A comprehensive review of existing literature has revealed no proof that physical activity, in the absence of rhabdomyolysis (muscle breakdown) or heat injuries, can lead to sudden death in individuals with sickle cell trait (SCT). Additionally, there is no robust evidence linking SCT to acute pain crises. These findings were published today in the American Society of Hematology’s main journal, Blood, and have contributed to the Society’s updated stance on SCT.
A comprehensive review of existing literature has revealed no proof that physical activity, in the absence of rhabdomyolysis (muscle breakdown) or heat injuries, can lead to sudden death in individuals with sickle cell trait (SCT). Additionally, there is no robust evidence linking SCT to acute pain crises. These findings were published today in the American Society of Hematology’s main journal, Blood, and have contributed to the Society’s updated stance on SCT.
“SCT has faced many misconceptions, leading to misleading information and false medical claims regarding its potential to cause sudden death. This misunderstanding has often been highlighted in cases involving Black men with SCT,” stated Belinda Avalos, MD, president of ASH. “Due to the harmful and widespread nature of this myth, the Society is committed to sharing accurate information to protect and empower the communities affected.”
People with SCT carry one copy of the gene linked to sickle cell disease (SCD). SCD is a blood disorder marked by irregularly shaped blood cells that can lead to blockages, resulting in infections and acute episodes of severe pain, known as acute pain crises. In contrast, SCT, which impacts over 100 million individuals globally—including 8 to 10% of Black Americans—is not classified as a disease. Those with SCT do not progress to SCD and typically do not face any related health issues.
“This is the most authoritative and comprehensive systematic review conducted on this topic to date,” remarked Michael R. DeBaun, MD, MPH, a professor at Vanderbilt University School of Medicine and the founding director of the Vanderbilt-Meharry Sickle Cell Disease Center of Excellence. “The review indicates that attributing any primary, secondary, or tertiary cause of death to SCT lacks medical evidence.”
ASH brought together a panel of experts, including hematologists and forensic pathologists, to thoroughly examine all available research to address two main questions: 1) Do uncomplicated acute pain crises occur in individuals with SCT? and 2) Can physical activity beyond normal levels lead to sudden death in these people?
The panel conducted a search of multiple databases for English-language studies concerning SCT, pain crises, or mortality, yielding 1,474 potential citations. However, only seven studies provided original data, included lab tests for SCT in subjects, and answered the two primary research questions.
Among these studies, none compared the incidence of acute pain crises in individuals with SCT to those with SCD, and only one reported on fatalities in people identified as having SCT. This study focused on active-duty U.S. soldiers and found that SCT was linked to an increased risk of heat-related rhabdomyolysis but not to an elevated risk of death from any cause. After implementing measures to prevent heat and environmental injuries, the risk of death among individuals with SCT was similar to those without SCT.
“In the absence of two medical conditions—exertional rhabdomyolysis or crush injuries leading to rhabdomyolysis—individuals with SCT do not have an increased risk of sudden death. Even in extreme environmental conditions, unexplained sudden deaths cannot be ascribed to SCT,” Dr. DeBaun emphasized. Collectively, these findings indicate that “in individuals with SCT, it is medically impossible for SCT alone or related pain crises to be the primary cause of sudden death,” he added.
During the review, experts came across multiple studies where the presence of sickled cells at autopsy was used as evidence for death due to acute pain crises in individuals with SCT. However, they failed to find any human data supporting this theory or sufficient clinical descriptions to establish that an acute pain crisis occurred just before death.
“In medicine, even post-mortem, it is essential to base our findings on scientific evidence,” explained Lachelle D. Weeks, MD, PhD, an assistant professor at Harvard Medical School and a physician-scientist at Dana-Farber Cancer Institute. “Our diagnoses need to be valid and grounded in medical evidence. Given this study’s results, we must ensure that post-mortem examinations look for signs of rhabdomyolysis or other medical or traumatic causes for death.”
The review faced limitations, particularly a shortage of high-quality, peer-reviewed direct evidence. To address this, experts were encouraged to consider indirect evidence while evaluating abstracts and assessed evidence based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework. Nevertheless, due to the lack of data, the experts hope this review will stimulate further research on SCT.
As a result of this study, ASH has updated its position statement on SCT, asserting that noting “sickle cell crisis” or “sickle cell trait” as causes of death on autopsy reports for individuals with sickle cell trait is medically incorrect and lacks supporting medical evidence for causation.
