Debunking the Myth: Sickle Cell Trait and Exertion-Related Deaths — A Review of the Evidence

Sickle cell trait (SCT), a genetic carrier state of sickle cell disease (SCD), occurs when an individual inherits a single copy of the SCD gene. Unlike with SCD, individuals with SCT have an expected lifespan similar to that of the general population and are often considered asymptomatic.¹  Despite being regarded as benign, SCT has been associated with adverse health outcomes, including exertional rhabdomyolysis, sudden death, chronic renal dysfunction, and venous thromboembolism (VTE) in large epidemiological studies.²  For decades, how much weight to give SCT as a clinical risk factor has been debated among clinicians, researchers, athletic organizations, military and government agencies, public health officials, and the media.³  The ongoing debate has been driven by anecdotal reports and heavily biased studies, leading to miscalculations of SCT-related risks, although some high-quality studies have shown small but measurable associations between SCT and chronic kidney disease (CKD) and VTE.⁴  Despite studies showing exertional-related deaths to be limited to cases of rhabdomyolysis, the lay media and non-specialists have persisted in questioning the link, often overlooking the lack of reliable evidence supporting such claims. Recently, this purported link has been used to exonerate officers in custody-linked deaths for which there is no supportive evidence.⁵ 

Under normoxic conditions, sickle hemoglobin in SCT erythrocytosis does not polymerize, so how can SCT be linked to adverse outcomes? Hypoxic and/or acidotic conditions, such as in high altitude or in the kidneys, lungs, and muscle after exercise, may be sufficient to promote sickling.⁶  One proposed mechanism of vaso-occlusive events and sudden death in SCT is that high blood lactate levels and red blood cell stiffening during intense exercise may promote sickling and hemolysis.^7,8  However, a study by Laurent A. Meissonier, PhD, and colleagues of 30 adults with SCT in Cameroon found that individuals with the trait exhibited lower blood and muscle lactate concentrations than healthy subjects after short, intense exercise, suggesting some protection from worse outcomes.^9,10  Cycling exercise, but not running, has also been shown to alter blood rheology by affecting red blood cell deformability, hematocrit, and blood viscosity, with variations between athletes and non-athletes at maximal effort. Running showed no significant impact on blood properties in hot environments, while cycling increased viscosity.¹¹  Despite several postulations linking heat, dehydration, and exercise-induced exertion as triggers for sickling in SCT, none of these factors was associated with strong evidence linking SCT to morbidity or mortality.¹² 

After the public outcry surrounding the George Floyd murder and incrimination without a proven mechanism, ASH conducted a systematic review of SCT and exertion-related deaths. Lachelle D. Weeks, MD, PhD, and colleagues, examined whether individuals with SCT experience uncomplicated acute pain episodes and whether physical activity beyond baseline levels is associated with sudden death in those with SCT. Out of the 1,474 citations reviewed, only seven studies met the inclusion criteria, with the remainder excluded due to absence of original data, insufficient laboratory determination of SCT status, or lack of relevant outcomes. Among the seven qualifying studies, four focused on acute pain episodes in individuals with SCT, while the remaining three reported cases of exertion-related death. The four studies suffered from methodological issues and were insufficient to support an association between SCT and vaso-occlusive pain. None of the studies directly compared pain episodes between individuals with SCT and those with SCD, and available case reports lacked sufficient diagnostic clarity.

Furthermore, the review found no reliable evidence linking SCT to sudden unexplained death, except in cases involving exertion-related rhabdomyolysis. A large retrospective cohort study of approximately 48,000 Black military personnel demonstrated that SCT was not associated with an increased risk of death from any cause.¹³  However, it did indicate a higher risk of heat-related rhabdomyolysis. This distinction is critical, as there remains significant confusion regarding the risks associated with SCT. Notably, it is still unclear whether rhabdomyolysis itself is more prevalent in individuals with SCT, with the military study being the only high-quality epidemiological study examining this question. Future efforts should focus on this area rather than perpetuating concerns about “sudden death,” which has disproportionately dominated public discourse without a strong evidentiary basis. The other remaining studies suffered from methodological weaknesses, including inferred diagnoses and conflation of different causes of death. Given the paucity of supporting evidence, the review panel strongly recommended using postmortem findings of sickled erythrocytes as proof of a sickle cell crisis, which can be studied definitively with relative ease. The panel also emphasized the need for listing accurate terminology on the death certificates of individuals with SCT, raising the need for thorough postmortem evaluation for rhabdomyolysis, along with careful consideration of environmental and clinical factors linked to heat-related exertional illness. This review has led to an update of ASH’s position statement on SCT.¹⁴