A Series of Unfortunate Clotting Events

Introduction Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT), pulmonary embolism (PE), and superficial venous thrombosis (SVT), is a significant health concern that can affect individuals across various age groups. The general population experiences an annual VTE (superficial and deep) incidence of approximately 1.43 per 1000 person-years, with DVT occurring at a rate of 0.83 per 1000 person-years and PE at 0.50 per 1000 person-years (1). The rate is notably lower in individuals under 40 years, estimated at about 1 to 2 per 9000 person-years. The estimated number of VTE cases in the United States annually is around 1,220,000 (2). The incidence of VTE in athletes is estimated to be significantly lower than in the general population, though exact figures vary depending on the sport and level of competition (3). Accurate estimations are challenging due to underreporting, variations in training intensity, differences in medical surveillance across sports, and the potential for misdiagnosis as musculoskeletal injuries. At our institution, we had three cases of VTE in NCAA Division I contact athletes between June 2024 and September 2024, all of whom required direct oral anticoagulants (DOACs). This was unprecedented given the relatively low risk for VTE in college athletes. In this paper, we present these three cases, review signs and symptoms of VTE, describe our approach to diagnosis, explore evidence-based approaches to both initial management and long-term treatment of VTE in athletes, use DOACs in contact athletes, and discuss safe return to contact sports. Case 1: Saphenous Vein Superficial Venous Thrombophlebitis in a Football Player A healthy 21-year-old male football player presented with 1 wk of right medial thigh pain. He reported a gradual onset of symptoms after a conditioning workout. The athlete reported driving a long distance to the university the week prior but denied any other risk factors for VTE. Physical exam demonstrated mild warmth and prominence of the great saphenous vein on exam, with tenderness to that area. An urgent lower extremity venous duplex showed an acute, completely occlusive superficial venous thrombophlebitis (SVT) in the right anterior accessory saphenous vein that was nearly the entire length of the thigh. The patient began a course of rivaroxaban 10 mg daily for treatment. He was allowed to continue noncontact off-season training. Given he was to start training camp (with contact practice) 43 d after initiation of DOAC, which is 2 d shorter than the typical recommended treatment duration (4), a shared decision was made with the athlete that he could discontinue it 2 to 3 d prior to the start of training camp. While on rivaroxaban, the athlete was performing drills in a metal chute frame and hit his head on a metal bar at high speed. He reported a headache and felt “off.” Neurological exam was benign, and an outpatient head CT was negative for intracranial bleeding. He was diagnosed with a concussion and had an unremarkable progression through our concussion protocol. The patient had clinical resolution of his superficial venous thrombophlebitis after remaining on rivaroxaban for approximately 40 d. Given the improvement compared to his presentation, rivaroxaban was discontinued based on exam and symptom resolution alone, and he was cleared to start contact practices. After returning to contact play, he did not have any recurrence of VTE. Case 2: Bilateral PE and Popliteal Vein DVT in a Football Player A healthy 23-year-old male football player presented with 2 to 3 d of nontraumatic left rib and shoulder pain that was worse with exertion or lying flat. His mother had a history of a lower extremity DVT and took apixaban. He denied other risk factors for VTE. Physical exam was normal besides borderline tachycardia, with HR 100. A computed tomography angiography (CTA) was completed that same day, which showed bilateral diffuse segmental and subsegmental pulmonary emboli. The patient was sent to the emergency department (ED), where a duplex ultrasound of the lower extremity revealed an acute nonocclusive popliteal vein DVT. The patient was admitted overnight and discharged on apixaban. Hypercoagulable lab workup including protein C, protein S, antithrombin III, prothrombin 2, factor V Leiden, anticardiolipin labs, and beta 2 glycoprotein labs was negative. Initially, his antiphospholipid antibody result was positive for lupus-like inhibitor but was thought to be false positive; when repeated after 3 months, it was negative. After 5 months on apixaban, the patient had an echocardiogram, which was normal. With hematology guidance, apixaban was discontinued after 5 months to help determine his risk of reclotting. The timing of this was modified from hematology's original recommendation of 6 to 5 months in preparation for spring football camp. After 1 month off apixaban and several days of rest prior to the blood draw, his D-dimer was normal at 259. Based on his calculated risk (DASH) (5) of around 3% of recurrent VTE annually off anticoagulation, shared decision-making was utilized with the patient and his family. He was cleared to remain off apixaban and resumed playing football. Long term, the patient was counseled that there should be consideration of resuming a DOAC after his college football career was completed. At the time of these decisions, the athlete had one more year of NCAA eligibility. Case 3: Right Upper Extremity DVT in Cheerleader A 21-year-old male collegiate cheerleader presented with 1 wk of right axillary numbness and exertional shortness of breath. His primary concern was that, during practice just prior to his visit, his entire right arm turned purple and became numb along the medial aspect to his fingers. He denied prior similar episodes, clotting disorders, or significant trauma. His father had a history of provoked DVT after surgery. His cheerleading role involved frequent overhead lifting, and he reported generalized joint hypermobility with occasional right shoulder subluxations. He denied recent immobilization, long-distance travel, or use of anabolic steroids, performance-enhancing substances, or tobacco. On examination, his right upper extremity (RUE) had prominent superficial veins, mild swelling, and discoloration. He had a 2+ radial pulse that was unchanged with Adson's maneuver. Doppler ultrasound confirmed an acute DVT in the subclavian and axillary veins. He was referred to the ED for further evaluation. A CTA demonstrated multiple segmental and subsegmental pulmonary emboli without right heart strain. An EKG showed sinus arrhythmia and right axis deviation. He was admitted to vascular surgery. The diagnosis of Paget–Schroetter syndrome, a form of venous thoracic outlet syndrome (VTOS), was established based on clinical presentation, imaging findings, and his history of repetitive upper extremity motion. On hospital day 2, he underwent percutaneous mechanical thrombectomy without complications. He was started on therapeutic anticoagulation with apixaban and discharged with plans for vascular surgery follow-up. He was held from cheerleading due to risk of trauma causing bleeding related to stunting and tumbling. At his 4-day postdischarge follow-up, he reported improvement in arm swelling and resolution of exertional dyspnea. DOAC therapy with apixaban was continued until further surgical intervention. At his 2-wk post-op visit, given the high recurrence risk of DVT in VTOS, vascular surgery recommended surgical decompression of the thoracic outlet. One month later, he underwent transaxillary first rib resection and thoracic outlet decompression with no postoperative complications. He was treated with apixaban for 3 months postoperatively. At his 3-month follow-up, he had no recurrent swelling, numbness, or neurologic deficits. While he had mild numbness at the incision site, there were no signs of intercostobrachial nerve dysfunction. Given his stable postoperative recovery and completion of 3 months of therapeutic anticoagulation, apixaban was discontinued, and he was cleared to return to cheerleading. Background and Epidemiology While VTE incidence is lower in younger populations, including athletes, research has indicated both long-duration endurance activity and high-intensity, contact sports may influence VTE risk (6,7). A cohort study with a 27-year follow-up found that individuals engaging in the highest levels of physical activity had a more than twofold increased risk of VTE compared to those with the lowest activity levels (adjusted hazard ratio [HR], 7.22; 95% confidence interval [CI], 2.05–4.67) (1). This suggests that while regular exercise is generally protective, extreme physical exertion may elevate VTE risk. In the context of professional sports, data from 1999 to 2015 identified 55 VTE events among athletes in major American male sports leagues. The National Hockey League (NHL) reported 22 cases, Major League Baseball (MLB) 16, the National Football League (NFL) 11, and the National Basketball Association (NBA) 5. The mean age at the time of VTE was 22.3 years, with an average time lost from play of 6.7 months (2). These findings highlight that, although VTE is relatively uncommon among athletes, it can lead to significant time away from sport. Specific risk factors for athletes include trauma and repetitive motion, particularly in high-contact sports and activities involving repetitive upper-body movements, which can lead to vascular injury (8). Extended periods of immobility, such as during long-distance travel or immobilization due to injuries, can result in venous stasis, a known risk factor for VTE. Intense training without adequate hydration may increase blood viscosity, further elevating the risk of clot formation (3,9). Several studies have shown a correlation between high altitude and increased incidence of postoperative VTE and general VTE. It is hypothesized that hypoxia may induce physiologic changes to include increased red cell volume, increased fibrinogen levels, increased platelet count, and increased platelet activation (10,11). Upper extremity DVT or upper extremity deep vein thrombosis (UEDVT) is a less common form of DVT accounting for 4% to 10% of all DVT cases (12). It is often associated with repetitive arm motions associated with thoracic outlet syndrome, especially pitching, weightlifting, swimming, rowing, tennis, softball, volleyball, water polo, and wrestling. Among these, baseball pitchers and weightlifters have the highest reported incidence (13). Early recognition and intervention are crucial, as untreated UEDVT can result in long-term complications such as post-thrombotic syndrome or pulmonary embolism. PEs are uncommon in athletes but can lead to life-threatening complications. The CDC estimates that 60,000 to 100,000 Americans die annually from PE (14), underscoring the importance of early detection and management; there is no reliable estimated annual number of deaths from pulmonary embolism in athletes specifically reported in the medical literature. SVT, once considered benign, is now recognized as a condition that may precede more severe thrombotic events. In athletes, SVT may result from localized trauma, overuse, or underlying venous insufficiency. It presents similarly to DVT but is not always treated with anticoagulation; this will be further explained in the “Discussion” section. While the incidence in this population is unknown, the potential for progression to deeper venous thrombosis necessitates further investigation. In addition to the physical and mechanical factors that contribute to VTE risk, biological influences also play a crucial role. Hormonal factors, particularly in female athletes, can further modify susceptibility. Female athletes using combined oral contraceptives (COCs) may face an increased risk of VTE. Studies have shown that COC use is associated with a three- to fivefold higher risk of VTE compared to nonusers (15). This risk is influenced by factors such as estrogen dose, type of progestin, and duration of therapy. Notably, the absolute risk for a healthy adolescent on COCs remains low, at approximately 0.05% per year. However, the risk is further amplified in individuals with inherited thrombophilia, such as factor V Leiden mutation, where the combination can lead to a significantly higher likelihood of thrombotic events (16). It is essential for female athletes to consult with healthcare providers to assess individual risk factors when considering contraceptive options. Pathophysiology Venous thromboembolism (VTE) results from an imbalance in normal hemostatic mechanisms, leading to inappropriate thrombus formation. The pathogenesis of VTE is best explained by Virchow's triad: endothelial injury, venous stasis, and hypercoagulability. These three interrelated factors contribute to thrombus initiation, propagation, and potential embolization (17,18). DVT and PE DVT typically originates in the lower extremities due to slow venous flow and localized clot formation (19). The stabilization of the thrombus occurs through interactions between fibrin, red blood cells, and activated platelets (20). If a thrombus embolizes, it can travel to the pulmonary arteries, leading to PE (21). Pulmonary vascular obstruction results in increased pulmonary artery pressure, right ventricular strain, and ventilation-perfusion mismatch (22). Severe cases may lead to cardiogenic shock and hemodynamic collapse. UEDVT and SVT UEDVT follows similar pathophysiologic mechanisms to lower extremity DVT. This condition arises when the subclavian vein is compressed between the first rib and clavicle or by hypertrophied scalene muscles, often due to repetitive overhead movements, seen in overhead athletes. In some cases, athletes may develop Paget–Schroetter syndrome, a condition leading to effort-induced thrombosis of the subclavian vein leading to subclavian vein trauma and clot formation (23). SVT, while typically less severe, shares common mechanisms with DVT and may extend into the deep venous system (19). It is more likely to occur in those with varicose veins. When SVT involves the saphenous vein, there is an increased risk of progression to DVT and PE due to the proximity to the saphenofemoral junction, requiring close monitoring and potential anticoagulation (24). Discussion Diagnostic Challenges in Athletes VTE symptoms may mimic common minor sports injuries. Additionally, athletes have a high level of conditioning, leading to lower resting heart rate, which may mask tachycardia associated with VTE. VTE may go undetected in an athlete due to their physiologic reserves until there is significant enough clot burden to cause classic signs and symptoms of a clot. Clinicians should maintain a low threshold for VTE evaluation in athletes with unexplained limb swelling, dyspnea, or slow recovery from minor injuries. Duplex ultrasonography is the first-line imaging for suspected DVT or SVT, while CT pulmonary angiography remains the gold standard for PE diagnosis (1). D-dimer testing may help rule out VTE in low-risk individuals but is less useful in athletes with training-induced inflammation (19). Anticoagulation Therapy The cornerstone of VTE treatment is anticoagulation, which typically involves DOACs, vitamin K antagonists (VKAs) such as warfarin, or low-molecular-weight heparin (LMWH). DOACs, including rivaroxaban and apixaban, are increasingly preferred due to their predictable pharmacokinetics, reduced need for laboratory monitoring, and lower risk of major bleeding compared to VKAs. Warfarin remains an option but requires frequent International Normalized Ratio monitoring and dietary considerations (25). Duration of Therapy The long-term management of venous thromboembolism (VTE) focuses on reducing recurrence risk, preventing complications, and minimizing the impact on an individual's lifestyle. Athletes diagnosed with VTE require careful treatment planning to balance anticoagulation therapy with their training and competition schedules. The recommended duration of anticoagulation depends on the nature of the thrombotic event. In cases of provoked DVT or PE (e.g., following surgery, trauma, or prolonged immobility), a 3- to 6-month course of anticoagulation is recommended (4,26). Unprovoked or recurrent events often warrant extended anticoagulation, potentially lifelong, especially in individuals with inherited thrombophilia (18,27). Treatment of SVT with anticoagulation is recommended in high-risk locations (e.g., close to the saphenofemoral junction), severe symptoms, active malignancy, history of VTE, and/or large clots (>5 cm) (4). Fondaparinux and rivaroxaban have been shown to be effective treatments for SVT, at a duration of 45 d (28,29). Lifestyle Modifications and Adjunctive Therapies Compression therapy with graduated compression stockings may reduce risk of post-thrombotic syndrome, a chronic complication of DVT that occurs from chronic venous hypertension, resulting from residual venous obstruction and valvular reflux after DVT, leading to impaired venous return and tissue edema (30). Maintaining adequate hydration, avoiding prolonged immobilization, delaying travel for 24 h after a sporting event, and considering prophylactic anticoagulation during high-risk situations (e.g., long-haul travel) are preventive considerations (31). Emerging and Alternative Therapies Strategically timed periods of DOAC interruptions for treatment of DVT or PE can be considered if the athlete desires return to contact sport. One treatment algorithm is similar to perioperative therapy: discontinuation 24 to 48 h prior to an event, and resumption 24 h after the event assuming no trauma has occurred (32). Another possible method proposed is intermittent dosing once the athlete has completed at least 3 months of anticoagulation therapy with a DOAC. Concentration levels of the DOAC are assessed via complex and expensive pharmacokinetic studies, with a goal of <30 ng·mL−1 as the ideal concentration during the sporting activity. The time that the DOAC is taken is adjusted to coincide with the trough. The risk of fatal VTE is relatively low at <1/100,000·d−1, and the risk of VTE in general is <1/3500·d−1 off anticoagulation after 3 months of treatment. This should be discussed with the athlete to arrive at an individualized approach, with the risk of bleeding during sport and the hematologist's recommendations in mind (33). While oral anticoagulation therapy remains the standard, newer approaches such as catheter-directed thrombolysis, mechanical thrombectomy, and intermittent anticoagulation strategies tailored for athletes are being explored. Research continues to assess the efficacy and safety of such interventions in reducing VTE recurrence while allowing for optimized performance in high-level sports (32). Conclusions While VTE remains rare in athletes, it poses a significant concern to an athlete's overall care and playing status. It is important to consider that in locations at high altitude, such as at our institution, further discussions about VTE prevention may be indicated (9). We support an individualized, evidence-based approach to treatment of VTE and return-to-play after VTE.