Does sickle cell trait cause rhabdomyolysis?

Does Sickle Cell Trait Cause Rhabdomyolysis?

Yes, sickle cell trait can cause exertional rhabdomyolysis under specific high-risk conditions, particularly during intense exercise when hemoglobin S polymerization triggers vascular occlusion, impaired muscular blood flow, and ischemic muscle breakdown. 1

Pathophysiologic Mechanism

The cascade begins when intense exercise creates conditions that promote hemoglobin S polymerization and erythrocyte sickling—specifically hyperthermia, dehydration, acidosis, and hypoxemia. 1 This exertional sickling scenario triggers:

• Vascular occlusion from sickled red blood cells "logjamming" blood vessels 2
• Endothelial damage and impaired blood flow to muscles 1
• Ischemic rhabdomyolysis from muscle tissue undergoing anaerobic metabolism 3
• Disseminated intravascular coagulation that can progress to multi-organ failure 1

Sickling can begin within 2-3 minutes of all-out exertion and reach grave levels rapidly if the athlete continues despite warning signs. 2

High-Risk Clinical Scenarios

Events typically occur under these specific conditions: 1

• Early training season or after periods of deconditioning
• Ambient temperatures ≥80°F
• High altitude exposure
• Intense, sustained exertion (particularly military training and college football) 1

The American Heart Association and American College of Cardiology explicitly recognize sickle cell trait as associated with rhabdomyolysis in military recruits and competitive athletes, predominantly college football players. 1

Evidence from Clinical Cases

Multiple case reports document this association:

• A 26-year-old SCT-positive male developed acute kidney injury with BUN/Cr rising to 122/14 mg/dL after 2 hours of dancing, with renal biopsy revealing heavy myoglobin deposits and delayed CPK measurement of 334 U/dL. 4
• An active duty soldier suffered exertional rhabdomyolysis following an Army Physical Fitness Test, complicated by acute renal failure requiring hemodialysis. 5
• A 31-year-old male with SCT developed extensive compartment syndrome, rhabdomyolysis, severe acidosis, acute renal failure, and coagulopathy leading to death despite multiple fasciotomies and aggressive resuscitation. 6

Nine athletes, including five college football players, have died from exertional sickling in recent years. 2

Critical Distinction from Other Causes

This is NOT typical exertional rhabdomyolysis. Unlike cardiovascular collapse from ventricular tachyarrhythmias (which is virtually instantaneous), SCT-related collapse results from a more gradual deterioration and cascade of events. 1 The progression involves:

1. Intravascular sickling → vascular occlusion
2. Impaired muscular blood flow → ischemic rhabdomyolysis
3. Metabolic cascade: lactic acidosis, hyperkalemia, hypocalcemia 3, 7
4. Potential pulseless electrical activity (where external defibrillation may be ineffective) 1, 7

Multifactorial Considerations

Important caveat: SCT is often not the sole cause. One case series revealed multifactorial origins including: 8

• Prescription medications associated with rhabdomyolysis
• Coinheritance of pathogenic mutations (NPHS2 p.V260E)
• Drug-to-drug interactions coupled with exercise stress

This underscores that comprehensive clinical and genetic evaluations are necessary to identify all contributing factors. 8

Emergency Management Protocol

Collapse of an SCT athlete is a medical emergency requiring: 1, 7

1. Immediate cessation of physical activity at first warning signs (muscle weakness, cramping, pain, fatigue, disproportionate dyspnea)
2. Supplemental oxygen administration
3. Aggressive IV hydration (target urine output 300 mL/hour) 7
4. Cooling measures to protect against fulminating rhabdomyolysis 1, 7
5. Rapid transport to medical facility
6. Close monitoring for hyperkalemia, lactic acidosis, and hypocalcemia 3, 7

Prevention Strategies

The American Heart Association and American College of Cardiology recommend specific precautions: 1

• Gradual conditioning at beginning of training season
• Modified pace with adequate rest and hydration during drills
• High index of suspicion to immediately cease activity when warning signs appear
• Avoidance of strenuous exercise in hot climates 6

Critical point: Recognition of SCT status is NOT justification for disqualification from competitive sports (Class I; Level of Evidence C), but preventive strategies must be implemented (Class I; Level of Evidence B). 1

Common Pitfalls

• Delayed diagnosis despite typical clinical presentation and available SCT screening results 5
• Misattribution of microscopic hematuria masking underlying myoglobinuria 4
• Failure to recognize that SCT-positive individuals have impaired ability to concentrate urine, making them prone to intravascular depletion and renal failure 4
• Inadequate awareness that fractional excretion of sodium may be >3% (not <1% as typical for rhabdomyolysis) due to underlying sodium/water reabsorption defects in SCT 4