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Testing for performance-enhancing drugs is expected by elite athletes as they arrive in Paris for the 2024 Olympic Games, but what happens if a red-flag result for doping isn't one at all?

This appeared to be the case for two athletes whose previous doping allegations -- and contrasting findings years later -- were detailed by François Girodon, MD, PhD, of Université de Bourgogne in Dijon, France, and colleagues in a research letter published .

Suspicion in these cases centered on high levels of hemoglobin and hematocrit in both a teenage soccer player and top-level Taekwondo athlete.

At issue is the notion that an individual who has more red blood cells and more hemoglobin, and who is carrying more oxygen around their body as a result, could have an advantage as an athlete, Charles Abrams, MD, of the University of Pennsylvania in Philadelphia, who is a member of the American Society of Hematology, told 番茄社区app.

In the cases of the male soccer player and the female Taekwondo athlete, hemoglobin levels were recorded at 20.3 g/dL in the former and 17.4 g/dL in the latter, compared with a normal range for adults of 13.0 to 17.0 g/dL in males and 11.5 to 16.0 g/dL in females, Girodon and colleagues reported.

Additionally, hematocrit levels were measured at 56.7% in the soccer player and 51% in the Taekwondo athlete, compared with a normal range for adults of 40% to 54% in males and 37% to 47% in females.

Ultimately, doping was alleged, with consequences in both cases.

"Among classic doping products used in endurance sports, erythropoietin (EPO) drug, the biological copy of the main EPO hormone responsible for substantial increases in hemoglobin concentration and hematocrit, is one of the originals, both in terms of its age (available since the 1980s) and frequency of use (61 doping cases worldwide in 2022)," Girodon and colleagues wrote.

But there may be other reasons for high hemoglobin and hematocrit levels, they said.

In the case of the soccer player, who had applied to enter a sports-study high school, his application was rejected, and he was banned from competition when a doctor suspected doping. However, 18 years later, the athlete's son was diagnosed with polycythemia, a high red blood cell count, suggesting a familial condition.

Blood samples from the father and son were analyzed using next-generation sequencing with a gene panel specific to the study of polycythemia. A pathogenic mutation in the EPAS1 gene, which "encodes the hypoxia-inducible factor HIF2α, which regulates the expression of EPO when oxygen concentrations go down," was identified in the athlete and his son, as well as in three other relatives.

In the second case, the national Taekwondo athlete was also banned from competition after a routine examination. But 10 years later, her sister was referred to the hospital for absolute idiopathic polycythemia.

Subsequent sequencing of hypoxia-regulating genes revealed a pathogenic mutation in the EGLN1 gene, which "encodes the PHD2 protein, which plays a major role in the degradation of HIF2α," in the athlete and her sister, as well as in three other relatives.

"These mutations that they described are very rare. But if you start looking for them, you will find them," Abrams said.

For example, patients who were known to have lifelong high hemoglobin levels, and who tested negative for a malignant disease, have made their way to Abrams on occasion, he said, adding that there are a number of genes that can create this anomaly, and blood samples can be sequenced to determine which one is the cause.

"I would say the majority of hematologists have never seen a case like this," he said, but it has become much easier to identify these cases. This type of sequencing was "unheard of 20 years ago," he pointed out.

Notably, mutations in the EPO receptor gene, EPOR, were discovered in the 1990s, with the first mutation identified in Eero Mäntyranta, a Finnish cross-country skier who won multiple Olympic and world champion medals, Girodon and colleagues said.

As for the soccer player and the Taekwondo athlete, their cases may have had different outcomes today.

"Although these two case reports sadly emphasize the difficulties in the past to differentiate blood doping from atypically high [hemoglobin], they also show how progress in science, in particular genetic analyses, can now bring answers to uncommon cases," the authors wrote.

Abrams concurred, noting that the benefits of this progress extend to patients more broadly.

"The ability to sequence genes and understand what is causing the person's underlying disease has been a revolution in medicine," he said.

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