The primary benefits of hydroxyurea therapy in sickle cell anemia relate to its ability to increase fetal hemoglobin (HbF) levels, which inhibits intracellular HbS polymerization and prevents the sickling process within erythrocytes. Temporary arrest of hematopoiesis through once-daily hydroxyurea results in altered erythroid kinetics upon recovery; such “stress erythropoiesis” features higher HbF through recruitment of early erythroid progenitors that maintain their HbF-producing capacity.

Hydroxyurea treatment of patients with sickle-cell disease increases fetal hemoglobin (HbF), which reduces hemoglobin S polymerization and clinical complications. ... In summary, our results strongly suggest that HbF induction by hydroxyurea is mediated by the NO-dependent activation of sGC.

Hydroxyurea, a widely used cytotoxic/cytostatic agent that does not influence methylation of DNA bases, increases fetal hemoglobin production in anemic monkeys. To determine its effect in sickle cell anemia, we treated two patients with a total of four, 5-day courses (50 mg/kg per day, divided into three oral doses). Additional single-day courses of hydroxyurea every 7-20 days maintained the fetal hemoglobin of patient I at 10.8-14.4%, and the total hemoglobin at 8.7-10.8 g/dl for an additional 60 days. This observation suggests that hydroxyurea is a potentially useful agent for the treatment of sickle cell anemia and that demethylation of the gamma-globin genes accompanies increased gamma-globin gene activity.

Elevated fetal hemoglobin (HbF) serves as the most important treatment response, as HbF delays sickle hemoglobin polymerization and reduces erythrocyte sickling. Increased amounts of HbF, especially when distributed across the majority of erythrocytes, improve clinical outcomes by reducing hemolytic anemia and preventing vaso-occlusion.

Hydroxyurea treatment helps the red blood cells stay round and flexible. This lets them travel more easily through tiny blood vessels. In part, this happens because hydroxyurea increases the amount of fetal hemoglobin (Hb F) in red blood cells. With an increased amount of Hb F, red blood cells are less likely to change into the sickle or banana shape.

“Hydroxyurea is one of several cytostatic agents that have been shown to increase the production of fetal hemoglobin in some patients with sickle cell disease.” “We conclude that hydroxyurea is effective in increasing the production of fetal hemoglobin, which in this study was found to be associated with a small decrease in hemolysis and an increase in hemoglobin levels despite myelosuppression.” “As shown in Table 2, the increase in fetal hemoglobin observed in the patients who responded (Group 1) resulted primarily from an augmentation of F-cell production… The preferential survival of F cells, presumably the result of decreased intracellular polymerization of hemoglobin S, became a more prominent factor….”

Hydroxyurea (HU) is a widely used cytotoxic agent that is known to induce fetal hemoglobin (HbF) production and is presently used to ameliorate the severity of pain episodes in patients with sickle cell anemia (HbSS). The HbF levels were increased in BFU-E colonies from HbSS patients (control, 4.0% ± 1.15% vs. +HU, 22.67% ± 2.03%).

The medicine does this by increasing a special kind of hemoglobin called hemoglobin F. Hemoglobin F is also called fetal hemoglobin because newborn babies have it. When you have higher levels of hemoglobin F, your red blood cells are less likely to cause problems. Hydroxyurea makes your red blood cells bigger. It helps them stay rounder and more flexible — and makes them less likely to turn into a sickle shape.

Hydroxyurea (HU) is the most widely used therapy for adults and children with sickle cell disease (SCD). It is believed to act largely by inducing the transcription of fetal γ-globin genes to generate fetal hemoglobin (HbF), which inhibits the pathological polymerization of sickle hemoglobin (HbS). However, the mechanism by which HU increases HbF levels has been unclear. Here, we show that HU can act in erythroid cells to reduce the levels and activity of two direct fetal γ-globin transcriptional repressors with accompanying de-repression of the γ-globin genes and induction of HbF, which may explain the mechanism of action leading to amelioration of symptoms in SCD patients treated with this drug.

Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients (106 children and 44 adults). In this group HU led to significant increases in HbF levels, which were associated with clinical improvement and reduced hemolysis.

“Aims. To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Various molecular pathways have been reported to explain the mode of action of hydroxyurea… Epigenetic modifications, transcriptional events and signalling pathways… Post-transcriptional pathways.” “The cGMP pathway has been implicated as a role player in the induction of HbF in vitro… as well as in vivo in SCD patients. The pivotal role of the cGMP-dependent pathway in γ-globin expression regulation has previously been described with sGC-PKG being involved in γ-globin induction in response to HU.” “Reactive oxygen species (ROS) such as… NO have been shown to mediate the phosphorylation of p38 MAPK, whose association with HbF production was discussed above.”

St. Jude Children’s Research Hospital investigators have shown that using the drug hydroxyurea to boost average fetal hemoglobin levels above 20 percent in children and teenagers with sickle cell anemia was associated with at least a two-fold reduction in hospitalization for any reason. The drug increases production of fetal hemoglobin, which functions normally in individuals with sickle cell anemia. Average fetal hemoglobin levels in patients rose from 9.7 percent prior to treatment to 21.7 percent, a level that was sustained for the four years covered in this analysis. “Our analysis showed that using this approach, hospitalizations for the average patient fell to less than one every couple of years rather than four to six annually,” said lead author Jeremie Estepp, M.D.

“Hydroxyurea, an inducer of HbF, has already been approved for the treatment of patients with moderate and/or severe SCD. Recent clinical trials… resulted in significant increases in mean γ-globin synthesis, HbF levels and the fraction of F cells in the treated patients.” “The mechanism of induction of HbF by hydroxyurea is also not fully understood. It was originally proposed that hydroxyurea may elevate HbF levels by accelerating erythropoietic differentiation in the bone marrow, leading to the appearance of more ‘fetal-like’ cells in the peripheral blood. More recent studies have suggested that hydroxyurea generates nitric oxide (NO) in vivo and that the resulting activation of the NO/cGMP signaling pathway might upregulate γ-globin expression in patients with SCD.”

Children with sickle cell anemia (SCA) immediately reached optimal doses of hydroxyurea with pharmacokinetic (PK)-guided dosing, resulting in higher fetal hemoglobin (HbF) compared with standard dosing, according to the final results of the HOPS study. In the multicenter, phase 3 study, 114 patients were randomly assigned to receive hydroxyurea via standard weight-based dosing or PK-guided dosing. The HbF was significantly higher in the PK-guided group at +10.8% compared with +5.2% in the standard dosing group (P = .04). Hydroxyurea was effective in both arms, with an HbF at 6 months of 35.9% in the PK-guided group and 32.6% in the standard dosing group, with pan-cellular HbF expression noted in both groups. “All children benefited from hydroxyurea with significant improvement in all hematologic parameters, despite their very young age,” the presenter stated.

While its primary effect is the elevation of fetal hemoglobin (HbF), hydroxyurea's mechanisms of action are multifaceted.

Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some cultured erythroid cells.

Hydroxyurea induces hemoglobin F and affects the adherence of cells to the endothelium of blood vessels, which helps to reduce the incidence of vaso-occlusive crises and other complications of sickle cell disease. The speaker states that induction of hemoglobin F helps red cells not to sickle as readily.

Hydroxyurea causes an increase in the amount of fetal (or baby) hemoglobin (hemoglobin F) in the red blood cells. Fetal hemoglobin blocks the effects of the sickle hemoglobin in the red blood cell. A research study in adult patients with serious problems from sickle cell disease showed that treatment with hydroxyurea led to fewer pain crises, fewer episodes of acute chest syndrome, fewer hospitalizations and less need for transfusions.

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. By inducing HbF, hydroxyurea reduces the tendency of sickle hemoglobin to polymerize, which in turn decreases red blood cell sickling and related vaso-occlusive events. However, long-term use requires careful monitoring because of potential toxicities.

Hydroxyurea is our oldest disease-modifying medication for sickle cell disease. It works primarily by increasing fetal hemoglobin (HbF) and improving outcomes such as pain crises and acute chest syndrome. By raising HbF and thereby reducing sickling of red blood cells, hydroxyurea can significantly decrease vaso-occlusive complications, although optimization of its dosing and adherence remain challenges in clinical practice.

Evidence suggests that the therapy can increase levels of fetal hemoglobin, which is an alternative version of hemoglobin that is normally made in early fetal development, but stops being produced shortly after birth. By increasing the levels of fetal hemoglobin, hydroxyurea may help counteract the effects of the mutated adult version of the protein. In patients, it works to reduce red blood cell sickling and destruction, lowering the frequency of painful crises and the need for blood transfusions.

Hydroxyurea was originally investigated in sickle cell disease because of its ability to raise fetal hemoglobin (HbF), which reduces HbS polymerization and red cell sickling. Long-term studies have shown that chronic hydroxyurea therapy increases HbF to 20–30% or higher in many patients, resulting in fewer vaso-occlusive crises and improved anemia. These effects are attributed largely to increased production of HbF-containing red blood cells that are less prone to sickling under deoxygenated conditions.