In 2010, the National Collegiate Athletic Association mandated testing for sickle cell trait in all athletes planning to participate in division I sports (18). Concerned with the implications of such a policy on the health, safety, and privacy of competitive athletes, the Sickle Cell Disease Association of America and the National Athletic Trainers’ Association put forth consensus statements to direct the implementation of these guidelines (17,23).
The origin of these efforts can be traced back to a handful of tragic health outcomes and resultant medicolegal disputes revolving around athletes with sickle cell trait, the carrier state of sickle cell disease (3,19,22). A number of cases of sudden death have been documented in athletes with sickle cell trait. In a recent case report, a 19-year-old football player with sickle cell trait developed a fatal case of rhabdomyolysis minutes after running 16 successive 100-yd sprints (1). Seven cases of fatal exertional rhabdomyolysis associated with sickle cell trait were documented in a review of nontraumatic causes of sports-related death in athletes (26). In such cases, sickle cell trait increases the risk of rhabdomyolysis, which may be triggered by periods of intense dehydration or hyperthermia produced during exercise (5). As a result of such tragic cases and the resultant policy changes, the sports medicine community has redirected its attention to the relevant health sequelae of sickle cell trait and sickle cell disease in athletes.
Approximately 5.2% of the global population has at least one abnormal variant of hemoglobin, with an especially high prevalence (18.2%) among African populations (14). The aforementioned policies most directly are related to athletes with sickle cell trait, a carrier state in which an individual possesses only one allele for an abnormal form of hemoglobin — HgS. The HgS allele produces an abnormal beta-globin chain of hemoglobin that is poorly soluble in environments with low oxygen content (4). Having one abnormal HgS allele and one normal hemoglobin allele leads to the carrier state, sickle cell trait. In contrast, sickle cell disease is composed of different permutations of abnormal forms of hemoglobin, such as HgS. Having two HgS alleles, for example, leads to one form of sickle cell disease — sickle cell SS. There is yet another abnormal form of hemoglobin (HgC) that can be combined in various permutations with normal hemoglobin and HgS to produce even more abnormal phenotypes. In sickle cell SC, a form of sickle cell disease, the abnormal variant HgC is combined with HgS to produce a disease phenotype. In total, there are roughly 16 different variations of sickle cell disease that span a spectrum of disease severity (21).
The spectrum of disease ranges from asymptomatic to life-threatening complications, such as myocardial infarction and stroke (11,27). These manifestations are the result of vaso-occlusive crises that ensue when abnormal variants of hemoglobin sickle in blood are exposed to low oxygen levels and inflammation (9). Individuals with sickle cell disease are prone to painful crises when sickling of abnormal cells causes entrapment and occlusion of microvasculature in the chest (acute chest syndrome) or other body parts (10). Recent evidence suggests that even with the most benign genotype, sickle cell trait, there is increased risk of exercise-related rhabdomyolysis, deep venous thrombosis (DVT), and kidney disease (6,8,12).
The evidence for life-threatening sequelae and exercise-related adverse events highlights the relevance of sickle cell trait and disease to the sports medicine community and lends credence to the screening and testing programs that have been implemented in athletes. Understandably, the life-threatening sequelae have received most of the attention in the literature thus far, while the subacute and chronic sequelae have received less. These complications pose a challenge to sports medicine practitioners, since they are composed of clinically significant disease processes that can mimic more benign pathology seen commonly in athletes. This case study illustrates many of the relevant disease processes in sickle cell disease and also documents a possible connection between exercise and one of these clinical entities in a high-performance athlete.
A 50-year-old African American athlete, who was a former college football player, presented to our emergency room with asymmetric lower leg pain after an intense calf workout. The athlete engaged in competitive sports since the age of 15 years and played as a safety for the football team at the University of Southern California. He also played football competitively through his 30s, as a member of a semipro team. He continued his active lifestyle thereafter with weight lifting, giving special attention to strength conditioning of his lower body musculature. At his peak, he was able to lift greater than 1,000 lb in multiple repetitions with seated leg press.
At time of presentation to our emergency department, the athlete was known to have a history of type 2 diabetes, hypertension, chronic kidney disease, and gout. The patient also recalled a history of what he thought was “sickle cell trait,” reportedly diagnosed when he immigrated to the States at the age of 5 years. He was screened for sickle cell trait at that time because his mother and sister both had sickle cell disease. From his recollection, he was only a carrier and did not have the full disease genotype.
As an athlete with sickle cell trait, the patient did not have any medical limitations to his physical activity throughout his career as a football player. He did not suffer from any hospitalizations or medical complications as a result of his high performance activity. At no point did the athlete feel that his genetic condition limited his ability to perform.
A couple of weeks prior to presenting to our emergency room with asymmetric calf pain, the athlete had more than doubled the weight used in his calf raise exercises. After this intense work out, the athlete immediately felt sore in his calves and thought he had overworked his muscles. When his symptoms had not resolved after a couple of weeks, he decided to seek care in our emergency room. He particularly was concerned because his soreness was mainly in the right calf rather than in both calves.
In the emergency room, the athlete was noted to have tenderness along the right calf with no palpable cords. He had good strength and range of motion of his lower leg but demonstrated pain when flexing his right calf muscle with plantarflexion of the foot. He denied long distance travel, immobilization, surgery, smoking, or prior malignancy. His vitals signs were unremarkable, with no tachycardia or respiratory distress. Routine laboratory tests were not drawn for the patient at that time. A lower extremity venous ultrasound examination was performed and revealed a clot in his right peroneal and posterior tibial veins. To thin his blood and prevent further clotting, the patient was started on enoxaparin and bridged to warfarin, which was continued for 6 months.
In the ensuing months after presenting with DVT, the patient returned to the emergency room six times for a variety of complaints, including chest pain, hip pain, and shoulder pain. In working up the patient’s chest pain, pulmonary embolism was a primary concern given the patient’s history of DVT. Due to the patient’s impaired renal function from chronic kidney disease, ventilation-perfusion (V-Q) lung scans were performed to evaluate for pulmonary embolism rather than spiral computed tomography (CT) with intravenous contrast. On three separate occasions, the patient received V-Q lung scans that showed very low likelihood of pulmonary embolism. To evaluate for a possible cardiogenic cause of his chest pain, the patient also received a cardiac stress test. This test showed no evidence of cardiac ischemia.
The patient’s chest pain was evaluated further with noncontrast chest CT, which showed puzzling parenchymal opacities on the side of the chest corresponding to his pain. These abnormalities appeared first in the right lower and middle lobes and subsequently in the middle and upper lobes of the right lung (Fig. 1). Although these radiological findings were read initially as likely infectious or inflammatory in etiology, upon retrospective review with a staff radiologist, they were interpreted as being consistent with acute chest syndrome.
In evaluating the patient’s hip pain, recurrent DVT was a primary concern given the patient’s history. To evaluate this, repeat lower extremity ultrasounds were performed to evaluate for thrombosis in the proximal veins of the lower extremities. These ultrasound studies did not show evidence of recurrent thrombosis. The source of the patient’s hip pain was revealed eventually with magnetic resonance imaging (MRI), which demonstrated avascular necrosis of both femoral heads (Fig. 2).
While off warfarin, the athlete also presented on one occasion with left-sided shoulder and upper arm pain that occurred 14 h after heavy bench pressing exercise. A rotator cuff tear was suspected in the emergency room, and the patient was referred to a sports medicine specialist for further evaluation. The patient did not follow up, however, since the pain resolved spontaneously before he saw a specialist.
During the athlete’s most recent admission, our clinical team investigated a possible unifying diagnosis to bring together the multiple complaints the patient had experienced. We honed in on the patient’s purported status as a carrier for sickle cell. A previous hemoglobin electrophoresis test performed decades earlier demonstrated 52% HgS and 48% HgC. This was consistent with a more severe form of sickle cell disease called hemoglobin SC rather than simple sickle cell trait.
After this hospitalization, the athlete finally was referred to a hematologist for ongoing care for his hematologic condition. He was started recently on folic acid supplementation to support the high level of red blood cell production (erythropoiesis) required to replace cells lost in his sickling episodes. He was instructed also to discontinue the use of glucocorticoids, which previously had been used to treat his gout, but were likely accelerating the progression of his hip avascular necrosis.
This athlete with hemoglobin SC presented with many characteristic sequelae of sickle cell disease that have been documented in the literature: DVT, acute chest syndrome, avascular necrosis of the hip, and chronic kidney disease. This case illustrates relevant clinical sequelae that sports medicine practitioners need to keep in mind when caring for athletes with sickle cell disease. This is especially important since these clinical entities specific to sickle cell disease can mimic common clinical complaints with more benign etiologies (Table). Chest pain, calf pain, shoulder pain, and hip pain can all be symptoms associated with acute chest syndrome, DVT, and avascular necrosis.
These clinical sequelae develop over a subacute to chronic time course, and sports medicine practitioners have the opportunity to catch these problems before they lead to significant morbidity. This can occur in the form of chronic pulmonary, vascular, and musculoskeletal complications in this population of athletes. Repetitive episodes of acute chest syndrome, for example, can lead to significant scarring and reduction in pulmonary function. Recurrent thromboses require lifelong anticoagulation, which comes with the risk of life threatening hemorrhage from minor trauma. Avascular necrosis causes destruction of the hip joints and can lead to functional impairment with chronic pain. With a better awareness of these sequelae of sickle cell in athletes, sports medicine providers will have an appropriately broad differential when caring for their athletes with sickle cell.
This case also reveals some of the unanswered questions that remain with regard to athletes with sickle cell. One specific question that arises from the case is whether there are relevant exercise-related risk factors for DVT in athletes with sickle cell. In this report, an athlete presented with a DVT associated with antecedent exercise of the muscles in the area affected by clot. Other risk factors for DVT — such as surgery, long travel, smoking, malignancy, hemoconcentration, and polycythemia — were absent.
Although sickle cell alone affords an increased risk of clot, exercise could possibly increase that risk through a mechanism associated with microvascular injury to the endothelial wall through sheer forces generated through flexion and stretching of muscle, consistent with the traditional association of vessel injury to thrombosis, through Virchow’s triad (2). Alternatively, external compression of the affected veins from hypertrophic musculofascial bands or anatomic variants could confer the risk. Also possible is a mechanism whereby deoxygenation of tissue during exercise increases risk of thrombosis through molecular changes to plasma adhesions molecules (15). These molecular changes to plasma adhesion molecules could increase risk of thrombosis and clot in the setting of exercise.
Dehydration also may play a role. In addition to examining the broader relationship between exercise and DVT formation, the more specific role of dehydration also demands further investigation. Hemoconcentration and polycythemia vera are well-known risk factors for the formation of DVT in athletes (16). The hemoconcentrated state of the dehydrated athlete thus may confer an increased risk of DVT formation during and after intense exercise. Furthermore, medications causing increased urine output (including commonly prescribed diuretics such as furosemide and hydrochlorothiazide) may increase the risk of clot formation by depleting intravascular volume. High urine output, as would occur in the diabetic athlete with polyuria, also similarly would increase risk. This line of research underscores the importance of proper hydration and fluid balance in athletes with sickle cell disease.
The possibility of exercise-induced DVT as a clinical entity in patients with sickle cell disease is plausible considering previous documentation of exercise-induced thrombosis in patients without clotting disorders. In the so-called subclavian vein effort-induced thrombosis (Paget-Schroetter syndrome), patients without underlying coagulopathies have presented with thrombosis of upper extremity veins with exercise (7,13,24,25). In our case, the athlete presented on one occasion with upper extremity pain after intense bench pressing exercise. This could have been due to an undetected episode of exercise-induced upper extremity thrombosis.
Further investigation and research will be helpful in elucidating the connection between exercise and DVT formation in athletes with sickle cell disease in order to confirm this relationship and to guide practitioners on how they can reduce risk of DVT in this population. Establishing a causal relationship between exercise and DVT in athletes with sickle cell disease would be the first step. This report is limited because it represents a single case; further research with case series, retrospective analyses, and ultimately prospective studies would be instructive.
Investigation of the causal pathophysiologic mechanism connecting increased risk of DVT with exercise in patients with sickle cell disease is also necessary to better delineate whether vascular injury, external compression, deoxygenation, dehydration, or another mechanism is responsible for increased risk of thrombosis. This will be especially helpful in later translating this research into practical recommendations that can inform existing guidelines regarding how sports medicine practitioners design exercise regimens for athletes with sickle cell trait and disease.
Of course, these guidelines should be individualized depending on the disease severity of each athlete. Current guidelines stipulate that “athletes need individual assessment” and that “if illness permits, all but high exertion, collision, and contact sports may be played.” They further state that “overheating, dehydration, and chilling must be avoided” (20). Confirmatory research will be required to substantiate these recommendations and will inform also the individual recommendations that are made for each athlete based on more general guidelines. In the case presented, for example, the athlete may have ramped up his weight lifting too quickly. The patient also may have not been hydrated adequately or may have been on medications, such as diuretics, which were depleting his intravascular volume. Based on confirmatory research, athletic trainers justifiably would be able to recommend conservatively graded weight increases and optimal hydration in such athletes.
This case also touches upon relevant questions surrounding the recently implemented screening programs that have drawn attention in the sports medicine community. On the one hand, the case demonstrates how athletes with sickle cell disease can participate safely in competitive sports with no serious health outcomes or perceived limitations to performance. The athlete in this case successfully played in division I football without any adverse health events or subjective limitations to physical performance. Moreover, the athlete had a more severe form of sickle cell than the athletes that would be identified through present screening programs. This may support the view of those who claim that athletes with sickle cell disease are safe to participate in competitive sports and that screening programs are nonessential. However, in counterargument, the rare but life-threatening complications that can occur in this population support the need for such screening programs.
Disagreement regarding the need for such screening programs will continue invariably, but in the meantime, research can contribute to the understanding of the health sequelae of sickle cell trait and disease in athletes. By doing so, research can inform how sports medicine practitioners care for and respond to athletes who are identified through screening. Although initial concern has focused on the life-threatening complications that drove the inception of these screening programs in the first place, this case illustrates how the long-term health sequelae in these athletes are just as important to investigate and better understand.
Sickle cell disease is a condition that has both immediate life-threatening health threats as well as longer-term, subacute, and chronic medical sequelae that are relevant to athletes. Screening programs have been implemented in college athletics to help identify individuals with this condition, primarily in hopes of reducing the risk of life-threatening adverse health events. These programs have helped focus the attention of sports medicine providers on the life-threatening health sequelae of this genetic condition. However, equal attention should be directed toward the longer-term chronic medical complications of sickle cell that pose a lifelong threat to these athletes. These clinical entities pose a diagnostic challenge to sports medicine practitioners, because they mimic common clinical complaints with more benign etiologies in the general population. Adequate understanding of the sequelae of sickle cell is thus essential for sports medicine practitioners to appropriately care for athletes with sickle cell. A better understanding through research of the disease as it relates to sports and exercise will be instrumental in reducing the risk of both immediate and lifelong health sequelae that threaten the athlete with sickle cell.
The authors would like to thank Drs. Jonathan Edlow and Leon Adelman from the Department of Emergency Medicine as well as Drs. Roger Yu and Rebecca Karp from the Department of Internal Medicine for their efforts providing clinical care to the patient while in the hospital.
The authors declare no conflict of interest and do not have any financial disclosures.
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