Death Not Due to Vaso-occlusion in Sickle Cell Trait

Source: Weeks LD, Wilson AM, Naik RP, et al. Sickle cell trait does not cause “sickle cell crisis” leading to exertion-related death: a systematic review. Blood. 2025;145(13):1345-1352; doi: 10.1182/blood.2024026899.A panel of investigators from multiple institutions was convened by the American Society of Hematology to conduct a systematic review to evaluate whether, compared to those with sickle cell disease (SCD), individuals with sickle cell trait (SCT) have uncomplicated acute vaso-occlusive (pain) crises, and if individuals with SCT are at increased risk form sudden death associated with physical activity. A comprehensive process was used to identify relevant publications. When identifying studies on uncomplicated vaso-occlusive crises, reports in which the authors reported on complicated pain conditions involving organ infarction, abdominal pain due to splenic sequestration, and rhabdomyolysis were excluded because these typically are not observed in patients with SCD who have uncomplicated vaso-occlusive crises. For included studies, the certainty of the evidence was systematically assessed using the Grading of Recommendations, Assessments, Development, and Evaluation (GRADE) guidelines.Among 1,471 initially identified studies, 7 met criteria for the systematic review. The main reasons for exclusion included lack of laboratory data to confirm the diagnosis of SCT, missing outcomes of interest, and reporting only on abdominal pain that may have been related to splenic infarction or sequestration. There were no included studies directly comparing uncomplicated vaso-occlusive crises among individuals with SCT or SCD. There were 4 studies which purported to describe SCT-related, uncomplicated, acute pain crises. The studies lacked a clear diagnosis of SCT associated with a clear description of an acute pain crisis. Overall, the certainty of evidence in the 4 studies was considered to be very low. Three studies evaluating the risk of sudden death while participating in physical activity among individuals with SCT were included in the systematic review. Assessment of the results in 2 of the studies was complicated by significant methodologic flaws. In the remaining study, the rate of death from any cause was compared in 47,944 Black soldiers with, or without, laboratory-confirmed SCT. No increased risk death was found among those with SCT (hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.46, 2.13). There also was no increased risk of battle-related death among soldiers with SCT (HR, 0.96; 95% CI, 0.13, 7.3). Compared to those without SCT, soldiers with SCT were found to be at increased risk of heat-related exertional rhabdomyolysis (HR, 1.54; 95% CI, 1.12, 2.12). Considering all the included studies, the certainty of evidence that SCT was associated with an increased risk of sudden death associated with physical activity was judged to be low.The authors conclude that no evidence was found to support the diagnosis of acute vaso-occlusive crisis as a cause of death in individuals with SCT.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.SCT, caused by heterozygous inheritance of 1 sickle beta-globin and 1 normal beta-globin allele, is found in approximately 300 million people worldwide.1 SCT is detected on US newborn screening as an FSA or FAS pattern (found in 15.5 per 1,000 newborns) and confirmed by hemoglobin electrophoresis with Hb S concentration between 25% and 45%.2 Unlike SCD, SCT is not associated with chronic hemolysis, nor increased risk of heart failure, stroke, arterial disease, poor growth/development/fitness, respiratory issues, premature death, or vaso-occlusive painful episodes.3Rarely, under conditions of hypoxia, dehydration, acidosis, or hyperthermia, adolescents and adults with SCT have a 1.4- to 4-fold increased relative risk for chronic kidney disease, venous thromboembolism, and heat- or exertion-related illness.1-3 Other increased risks reported include renal medullary carcinoma, high-altitude splenic infarct, and injury-related glaucoma post-hyphema.1-3 Some HbA1c test methods result in falsely high or low values in individuals with SCT.4The current researchers sought to clarify whether exertion-related deaths are due to a “sickle cell crisis” in individuals with SCT.5 Few publications were analyzed, because many lacked direct evidence of SCT, non-SCT comparison groups, and physical activity intensity. Since reports of heat- and exertion-related rhabdomyolysis in college athletes and military trainees have become more prevalent, parents of infants with SCT have received education about acclimatization to high altitude, heat, humidity, and heavy exercise.6 Hematologists suggest revisiting education for adolescents with SCT by addressing hydration, blood pressure monitoring, and weight management while reminding them to seek medical evaluation for hematuria, eye trauma, flank pain, muscle pain, cramping, weakness, and overheating.7SCT is not associated with death due to vasoocclusive sickle cell crises or exertion-related death without rhabdomyolysis. (See AAP Grand Rounds. 2019;41[3]:33.)8