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Ferrata Storti Foundation
Haematologica 2019 Volume 104(6):1106-1111
The carrier state for sickle cell disease is not completely harmless
Julia Zhe Xu and Swee Lay Thein
Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MA, USA
Introduction
Sickle cell disease (SCD) is a clinical syndrome caused by the presence of hemo- globin S (HbS), in which glutamic acid in position 6 of the b chain of hemoglobin is substituted by valine (bGlu6Val). It is generally recognized as an autosomal reces- sive disorder, in that individuals who have inherited one copy of the HbS allele and one normal HbA allele (i.e. have HbAS or sickle cell trait, SCT), are typically asymptomatic and spared the serious complications associated with possessing two copies of the mutant allele (i.e. HbSS). It is estimated that 300 million people (~5% of the world’s population) carry the HbS allele, and nearly 5.5 million births are affected annually.1
Individuals with SCD die prematurely, but the life expectancy of individuals with SCT is similar to that of people without the trait.2 However, early literature attributed a number of possible disease associations to this heterozygous state, partly as a result of unreliable diagnostic laboratory testing for hemoglo- binopathies and partly due to questionable conclusions drawn from uncontrolled observational studies, individual case reports, and small case series.3,4 Nevertheless, while some of the associations historically attributed to SCT are unfounded, recent meta-analyses found high-quality evidence that SCT is indeed a risk factor for a handful of complications common to SCD.2
Exercise in individuals with sickle cell trait
Sudden death is the most feared complication of SCT. Despite a lack of clear evidence, early concerns about SCT-related sudden death led to the initial adop- tion of universal SCT screening in the 1970s for all United States (US) Armed Forces recruits and mandatory occupational restrictions for those recruits found to have SCT. The complication of sudden death was reinforced in a study in 1987 which evaluated deaths among two million US military recruits during training; African-American recruits with SCT had a 28-fold increase in relative risk [95% confidence interval (CI): 9-100] of sudden unexplained death compared to those without SCT.5 Although the relative risk was seemingly very high, the study was limited by the small absolute number of deaths in each group and its inability to examine separately subsets of sudden unexplained death (cardiac, exertional heat stroke, heat stress, and rhabdomyolysis), which may not share the same disease mechanism. Various other studies have examined physiological responses to exer- cise – e.g. aerobic metabolism, energy expenditure, maximal oxygen consump- tion, and maximal exercise performance – in subjects with HbAS and have found no difference compared to those in subjects with normal HbAA,6-9 even when intravascular sickling in subjects with SCT is observed. Additionally, a recent lon- gitudinal analysis of a large cohort found no association of SCT with fitness, or with the development of hypertension, diabetes, and metabolic syndrome.7
On the civilian side, the sudden death of a college football player during training in 2006 led to a lawsuit whose settlement prompted the National Collegiate Athlete Association (NCAA) to adopt universal SCT screening for incoming Division I athletes in 2010, a policy that was later extended to Division II and III athletes.10 A retrospective analysis of athletes in the NCAA also found a 37-fold increase of exertional death in Division I football players with SCT compared to those without, but again the absolute risk was low.11
A more recent retrospective study of 47,944 black soldiers showed that with adoption of universal preventive measures, the risk of sudden death attributed to SCT appears to be completely mitigated.12 An outcome of these events and reports is the recommendation that preventive measures should be universally adopted to protect all soldiers and athletes, rather than singling out individuals with SCT with mandatory screening practices.4 Indeed, there are a handful of
Correspondence:
SWEE LAY THEIN
sl.thein@nih.gov
Received: February 1, 2019. Accepted: April 29, 2019. Pre-published: May 16, 2019.
doi:10.3324/haematol.2018.206060
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1106
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