Fetal hemoglobin protects against sickle cell lung problems: Study
Higher levels may also delay bone damage, single-center study finds
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Higher levels of fetal hemoglobin (HbF) seem to protect people with sickle cell disease (SCD) by reducing the risk of lung problems, such as pulmonary hypertension, and delaying bone damage, at least in men, according to a study from a single center in Georgia.
The study, “The Role of Hemoglobin F in Sickle Cell Disease Complications: A Descriptive Secondary Analysis,” was published in Blood Vessels, Thrombosis & Hemostasis by researchers at Augusta University and the Center for Blood Disorders, in Augusta, Georgia.
Sickle cell disease is caused by the production of a faulty version of adult hemoglobin, the oxygen-carrying protein in red blood cells. This faulty hemoglobin causes red blood cells to bend into a sickle shape, making them more prone to destruction (hemolysis) and to forming clumps that block blood flow in small vessels, thereby reducing oxygen delivery to tissues.
Before birth, babies produce HbF, which carries oxygen more efficiently than adult hemoglobin. During infancy, the body switches from producing fetal to adult hemoglobin.
“Higher concentrations of HbF are shown to increase life expectancy in patients with SCD, whereas decreased levels are associated with an increased risk of early death,” the researchers wrote. However, they added, “the impact of HbF concentration on chronic SCD complications has previously shown inconsistent results.”
Review of medical records finds trend
To explore the relationship between the amount of HbF in a patient’s blood and various complications, the researchers reviewed the medical records of 496 older adolescents and adults with SCD, focusing on 273 patients aged 17 to 71 who had severe forms of the disease.
All were treated with hydroxyurea, a standard SCD treatment previously shown to increase HbF levels.
A total of 114 thrombotic events, which occur when a blood clot forms and blocks blood flow, were recorded in 271 patients (99.3%). Sixty-one of these (in 38 patients) occurred within six months of a blood test for HbF. Ten patients experienced more than one thrombotic event.
Of the 61 thrombotic events, the greatest proportion (41%) corresponded to pulmonary embolisms (sudden blockage of a lung artery), followed by deep vein thromboses (blockage of a deep vein, usually in the leg) (29.5%) and stroke (26.2%). Median HbF levels were significantly higher in patients with thrombosis than in those without (11.2 vs. 8.6).
“Though to our knowledge there is no robust research on this topic, this finding came as a surprise since it was hypothesized that high HbF values may serve a protective role against [thrombotic events],” the researchers wrote.
Given that the two groups, with and without thrombotic events, “are not equal in size, there may be an exaggerated finding with regard to HbF and [thrombotic events],” the team wrote. “Furthermore, since patients are often prescribed hydroxyurea for primary prevention of stroke, which most commonly arises due to hemolysis-related [blood vessel disease], this association could be present in spite of, not because of, higher HbF levels.”
Of the 273 patients, 67 (24.5%) had sickle cell retinopathy, or SCD-related damage to the light-sensitive layer of the eye, similar to what is often observed in diabetes. Those with retinopathy had median levels of HbF similar to those of patients without retinopathy (7.3 vs. 8.9), but risk increased by 3% with each additional year of age.
Pulmonary hypertension, or high blood pressure in blood vessels of the lungs, was diagnosed in 59 people (21.6%). Those with pulmonary hypertension had significantly lower median HbF (6.2 vs. 9.35). Higher levels of HbF reduced the risk of pulmonary hypertension by 5.5%. However, this risk increased by 5.8% with each additional year of age.
About one-third of patients (34.8%) developed avascular necrosis, in which bone tissue dies due to poor blood flow. Although there was no significant difference in median HbF levels between patients with and without avascular necrosis (9.5 vs. 8.2), higher HbF levels were significantly associated with a later age at avascular necrosis onset in men, but not in women. Also, each additional year of age increased the risk of avascular necrosis by 3.47%.
These findings suggest that HbF plays a complex role in SCD. While it is not possible to “establish a causal relationship,” HbF may reduce the risk of some complications and affect others in unexpected ways, the researchers wrote. Further studies are needed to confirm these findings and to understand if treatment for SCD changes levels of HbF in similar ways, they said.
“Emerging gene therapies for sickle cell disease aim to boost HbF levels in SCD patients,” the team wrote. “Whether such therapies would mitigate the increased risk of thrombosis associated with SCD remains to be determined.”
