Is there more to red blood cell production than we think?

Control of red blood cell production in the body may be more complex than previously thought, a study from the University of Illinois at Chicago suggests.

Erythrocytes are the most common type of blood cell in the body. Doughnut-shaped and flexible, they move freely through even the tiniest blood vessels to deliver oxygen to organs and tissues. When blood oxygen levels or the number of red blood cells in the body are low, the kidneys release a hormone called erythropoietin, or EPO, into the blood stream. EPO stimulates the bone marrow to produce more red blood cells.

For patients with sickle cell disease, who have inflexible, abnormally-shaped red blood cells that slow or stop the flow of blood and oxygen to tissues, EPO levels become elevated to increase red blood cell production. The drug hydroxyurea is prescribed to prevent the development of abnormal or sickle-shaped cells, but EPO levels remain high in sickle cell patients, even when the medication is working to keep oxygen levels normal.

Dr. Victor Gordeuk, director of the sickle cell program and professor in the department of hematology and oncology in the UIC College of Medicine

Dr. Victor Gordeuk, professor of hematology and oncology in the UIC College of Medicine and principal investigator on the study, says this suggests that something in addition to cell count and oxygen levels may be regulating EPO levels in the body.

“For a long time, we have observed paradoxically higher serum EPO levels with hydroxyurea treatment in sickle cell disease,” said Gordeuk, who is director of the sickle cell program at UIC. “While we already understand basic EPO regulation, this observation suggested that there may be additional, independent and unidentified mechanisms that come into play.”

Gordeuk and Xu Zhang, assistant professor of hematology and oncology, collaborated with an international team of researchers to study this phenomenon. They collected DNA from nearly 1,000 sickle cell patients and analyzed the samples for genetic variations associated with EPO.

They found an association between a specific part of a DNA sequence and increased EPO. The results are published in the journal Human Molecular Genetics.

“It was encouraging to find an independent genetic variation associated with EPO levels,” said Zhang. “The better we can understand how EPO is regulated, the better we can design treatments and consider new therapeutic agents for patients with blood disorders like sickle cell disease, certain cancers, and a number of other diseases.”

Zhang says some limitations of the study—such as a small sample size, for a genetic study—mean that additional research is needed to validate the findings in multiple cohorts before this discovery will translate into new treatments.

Co-authors on the paper from UIC are Binal N. Shah, research assistant professor of hematology and oncology; Dr. Santosh L. Saraf, assistant professor of hematology and oncology; and Dr. Roberto F. Machado, associate professor of pulmonary, critical care, sleep and allergy.

Other co-authors are Wei Zhang of Northwestern University; Galina Miasnikova of the Chuvash Republic Clinical Hospital 1; Adelina Sergueeva of the Cheboksary Children’s Hospital; Tatiana Ammosova, Xiaomei Niu, Mehdi Nouraie, Sergei Nekhai and Oswaldo Castro of Howard University; Mark T. Gladwin of the University of Pittsburgh; Josef T. Prchal of the University of Utah; and Joe G. N. Garcia of the University of Arizona.

This study was funded in part by National Institutes of Health grants RO1 HL079912-04, 2 R25-HL03679-08, and 1P30HL107253; 1P50HL118006; R01HL111656 and R01HL127342; KL2TR000048 and K23HL125984; UL1TR000050.