Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients.
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Hydroxyurea is used for sickle-cell disease patients in order to increase fetal hemoglobin synthesis and consequently decrease the severity of pain episodes. Fetal hemoglobin, which is formed by gamma-globin chains A and G, is present in a constant composition throughout fetal development: about 75% of Ggamma and 25% of Agamma. In contrast, adult red cells contain about 40% of Ggamma and 60% of Agamma. In the present study, we analyzed the effect of hydroxyurea induction on the gamma chain composition of fetal hemoglobin in 31 sickle-cell disease patients treated with hydroxyurea. The control group was composed of 30 sickle-cell disease patients not treated with hydroxyurea in clinical steady state. The patients were older than 13 years and were not matched for age. All patients were seen at Hemocentro/UNICAMP and Boldrini Infantile Center, Campinas, SP, Brazil. The levels of total hemoglobin were significantly higher in patients treated with hydroxyurea (mean +/- SD, 9.6+/-2.16 g/dl) than in untreated patients (8.07+/-0.91 g/dl). Fetal hemoglobin levels were also higher in treated patients (14.16+/-8.31%) than in untreated patients (8.8+/-4.09%), as was the Ggamma/Agamma ratio (1.45+/-0.78 vs 0.98+/-0.4, P < 0.005). The increase in the Ggamma/Agamma ratio in patients treated with hydroxyurea suggests the prevalence of a pattern of fetal hemoglobin synthesis, whereas patients not treated with hydroxyurea maintain the adult pattern of fetal hemoglobin synthesis. Because no correlation was observed between the Ggamma/Agamma ratio and total hemoglobin or fetal hemoglobin levels, the increase in Ggamma chain synthesis may not imply a higher production of hemoglobin. (+info)
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease.
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Hydroxyurea improves hematologic parameters for children with sickle cell disease (SCD), but its long-term efficacy at maximum tolerated dose (MTD) has not been determined. Between 1995 and 2002, hydroxyurea therapy was initiated for 122 pediatric patients with SCD including 106 with homozygous sickle cell anemia (HbSS), 7 with sickle hemoglobin C (HbSC), 7 with sickle/beta-thalassemia (HbS/ beta-thalassemia [6 HbS/beta0, 1 HbS/beta+]), and 2 with sickle hemoglobin OArab (HbS/OArab). Median age at initiation of therapy was 11.1 years. Hydroxyurea was escalated to MTD, with an average dose of 25.4 +/- 5.4 mg/kg per day; the average duration of hydroxyurea therapy has been 45 +/- 24 months (range, 6-101 months). Hydroxyurea was discontinued for 15 (12%) children with poor compliance. Mild transient neutropenia occurred, but no hepatic or renal toxicity was noted. Hydroxyurea therapy led to significant increases in hemoglobin level, mean corpuscular volume, and fetal hemoglobin (HbF) level, whereas significant decreases occurred in reticulocyte, white blood cell, and platelet counts and serum bilirubin levels. Children with variant SCD genotypes also had hematologic responses to hydroxyurea. HbF induction has been sustained for up to 8 years without adverse effects on growth or increased numbers of acquired DNA mutations. Long-term hydroxyurea therapy at MTD is well tolerated by pediatric patients with SCD and has sustained hematologic efficacy with apparent long-term safety. (+info)
Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.
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BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. (+info)
Effects of hydroxyurea on the membrane of erythrocytes and platelets in sickle cell anemia.
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BACKGROUND AND OBJECTIVES: Adhesion molecules on the surface of erythrocytes, leukocytes and platelets are involved in vascular occlusion in sickle cell anemia. Hydroxyurea treatment of sickle cell anemia patients leads to clinical improvement and reduces the incidence of vaso-occlusive episodes. It has been previously demonstrated that hydroxyurea treatment also reduces the expression of adhesion molecules on the surface of erythrocytes. Phosphatidylserine (PS) exposure on the surface of erythrocytes has been considered to be the main determinant of altered erythrocyte adhesion in sickle cell anemia. In this study we examine the expression of PS on the surface of erythrocytes and platelets of sickle cell anemia patients before and during treatment with hydroxyurea. DESIGN AND METHODS: Blood samples from 15 sickle cell anemia patients were analyzed before and during treatment with hydroxyurea. The profile of PS expression was examined by flow cytometry. RESULTS: Hydroxyurea was effective, as determined by the patients clinical improvement and increased hemoglobin (8.3 vs 9.1 g/dL, p< 0.005), F cells (15.9% vs 37.1%, p< 0.005) and mean corpuscular volume ( 82 fL vs 101 fL, p< 0.005). PS expression on the surface of erythrocytes and platelets decreased from 6.27% to 2.96% (p< 0.005) and from 13.5% to 4.7% (p< 0.005), respectively. INTERPRETATION AND CONCLUSIONS: Hydroxyurea treatment reduces PS expression on the surface of erythrocytes and platelets, thus contributing to the favorable effects of this therapy. (+info)
Established and experimental treatments for sickle cell disease.
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Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin (HbS), which has the unique property of polymerizing when deoxygenated. The sickling process is markedly accelerated when intracellular concentration of HbS is increased. Due to the unique dependence of HbS polymerization on its cell concentration, a slight reduction in HbS concentration is likely to have a beneficial effect on the kinetic of polymerization and on the generation of dense, dehydrated red cells. The pathophysiology of acute and chronic clinical manifestations of SCD is strictly related to the hemoglobin cyclic polymerization, to the generation of dense, dehydrated red cells and to the interaction between sickle red cells and abnormal activated vascular endothelial cells. In the present paper we have reviewed the principal therapeutic strategies and we have explored the future treatment options for sickle cell disease. Therapy of sickle cell disease is based on two major goals. The first one is the decrease in intracellular HbS concentration obtained with agents activating fetal hemoglobin synthesis, such as hydroxyurea (HU) or with erythrocyte-active agents blocking different red cell membrane ion pathways and preventing sickle cell dehydration. The second one is based on therapeutic strategies, which may reduce sickle cell-endothelial adhesive events. (+info)
Circulating endothelin-3 levels in patients with sickle cell disease during hydroxyurea treatment.
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Abnormal adhesion of red blood cells to the endothelium and the production of cytokines and vasoactive substances, such as endothelin-1 contribute to the pathogenesis of microvascular occlusion in sickle cell disease (SCD), even during the steady state. Endothelin-3 (ET-3) is a vasoconstrictive agent, which has not yet been studied in SCD. (+info)
A recombinant human hemoglobin with anti-sickling properties greater than fetal hemoglobin.
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A new recombinant, human anti-sickling beta-globin polypeptide designated beta(AS3) (betaGly(16) --> Asp/betaGlu(22) --> Ala/betaThr(87) --> Gln) was designed to increase affinity for alpha-globin. The amino acid substitutions at beta22 and beta87 are located at axial and lateral contacts of the sickle hemoglobin (HbS) polymers and strongly inhibit deoxy-HbS polymerization. The beta16 substitution confers the recombinant beta-globin subunit (beta(AS3)) with a competitive advantage over beta(S) for interaction with the alpha-globin polypeptide. Transgenic mouse lines that synthesize high levels of HbAS3 (alpha(2)beta(AS3)(2)) were established, and recombinant HbAS3 was purified from hemolysates and then characterized. HbAS3 binds oxygen cooperatively and has an oxygen affinity that is comparable with fetal hemoglobin. Delay time experiments demonstrate that HbAS3 is a potent inhibitor of HbS polymerization. Subunit competition studies confirm that beta(AS3) has a distinct advantage over beta(S) for dimerization with alpha-globin. When equal amounts of beta(S)- and beta(AS3)-globin monomers compete for limiting alpha-globin chains up to 82% of the tetramers formed is HbAS3. Knock-out transgenic mice that express exclusively human HbAS3 were produced. When these mice were bred with knock-out transgenic sickle mice the beta(AS3) polypeptides corrected all hematological parameters and organ pathology associated with the disease. Expression of beta(AS3)-globin should effectively lower the concentration of HbS in erythrocytes of patients with sickle cell disease, especially in the 30% percent of these individuals who coinherit alpha-thalassemia. Therefore, constructs expressing the beta(AS3)-globin gene may be suitable for future clinical trials for sickle cell disease. (+info)
Mortality in sickle cell patients on hydroxyurea therapy.
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The efficacy of hydroxyurea (HU) and its role in the reduction in mortality in sickle cell patients has been established. Nevertheless, many patients still die of complications of this disease while on HU. Of the 226 patients treated with HU at our center, 38 died (34 of sickle cell-related causes). Acute chest syndrome (ACS) was the most common (35%) cause of death. Deceased and surviving patients did not differ significantly in average HU dose, baseline fetal hemoglobin (Hb F), or maximum Hb F response. However, the deceased patients were significantly older when HU was instituted, were more anemic, and more likely to have BAN or CAM haplotypes. They also had significantly higher serum blood-urea-nitrogen (BUN) and creatinine levels. Sickle cell patients who die while on HU therapy may represent a subgroup of older patients, possibly with more severe disease and more severe organ damage. Such patients need early identification and prompt HU institution. (+info)