Elevated levels of hormone EPO tied to risk of blood clots in SCD: Large study
Researchers also identified EPOR protein as potential therapeutic target
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Higher blood levels of erythropoietin (EPO), a hormone that stimulates the production of red blood cells, increase the risk of blood clot-related, or thrombotic, events in people with sickle cell disease (SCD), according to a study involving more than 500 patients.
Researchers also discovered a relationship between the production of the EPO receptor (EPOR) protein and blood EPO levels, suggesting that EPOR may be a therapeutic target for preventing abnormal blood clotting in SCD.
“Our study indicates that higher [blood] EPO concentration associates with [thrombotic] risk in SCD and reveals a novel role of EPOR … variation in modulating EPO concentration and, possibly, [thrombotic] risk in this condition,” the scientists wrote.
The study, “Circulating erythropoietin concentration associates with thromboembolism in sickle cell disease,” was published in the British Journal of Haematology.
Sickle cell patients produce more EPO
SCD is an inherited disease marked by sickled red blood cells that die much more quickly than healthy cells, leading to a shortage of red blood cells (a condition called anemia). As a result, oxygen delivery to the body’s tissues is compromised, causing symptoms such as fatigue, shortness of breath, and dizziness.
To compensate for anemia and chronically low oxygen levels, people with SCD produce more EPO, a hormone primarily secreted by the kidneys that stimulates the bone marrow to produce red blood cells.
While high EPO levels have been linked to increased thrombotic risk in other conditions, it’s not clear whether this risk applies specifically to SCD.
“Improved understanding of EPO regulation and its impact on thrombotic risk may facilitate therapeutic innovation,” wrote a team led by scientists at the University of Illinois at Chicago (UIC) who designed a study to address this knowledge gap.
Elevated EPO levels associated with 60% higher risk of blood clotting
Researchers examined two groups of SCD patients. The first included 210 people followed at the UIC for a median of 6.4 years for clotting events, including deep vein thrombosis (blood clots in the deep veins, usually in the legs) and pulmonary embolism (a clot in the lungs). The second included 547 participants in a multicenter study, called Walk-PHaSST, which also involved the UIC.
EPO levels were measured during periods without painful crises, emergency room visits, or hospitalizations.
Among 204 UIC patients analyzed, 53 experienced a thromboembolism (clotting event) during follow-up, including 34 with deep vein thrombosis and 23 with pulmonary embolism. In the Walk-PHaSST group, 26 patients reported a prior history of pulmonary embolism.
Statistical analyses combining data from both groups and adjusted for potential influencing factors showed that higher EPO levels were significantly associated with a 60% higher risk of blood clotting. In patients without a recent blood transfusion, the risk nearly doubled. Results were similar when the analysis was restricted to those with severe SCD.
Researchers then examined which clinical factors were most closely associated with EPO levels using Walk-PHaSST data.
Higher EPO levels correlated with lower levels of adult hemoglobin, the protein in red blood cells that carries oxygen, and a higher percentage of fetal hemoglobin (HbF), which transports oxygen during fetal development.
Our study indicates that elevated [blood] EPO concentration may be a risk factor for thromboembolism in SCD.
Other factors associated with high EPO included lower blood oxygen saturation (or the percentage of red blood cells carrying oxygen), better kidney function, iron deficiency, better liver function, older age, and male sex.
When the scientists investigated certain inherited genetic differences known to affect HbF levels in SCD, they found that changes in one of the genes, BCL11A, were strongly associated with the percentage of fetal hemoglobin in SCD patients, which, in turn, influenced EPO levels. Other HbF-related genetic regions, HBS1L-MYB and HBB, showed more modest effects.
The team also examined gene activity in immune cells isolated from 159 SCD patients from the UIC group. They identified a specific DNA region where genetic variants influenced the activity of EPOR, the gene that encodes EPOR. SCD patients who carried the G version (allele) of a genetic variant called rs322139 had higher EPOR gene activity.
In both groups, adjusted statistical analyses showed that the G allele was significantly associated with lower EPO levels. Pooled data from both groups showed a link between the G allele and a lower clotting risk that nearly reached statistical significance.
The team noted that the association between the G allele and lower EPO levels was not observed in studies involving non-SCD populations, suggesting it’s specific to SCD.
Lastly, high EPO also correlated with larger platelets, the cell fragments involved in blood clotting. The researchers noted that prior studies have shown that high EPO levels can stimulate the production of larger, more reactive platelets, which may explain the link between high EPO and elevated thrombotic risk in SCD.
“Our study indicates that elevated [blood] EPO concentration may be a risk factor for thromboembolism in SCD,” the scientists wrote. “Our finding of the relationship between EPOR expression and circulating EPO levels may suggest EPOR signalling as a potential therapeutical target for ameliorating prothrombotic conditions in SCD.”
