Context Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease. Objective To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals. Design, Setting, and Participants Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level ≤10 mg/dL) aged 19 to 55 years and of African descent (n=149) or community controls (Hb AA and normal hemoglobin level) (n=47). Participants were stratified on age, sex, and education. Main Outcome Measures The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae. Results The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, −5.50; 95% confidence interval {CI}, −9.55 to −1.44]; P =.008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, −5.19; 95% CI, −9.24 to −1.13]; P =.01), working memory (90.75 vs 95.25 [mean difference, −4.50; 95% CI, −8.55 to −0.45]; P =.03), processing speed (86.50 vs 97.95 [mean difference, −11.46; 95% CI, −15.51 to −7.40]; P <.001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function. Conclusion Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.
Screening for pulmonary hypertension (pHTN) has not yet become routine in sickle cell disease (SCD), despite clinical evidence of its high prevalence and associated mortality. Our objectives are to identify clinical conditions and laboratory findings predictive of/or associated with pHTN. One hundred twenty-five adult outpatients with Hb SS, SC, SOArab, Sb 0 , or Sb 1 thalassemia, who underwent echocardiography and/or right heart catheterization due to cardiorespiratory symptoms, were studied. pHTN was identified in 36% (28/77) of SS/Sb 0 and in 25% (12/48) of SC/SOArab/Sb 1 patients studied. In SS/Sb 0 patients, pHTN was associated with low hemoglobin, low GFR, increasing age, no history of treatment with hydroxyurea and a history of leg ulcers, with trends for associations with higher total bilirubin, LDH levels, systolic systemic blood pressure, history of avascular necrosis, seizures, and cerebrovascular events. Twelve (40%) of the SS/Sb 0 patients with pHTN had ≥11 proteinuria. (P < 0.039). The presence of proteinuria correlated with lower GFR and had a high positive predictive value (0.60) for pHTN in subjects with SS/Sb 0 . The data also provided evidence that pHTN in this population is associated with right heart failure, with echocardiographic evidence of right ventricle enlargement and pericardial effusion. This study confirmed that even relatively mild elevations in pulmonary pressure are associated with high prospective mortality (hazard ratio: 15.9). We concluded that pHTN has a high prevalence in all Hb S related syndromes and is associated with increased mortality in SS/Sb 0 . Kidney dysfunction, as indicated by proteinuria or decreased GFR, also represents sufficient reason to screen for pHTN. Am. J. Hematol. 83:19-25, 2008. V
We examined the relationship of clinical differences among sickle cell disease (SCD) patients in order to understand the major contributors to early mortality in a contemporary cohort. Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis. Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sβ0 was 58 years and for Hb SC and Sβ+ was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM-1 and short-acting narcotics use were significantly associated with decreased survival. 42% of subjects were on hydroxyurea therapy, which was not associated with survival. SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ0 and SS. Not only were comorbidities individually associated with decreased survival, but an additive effect was observed, so that those with a greater number of negative endpoints had worse survival (p<0.0001). The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial.
The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD) has not been previously explored. We have now found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation. The major counter receptor for LW was identified as the ␣v3 integrin on ECs. These data suggest that adrenergic hormones such as epinephrine may initiate or exacerbate vaso-occlusion and thus contribute to the association of vasoocclusive events with physiologic stress. IntroductionIn sickle cell disease (SCD), abnormal adherence of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) has been postulated to be important in the initiation and/or progression of vaso-occlusive crises. [1][2][3] Although many vaso-occlusive episodes are associated with intercurrent illnesses, and thus with release of endotheliumactivating cytokines such as tumor necrosis factor ␣ (TNF-␣), other vaso-occlusive episodes are associated with other types of stressors. We are interested in exploring whether physiologic stress may precipitate vaso-occlusion via activation of red cell adhesion.Human erythrocytes are equipped with a diversity of receptors and effectors that are known to mediate well-characterized signal transduction pathways in nonerythroid cells. 4 Although activation of adhesion receptors via signal transduction is well accepted in nonerythroid cells, until recently, little attention had been paid to the possibility that abnormal SS RBC adhesion might be mediated via signaling mechanisms inducing activation of RBC adhesion receptors. 5,6 Nevertheless, such events could promote, or even initiate, vaso-occlusion.A variety of stimuli, including epinephrine, have been shown to activate the basal cell adhesion molecule-Lutheran (B-CAM/LU) laminin receptor on SS RBCs through a cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway. 7 Epinephrine is a major stress mediator that elevates cAMP in SS RBCs through stimulation of adrenergic receptors. 7 Cyclic AMP mediates at least some of its effects through activation of PKA. Based on these observations, we postulated that activation of SS RBC adhesion via known signaling pathways might lead to upregulation of SS RBC adhesion to endothelium, even in the absence of plasma bridging proteins. Study of up-regulation of cAMPdependent PKA signaling pathway by epinephrine in SS RBCs has now led to the identificatio...
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