Sickle cell trait increases risk for rhabdomyolysis, not death

Sickle cell trait significantly increased the risk for exertional rhabdomyolysis, but not the risk for death, according to a study of active-duty soldiers published in The New England Journal of Medicine.

Sickle cell trait — a condition in which individuals are heterozygous for the sickle cell mutation in the beta-globin gene — has been attributed as a potential cause of rhabdomyolysis and death in a number of cases.

“There was a concern that individuals with sickle cell trait were at a higher risk for exertion-related collapse and death,” Lianne M. Kurina, PhD, associate professor of medicine at Stanford University School of Medicine and director of the Stanford Military Data Repository, told HemOnc Today. “Our observation of no difference in the risk for death among African American U.S. Army soldiers with sickle cell trait contradicts the past literature, which is dominated by case reports and case series of exertion-related deaths among athletes and warriors with sickle cell trait. Two past population-based studies reported very high increases — between 20- and 30-fold —in the risk for sudden death or exertion-related death.”

Kurina and colleagues used the Stanford Military Data Repository — which includes comprehensive medical and administrative data on active-duty military personnel — to identify 47,944 active-duty soldiers who underwent hemoglobin AS laboratory tests between January 2011 and December 2014.

Because sickle cell trait predominates in individuals of African ancestry. all included data were taken from soldiers who self-identified as black or African American.

The researchers used these data to study the relationship between sickle cell trait, exertional rhabdomyolysis and death.

The analysis controlled for potential known risk factors, including age; sex; physical fitness level; BMI; and self-reported use of tobacco, statins, antipsychotic drugs or stimulants.

The researchers observed 391 exertional rhabdomyolysis events during the course of the study. Events occurred significantly less frequently among women (HR = 0.51; 95% CI, 0.38-0.67).

The risk for exertional rhabdomyolysis events significantly increased with age. Soldiers aged 36 years or older had a 57% higher risk for events than their younger counterparts (HR = 1.57; 95% CI, 1.06-2.32).

Greater exertional rhabdomyolysis risk also occurred among obese individuals (HR = 1.39; 95% CI, 1.04-.186) and soldiers who reported tobacco use in the previous 6 months (HR = 1.54; 95% CI, 1.23-1.94), suggesting that modifiable factors can contribute to risk. The researchers further observed significant risk increases among recent users of antipsychotic medications (HR = 3.02; 95% CI, 1.34-6.82) and statins (HR = 2.89; 95% CI, 1.51-5.55).

Researchers identified sickle cell trait in 7.4% (n = 3,564) of the study population. Its presence was associated with a 54% increased risk for exertional rhabdomyolysis (HR = 1.54; 95% CI, 1.12-2.12).

A total of 96 deaths occurred (sickle cell trait, n = 7; no sickle cell trait, n = 89). The researchers observed no significant association between the presence of sickle cell trait and death (HR = 0.99; 95% CI, 0.46-2.13).

Fourteen deaths were classified as battle related (sickle cell trait, n = 1; no sickle cell trait, n = 13); the remaining deaths were not considered related to battle (sickle cell trait, n = 6; no sickle cell trait, n = 76). Records of the six participants with sickle cell trait who died of non–battle-related causes showed diverse medical histories that included cancer, substance abuse, mental disorders, heart disease and postoperative complications.

One soldier with exertional rhabdomyolysis died; however, this individual did not have sickle cell trait.

The researchers acknowledged several study limitations, including the U.S. Army’s lack of universal testing for sickle cell trait among black soldiers. They also noted that they could not fully control for participants who may have had an exertional rhabdomyolysis event prior to January 2011, and that health records used in the study may be open to coding errors or bias.

“It is true that sickle cell trait was associated with an increased risk for exertional rhabdomyolysis in our study, although that increase was comparable in size to that associated with obesity and tobacco use and smaller than the risks seen with some prescription medicines,” Kurina said. “We think that it will be important to repeat our study in different populations, such as other military branches or among athletes, to maximize our understanding of the impact of sickle cell trait on exertion-related outcomes in physically active populations.” – by Cameron Kelsall

For more information:

Lianne M. Kurina, PhD, can be reached at lkurina@stanford.edu.

Disclosure: Kurina reports grant support from the NHLBI during the conduct of this study. Please see the full study for a list of all other researchers’ relevant financial disclosures.