAIDs) and prednisone. Both can cause GI bleeding and their use is common among athletes (see Chapter 12 for further discussions on GI bleeding in athletes).
Other areas of iron loss have been described in athletes (15). Their significance is most often minimal. Loss of iron from sweat is negligible and unlikely to be the cause of iron deficiency. Losses from hematuria and foot-strike destruction are seen in the same group of athletes that have blood loss from the GI tract. Therefore, evaluation of possible GI losses of blood should be thoroughly investigated first.
In female athletes, obtaining a menstrual history is important in the evaluation. Heavy or prolonged menses is a common source of blood and iron loss. Menstrual history may lead to the diagnosis of amenorrhea, and if so, further questions need to address the possibility of disordered eating. In the amenorrheic athlete, evaluation of GI blood loss is important, once again, as this is still the most common source of iron-deficiency anemia.
Nutritional deficiencies are common in the general population as well as in athletes. Iron intake is as important as iron loss as the causes of iron-deficiency anemia. There are many athletes who adhere to restrictive and fad diets trying to get a real or perceived competitive advantage. In addition, anemia may be a sign of an eating disorder. A thorough dietary history is needed to identify low iron intake. A 2-week diet record is helpful in identifying iron nutritional deficiencies.
Evaluating anemia is best done in a stepwise approach. A complete blood count (CBC) with manual differential (diff) to identify and evaluate the anemia is very useful. The manual differential is an evaluation of all the cell types (white blood cells (WBC), RBC, Platelets). The CBC with differential will guide you to decide on the other needed studies. Additional blood can be drawn and held for further studies. The presence of target cells, Howell-Jolly bodies, schistocytes, elliptocytes, and other abnormal cell types can be found in the differential and will help in determining the cause of anemia. Also, the differential will identify if the anemia is microcytic or macrocytic.
If a microcytic anemia is diagnosed, then the reticulocyte count and ferritin level should be performed. A low ferritin (less than 20) and a reticulocyte index less than 1 almost confirm an iron-deficiency anemia. The athlete should be started on iron replacement. Follow-up hemoglobin and reticulocyte count is performed in 14 days. The reticulocyte index should be greater than two.
When the ferritin level is low normal, other tests can help identify an iron-deficiency anemia. Iron studies including serum iron and total iron binding capacity are useful tests. At times, differentiating the anemia is complex. A helpful test in separating iron-deficiency anemia from the anemia of chronic disease is the serum transferrin receptor ferritin ratio. It is elevated in iron-deficiency anemia, whereas normal in the anemia of chronic disease.
When the reticulocyte index does not increase after the start of iron replacement or a microcytic anemia is concurrent with normal iron studies, then performing hemoglobin electrophoresis is appropriate. Many forms of abnormal hemoglobin will produce low hematocrit levels with microcytosis but have normal or elevated reticulocyte counts. In addition, full compliance with iron replacement may not be tolerated, and questioning the athlete regarding barriers to compliance can identify why there is no bone marrow response to treatment.
Oral iron replacement is the treatment of choice. There is rarely, if ever, a reason for the use of parental iron therapy. Replacement should be 20 to 60 mg of elemental iron divided into three doses and given between meals. Ferrous sulfate tablets of 30 mg will supply 60 mg of elemental iron. There is a large reduction (50%) in absorption if given at mealtime. Some evidence supports the use of vitamin C with iron to increase absorption. The length of treatment to fully replenish iron stores is generally 3 to 6 months.
When the athlete expresses difficulty with iron replacement, you should investigate the reason. If it is an upset stomach, then taking the dose with food will help. Constipation can be corrected with a stool softener. Diarrhea is seldom a problem, but taking the iron with food can help. If needed, pediatric liquid formulation can be used. Altering oral iron therapy is far better than using parental iron. Because of the many serious local and systemic reactions, parental iron should be avoided.
Thalassemia
Thalassemia is the result of deletion or mutation of the genes responsible for the alpha and beta globin chains. Hemoglobin consists of two alpha and two beta globin units. The alpha globin is located on chromosome 16 along with the alpha-like globin zeta. The beta globin is on chromosome 11 in a linked cluster in the order epsilon, gamma, delta, and beta. There are many variations and degrees of deletion of the globin units. The presentation can range from asymptomatic to fetal death in-utero.
Mediterranean, African, and Middle Eastern patients commonly have alpha-thalassemia. African-Americans have alpha-thalassemia trait at a rate of approximately 2%. Beta-thalassemia presents in people from the Middle East, Indian Subcontinent, Northern Africa, and the Mediterranean at a rate of 1%. It is often seen with other hemoglobinopathies, such as sickle cell.
Beta-thalassemia
Beta-thalassemia minor or thalassemia trait describes the asymptomatic forms of the disease. The athlete’s CBC with differential usually presents as profound microcytosis and hypochromia with target cells and elliptocytes, but the anemia is only mild. The reticulocyte count is elevated. Hemoglobin electrophoresis classically reveals an elevated hemoglobin A2 (Hgb A2) (3.5% to 7.5%). Normal Hgb A2 with elevated fetal hemoglobin (HgbF) can be seen in some forms. Genetic counseling and patient education are essential.
In athletes with beta-thalassemia trait, their CBC with differential will often resemble iron deficiency and can be misdiagnosed as such. Ferritin and reticulocyte counts are useful in differentiating beta-thalassemia and iron-deficiency anemia. Athletes should avoid the unnecessary use of iron but must be aware that iron-deficiencies may develop with heavy menses, pregnancy, and GI bleeds.
Alpha-thalassemia
Alpha-thalassemia is characterized by the number of deletions in the four alpha gene loci. A single locus deletion, most common in Southeast Asians, produces the common alpha-thalassemia-2 trait. This form is asymptomatic. Two loci deletions produce alpha-thalassemia-1 trait, which resembles beta-thalassemia minor.
Presentation
Normally, the athlete presents with the signs or symptoms of anemia. Tests reveal a microcytic anemia that does not respond to iron therapy or, if iron studies are done, normal levels are found. Ferritin may be low in athletes without anemia. That is why follow-up laboratory studies are needed to determine the response to iron therapy. The reticulocyte count in thalassemia is elevated, not low as in iron-deficiency anemia, on initial presentation.
Hgb electrophoresis in alpha-thalassemia group shows a decrease in Hgb A2, and beta group shows increases in Hgb F and Hgb A2. The other tests are summarized by normal iron studies, low mean cell volume (MCV) (often 60 or less) and occasionally basophilic stippling seen on manual differential. Care must be taken not to cause iron overload in these athletes.
Macrocytic Anemia
Macrocytic anemias are not nearly as common as microcytic anemias in athletes. The main causes of macrocytic anemia are vitamin B12 deficiency, folate deficiency, drugs that effect folate metabolism (see Table 19.2), and hypothyroidism (16). Ethanol can cause a macrocytosis with a MCV greater than 100, without signs of liver damage.
Vitamin B12 Deficiency
Macrocytic anemia from vitamin B12 deficiency is uncommon. The cause is frequently from an absorption problem
due to the lack of an intrinsic factor. Deficiency in the intake of vitamin B12 is possible in vegans (people who eat no animal products, including dairy and eggs). Most vegans are well aware of the need for vitamin B12 and will use supplements. It is rare to find of a person with vitamin B12 deficiency who does not have pernicious anemia or a chronic GI disorder.
due to the lack of an intrinsic factor. Deficiency in the intake of vitamin B12 is possible in vegans (people who eat no animal products, including dairy and eggs). Most vegans are well aware of the need for vitamin B12 and will use supplements. It is rare to find of a person with vitamin B12 deficiency who does not have pernicious anemia or a chronic GI disorder.
TABLE 19.2 Drugs That Cause Macrocytic Anemia |
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