Sickle Cell Trait Widely Misinterpreted As Cause of Death

Contrary to misconceptions among medical professionals and patients alike, individuals born with sickle cell trait (SCT) show no risk of experiencing the acute pain crises known to occur with sickle cell disease (SCD), nor is SCT a valid cause of death, a systematic review concluded.

“To date, this is the most authoritative and definitive systematic review on this subject,” said study author Michael R. DeBaun, MD, MPH, professor of pediatrics and medicine at Vanderbilt University School of Medicine, Nashville, Tennessee, in a press statement for the review published in the journal Blood.

“This review shows that any primary, secondary, or tertiary cause of death attributable to sickle cell trait is not a diagnosis substantiated by the medical evidence,” said DeBaun, who is also founder and director of the Vanderbilt-Meharry Sickle Cell Disease Center of Excellence.

Based on the review’s results, the American Society of Hematology (ASH) updated its position statement regarding sickle cell trait to conclude that “listing ‘sickle cell crisis’ or ‘sickle cell trait’ as a cause of death on an autopsy report for an individual with sickle cell trait is medically inaccurate and without medical evidence of causation.”

Commenting on the update, ASH president Belinda Avalos, MD, emphasized that “sickle cell trait has long been misunderstood, fueling widespread misinformation and medically inaccurate claims that it can lead to sudden death.”

“This misconception has been especially prominent in cases of Black men with sickle cell trait,” she said in a press statement.

Unlike SCD, SCT Typically Lacks Symptoms

Individuals with SCD are born with two copies of the sickle cell gene, causing their blood cells to be misshapen, and ‘sickle-like,’ impeding blood flow. The disease is characterized by episodes of severe pain, often referred to as acute vaso-occlusive pain crises, and patients can have a potentially shortened lifespan.

In contrast, with SCT, individuals inherit only one sickle cell gene; they are generally asymptomatic and do not have a risk of going on to develop SCD.

SCT is much more common than SCD, occurring in about one of every 13 African Americans, or 8%-10%, compared with sickle cell disease, which affects about 1 out of every 365 African Americans. While newborns in the United States are routinely screened for sickle cell trait, many adults carrying the trait aware of their status, DeBaun said in an interview.

A key concern with the widespread lack of awareness of the differences between the 2 etiologies is the misattribution of “sickle cell crisis” as being a cause of death among people with SCT.

While research has shown that some people with SCT do have a higher risk for rhabdomyolysis, a serious medical condition in which skeletal muscle breaks down, either from exertion or traumatic injury-related causes, among those who die from the condition, “the sickle cell trait is not the cause of death; the cause of death is the muscle injury leading to rhabdomyolysis and the sequelae,” ASH explains in the position statement.

That misunderstanding has had important implications for athletes, military personnel, and individuals in police custody.

Incidents involving the latter were detailed in a 2021 New York Times investigation, uncovering at least 46 instances over 25 years in which “medical examiners, law enforcement officials or defenders of accused officers pointed to sickle cell trait as a cause or major factor in deaths of Black people in custody.”

Approximately two thirds of those cases involved forceful restraint, pepper spray or use of stun guns by authorities, and “the determinations of sickle cell trait often created enough doubt for officers to avert criminal or civil penalties,” the New York Times reported.

Systematic Review Evaluates Pain Crises, Sudden Death

To assess and clarify the evidence surrounding SCT, DeBaun and a panel of hematology and forensic pathology experts were assembled by ASH to conduct the systematic review focusing on two key questions: Whether uncomplicated acute pain crises occur in people with SCT and whether physical activity above baseline results in sudden death among those individuals.

Of 1474 citations identified in a search of studies on SCT and pain crises or mortality, only seven had original data, included laboratory testing for SCT in individuals, and addressed the two primary research questions.

None of the studies assessed acute pain crises in individuals with SCT compared with those with SCD.

One study described death in individuals reported to have SCT — a trial involving 47,944 Black soldiers identified in the Stanford Military Data Repository between January 2011 and December 2014, who had laboratory confirmation of SCT. 

That study did find that SCT was associated with a higher risk for heat-related-exertional rhabdomyolysis, (hazard ratio [HR], 1.54, P = .008).

Comparatively, the risk was similar to that of smokers and having obesity (body mass index 30 or higher); however, the risk was substantially lower than that of people on statins or on antipsychotic medications, which each were associated with nearly tripling the risk for exertional rhabdomyolysis (HR, 2.89 and 3.02, respectively).

Importantly, the study showed no increased risk in death from any cause among those with SCT vs the those without SCT, including in terms of death from battle or non–battle-related causes.

Sickled Cells on Autopsy Not a Sign of Death From SCT

The review also found that several studies incorrectly concluded that the presence of sickled blood cells at autopsy was evidence of death by acute pain crisis in individuals with SCT, with none showing any clinical evidence of an acute pain crisis immediately before death.

In its position statement, ASH underscores that such post-mortem sickling is not uncommon in SCT, and “is frequently likely to be observed on autopsy because lack of obligatory oxygen after death,” they explain. “Therefore, postmortem sickling and sickled red blood cells seen after death are not medical evidence of a sickle cell crisis as a primary or secondary cause of death.”

Taken together, the findings demonstrate that “in individuals with sickle cell trait, the likelihood of sickle cell trait alone or pain crises being the root cause of sudden death is medically impossible,” DeBaun said.

Military, Athlete, and Stem Cell Transplant Implications

In a recent editorial in the New England Journal of Medicine, the troubling consequences of misinterpreting risks of SCT are further detailed.

In basic training, for instance, the US Air Force requires recruits with SCT to wear red dog tags, while Navy recruits wear a red belt, but do not have such requirements for people who smoke — despite their similar risk, and those on statins, despite their significantly higher risk for rhabdomyolysis.

“We are unaware of another genetic condition or carrier state that comes with a similar possibility of public identification,” wrote the editorial authors, led by Brian J. Carney, MD, of the Division of Hematology and Hematologic Malignancies and the Department of Pathology, at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.

Key measures Carney and colleagues recommend include better addressing inequitable SCT-related policies in advocacy as well as improving undergraduate and graduate medical education programs that address SCT knowledge gaps. 

“My colleagues are I are working on this,” he said in an interview. “We are in the process of conducting a national educational needs assessment survey to determine how well healthcare equity issues are covered in graduate medical training (residency and fellowship).”

While agreeing that the updated ASH position statement is encouraging, Carney underscores the need to extend the awareness to medical examiners.

“I think that a strong position from ASH has the potential to be impactful, but only if there is continued advocacy on the part of ASH and other organizations, [such as] the National Association of Medical Examiners,” he said.

The authors Carney and Thompson had no disclosures to report.