Hydroxyurea for Sickle Cell Anemia- An Overview

Introduction

Sickle cell anemia (SCA) is a variant of inherited hemoglobinopathy (a disorder affecting hemoglobin) that affects many people worldwide. Red blood cells (RBCs) are round and flexible. As a result, it allows their easy movement through the blood vessels. In SCA, the RBCs tend to become sickle-shaped. The sickle cells are firm and sticky. As a result, they can block blood flow in the body and cause serious health problems. Hydroxyurea (HU, an antimetabolite) is a Food and Drug Administration (FDA) drug and one of the most promising treatments for SCA.

How Does Hydroxyurea Work in Treating Sickle Cell Anemia?

HU is used to treat people with different types of sickle cell disease (SCD, a broader group of inherited blood cell disorders). However, the FDA approved it for treating adults with severe SCA in 1998. Further, in 2017, the FDA approved treating children two years of age and older with SCA.

1. HU increases the size of the RBCs. Moreover, it facilitates their round shape and flexibility. Hence, the RBCs in SCA become less sickle-shaped.

2. HU increases hemoglobin F (HbF; fetal hemoglobin). HbF is also present in newborn babies. When an SCA patient has higher HbF levels, RBCs cause fewer issues.

The exact mechanism by which HU induces HbF formation remains unclear. The primary benefit of HU for SCA is its ability to increase HbF levels. It further inhibits HbS polymerization (small molecules form larger molecules) and prevents RBC sickling. However, the benefits of HU therapy in SCA are manifold. It is because the actions extend beyond HbF production.

HU is also used with other medications, radiation therapy, or as a sole treatment to treat chronic myelogenous leukemia (CML, a white blood cell cancer) and certain head and neck cancer types.

How Does Hydroxyurea Work for Sickle Cell Anemia?

SCA includes SCD type SS and sickle beta zero (Sβ0) thalassemia.

1. Sickle Cell Disease Type SS: People with this disorder inherit one gene that codes for hemoglobin "S" from both parents. It is the most severe form of SCD.

2. Sickle Beta Zero (Sβ0) Thalassemia: Sickle cell beta thalassemia is an inherited type of SCD that affects the production of normal hemoglobin.

HU is effective in both forms of SCA. It can further treat mild, moderate, and severe symptoms of SCA. HU is also effective in other forms of SCD, such as type SC or type sickle beta plus (Sβ+) thalassemia. However, there is less research on HU use in these SCD types.

What Are the Clinical Effects of Hydroxyurea in Sickle Cell Anemia Patients?

Laboratory Measurements: HU affects various clinical parameters in an SCA patient.

• Elevated HbF Levels: Increased HbF is seen with sustained HU use. HbF is beneficial to combat SCA.

• Increased Hemoglobin: HU increases hemoglobin levels and reduces the need for blood transfusions.

• Increased Mean Corpuscular Volume (MCV): HU increases the size of blood cells. MCV is a measure of average RBC size. Hence, HU raises the MCV.

• Decreased Hemolysis: RBCs in SCA are weak and can break down quickly. As a result, hemolysis ensues, and chronic organ damage can occur. Long-term HU therapy decreases hemolysis. Hence, there is improved blood flow to the brain, spleen, lungs, and kidneys.

• Increased Nitric Oxide (NO): NO is a vasodilator and a painkiller that relaxes the obstructed blood vessels to widen and allow the sickled RBCs to pass. HU increases the endothelium's NO level (the blood vessels inner cell lining).

Well-Being: HU reduces the clinical symptoms of SCA. Hence, there is improved quality of life for SCA patients. Patients with SCA who take HU have:

• Reduced Pain- Pain is the most frequent complication of SCA. Sickled RBCs traversing through small blood vessels get stuck, causing blood flow obstruction and pain. It is also called a vaso-occlusive crisis (VOC). A pain crisis is a sudden, mild to severe pain episode lasting long. Unfortunately, pain can happen in any body part. However, it frequently affects the hands, feet, chest, and back.

• Reduced Episodes of Acute Chest Syndrome (ACS) - ACS is SCA patients' most common acute lung disorder. It is a life-threatening complication of SCA with high disease and death rates. HU decreases ACS episodes and also prevents future recurrences.

• Fewer Blood Transfusions: Blood transfusion is an essential intervention in SCA patients. However, there are many adverse effects associated with blood transfusions. HU reduces the number of blood transfusions for an SCA patient. It is because it also aims at increasing the oxygen-carrying capacity of the blood (similar to a blood transfusion).

• Fewer Hospital Stays: An Indian study 2022 revealed that HU use in SCA patients reduced the hospital stay duration in VOC patients. Further, the patients on HU had less pain intensity than controls at admission. The authors also noted that the hemoglobin level in SCA patients at the entrance was higher than controls.

How Is Hydroxyurea Taken for Sickle Cell Anemia?

1. HU is an oral capsule or tablet to be taken as a whole. It is prescribed for once-daily use. If a patient cannot swallow a tablet, it is recommended to dissolve it in water. Then, the mixture should be swallowed.

2. The hematologist (a doctor who treats blood disorders) can delay the treatment or adjust the dose depending on the response and side effects.

3. It is important to take folic acid to decrease some of the side effects of HU.

Is It Safe To Take Hydroxyurea for Sickle Cell Anemia for a Long Time?

Studies have shown that HU is safe for long-term use in children and adults with SCA. Patients need to get their blood counts checked every month. The increased blood counts can be a good sign that HU is working. However, some patients may experience thinning hair or mild hair loss (alopecia), darker fingernail beds, weight gain, mouth and throat sores, constipation, rash, pale skin, nausea, and vomiting. HU rarely causes severe side effects. A hematologist's consultation is required if a patient develops new symptoms after taking HU. The hematologist will prescribe a lower dose that is well-tolerated.

Conclusion

Sickle cell anemia negatively impacts a person's life. It can cause pain, crises, and other issues. A patient may even end up in the emergency room of the hospital. Hydroxyurea can decrease pain crises and increase the lifespan of a patient. However, as HU is ineffective in all types of SCD, newer therapies (alone or combined with HU) are needed to maximize the pharmacologic advantages for patients with SCD.