Stephen H. Embury

Sickle cell disease as a cause of osteonecrosis of the femoral head.

BACKGROUND AND METHODS Osteonecrosis of the femoral head is an important complication of sickle cell disease. We studied 2590 patients who were over 5 years of age at entry and followed them for an average of 5.6 years. Patients were examined twice a year, and radiographs of the hips were taken at least twice: at study entry and approximately three years later. RESULTS At study entry, 9.8 percent of patients were found to have osteonecrosis of one or both femoral heads. On follow-up, patients with the hemoglobin SS genotype and alpha-thalassemia were at the greatest risk for osteonecrosis (age-adjusted incidence rate, 4.5 cases per 100 patient-years, as compared with 2.4 in patients with the hemoglobin SS genotype without alpha-thalassemia and 1.9 in those with the hemoglobin SC genotype). Although the rate of osteonecrosis in patients with the hemoglobin SC genotype did not differ significantly from that in patients with the hemoglobin SS genotype without alpha-thalassemia, osteonecrosis tended to develop in these patients later in life. Intermediate rates of osteonecrosis were observed among patients with the hemoglobin S-beta zero-thalassemia and the hemoglobin S-beta(+)-thalassemia genotypes (3.6 and 3.3 cases per 100 patient-years, respectively). Osteonecrosis was found in patients as young as five years old (1.8 cases per 100 patient-years for all genotypes). The frequency of painful crises and the hematocrit were positively associated with osteonecrosis. The mean corpuscular volume and serum aspartate aminotransferase level were negatively associated. Twenty-seven patients had hip arthroplasty during the study; 10 were under 25 years of age. Five of the 27 required reoperation 11 to 53 months after the initial operation. CONCLUSIONS Osteonecrosis of the femoral head is common in patients with sickle cell disease, with an incidence ranging from about 2 to 4.5 cases per 100 patient-years. Patients with the hemoglobin SS genotype and alpha-thalassemia and those with frequent painful crises are at highest risk. The overall prevalence is about 10 percent. The results of hip arthroplasty are poor.

Concurrent sickle-cell anemia and α-thalassemia: effect on severity of anemia.

Abstract We studied 47 patients with sickle-cell anemia to determine the effect of α-thalassemia on the severity of their hemolytic anemia. We diagnosed α-thalassemia objectively by using α-globin-gene mapping to detect α-globin-gene deletions, studying 25 subjects with the normal four α-globin genes, 18 with three, and four with two. The mean hemoglobin, hematocrit, and absolute reticulocyte levels (±S.D.) were 7.9±0.9 g per deciliter (4.9±0.6 mmol per liter), 22.9±2.9 per cent, and 501,000±126,000 per cubic millimeter, respectively, in the non-thalassemic group; 9.8±1.6 g per deciliter (6.1±1.0 mmol per liter), 29.0±5.0 per cent, and 361,000±51,000 per cubic millimeter in the group with three α-globin genes; and 9.2±1.0 g per deciliter (5.7±0.6 mmol per liter), 27.5±3.0 per cent, and 100,000±15,000 per cubic millimeter in the group with two α-globin genes. Deletion of α-globin genes was also accompanied by a decreased mean corpuscular hemoglobin concentration (MCHC) in post-reticulocyte erythrocytes and...

Concurrent sickle cell anemia and alpha-thalassemia. Effect on pathological properties of sickle erythrocytes.

The concurrence of sickle cell anemia and alpha-thalassemia results in less severe hemolytic anemia apparently as a result of reduced intraerythrocytic concentration of hemoglobin S and its retarded polymerization. We have evaluated the effect of alpha-globin gene number on several interrelated properties of sickle erythrocytes (RBC) that are expected to correlate with the hemolytic and rheologic consequences of sickle cell disease. The irreversibly sickled cell number, proportion of very dense sickle RBC, and diminished deformability of sickle RBC each varied directly with alpha-globin gene number. Sickle RBC density was a direct function of the mean corpuscular hemoglobin concentration (MCHC). Even in nonsickle RBC, alpha-globin gene number varied directly with RBC density. Despite differences in alpha-globin gene number, sickle RBC of the same density had the same degree of deformability and dehydration. These data indicate that the fundamental effect of alpha-thalassemia is to inhibit the generation of sickle RBC having high density and MCHC, and that the other beneficial effects of sickle RBC are secondary to this process. The less consistent effect on overall clinical severity reported for subjects with this concurrence may reflect an undefined detrimental effect of alpha-thalassemia, possibly on the whole blood viscosity or on sickle RBC membrane-mediated adherence phenomena.

Revised transthyretin Ile 122 allele frequency in African-Americans

Abstract The transthyretin (TTR) Ile 122 variant is associated with cardiac amyloidosis in individuals of African descent. To determine the prevalence of the allele encoding TTR Ile 122 in African-Americans, we have used PCR and restriction analysis to test DNA from African-Americans from various geographic areas, and found an allele frequency of 66/3376 (0.020), which is higher than the value we previously reported in a much smaller pilot study. Our data indicate that this TTR variant is present at equal frequency in African-Americans throughout the U.S., and suggest that this mutation may be a common, often unrecognized cause of cardiac disease in African-Americans.

Alpha thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia

Purpose: Cerebrovascular complications of sickle cell disease (SCD) are common, but the risk factors remain unclear. The multicenter Stroke Prevention Trial in Sickle Cell Anemia (STOP) provided an opportunity to examine alpha thalassemia‐2 as a modifying risk factor, using abnormal transcranial Doppler ultrasonography (TCD) as a surrogate marker for cerebrovascular disease. The authors hypothesized that children with abnormal TCD are less likely to have alpha thalassemia‐2, and an increased hemoglobin level accounts for this protective effect. Methods: A retrospective study was conducted of children with SCD who had both alpha gene and TCD data from STOP: 128 with TCD of at least 200 cm/s (abnormal TCD) and 172 with TCD less than 170 cm/s (normal TCD). Results: Alpha thalassemia‐2 was more frequent in the normal TCD group compared with the abnormal TCD group. The odds ratio for normal TCD and alpha thalassemia‐2 was 4.1. Adjusting for either hemoglobin level or red cell size (mean corpuscular volume) reduced the odds ratio only slightly. Age, normal TCD, and alpha thalassemia‐2 had significant statistical interaction, so that alpha thalassemia‐2 was not related to TCD for age 10 years or older. Conclusions: The frequency of alpha thalassemia‐2 was significantly higher in children with normal TCD. Speculation on mechanisms of effect includes improved erythrocyte deformability, reduced red cell adhesion, and reduced nitric oxide scavenging in alpha thalassemia‐2. The association of alpha thalassemia‐2 and normal TCD adds to the evidence on the protective effects of alpha thalassemia‐2 in SCD and highlights the contribution of epistatic factors.

Effects of Oxygen Inhalation on Endogenous Erythropoietin Kinetics, Erythropoiesis, and Properties of Blood Cells in Sickle-Cell Anemia

The role of oxygen therapy in sickle-cell anemia is not established, and its effects on erythropoiesis and on the rheologic properties of sickled erythrocytes are controversial. When three patients with sickle-cell anemia who were not in crisis or infected breathed oxygen at a rate of 5 liters per minute continuously through nasal prongs for five days, there was a rapid decline in erythropoietin levels that had initially been elevated, a delayed fall in the number of reticulocytes, and a fall in the number of irreversibly sickled cells, which, in two of the subjects, preceded the suppression of reticulocytosis. After cessation of oxygen therapy, erythropoietin levels and the number of irreversibly sickled cells increased promptly, followed by an increase in the number of reticulocytes. Calculated erythropoietin half-lives were 1.51 to 2.92 hours, and clearances were 43 to 84 ml per minute during oxygen administration. These are normal values. In two subjects, the number of irreversibly sickled cells rose to exceed base-line values after oxygen therapy was discontinued, and both subjects had acute painful episodes at this time. We conclude that in patients with sickle-cell anemia, substantial changes in erythropoiesis and in the rheologic properties of blood occur in association with oxygen inhalation and that when oxygen therapy is administered to such patients, it should be given intermittently rather than continuously.

Cost-effectiveness of hydroxyurea in sickle cell anemia

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost‐effectiveness of hydroxyurea. The MSH was a randomized, placebo‐controlled double‐blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea‐ and placebo‐receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of

Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia

12,160 (95% CI:

The Not-So-Simple Process of Sickle Cell Vasoocclusion

9,440,

Osteonecrosis of the humeral head in sickle cell disease

14,880) for hydroxyurea and