An international consortium of scientists, including five researchers from the University of Fribourg, has located the genetic mutations behind certain forms of erythrocytosis, a disease that causes the body to produce an excess of red blood cells. The disorder can lead to thrombosis, in other words, blood clots that form locally.

Fans of cycling and endurance sports are all too familiar with EPO, erythropoietine, the hormone that naturally stimulates the body to produce red blood cells. Illegally injected, it has been at the heart of several doping scandals, like the Festina affair in the late 1990s. In some cases, though, the body itself produces too much of the hormone, no cheating or doping required.

Regulating red blood cell production
When the body detects a state of hypoxia (not enough oxygen getting to its tissues), specialized cells in the kidneys are activated and begin secreting erythropoietine. This hormone acts like a signal and instructs bone marrow to produce red blood cells. As Dr. Darko Maric explains, “More red blood cells means greater capacity for transporting oxygen to the body’s organs.” This helps the body reestablish a balance. Usually, when oxygen levels return to normal, the signaling stops to avoid an overproduction of red blood cells.

When the body produces too many red blood cells
Erythrocytosis is an overproduction of red blood cells. Patients may experience symptoms that include headaches, dizziness, and fatigue. More importantly, if the disorder is not diagnosed and treated, it causes excessive thickening of the blood (hyperviscosity), which can lead to complications like blood clots (thrombosis), strokes, and heart attack.

Current treatment relies on an ancient practice, bloodletting
At present, one of the main ways for treating erythrocytosis is the ancient practice of bloodletting. This involves regularly removing a certain amount of blood from patients to reduce their red blood cell count and decrease the blood’s viscosity. Although effective, the treatment makes demands on the patient, requires regular monitoring, and does not cure the disorder.

A disorder whose cause is unknown
It is important to note that in some 70% of cases of erythrocytosis, the cause remains unknown. This makes diagnosing and treating the condition particularly difficult. A better understanding of the underlying mechanisms and identifying genetic or environmental factors that might be involved would occasion better diagnoses and faster treatments.

Slight errors in the EPO gene
By studying families in which several members had high red blood cell counts, a European team of researchers has discovered slight mutations in certain regions of the EPO gene – the gene that regulates erythropoietine production. These mutations make the gene more aggressive, so to speak, when there is no real need, inducing a more active form that is biochemically closer to what is found in newborns. This causes an overproduction of red blood cells. “This is an important discovery,” stressed an enthusiastic Dr. Maric, a leading coauthor of the study and a member of the laboratory of Prof. David Hoogewijs at the Department of Endocrinology, Metabolism and Cardiovascular System (EMC) of the University of Fribourg .

Medical implications
By showing that mutations located outside the coding regions of the EPO gene are involved, the study helps explain certain cases that have baffled physicians until now. The study could also change the way these diseases are diagnosed, with physicians analyzing not only the amount of erythropoietine that is present but also its form.

In the longer term, this discovery opens new ways forward, including improved diagnostic tools for detecting erythrocytosis and the development of new therapeutic approaches, notably CRISPR-Cas9 genetic treatment. Moreover, these discoveries could be made a part of genetic screening protocols to better identify rare erythrocytosis syndromes. Additionally, adjusting the production of this form of EPO may offer innovative solutions for treating anemia, beta-thalassemias (inherited blood disorders), and hypoxia-related diseases. In other words, a rare genetic error could pave the way for future tailor-made treatments.

Researchers and members of the University of Fribourg teaching staff involved in the study:

Dr. Darko Maric, Dr. Anna Keppner, Sarah Mathilda Vincent, MSc, Vincent Antunes, MSc, Prof. David Hoogewijs (PI)

Martin, Laurent, Darko Maric, Salam Idriss, et al. “Identification of Hepatic-like EPO as a Cause of Polycythemia.” The New England Journal of Medicine, 1 May 2025, DOI: 10.1056/NEJMoa2414954