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Treatment with hydroxyurea — approved to help reduce pain crises and the need for blood transfusions in sickle cell disease (SCD) — is associated with a higher incidence of spleen removal surgery among children with SCD, according to a recent study.

The findings also indicated that SCD children treated with hydroxyurea underwent surgery, called a splenectomy, at a significantly younger age compared with those not given the oral medication.

That result came as a surprise to researchers, who expected contrary findings.

“We hypothesized that as hydroxyurea gained widespread use, surgical splenectomy among pediatric patients with SCD occurred at a higher rate and older age among those taking hydroxyurea,” the team noted.

The study, “Pediatric Sickle Cell Disease Patients on Hydroxyurea Have Higher Rates of Surgical Splenectomy,” was published in the Journal of Surgical Research.

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Investigating the use of hydroxyurea in SCD children
SCD is caused by mutations in the beta-globin (HBB) gene that contains instructions to produce a component of hemoglobin — the protein in red blood cells that carries oxygen through the bloodstream. These mutations result in the production of a defective form of hemoglobin, called hemoglobin S, which causes red blood cells to acquire a sickle-like shape.

These cells do not move properly through blood vessels, resulting in blood flow blockage. This in turn leads to ischemia, or loss of blood and oxygen supply to body tissues, and pain. These episodes are known as vaso-occlusive crises (VOCs).

Treatment with hydroxyurea, a small molecule that increases the production of fetal hemoglobin — a form of hemoglobin that is more effective at transporting oxygen than its adult counterpart — was shown to decrease the frequency of VOCs and the need for blood transfusions in SCD patients.

However, it is unclear whether hydroxyurea contributes to reduce spleen ischemia, and potentially increase the need for splenectomy, or spleen removal surgery.

The spleen is an immune system organ that is important for removing old red blood cells from circulation. However, it is highly susceptible to SCD-related ischemia. It is believed that repetitive ischemic episodes might lead to spleen damage and loss of function, a process called auto-splenectomy.

To learn more, researchers in the U.S. analyzed data from 28,520 children with SCD identified in the Pediatric Health Information System (PHIS), a database that comprises information from 49 U.S. children’s hospitals. The data was collected between 2005 and 2020.

Approximately half of the patients were boys (51.5%), and 58.6% were non-Hispanic Black children. Nearly half had Medicaid insurance (45.6%) and 34.2% were treated with hydroxyurea.

More than half of the children — 17,717 or about 62% — were diagnosed with sickle cell anemia, the most common and often the most severe type of SCD. In this type, patients inherit two gene copies encoding hemoglobin S, one from each parent. A total of 2,738 patients had a less severe form of the disease, in which they inherited one gene copy encoding hemoglobin S and another encoding hemoglobin C, another faulty form of the protein. The remaining 2,219 patients had other forms of SCD.

Children treated with hydroxyurea had a significantly higher rate of splenectomy compared with those not treated with the medication (7.2% vs. 3.2%). The treated patients also were younger at the time they underwent surgery compared with those not on hydroxyurea (median age of 6.2 vs. 7.8). There were no differences in the length of hospital stay or the incidence of blood transfusion during surgery admission between the groups.

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Comparing impact in SCD versus sickle cell anemia
Among children with sickle cell anemia, total splenectomy rate was 4.2% and was higher among those receiving hydroxyurea (5.9% vs. 3.1%). Also, children receiving hydroxyurea underwent splenectomy at a significantly younger age (median of 5.7 vs. 6.6 years).

Hydroxyurea use in these patients significantly increased from the period before 2010 to the period right after (28.9% vs. 41.7%). Simultaneously, splenectomy rates increased (3.4% vs. 4.4%), and the median age at the time of surgery declined (6.9 vs. 5.8 years) after 2010.

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Children with one gene copy encoding hemoglobin S and another encoding hemoglobin C were less frequently treated with hydroxyurea than those with sickle cell anemia (4.9% vs. 39.2%), and had a much lower rate of splenectomy (0.9% vs. 4.2%), at a much older age.

In children with both forms of hemoglobin receiving hydroxyurea, the rate of splenectomy was much higher than the non-treated ones (3.0% vs 0.8%). However, age at time of surgery was not different between those groups.

“Overall, this study highlights a novel observation that hydroxyurea therapy is associated with a higher rate of surgical splenectomy among patients with SCD, regardless of genotype [genetic background],” the researchers wrote.

This might be related to “the preservation of the spleen from auto-splenectomy, perhaps through fewer vaso-occlusive crises known to result in tissue loss,” the team wrote. “In maintaining or even regaining functioning tissue, the spleen remains at risk for sequestration crisis or hypersplenism [overactive spleen], two common indications for a surgical splenectomy.”

“These findings provide useful information for clinicians and patients who benefit from this therapy,” the team wrote.

However, they noted that further investigation is needed to clarify the reasons for surgical splenectomy at a younger age in children with sickle cell anemia.