What is the recommended treatment for sickle cell anemia (SCA) with frequent painful crises?

From the Guidelines

Hydroxyurea is the recommended treatment for sickle cell anemia (SCA) with frequent painful crises, as it increases total and fetal hemoglobin and decreases vaso-occlusive complications. The treatment of SCA with frequent painful crises involves targeting the cells' alterations to reduce the frequency and severity of these crises. Hydroxyurea, taken once a day orally, is the cornerstone therapy, and its use has a positive impact on health-related quality of life in people with HbSS or Sb0-thalassemia 1.

The mechanism of action of hydroxyurea in SCA is to increase fetal hemoglobin production, which reduces the formation of sickled cells and prevents vaso-occlusive crises. This is achieved by increasing the levels of fetal hemoglobin, which is less prone to sickling than adult hemoglobin. As a result, hydroxyurea decreases the frequency of painful events, acute chest syndrome, hospitalizations, and the need for transfusions 1.

Key points to consider when using hydroxyurea in SCA patients include:

• Starting dose: typically 15-20 mg/kg/day
• Titration: based on response and blood counts
• Monitoring: regular CBC and reticulocyte count every 1 to 3 months
• Potential adverse effects: myelosuppression, which can be managed with dose adjustments and monitoring

In addition to hydroxyurea, other treatments may be necessary to manage SCA, including:

• Monthly red blood cell transfusions to suppress the bone marrow and decrease HbS percentage
• Iron chelation therapy to treat iron overload after 12 to 20 transfusions
• Hematopoietic stem cell transplantation as a curative treatment for eligible patients with severe disease
• Gene therapy, which is currently being studied as a potential curative treatment for SCA 1.

Overall, the goal of treatment in SCA is to reduce the frequency and severity of painful crises, prevent complications, and improve quality of life. Hydroxyurea is a crucial component of this treatment plan, and its use should be considered in all patients with SCA and frequent painful crises.

From the FDA Drug Label

The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD The pyridine nucleotides, NAD+ and its reduced form NADH, play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione.

The current treatment L-glutamine may target the cells alterations of sickle cell anemia by reducing oxidative stress and improving the NAD redox potential in sickle red blood cells (RBCs) through increasing the availability of reduced glutathione 2.

• Key points:
  • Oxidative stress is involved in the pathophysiology of sickle cell disease (SCD)
  • L-glutamine may improve the NAD redox potential in sickle RBCs
  • Reduced glutathione availability is increased by L-glutamine However, the exact mechanism of action of L-glutamine in treating SCD is not fully understood. Hydroxyurea is also mentioned as a treatment that patients were allowed to continue during the study, but its mechanism of action is not described in this context.

From the Research

Mechanism of Hydroxyurea in Sickle Cell Anemia

• Hydroxyurea stimulates the production of fetal hemoglobin (HbF), which is resistant to sickling, thereby reducing the incidence of hemolytic and vaso-occlusive manifestations 3.
• The exact mechanism by which hydroxyurea increases HbF is not known, but one possible explanation is that hydroxyurea is cytotoxic to the more rapidly dividing late erythroid precursors, leading to the recruitment of early erythroid precursors that have demonstrated increased capacities to produce HbF 3.
• Hydroxyurea has been shown to increase HbF concentrations, which can lead to a reduction in the frequency of painful crises in patients with sickle-cell anemia 3, 4.

Clinical Benefits of Hydroxyurea

• Hydroxyurea has been effective in reducing the frequency of painful crises, hospitalizations, and transfusions in patients with sickle-cell anemia 3, 4.
• The use of hydroxyurea has been associated with a reduction in mortality in patients with sickle-cell anemia 4.
• Hydroxyurea has been shown to be safe and effective in children with sickle-cell anemia, with a significant reduction in hospitalizations for vaso-occlusive pain and acute chest syndrome 5.

Dosage and Monitoring of Hydroxyurea

• The dosage of hydroxyurea is typically started at 10-15 mg/kg/d and adjusted based on platelet count, complete blood count, and HbF levels 3.
• The goal of hydroxyurea therapy is to achieve a HbF level of >20%, which has been associated with fewer hospitalizations and reduced toxicity 5.
• Regular monitoring of blood counts and HbF levels is necessary to adjust the dosage of hydroxyurea and minimize the risk of toxicity 3, 5.

Determinants of Response to Hydroxyurea

• The response to hydroxyurea is influenced by several factors, including baseline neutrophil and reticulocyte counts, and the ability of the bone marrow to withstand hydroxyurea treatment 6.
• The absence of a Central African Republic (CAR) haplotype has been associated with a better response to hydroxyurea 6.
• Compliance with hydroxyurea therapy and the ability to achieve a high enough dose to induce a significant increase in HbF are also important determinants of response 6.