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Rev Bras Hematol Hemoter. 2012;34(4):254-64

Nitric oxide status in sickle cell anemia

In this issue of the Revista Brasileira de Hematologia e Hemoterapia, Elias et al.(1) show the negative correlation between nitrite serum levels and the concentration of fetal hemoglobin (Hb F) in adult patients with sickle cell anemia. Hb F is a predictor of good prognosis in sickle cell anemia suggesting that the nitrite concentration might be used as a biomarker of the disease prognosis(1). Decreased levels of nitrite can indicate a better prognosis as it may be related to an increased production of NO via Hb F(2) .

Sickle cell disease (SCD) is an inherited disorder of hemoglobin synthesis. The cause of SCD is a point mutation in the β-globin gene. This genetic abnormality leads to the production of sickle hemoglobin, a protein that has the unique property of polymerizing into long ibers when deoxygenated, thereby decreasing red blood cell deformability and damaging the cell membrane. Sickle cell anemia is characterized by episodes of vaso-occlusion and hemolysis, which are responsible for the clinical manifestations of the disease(3) .

This disease is a chronic inlammatory condition that diminishes the reserves of nitric oxide (NO). NO is normally produced by the endothelium and regulates the basal vessel tone, inhibits platelet and hemostatic activation, inhibits adhesion molecules and reduces reactive oxygen species (ROS) levels. The potential importance of NO in SCD has been the subject of much research over the last decade. It is now accepted that the decreased availability of NO is an important mechanism in the pathophysiology of SCD(3).

Serum levels of L-arginine, the precursor of NO, are decreased in patients with sickle cell anemia, particularly during vaso-occlusive and acute chest syndrome episodes; these levels are inversely proportional to painful crisis. In the vascular compartment, the hemolytic process causes the release of large amounts of free hemoglobin, heme and arginase. Free plasma hemoglobin, in addition to generating ROS, such as the hydroxyl and superoxide radicals, is also a potent scavenger of nitric oxide. The hydrophobic heme enters the plasma membrane of endothelial cells, releasing iron, which damages the cells causing the release of ROS(3). Arginase, released in plasma L-arginine acts in transforming it into urea and ornithine. The increase in plasma L-ornithine competes with low levels of L-arginine uptake in cellular compartments and may generate pulmonary hypertension and the production of ROS. The half-life of NO in the blood is extremely short because of its rapid reaction with hemoglobin to form methemoglobin and nitrate(4).

In conclusion the analysis of the metabolism of NO is important to monitor patients with SCD and biomarkers may be associated with disease progression. This represents the most important advance in understanding the pathogenesis, contributing to a more accurate management of patients(5).

References

1. Elias DB, Rocha LB, Cavalcante MB, Pedrosa AM, Justino IC, Gonçalves RP. Correlation of low levels of nitrite and high levels of fetal hemoglobin in patients with sickle cell disease at baseline. Rev Bras Hematol

Hemoter. 2012;34(4):265-9.

2. Salhany JM. Reaction of nitrite with human fetal oxyhemoglobin: A model simulation study with implications for blood low regulation in sickle cell disease (SCD). Blood Cells Mol Dis. 2010;44(2):111-4. 3. Mack AK, Kato GJ. Sickle cell disease and nitric oxide: A paradigm shift? Int J Biochem Cell Biol.

2006;38(8):1237-43.

4. Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ; CURAMA Study Group. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. Am J Hematol. 2011;86(6):484-9.

5. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sanchdev V, Hazen SL, et al. Dysregulated

arginine metabolism, hemolysis-associated pulmonary hypertension and mortality in sickle cell disease. JAMA. 2005;294(1):81–90. Comment in: JAMA. 2005;294(19):2433; author reply 2433-4.

Romélia Pinheiro Gonçalves

Faculdade de Farmácia da Universidade Federal do Ceará - UFC, Fortaleza, CE, Brazil

Conlict-of-interest disclosure:

The authors declare no competing inancial

interest

Submitted: 6/4/2012 Accepted: 6/5/2012

Corresponding author:

Romélia Pinheiro Gonçalves

Faculdade de Farmácia da Universidade Federal do Ceará-UFC

Rua Pereira Valente, 640, apto 701, Meireles 60160-250 Fortaleza, CE, Brazil

Phone: 55-85-87879459

romeliapinheiro@ig.com.br or romelia.pinheiro@pq.cnpq.br

www.rbhh.org or www.scielo.br/rbhh

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