Role of α thalassemia in sickle cell anemia

The purpose of this study was to ascertain whether α thalassemia heterozygotes (α thal) who have sickle cell anemia (SCA) suffer fewer cardiac effects of their SCA due to an increased oxygen carrying capacity or decreased sickling. Echocardiograms and graded, maximal exercise tests were performed in 22 subjects with α thal and SCA, and in 22 age and sex matched controls (C) with SCA alone.peer-reviewe

Causes and Outcomes of the Acute Chest Syndrome in Sickle Cell Disease

Background The acute chest syndrome is the leading cause of death among patients with sickle cell disease. Since its cause is largely unknown, therapy is supportive. Pilot studies with improved diagnostic techniques suggest that infection and fat embolism are underdiagnosed in patients with the syndrome. Methods In a 30-center study, we analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. We evaluated a treatment protocol that included matched transfusions, bronchodilators, and bronchoscopy. Samples of blood and respiratory tract secretions were sent to central laboratories for antibody testing, culture, DNA testing, and histopathological analyses. Results Nearly half the patients were initially admitted for another reason, mainly pain. When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospitalization was 10.5 days. Thirteen percent of patients required mechanical ventilation, and 3 percent died. Patients who were 20 or more years of age had a more severe course than those who were younger. Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, with a 1 percent rate of alloimmunization. One fifth of the patients who were treated with bronchodilators had clinical improvement. Eighty-one percent of patients who required mechanical ventilation recovered. A specific cause of the acute chest syndrome was identified in 38 percent of all episodes and 70 percent of episodes with complete data. Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens. Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia. Infection was a contributing factor in 56 percent of the deaths. Conclusions Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure. Treatment with transfusions and bronchodilators improves oxygenation, and with aggressive treatment, most patients who have respiratory failure recover

Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen

BACKGROUND: The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. High transcranial doppler (TCD) velocities define a subgroup of children with sickle cell disease who are at increased risk for developing ischemic stroke. The genetic factors leading to the development of a high TCD velocity (i.e. cerebrovascular disease) and ultimately to stroke are not well characterized. METHODS: We have designed a case-control association study to elucidate the role of genetic polymorphisms as risk factors for cerebrovascular disease as measured by a high TCD velocity in children with sickle cell disease. The study will consist of two parts: a candidate gene study and a genomewide screen and will be performed in 230 cases and 400 controls. Cases will include 130 patients (TCD ≥ 200 cm/s) randomized in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study as well as 100 other patients found to have high TCD in STOP II screening. Four hundred sickle cell disease patients with a normal TCD velocity (TCD < 170 cm/s) will be controls. The candidate gene study will involve the analysis of 28 genetic polymorphisms in 20 candidate genes. The polymorphisms include mutations in coagulation factor genes (Factor V, Prothrombin, Fibrinogen, Factor VII, Factor XIII, PAI-1), platelet activation/function (GpIIb/IIIa, GpIb IX-V, GpIa/IIa), vascular reactivity (ACE), endothelial cell function (MTHFR, thrombomodulin, VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1), inflammation (TNFα), lipid metabolism (Apo A1, Apo E), and cell adhesion (VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1). We will perform a genomewide screen of validated single nucleotide polymorphisms (SNPs) in pooled DNA samples from 230 cases and 400 controls to study the possible association of additional polymorphisms with the high-risk phenotype. High-throughput SNP genotyping will be performed through MALDI-TOF technology using Sequenom's MassARRAY™ system. DISCUSSION: It is expected that this study will yield important information on genetic risk factors for the cerebrovascular disease phenotype in sickle cell disease by clarifying the role of candidate genes in the development of high TCD. The genomewide screen for a large number of SNPs may uncover the association of novel polymorphisms with cerebrovascular disease and stroke in sickle cell disease

Developmental hematology of homozygous HB C disease

Little is known about the changes of hematological values accompanying the growth and development of young Hb C homozygotes (CC) and their clinical correlates. We have obtained complete blood counts and hemoglobin composition on 18 CC patients who were identified through cord blood testing and examined at intervals of at least six months.peer-reviewe

α-Thalassemia among pediatric Nb S homozygotes

The number of α globin genes have been documented among 255 active SS patients under the age of 15 years. Ascertainment in the area served by our clinical program is 84%. The common -3.7 Kb α+ -Thalassemia (Th) had a gene frequency of 0.17. The incidence of homozygotes was 2.9%, and heterozyqotes 30.6%. These values are consistent with Hardy-Weinberg expectations.peer-reviewe

Deletions and duplications of α or ζ globin genes in children with sickle cell anemia

DNA samples from 345 Black children, aged 0-18 years with SS, SC and Sβ+Thal were tested with restriction endonucleases and α or ζ globin DNA probes. A -3.7 kb type of α-Thal-2 (or -α/) was found in 34% with -α/αα and 4% with -α/-α (gene frequency= 0.20). None had the -4.2 kb type of α-Thal-2. The incidence of a-Thal-2 was the same among SS, SC and Sβ+Thal patients.peer-reviewe

Heart disease in thalassemia heterozygotes with sickle cell anemia

The purpose of this study was to ascertain whether thalassemia heterozygotes (α thal) who have sickle cell anemia (SCA) suffer fewer cardiac effects of their SCA due to an increased oxygen carrying capacity or decreased sickling. Echocardiograms and graded, maximal exercise tests were performed in 22 subjects with α thal and SCA, and in 22 age and sex matched controls (C) with SCA alone. The patients ranged in age from 8-32 years.peer-reviewe

Serum Ferritin in Children with Sickle Cell Disease on Chronic Transfusion: Measure of Iron Overload or End Organ Injury? STOP/STOP II Liver Iron Ancillary Study

Abstract Between 1995 and 2004, two NIH-sponsored studies (STOP/STOP II) showed that children with sickle cell disease (SCD) and abnormal transcranial Doppler blood flow measurements (high stroke risk) are protected from stroke with regular blood transfusions. Iron overload, which may lead to complications and requires iron removal therapy, was monitored by serum ferritin (SF). Liver iron concentration (LIC) measurement was not mandated by protocol and was performed at investigator discretion. Biopsy dates and lab values were captured during STOP/STOP II, providing an opportunity to validate SF against LIC. 75 LICs on 36 patients (19 female, 17 male) at 8 centers were obtained. No liver biopsy complications were reported. LICs were correlated with STOP/STOP II core laboratory SF and alanine aminotransferase (ALT) obtained within 180 days of LICs. Median age at first biopsy was 11.1 years (range, 4.5–17.8), median time from start of transfusion was 36 months (range, 2–100). Iron removal treatment was initiated a median 23 months (range, 4–108) from start of transfusion, with deferoxamine (n=27), and/or exchange transfusion (n=9). 21 pts (58%) had multiple LIC measures: 2 (n=9), 3 (n=8), 4 (n=2), 5 (n=2). Last LICs on iron removal therapy were obtained a median 72 months (range, 35–124) from start of transfusion. Correlation between SFs and LICs were r=-0.06 (n=18) for first LICs obtained prior to iron removal therapy, r=0.50 (n=17) for last LICs obtained on iron removal therapy, and r=0.51 for all LICs (n=60). Pts with single/last LIC >=15 mg/gram dry liver were significantly more likely to have ALTs >=45 IU/L compared to those with LICs =15 mg/gram and ALT >=45 IU/L tended to have higher SFs then those with normal ALT (mean SF 4927 ng/ml, 95% CI 1739–8115 vs. mean SF 2255 ng/ml, 95% CI 1599–2912). 37% (7/19) of pts with LIC >=15 mg/gram had SFs <2000 ng/ml. 55% (11/20) of pts with repeated LICs, had last LICs <15 mg/gram after initiation of iron removal therapy. SF did not correlate with LICs after initiation of blood transfusion therapy and correlated weakly after initiation of iron removal therapy. Over 1/3 of children with evidence of significant iron overload, as measured by LICs, had low serum SFs (<2000 ng/ml), leading to a potentially erroneous interpretation of low iron stores. A significant portion of pts with elevated LICs had evidence of liver injury (ALT elevation). SF elevation observed in some pts may be due in part to end organ injury. Sustained iron overload control was achieved in over 1/2 of pts examined with repeated LICs