Inflammatory Cytokines: TNFα, IL-1β, IL-6 and IL-8 in Pulmonary Hypertension of Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3787-3787
Author(s):  
Perla Vicari ◽  
Maria Aparecida E. Noguti ◽  
Vania M. Morelli ◽  
Rodolfo D. Cançado ◽  
Maria Stella Figueiredo
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Plasma Levels ◽  
Interleukin 1 ◽  
Fetal Hemoglobin ◽  
Lactic Dehydrogenase ◽  
Control Group ◽  
Cell Disease ◽  
Necrosis Factor Alpha

Abstract Background: Although pulmonary hypertension (PHT) is a common complication in patients with sickle cell disease (SCD), the rate of development of PHT and the factors that affect disease progression are unknown. Objectives: To evaluate the plasma levels of cytokines in SCD comparing with healthy subjects and to find out if there is a relationship among cytokines and PHT. Patients and methods: Dosage of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), interleukin-8 (IL-8) and interleukin-1 beta (IL-1β) had been evaluated in 107 steady-state sickle cell patients, from the UNIFESP/EPM and College of Medical Sciences of the Santa Casa de Misericórdia, and in 108 blood donors. The presence of PHT was evaluated in sickle cell patients by transthoracic Doppler echocardiogram and the results were associated with age, hemoglobin and fetal hemoglobin, lactic dehydrogenase and cytokines levels. Results: The presence of PHT was significantly related with age, low hemoglobin and high lactic dehydrogenase levels. There were no difference of plasma levels of IL-6, IL-1β and TNFα between patients and controls. The IL-8 levels were predominantly higher in patients than in controls (p=0.0001). Among patients with SCD, IL-8 levels were significantly higher in those with PHT (p=0.02). In addition, increased levels of IL-8 (>95th percentile of the control group) were detected in 33.3% in patients with PHT in comparison with 10.8% in those without (OR: 4.1; 95%CI 1.3–12.7). Conclusion: These results indicate that age, hemoglobin, lactic dehydrogenase levels, and elevated levels of IL-8 could be risk factors of PHT in SCD. However a larger study with SCD patients with PHT is required to clarify this question. (Funded by Fapesp 04/04498–4).

scholarly journals Incentive Spirometry to Prevent Acute Chest Syndrome in Adults with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3660-3660
Author(s):  
Bart J. Biemond ◽  
Charlotte F.J. Van Tuijn ◽  
Aafke E. Gaartman ◽  
Erfan Nur ◽  
A. W. Rijneveld
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Risk Score ◽  
Predictive Value ◽  
Plasma Levels ◽  
Adult Patients ◽  
Acute Chest Syndrome ◽  
Control Group ◽  
Cell Disease ◽  
Incentive Spirometry

Abstract Introduction: Amongst patients with sickle cell disease (SCD) the leading cause of death is the acute chest syndrome (ACS). This pneumonia-like complication frequently occurs during or shortly after a vaso-occlusive crisis (VOC). In pediatric patients hospitalized for VOC, incentive spirometry has demonstrated to prevent the development of ACS. This study was designed to determine if a comparable effect of incentive spirometry can be demonstrated in adult patients with SCD. Furthermore, we aimed to validate the ability of the Bartolucci score to identify patients at risk of ACS and assessed the value of procalcitonin as a potential biomarker for ACS . In addition, clinical characteristics and laboratory results were determined to identify potential risk factors. Methods: In this multicenter prospective randomized trial, we included consecutive adult patients (≥18 yr) admitted for VOC presenting with chest or back pain above the diaphragm. Patients were randomly assigned to spirometry or control group. Patients presenting with ACS were excluded. A chest radiograph was performed 5 days after admission, or sooner when clinically indicated, in order to diagnose pulmonary abnormalities. ACS was defined as a new infiltrate/atelectasis combined with pulmonary symptoms. At presentation, procalcitonin plasma levels were assessed and the Bartolucci risk score was calculated to determine to the risk of developing ACS for each patient. In addition, clinical and laboratory parameters were compared between patients with and without ACS during admission. Results: In total 66 episodes of hospitalization for VOC in 48 patients were included. Median age was 26 years and 46 of the hospitalizations concerned patients with a severe genotype (HbSS/HbSβ0 thalassemia) versus 20 hospitalization with a mild genotype (HbSC/HbSβ+thalassemia). The overall incidence of ACS in this study cohort was 19.7%. In the spirometry group, ACS was diagnosed in 5/34 (14.7%) hospitalizations compared to 8/32 (25%) hospitalizations in the control group (OR 0.5 [0.15-1.8]; P=.293). Twelve of the 13 ACS episodes occurred in patients with a severe genotype. The Bartolucci risk score could be calculated for 50 hospitalizations. The scores area under the curve (AUC) was 0.747 (P=.013), with a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 31%. No difference in procalcitonin plasma levels were found between patients with and patients without ACS (0.52 ± 1.56 μg/ml versus 0.56 ± 1.44 μg/ml, respectively). At baseline, hemoglobin levels were significantly lower while LDH plasma levels, leukocyte and platelet counts were significantly higher in ACS hospitalizations as compared to non-ACS hospitalizations. Patients who developed ACS showed significantly more documented fever during admission (61.5% vs 17.0%) and a longer length of hospital stay (median 10.0 days vs 4.5 days). Conclusion: Incentive spirometry did not significantly reduce the development of ACS in this prospective study in adult patients with SCD admitted with VOC and pain above the diaphragm. Procalcitonin plasma levels and the Bartolucci score could not accurately identify patients that at risk to develop ACS, but a low score appeared to be a reliable tool to identify patients with a low risk of ACS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Study of pulmonary hypertension as a complication of sickle cell disease

2020 ◽  
Vol 7 (2) ◽  
pp. 297
Author(s):  
Vijay Bakhtar ◽  
Niyati Bakhtar ◽  
Nikhil Bakhtar ◽  
Kirit Pandey
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Pulmonary Function Tests ◽  
Central India ◽  
Control Group ◽  
Older Individuals ◽  
Cell Disease ◽  
2D Echocardiography

Background: Sickle cell anaemia is the most common inherited hematological abnormality across human race, particularly prevalent in pockets of central India and pulmonary hypertension (PH) supposedly worsens prognosis. Data from central India is lacking though. Present study aims to study incidence of pulmonary hypertension as a complication in patients of sickle cell disease.Methods: Patients aged more than 12 years diagnosed to have sickle cell anaemia on hemoglobin electrophoresis during the study period (total- 94; 54 SS and 40 AS) were enrolled as cases. Sixty four age/sex matched healthy close relatives of the cases with ‘AA’ Hb electrophoresis pattern doubled up as controls. Participants were thoroughly assessed with complete history, examination, haematological and biochemical tests, X-ray chest, ECG, pulmonary function tests and 2D-echocardiography and Doppler studies and data analysed.Results: Pulmonary hypertension was observed in a total of five SS cases (5/54, 9.26%). No participant from the AS group or the control group developed pulmonary hypertension. It was more common in females (3/23, 13%) than males (2/26, 7.7%). The mean age of the SS cases with PH (32±5.15 years) was found to be significantly higher than that of the SS cases without PH (24.2±6.21 years) (p<0.01).Conclusions: The incidence of PH in sickle cell disease was relatively lower as compared to western countries and was found to affect females and older individuals more. Larger community-based studies are recommended for corroboration.

scholarly journals Association of FOXO3A Polymorphisms with Hematocrit, LDH and Longevity in Patients with Sickle Cell Anemia from CSSCD, Walk-Phasst, and PUSH Clinical Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2176-2176
Author(s):  
Harold T Bae ◽  
Paola Sebastiani ◽  
Victor R. Gordeuk ◽  
Yingze Zhang ◽  
Martin H. Steinberg ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Survival Analysis ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Reticulocyte Count ◽  
Fetal Hemoglobin ◽  
Human Longevity ◽  
Age At Death ◽  
Cell Disease

Abstract Background The FOXO3A genotype is strongly associated with longevity in humans. It encodes a transcription factor that appears to regulate anti-oxidant genes during erythroid differentiation in mice, resulting in a hemolytic anemia. The gene has also been implicated in the regulation of fetal hemoglobin expression in children with sickle cell disease. We performed a gene-wide association study to identify and replicate variants of FOXO3A that might be associated with seven biomarkers in patients with sickle cell anemia. Methods 1198 patients from the Cooperative Study of Sickle Cell Disease (CSSCD) study, 308 patients from the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) study, and 220 patients from the Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study were analyzed. Biomarkers included hematocrit, reticulocyte count, fetal hemoglobin (HbF), serum levels of lactate dehydrogenase (LDH), aspartate aminotransferase and bilirubin, and the calculated hemolytic component, each appropriately transformed to achieve normality. A total of 189 single nucleotide polymorphisms (SNP) that were either genotyped or imputed (quality r2 > 0.9) were used. Association between each biomarker and SNP was tested using linear regression assuming an additive genetic model, adjusted for age and sex. None of the patients in the CSSCD were treated with hydroxyurea at the time of measurements of the biomarker variables. In the Walk-PHaSST and PUSH, we first examined whether there was a significant association between the biomarker and treatment effect of hydroxyurea; if there was a significant treatment effect, then we looked at potential SNP-by-treatment interaction. For those with significant interactions, only patients without hydroxyurea treatment were included in the analysis. The genetic analysis results from the three studies were then combined to produce meta-analyzed results. Finally, a survival analysis using Cox regression was performed to model age at death in a subset of 54 patients in the CSSCD. Results Among the seven biomarkers, hematocrit showed the most robust enrichment of associations with FOXO3A SNPs. Eight of the 16 published variants had meta-analyzed p-value <0.05. Of those, six had a consistent direction of effects across all three cohorts. Overall, there were 8 loci with 34 SNPs that had meta-analyzed p<0.05 in hematocrit. The most significantly associated SNP (rs6911407; meta-analyzed Beta=-0.0127, meta-analyzed p=0.0013) is one previously associated with human longevity. LDH was most significantly associated with variant rs12206094 (meta-analyzed Beta=0.0256, meta-analyzed p=0.0072), another SNP previously associated with human longevity. Four of the allelic variants associated with LDH were also associated with hematocrit in the appropriate direction. There were also some evidence of enrichment of associations with reticulocyte counts (2 loci with 22 SNPs), HbF (1 locus with 11 SNPs; 10 SNP associations overlapped with reticulocyte count in the appropriate direction), and hemolytic component (2 loci with 8 SNPs); however, the strengths of associations in these biomarkers were marginal (0.01<p<0.05). The survival analysis revealed one locus significantly associated with age at death in the CSSCD patients (rs2802297; p=0.028). Conclusion FOXO3A genetic polymorphisms are associated with hematocrit and serum LDH in this meta-analysis of patients with sickle cell anemia, with less robust associations with fetal hemoglobin level and reticulocyte count. Our genetic findings are biologically consistent with published knockout mouse data indicating that FOXO3A regulates red cell antioxidant capacity and hemolytic severity. Our observation of fetal hemoglobin association with FOXO3A helps to validate previously presented results from Sheehan and colleagues. Parallel to well-documented results in the general population, we find preliminarily that a FOXO3A allelic variant predicts longevity in patients with sickle cell anemia. FOXO3A appears to play a significant role in phenotypic variation in sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

Prolonged QTc in Sickle Cell Disease: A Potential Risk Factor for Early Death?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2476-2476
Author(s):  
Sean Lindstedt ◽  
Lynne Neumayr ◽  
Gregory Kurio ◽  
Claudia Morris ◽  
Shanda Robertson ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sudden Death ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Toxicity ◽  
Control Group ◽  
Cell Disease ◽  
Qtc Prolongation ◽  
Cardiac Iron

Abstract Background: Sudden unexplained death is one of the leading causes of mortality in sickle cell disease (SCD). Prolonged QTc has been associated with sudden death in older patients and in those with cardiac disease. Sudden death due to cardiac arrhythmias occurs in thalassemia (Thal) patients from cardiac iron toxicity, and recently, QTc prolongation has also been identified in this transfusion-dependent population. Chronic transfusion and iron overload have become more frequent in patients with SCD due to treatment regimens aimed at stroke prevention and treatment of stroke, pulmonary hypertension (PH) and recurrent vaso-occlusive crisis. Cardiac iron toxicity is thought to be rare in SCD but other factors such as anemia, PH, and hemolysis-associated nitric oxide dysregulation may predispose SCD to prolongation of the QTc interval. The purpose of this study was to examine the prevalence of QTc prolongation in chronically transfused and iron-overloaded SCD (txSCD) patients compared to a control group of non-transfused SCD patients. Methods: In this study, electrocardiograms (EKGs) were reviewed from SCD patients participating in the MCSIO, a five-year prospective study of the complications of iron toxicity in SCD and Thal. Using Bazett’s formula, a subset of 96 EKGs were analyzed for QTc prolongation, defined as ≥ 0.45 seconds and borderline as 0.44 to 0.449 seconds. Echocardiograms (ECHOs) obtained within an average of seven months were analyzed for left ventricular dysfunction (LVD) --which was defined as an ejection fraction &lt; 55% or shortening fraction &lt; 28% --and the presence of PH, defined as a tricuspid regurgitant jet velocity (TRJV) of ≥ 2.5 m/second. Results: There was no difference in mean age (25.3 ± 13.6) or gender (64% female) between the 65 txSCD and 31 control SCD patients. The txSCD group had been transfused 10 ± 6.2 years and their baseline ferritin was 3107 compared to 116 in the controls. QTc prolongation was present in 32% of the txSCD and 29% of the control group (n.s.); borderline prolongation was seen in an additional 17% and 13%, respectively. Mean QTc in txSCD was also not significantly different from the SCD controls: 0.45±.04 vs. 43±.03 (n.s.). None of the 68 patients with ECHOs had LVD. 36 patients had TRJV measured during the study: 50% of the txSCD had PH compared to 30% of non-transfused SCD (n.s.). The average QTc in PH patients was 0.45 ± .04 compared to 0.43 ± .04 in those without PH (p=.09). However, the frequency of either prolonged or borderline QTc was significantly higher in patients with PH (72% vs. 22%, p= .007). No correlations between QTc and age, gender, or baseline laboratory values (hemoglobin, white blood count, or platelets) were found. In the txSCD, QTc was not correlated to ferritin or years of transfusion. Conclusions: Overall, QTc prolongation was found in 31 % of SCD patients and borderline prolongation in an additional 16%. QTc intervals ≥ 0.44 were more common in patients with PH. Transfusion exposure and iron overload were not associated with QTc prolongation in this group of txSCD patients. The frequency of QTc prolongation is concerning in SCD patients, who often have pulmonary hypertension and are treated with medications known to contribute to QTc prolongation. Routine screening for QTc prolongation appears warranted with treatment of high-risk SCD patients.

Elevated Circulating Stromal Derived Factor-1 Levels in Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1438-1438
Author(s):  
Precious Landburg ◽  
Erfan Nur ◽  
Naomi Maria ◽  
Bart J. Biemond ◽  
Dees P.M. Brandjes ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Cell Disease ◽  
Steady State Levels ◽  
Leukocyte Counts ◽  
Painful Crisis

Abstract Inflammation and angiogenesis are of importance in the pathophysiology of sickle cell disease (SCD). Recently, the chemokine Stromal Derived Factor-1 (SDF-1) has been shown to be a key mediator of angiogenesis and inflammation. In this study we determined serum SDF-1 levels in consecutive adult sickle cell patients during the clinically asymptomatic state as well as during painful crisis. Serum SDF-1 levels were significantly elevated in HbSS/HbSβ0-thalassemia patients ([n=39], 3805 pg/mL (2121–6790)) as opposed to HbSC/HbSβ+-thalassemia patients ([n=18], 2405 pg/mL (1365–3047)) and healthy HbAA controls (n=25, 2623 pg/mL (2435–2988)) (p=0.04). During painful crisis SDF-1 levels increased significantly in both HbSS/HbSβ0-thalassemia ([n=24]) 26040 pg/mL (20135–27960)) and HbSC/HbSβ+-thalassemia patients ([n=5], 12666 pg/mL (3936–24453)) (p&lt;0.001 and p=0.01, respectively). Paired sample analysis was possible in 8 patients (SDF-1 determined in steady state and during painful crisis) and all patients demonstrated a strong SDF-1 increment from steady state levels (p=0.01) and serial measurements, available from 11 patients, showed persistently elevated SDF-1 levels well beyond crisis abatement (data not shown). Furthermore, SDF-1 levels were significantly higher in sickle cell patients with pulmonary hypertension as compared to patients without pulmonary hypertension in both HbSS/HbSβ0-thalassemia (PHT+ [n=8]: 6549 pg/mL (3893–7159), PHT- [n=24]: 2945 pg/mL (1560–6627)) and HbSC/HbSβ+-thalassemia (PHT+ [n=4] 3316 pg/mL (2900–6417) and PHT- [n=12] 2146 pg/mL (1138–2592)) patients (p=0.02 and p=0.01, respectively). SDF-1 levels were not related to other forms of organ damage, nor were they significantly associated with hemoglobin levels, the percentage of fetal hemoglobin or leukocyte counts in the clinically asymptomatic state (data not shown). Taken together, elevated circulating SDF-1 levels occur in patients with SCD and may play a role in the pathophysiology of acute and specific chronic disease related complications.

scholarly journals Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 597-602 ◽  
Author(s):  
GP Rodgers ◽  
MS Roy ◽  
CT Noguchi ◽  
AN Schechter
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Microvascular Obstruction ◽  
Controlled Study ◽  
Control Group ◽  
Cell Disease ◽  
Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

scholarly journals DNA polymorphisms at the BCL11A, HBS1L-MYB, and  -globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease

2008 ◽  
Vol 105 (33) ◽  
pp. 11869-11874 ◽  
Author(s):  
G. Lettre ◽  
V. G. Sankaran ◽  
M. A. C. Bezerra ◽  
A. S. Araujo ◽  
M. Uda ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Dna Polymorphisms ◽  
Cell Disease
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