A 23-year-old woman with a history of sickle cell disease comes to the office for follow-up. The patient is homozygous for hemoglobin S and has had frequent episodes of painful vasoocclusive crises. She has no other medical conditions and takes folic acid supplementation. The patient does not use tobacco, alcohol, or illicit drugs. Physical examination shows no abnormalities. Additional therapy with hydroxyurea is planned. This medication is likely to improve this patient's symptoms primarily through which of the following mechanisms?

Question

A 23-year-old woman with a history of sickle cell disease comes to the office for follow-up.  The patient is homozygous for hemoglobin S and has had frequent episodes of painful vasoocclusive crises.  She has no other medical conditions and takes folic acid supplementation.  The patient does not use tobacco, alcohol, or illicit drugs.  Physical examination shows no abnormalities.  Additional therapy with hydroxyurea is planned.  This medication is likely to improve this patient's symptoms primarily through which of the following mechanisms?

Quizplus · Accepted Answer

11ec160b_3be7_c8d3_9249_f5a6fd67ca27_MD0001_00 Patients with sickle cell disease (SCD) have a missense mutation in the beta globin gene that leads to the substitution of valine for glutamic acid in the 6th position of the beta globulin chain. This altered form of hemoglobin is called hemoglobin S (Hb S); unlike normal adult hemoglobin (Hb A), Hb S polymerizes when deoxygenated or dehydrated, leading to erythrocyte membrane damage (ie, intravascular hemolysis) and clogging of small vessels (ie, painful vasoocclusive crises, ischemia). Heterozygotes for Hb S are usually asymptomatic because there is enough Hb A to prevent extensive polymerization of Hb S, but homozygotes typically have severe disease. These individuals often require repeated blood transfusions for symptomatic anemia and treatment with hydroxyurea, an antimetabolite that inhibits the ribonucleotide reductase enzyme. Although inhibition of ribonucleotide reductase leads to the myelosuppressive effects of hydroxyurea (it causes cell cycle arrest in rapidly dividing hematopoietic cells), hydroxyurea also shifts globin gene transcription from the beta globin locus to the gamma globin locus (via unclear mechanisms), thereby increasing circulating levels of fetal hemoglobin (HB F). HB F is unaffected by the sickle cell mutation (because it is not composed of beta chains) and has physiologic properties similar to hemoglobin A; therefore, hydroxyurea is often used in the treatment of SCD to improve oxygen delivery, reduce vasoocclusive crises, and lessen need for transfusions. (Choice A) The calcium-dependent (Gardos) potassium channel regulates the transport of potassium and water through the erythrocyte membrane; blocking this channel could help prevent erythrocyte dehydration but has not been shown to improve symptoms. (Choice B) Voxelotor directly inhibits polymerization of Hb S by binding to the alpha chain of the molecule and causing an allosteric change that results in increased oxygen binding. (Choice C) Hb A2 is a variant of normal adult hemoglobin that has 2 delta chains instead of 2 beta chains. Because it does not contain the abnormal beta chains, increased hemoglobin A2 could reduce sickle cell crises. However, hydroxyurea increases gamma globulin expression, not delta globulin expression. (Choice E) L-glutamine, a precursor to the antioxidant glutathione, reduces oxidative stress in erythrocytes with HB S. It is used for patients with SCD who have persistent vasoocclusive pain or those who cannot tolerate hydroxyurea. (Choice F) Stimulation of erythrocyte production (eg, erythropoietin) would likely worsen vasoocclusive crises by increasing circulating levels of Hb S. Hydroxyurea inhibits (not stimulates) the production of erythrocytes, leukocytes, and platelets by blocking ribonucleotide reductase; however, patients with SCD still benefit from administration due to stimulated HB F production. Educational objective: Hydroxyurea is used in patients with sickle cell disease to increase expression of gamma globin chains, which leads to increased circulating fetal hemoglobin (Hb F) concentration. This reduces vasoocclusive crises and symptomatic anemia episodes.

A 23-Year-Old Woman with a History of Sickle Cell Disease