September 12, 2024) The risk of venous thromboembolism (VTE), or blood clots, in individuals with sickle cell trait (SCT) is higher than in individuals without the trait. However, the risk is lower than for those with heterozygous factor V Leiden (FVL), according to a study published today in Blood Advances that analyzed genetic data from 23andMe research participants.
More than 100 million people worldwide and approximately 7% of Black individuals in the United States have SCT. Unlike sickle cell disease, which occurs in patients with two genes that cause abnormalities in the production of hemoglobin - the oxygen-carrying substance in red blood cells - individuals with SCT carry only one sickle hemoglobin gene and typically lead normal lives.
Although SCT is generally asymptomatic, it is a risk factor for some complications, including VTE, which manifests either as deep vein thrombosis (DVT), when a blood clot forms in the deep veins, or pulmonary embolism (PE), when a blood clot blocks an artery in the lung. In both cases, VTE can be life-threatening. However, VTE is not a risk unique to SCT; it can be triggered by surgery or major injury, and it is also associated with heterozygous FVL, the most common inherited blood-clotting disorder, which is caused by one defective factor V gene.
"SCT is erroneously associated only with Black individuals, even though it is found in very diverse populations," said study author Rakhi Naik, MD, MHS, associate professor of medicine at Johns Hopkins University. Dr. Naik added that this association is in part attributable to SCT research having been conducted solely in Black individuals. "When we do research within a specific population, we often make the incorrect assumption that the genetic trait is found only in that population, even though it is found quite broadly," she said.
This means that providers may omit FVL testing in Black patients with VTE, while testing for SCT is often limited to Black patients only. In combination with systemic racism, the association of SCT solely with Black individuals has led to general misinformation as well as over-attribution to systemic disease. As a result, Black individuals with SCT have historically faced employment and insurance discrimination; however, new genetic testing technology and a greater recognition of the inequities that accompany race-based research have given rise to easier, more affordable analysis of large, diverse SCT sample sizes.
In partnership with a research team led by Keng-Han Lin, PhD, senior statistical geneticist at 23andMe, Dr. Naik and her colleagues sought to contextualize the risk of VTE in SCT, irrespective of race or ethnicity, by comparing it to the risk associated with FVL, a condition with a known risk factor for VTE. In the largest study to date on SCT and blood clots, the researchers leveraged DNA samples from 4,184,082 participants from the 23andMe research cohort ages 18-100 with self-reported data on VTE, DVT, and PE.
Overall, the prevalence of SCT in the study cohort was 0.46% (19,055), with the highest prevalence observed in individuals with African ancestry (7.02%), Latine ancestry (0.67%), and South Asian ancestry (0.16%). In comparison, the overall prevalence of FVL was 4.45% (186,277), with the highest prevalence observed in individuals with European ancestry (5.19%), Latine ancestry (2.83%), and South Asian ancestry (2.55%).
A history of VTE was reported by 2.57% of individuals with SCT compared to 2.25% of individuals without SCT, while a history of VTE was reported by 6.93% of those with FVL compared to 2.04% of those without FVL.
After meta-analysis, the researchers found that independent of race or ancestry, the risk of VTE in individuals with SCT was 1.45 times that of those without SCT. However, this is lower than the risk associated with individuals with FVL, who have 3.35 times the risk of those without the disorder. Furthermore, they found that PE (1.58% of those with SCT vs. 0.90% of those without) was the most common manifestation of VTE in those with SCT, whereas DVT (4.59% vs. 1.21%, respectively) was the most common manifestation in those with FVL.
"We were able to show a PE-predominant pattern of blood clots for those with SCT, and our study was able to demonstrate this pattern with statistical significance, which has never been done before," Dr. Naik said. "This points to a unique mechanism of clotting in SCT, which warrants further research." The researchers want to see better contextualization of the risk of VTE in people with SCT so that it can inform clinical practice guidelines and minimize unintended bias.
"Very few clinicians know how to counsel someone with SCT," said Dr. Naik. "This study shows that SCT in itself is not a disease. It's a risk factor like FVL, and the risk is still very small."
"I hope this study informs health professionals, particularly hematologists, that when thinking about risks related to SCT, they need to be looking at all populations, not just one group," said study author Vence L. Bonham Jr., JD, acting deputy director of the National Human Genome Research Institute. "SCT is understudied, and this is an area of opportunity for more research, particularly for other studies with large sample sizes."
This study had several limitations, primarily the inclusion of self-reported data on DVT and PE phenotypes, as well as provoking factors. Additionally, the researchers did not have genotypic data on alpha-thalassemia, which can modify phenotype in SCT.
