ASH Position on Sickle Cell Trait

May 25, 2021

ASH Position

It is medically inaccurate to claim sickle cell crisis as the cause of death based solely on the presence of sickled cells at autopsy. Sudden death is an extraordinarily rare occurrence in sickle cell trait and the finding of sickle cell trait is unlikely to supersede other inflicted traumas as the cause or major factor in death. Millions of American men, women and children with sickle cell trait lead normal, healthy lives, and there have been no well-controlled studies on collapse due to exertion that would provide evidence to cite sickle cell trait as a cause of death. Because of the rarity of sudden death in persons with sickle cell trait, cases where this is cited as the sole cause of death, or a major contributor must be viewed with profound skepticism.

Background

The American Society of Hematology (ASH) represents approximately 18,000 physicians, scientists, and medical trainees committed to the study and treatment of blood and blood-related diseases. ASH members include clinicians who specialize in treating children and adults with sickle cell disease (SCD) and researchers who investigate the causes and potential treatments of SCD manifestations.

Sickle cell disease is an inherited blood disorder that affects 80,000 to 100,000 Americans, mostly but not exclusively of African ancestry. Sickle cell disease requires inheritance of two variants of the HBB gene which results in production of abnormal hemoglobin. The sickle variant of hemoglobin causes severe anemia, pain, other devastating disabilities, and, in some cases, premature death.

In contrast to sickle cell disease, patients with sickle cell trait inherit one variant of the HBB gene and one normal copy. Sickle cell trait affects hundreds of millions of people worldwide and millions of Americans – including 8 to 10 percent of all Black/African Americans. Individuals with sickle cell trait do not have sickle cell disease nor will they develop this condition. Their hemoglobin is predominantly normal. Therefore, these individuals do not have the classic clinical manifestations of sickle cell disease and most will enjoy normal life spans without serious health consequences.

Under normal conditions, sickle hemoglobin can be detected in patients with sickle cell trait, but is clinically insignificant. Complications experienced by persons with sickle cell trait have largely been described in case reports and series. Prospective, hypothesis-driven studies are limited; however, hypothesis-driven retrospective studies are increasingly being performed. Rarely, clinical issues such as exertional rhabdomyolysis (the rapid breakdown of skeletal muscle due to injury to muscle tissue) have been reported in individuals with sickle cell trait. These incidents have generally occurred under extreme conditions such as severe dehydration and high intensity physical activity.

Regarding sudden death, reports from the 1970s described increased mortality among athletes and military recruits with sickle cell trait because of strenuous exercise, dehydration, and high altitude (Jones 1970). However, it has been noted that these deaths occurred in conjunction with rhabdomyolysis (Harrykisson 2007), renal failure, heat stroke, disseminated intravascular coagulation and cardiac arrythmia (Kark 1987; Mitchell 2007; Thogmartin 2011).

Recently, a cohort study including 5 large, prospective, population-based cohorts found no association between sickle cell trait and increased risk of myocardial infarction or coronary heart disease in African American individuals and concluded that these disorders may not be associated with sickle cell trait-related sudden death in this population (Hyacinth 2021). A retrospective cohort study evaluating African American U.S. Army soldiers with sickle cell trait between January 2011 and December 2014 using the Stanford Military Data Repository found that sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis (Nelson 2016). A retrospective cohort using the Department of Defense Military Healthcare System Database examined active-duty personnel enlisted from 1992 to 2012 found that service members with sickle cell trait had no difference in crude mortality compared to sickle cell trait negative service members (Singer 2018). A systematic review of clinical outcomes associated with sickle cell trait evaluated observational controlled studies in children or adults that examined an association between sickle cell trait and clinical outcomes, including overall mortality (Naik 2018). None of the five studies which assessed overall mortality found an association between sickle cell trait and mortality.

Regarding non-military related exertion, individuals with sickle cell trait are not disqualified from competitive sports. The NCAA acknowledges that sickle cell trait is not a disease and is not a barrier to playing competitive sports (NCAA Sport Science Institute 2021). A scientific statement from the American Heart Association and American College of Cardiology notes sickle cell trait status is not itself a justification for disqualification from competitive sports (Maron 2015). ASH continues to hold the position that universal interventions to reduce exertion-related injury and death is effective for all athletes including those with sickle cell trait (ASH Statement on Screening for Sickle Cell Trait and Athletic Participation).

Under extreme instances of tissue hypoxia, such as on a post-mortem examination, it is not uncommon to observe a varied degree of sickled red cells in patients with sickle cell trait. It is not possible at autopsy to determine the percent of red blood cell sickling which occurred prior to death (Thoreson 2014; Kark 1987; Goldsmith 2012). The detection of red cell sickling in sickle cell trait in vitro (Bookchin 1976; Noguchi 1981), in vivo (Martin 1989), and post-mortem at autopsy is, alone, insufficient to label sickle cell trait as a cause of death, particularly given the rarity of reported deaths due to sickle cell trait.

References:

  1. American Society of Hematology Statement on Screening for Sickle Cell Trait and Athletic Participation
  2. Bookchin RM, Balazs T, Landau LC. J Lab Clin Med. 1976 Apr; 87(4):597-616
  3. Harrykisson RI et al. Chest. 2007 132(4), Supplement, 673A
  4. Hyacinth HI et al. JAMA 2021 Jan 4;4(1):e2030435
  5. Jones et al. NEJM 1970 10.1056/NEJM197002052820607
  6. Kark JA et al. N Engl J Med. 1987 Sep; 317:718-787
  7. Maron BJ et al. Circulation. 2015. 132:e343-e345
  8. Martin TW et al. AM J Med. 1989; 87(1):P48-56
  9. McCormick WF. Am J Med Sci. 1961 24:329
  10. Mitchell BL et al. J Natl Med Assoc. 2007; 99(3):300-305
  11. NCAA Sport Science Institute Webpage Accessed 5/23/2021
    https://www.ncaa.org/sport-science-institute/sickle-cell-trait
  12. Nelson DA et al. N Engl J Med. 2016; 375:435-442
  13. Naik RP et al. Ann Intern Med. 2018 Nov 6, 169(9): 619-627
  14. Noguchi CT, Torchia DA, Schechter AN. J Biol Chem. 1981 May; 256(9):4168
  15. Singer DE et al. Mil Med. 2018 Mar-Apr; 183(3-4):e213-e218
  16. Thogmartin JR et al. J Forensic Sci. 2011 Sep; 56(5):1352