Sickle cell disease (SCD) is inherited in an autosomal recessive manner, which means individuals need to inherit 2 copies of the hemoglobin S (HbS) allele to be diagnosed with this disease. An individual with one copy of the HbS allele and a normal HbA allele is considered a sickle cell carrier, or an individual with sickle cell trait.
Conventional wisdom dictates that individuals with sickle cell trait are asymptomatic and therefore live normal lives. In the early stages of our attempts to understand SCD, there were some studies that supposedly demonstrated the association between sickle cell trait and various diseases, but they have mostly been debunked upon further investigation.
However, researchers are now revisiting the issue and taking a closer look at whether sickle cell carriers do indeed suffer from impediments that negatively impact their quality of life. In Haematologica, Xu and Thein wrote, “While some of the associations historically attributed to [sickle cell trait (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.”
Read more about SCD etiology
If scientists have discovered that individuals with sickle cell trait do indeed suffer from health complications, then the scope of sickle cell trait health care would be expanded significantly. The key question here is: is there sufficient research to justify treating sickle cell trait as a pathological condition?
Xu and Thein provided a list of complications believed to be associated with the sickle cell trait:
- A higher incidence of exertion-related sudden death, compared to individuals without sickle cell trait
- Renal complications, such as hematuria and proteinuria
- Thromboembolic events, such as venous thromboembolism and pulmonary embolism.
Medical interest regarding sickle cell carriers is mainly in the realm of reproductive and genetic counseling. The probability of a child born with SCD (inheriting 2 copies of the HbS allele from both parents) is a matter of simple mathematics. The goal of reproductive and genetic counseling is to ensure that individuals who wish to become pregnant are aware of the risks associated if they and/or their partner are sickle cell carriers.
In Blood, Pecker and Naik wrote about the global efforts to educate sickle cell carriers about their reproductive healthcare options. They concluded, “The expansion of SCT screening and education efforts, the availability of reproductive technologies, and the increasing research on clinical complications of SCT have important implications for reproductive and genetic counseling guidelines.”
The Role of High-Intensity Exercise
In Nutrients, Messonnier and colleagues conducted a study on how sickle cell carriers respond to high-intensity exercise. The premise of this study was the unclear relationship between sickle cell trait and exercise intolerance.
“The occurrence of complications, collapse and sudden death during the first 30–60 min following high-intensity exercise demonstrates the need to pay particular attention to this apparently critical postexercise period in SCT carriers,” the authors of the study wrote.
One possible route to pathology in sickle cell carriers is the triggering of the polymerization-sickling-vaso-occlusion cascade, which causes accumulation-associated acidosis in response to high-intensity exercise.
To carry out their study, the research team recruited 30 male sickle cell carriers. The participants were instructed to carry out a graded exercise test using a leg-cycle ergometer. “The exercise stopped at volitional exhaustion, ie, when the subjects were no longer able to sustain the work rate at the required pedaling frequency of 70 rpm,” the authors of the study explained.
Read more about SCD patient education
At the end of the study, blood and muscle lactate concentrations were measured. Biopsies of the vastus lateralis muscle were extracted for additional biochemical tests.
The results demonstrated that the muscle content of lactate transporter MCT4 in sickle call carriers was higher, compared to the 15-member control group. This is significant as MCT4 is the main pathway by which lactate is released from the muscles. Meanwhile, the muscle content of β2-adrenergic receptors in sickle cell carriers was lower compared to controls.
The researchers also discovered that lactate removal was more efficient among sickle cell carriers during the recovery period. All this suggests that sickle cell trait is, to some extent, protective of exercise-related acidosis and subsequent sickling, as well as “the deleterious effects of intracellular lactate and associated acidosis on muscle function,” they wrote.
A Causal or Incidental Relationship?
In a way, the conclusion of this study raises more questions than it answers; it brings us no closer to the truth on why some reports suggest that exertion-related sudden death is higher among sickle cell carriers than in the general population. On the other hand, we must remember that “various other studies have examined physiological responses to exercise . . . in subjects with HbAS and have found no difference compared to those in subjects with normal HbAA,” wrote Xu and Thein.
We can therefore summarize our current understanding of sickle cell trait in this manner: we currently have data that reasonably demonstrates the possibility that sickle cell carriers experience health complications at a higher rate than the general population, but more research is needed to establish whether this relationship is truly causal (or merely incidental). We also need a better grasp of the biological mechanisms at work in sickle cell carriers, including when it comes to exercise.
Meanwhile, caution is our best defense, and health conditions in sickle cell carriers should be adequately treated, regardless of whether they are finally linked to the HbS allele or not.
Pecker LH, Naik RP. The current state of sickle cell trait: implications for reproductive and genetic counseling. Blood. 2018;132(22):2331-2338. doi:10.1182/blood-2018-06-848705
Xu JZ, Thein SL. The carrier state for sickle cell disease is not completely harmless. Haematologica. 2019;104(6):1106-1111. doi:10.3324/haematol.2018.206060
Messonnier LA, Oyono-Enguéllé S, Vincent L, et al. Lower muscle and blood lactate accumulation in sickle cell trait carriers in response to short high-intensity exercise. Nutrients. 2022;14(3):501. doi:10.3390/nu14030501