The Cornerstone of Care: Why Hydroxyurea for Sickle Cell is a Primary Treatment

October 14, 2025 •

4 min read

Sickle cell disease (SCD) affects approximately 100,000 people in the United States [1.9.3]. A key question for many is, 'Why hydroxyurea for sickle cell?' This medication is a primary therapy for reducing the disease's severe complications [1.2.3].

Quick Summary

Hydroxyurea is a crucial medication for sickle cell disease because it increases fetal hemoglobin (HbF), which prevents red blood cells from sickling. This leads to fewer pain crises, hospitalizations, and other complications.

Key Points

Increases Fetal Hemoglobin (HbF): Hydroxyurea's main function is to boost HbF, which inhibits the sickling process of red blood cells [1.2.3].
Reduces Pain Crises: It significantly decreases the frequency of painful vaso-occlusive crises, a hallmark of SCD [1.3.4].
Lowers Complication Risks: The medication reduces the incidence of acute chest syndrome and the need for hospitalizations and blood transfusions [1.3.2].
Multifaceted Action: Beyond HbF induction, it also reduces inflammation, lowers white blood cell counts, and decreases cell adhesion [1.10.4].
Standard of Care: It is recommended for children as young as 9 months and adults with severe SCD to prevent organ damage and improve survival [1.7.2, 1.2.3].
Manageable Side Effects: The primary side effect, myelosuppression, is manageable through regular blood monitoring and dose adjustments [1.11.3].
Proven Long-Term Safety: Studies with over 20 years of follow-up have shown hydroxyurea is safe for long-term use without evidence of increased cancer risk in SCD patients [1.2.2, 1.8.2].

Understanding Sickle Cell Disease (SCD)

Sickle cell disease is an inherited blood disorder where red blood cells, normally round, become crescent or "sickle" shaped [1.2.4]. This change is due to an abnormal version of hemoglobin, the protein that carries oxygen, called sickle hemoglobin (HbS) [1.2.3]. These rigid, sticky cells can block blood flow in small vessels, causing episodes of intense pain known as vaso-occlusive crises (VOCs), as well as more severe complications like acute chest syndrome (ACS), stroke, and organ damage [1.3.3, 1.2.2]. The disease affects about 1 in every 365 Black or African American newborns in the U.S. [1.9.1].

The Central Question: Why Hydroxyurea for Sickle Cell?

Hydroxyurea has been a cornerstone of SCD management for decades because it is a disease-modifying therapy that directly addresses the root cause of sickling [1.2.2, 1.3.4]. Its primary and most celebrated mechanism of action is its ability to increase the body's production of fetal hemoglobin (HbF) [1.5.4]. HbF is the main oxygen-carrying hemoglobin during fetal life but its production dramatically decreases after birth [1.2.2]. In individuals with SCD, higher levels of HbF within red blood cells interfere with the polymerization of HbS, preventing the cells from sickling [1.2.3]. This keeps the cells more round, flexible, and hydrated, allowing them to flow better through blood vessels and deliver oxygen more effectively [1.2.1].

The Multifaceted Mechanisms of Hydroxyurea

While HbF induction is its main benefit, the reasons for using hydroxyurea extend further. The medication has several beneficial effects:

Reduces Inflammation By lowering the counts of neutrophils (a type of white blood cell) and platelets, hydroxyurea helps decrease the chronic inflammation associated with SCD [1.3.4, 1.10.4].
Decreases Cell Adhesion The therapy reduces the expression of adhesion molecules on the surface of blood cells. This makes them less sticky and less likely to cling to the walls of blood vessels, which is a key step in forming blockages [1.10.4].
Nitric Oxide (NO) Donation The hydroxyurea molecule can release nitric oxide, which may help dilate blood vessels and can also contribute to HbF induction through the cGMP pathway [1.5.2, 1.3.4].
Improves Red Cell Properties Patients on hydroxyurea often show an increase in the size of their red blood cells (macrocytosis) and improved cell hydration, which further helps prevent sickling and hemolysis (the breakdown of red blood cells) [1.3.4].

Core Benefits and Patient Candidacy

The clinical benefits of these mechanisms are significant. Numerous studies have shown that hydroxyurea therapy leads to:

A 50% reduction in the frequency of painful VOCs [1.3.4].
Fewer episodes of acute chest syndrome [1.3.2].
A decreased need for blood transfusions and hospitalizations [1.3.2].
Improved survival rates in both adults and children [1.2.2].

Due to this strong evidence, the National Heart, Lung, and Blood Institute (NHLBI) recommends that hydroxyurea be offered to all children with the most severe forms of SCD (HbSS and HbSβ0-thalassemia) starting as early as 9 months of age, regardless of clinical severity [1.7.2]. It is also recommended for adults with recurrent moderate to severe pain crises or other significant complications [1.2.3]. The FDA has approved its use for pediatric patients aged 2 years and older [1.13.2].

Managing Risks and Side Effects

Like any medication, hydroxyurea has potential side effects. The most common is myelosuppression, which is a decrease in the bone marrow's production of blood cells [1.4.2]. This can lead to low neutrophils (neutropenia), low platelets (thrombocytopenia), or anemia [1.2.2]. This effect is dose-dependent, expected, and managed through regular blood count monitoring [1.11.3]. Dosing is carefully escalated to a maximum tolerated dose (MTD) that provides clinical benefit with only mild, manageable myelosuppression [1.2.2]. Other less common side effects can include nausea, hair thinning, and darkening of the skin or nails [1.8.4]. Long-term studies have not found an increased risk of cancer in patients with SCD taking hydroxyurea [1.8.2].

Hydroxyurea in the Modern Treatment Landscape

While hydroxyurea remains the standard of care, other disease-modifying therapies have been approved [1.6.3]. A comparison helps illustrate their different approaches:


Treatment	Mechanism of Action	Administration	Key Benefit
Hydroxyurea	Increases fetal hemoglobin (HbF); reduces inflammation and cell adhesion [1.5.3, 1.10.4].	Oral, once daily [1.2.1].	Reduces sickling, pain crises, and ACS [1.3.4].
L-glutamine (Endari™)	Reduces oxidative stress in red blood cells [1.6.2].	Oral powder, twice daily [1.6.4].	Reduces acute complications like pain crises [1.6.4].
Crizanlizumab (Adakveo®)	A P-selectin inhibitor that blocks adhesion of cells to blood vessel walls [1.2.3, 1.6.4].	Monthly intravenous (IV) infusion [1.12.1].	Prevents vaso-occlusive crises [1.2.3].
Voxelotor (Oxbryta®)	Inhibits HbS polymerization by increasing its oxygen affinity [1.2.3].	Oral, once daily [1.12.1].	Increases hemoglobin levels and reduces hemolysis [1.2.3].
Gene Therapy	Corrects the underlying genetic mutation or induces HbF production [1.6.3].	One-time procedure involving stem cell modification [1.5.3].	Potentially curative; eliminates or drastically reduces VOCs [1.5.3].

Conclusion: A Proven and Essential Therapy

For over two decades, hydroxyurea has been a foundational, life-altering treatment for individuals with sickle cell disease [1.2.2]. By increasing fetal hemoglobin and exerting other beneficial effects like reducing inflammation and cell adhesion, it significantly lowers the frequency of debilitating pain crises, reduces life-threatening complications, and improves overall survival [1.3.4, 1.8.1]. While newer therapies offer alternative mechanisms, hydroxyurea's oral administration, extensive long-term safety data, and proven efficacy make it an indispensable tool in managing SCD and improving patients' quality of life [1.8.4].

For more information, you can consult authoritative resources such as the National Heart, Lung, and Blood Institute (NHLBI): https://www.nhlbi.nih.gov/health/sickle-cell-disease

Frequently Asked Questions

Hydroxyurea works primarily by increasing the production of fetal hemoglobin (HbF). HbF interferes with the process of sickle hemoglobin (HbS) forming rigid polymers, which keeps red blood cells more flexible and less likely to sickle, thus improving blood flow [1.2.2, 1.2.3].

Experts recommend offering hydroxyurea to all children with sickle cell anemia (HbSS or HbSβ0 thalassemia) starting at 9 months of age. It is also recommended for adults with recurrent moderate to severe pain crises or a history of severe complications [1.7.2, 1.2.3].

The main benefits include a significant reduction in the frequency of painful crises (by about 50%), fewer episodes of acute chest syndrome, fewer hospitalizations, and a reduced need for blood transfusions [1.3.4, 1.3.2].

Yes, extensive clinical experience and long-term studies have shown that hydroxyurea is safe and well-tolerated for long-term use in patients with sickle cell disease. There has been no evidence of an increased risk of malignancy associated with its use in this population [1.8.2, 1.8.4].

The most common side effect is myelosuppression, which is a decrease in blood cell production. This can cause low white blood cells, red blood cells, or platelets and is managed by adjusting the dose. Other side effects can include nausea, hair thinning, and darkening of the skin or nails [1.2.2, 1.8.4].

The beneficial effects of hydroxyurea may take several months to become apparent. It takes time for the body to increase its production of fetal hemoglobin and for a doctor to find the optimal dose for the patient [1.3.2, 1.8.3].

Yes, other treatments like L-glutamine, crizanlizumab, and voxelotor have been studied and are often used in combination with hydroxyurea, especially for patients who need additional therapy [1.12.3].