Sickle blood contains tissue factor–positive microparticles derived from endothelial cells and monocytes

Abstract Blood microparticles (MPs) in sickle cell disease (SCD) are reportedly derived only from erythrocytes and platelets. Yet in SCD, endothelial cells and monocytes are activated and abnormally express tissue factor (TF). Thus, sickle blood might contain TF-positive MPs derived from these cells. With the use of flow cytometry to enumerate and characterize MPs, we found total MPs to be elevated in crisis (P = .0001) and steady state (P = .02) in subjects with sickle cell disease versus control subjects. These MPs were derived from erythrocytes, platelets, monocytes, and endothelial cells. Erythrocyte-derived MPs were elevated in sickle crisis (P = .0001) and steady state (P = .02) versus control subjects, as were monocyte-derived MPs (P = .0004 and P = .009, respectively). Endothelial and platelet-derived MPs were elevated in sickle crisis versus control subjects. Total TF-positive MPs were elevated in sickle crisis versus steady state (P = .004) and control subjects (P < .0001) and were derived from both monocytes and endothelial cells. Sickle MPs shortened plasma-clotting time compared with control MPs, and a TF antibody partially inhibited this procoagulant activity. Markers of coagulation were elevated in patients with sickle cell disease versus control subjects and correlated with total MPs and TF-positive MPs (P < .01 for both). These data support the concept that SCD is an inflammatory state with monocyte and endothelial activation and abnormal TF activity. (Blood. 2003;102:2678-2683)

Download Full-text

Platelets From Sickle Cell Disease Individuals Induce Endothelial Activation, Demonstrating ICAM-1 and E-Selectin Adhesion Molecule Expression, Inflammatory Cytokine Production and Activation of NFκB Transcription Factor Gene Expression.

Blood ◽

10.1182/blood.v120.21.2114.2114 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2114-2114

Author(s):

Renata Proença-Ferreira ◽

Ana Flavia Brugnerotto ◽

Vanessa Tonin Garrido ◽

Marilene de Fatima Reis Ribeiro ◽

Fabiola Traina ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Transcription Factor ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Adhesion Molecule ◽

Direct Contact ◽

Endothelial Activation ◽

Cell Disease ◽

Gene Encoding

Abstract Abstract 2114 Introduction: Sickle cell disease (SCD) pathophysiology is associated with a hypercoagulable state that may contribute to the initiation and propagation of vaso-occlusion. Increased platelet activation has been described in SCD and SCD platelets may present augmented adhesion to the vascular endothelium, potentially contributing to vaso-occlusion. Aim: This study investigated whether platelets (PLTs) from SCD individuals are able to activate endothelial cells per se. Methods: Human umbilical vein endothelial cells (HUVEC) were cultured (1×106cells/well) on 6-well plates (37°C, 5% CO2). Subsequently, HUVEC were co-cultured in direct contact, or not, with washed PLTs (1×108PLTs/well) from healthy control individuals (CON, n=23) or steady-state SCD patients (SCD, n=47; 26 of which were on hydroxyurea therapy; 20mg/Kg/day) for 4h, 37°C, 5%CO2. After incubation, PLTs were removed; supernatants were reserved for cytokine quantification by ELISA, and HUVEC were analyzed by flow cytometry for CD62E (E-Selectin) and CD54 (ICAM-1) surface expression; gene expressions of ICAM1 and NFKBIA were analyzed by qPCR. Results: Basal ICAM-1 expression on the surface of HUVEC (39.6±3.2%, n=15) was significantly increased following their incubation in direct contact with SCD PLTs (46.1±3.1%, n=26, p<0.05, Wilcoxon test), but not CON PLTs (41.3±4.7%, n=12). E-selectin expression was also low level on the surface of HUVEC (0.9±0.2%, n=17), and was slightly but significantly increased following incubation of cells with SCD PLTs (6.1±2.2%, n=26, p<0.001), but not CON PLTs (3.6±1.5%, n=12, p>0.05). Repetition of these assays, but with the placement of transwell inserts in culture plates to separate the PLTs from HUVEC resulted in a 45% decrease in ICAM-1 expression (p<0.05), and 85% decrease in E-selectin (p<0.05) expression on the surface of HUVEC, following their incubation with SCD PLTs. HUVEC produce and release interleukin-8 (IL-8); basal IL-8 production by HUVEC (1×106cells/well) was 1.160±0.187ng/mL (n=21); this production was augmented in the presence of SCD PLTs (1.280±0.149ng/mL, n=42, p<0.01), but not by CON PLTs (1.127±0.157ng/mL, n=23). The influence of PLT IL-8 production on these values was negligible, as shown by data (not shown) demonstrating that PLT IL-8 production is low level and does not differ between CON and SCD PLTs. IL-1β is produced and released by PLTs (CON, 3.4±1.4ρg/mL, n=12; SCD, 6.5±1.5 ρg/mL, n=25, p>0.05), but this production was further increased when PLTs were co-cultured with HUVEC: SCD PLTs (10.3±4.2ρg/mL, n=47; p<0.01) and CON PLTs (5.8±2.4ρg/mL, n=25; p>0.05), compared to HUVEC alone (1.27±0.4ρg/mL, n=24). Gene expression of ICAM1 by HUVEC increased 6.3-fold in the presence of SCD PLTs (n=25, p<0.01), compared to basal expression (n=11), but was not altered in the presence of CON PLTs (n=11, p>0.05). The expression of the gene encoding the NFkB transcription factor, NKBIA, increased 3.4-fold in HUVEC following incubation with SCD PLTs (n=25, p<0.05), compared to basal NFKBIA expression (n=12); however NFKBIA expression in HUVEC was not significantly altered by CON PLTs (n=10, p>0.05). Conclusions: Results indicate that the contact of platelets, or products released from platelets, from patients with SCD may activate endothelial cells, in vitro, increasing adhesion molecule and IL-8 production, associated with an augmented expression of the gene encoding NFkB. Platelets produce IL-1β in greater quantities in the presence of endothelial cells, possibly contributing to endothelial cell activation; however the fact that transwell inserts significantly reduced SCD PLT-mediated endothelial activation indicates that the direct contact of PLTs (possibly via adhesion) is required for this activation. Data indicate that platelets adhered to vessel walls may play an important role in endothelial activation and, therefore, vaso-occlusive mechanisms in SCD. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Proangiogenic Effects of Plasma From Sickle Cell Disease Patients and Antiangiogenic Effects of Hydroxyurea: Evaluation of Invasion and Proliferation of Human Endothelial Cells and Effects of Hydroxyurea in a Mouse Matrigel Plug Neovascularization Assay

Blood ◽

10.1182/blood.v120.21.377.377 ◽

2012 ◽

Vol 120 (21) ◽

pp. 377-377 ◽

Cited By ~ 1

Author(s):

Fláavia Cristine Mascia Lopes ◽

Raquel Costa ◽

Sara T Olalla Saad ◽

Raquel Soares ◽

Fernando Ferreira Costa ◽

...

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Steady State ◽

Endothelial Cell ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Invasion ◽

Cell Disease ◽

Matrigel Plug ◽

Key Steps

Abstract Abstract 377 Sickle Cell Disease (SCD) results from mutations in the β hemoglobin chain and is associated with a complex pathophysiology that often involves recurrent vasoocclusion in association with vascular inflammation, oxidative stress, ischemia-reperfusion injury and endothelial activation. Dysregulation of angiogenesis occurs in various pathologies and a newly recognized proangiogenic state is associated with SCD. Central to the process of angiogenesis are the endothelial cells (EC) that are activated by angiogenic signals and release degrading enzymes that allow EC to migrate, proliferate and finally differentiate to form new vessels. In keeping with this proposed proangiogenic state, we previously found that plasma from SCD patients increases human umbilical vein endothelial cell (HUVEC) tube formation on Matrigel. In contrast, plasma from SCD patients treated with hydroxyurea (HU; a drug that has been used successfully for SCD therapy) inhibited the ability of HUVEC to form branching and thick anastomosing capillaries in the same model. In the present study, we aimed to determine the effects of plasma from SCD patients on additional HUVEC functions associated with key steps of angiogenesis, including invasion and proliferation, as well as further evaluating the direct antiangiogenic effects of HU with a mouse Matrigel plug neovascularization assay. Steady-state HbSS (SS), steady-state HbSS treated with HU (SSHU, 20–30mg/kg/day HU) and healthy control individuals (CON) were recruited for the study. Invasive cell behavior in the presence of 10 % plasma was quantified in vitro using a double-chamber assay. Under the same conditions, cell proliferation analyses were carried out using cellular incorporation of bromodeoxyuridine. Interestingly, an effective increase of 39.66 ± 29.54% in EC invasion was observed in the presence of SS plasma (P<0.05, N=5) compared to basal cell invasion. In contrast, SSHU plasma resulted in a significant decrease in cell invasive ability (51.94 ± 7.82% reduction; N=5, P<0.001). Accordingly, when the proliferative activity of SS plasma was investigated, increased cell proliferation was observed (13.73 ± 3.41%, compared to basal EC proliferation; N=5, P<0.05). Plasma from SSHU individuals significantly reduced HUVEC proliferation by 24.90 ± 3.45% (P<0.0, N=5). In contrast, CON plasma did not modify either the invasive or proliferative activities of HUVECs. For the Matrigel plug assay, C57BL/6 mice received subcutaneous Matrigel plugs supplemented, or not, with 100μM HU in the presence or absence of vascular endothelial growth factor (VEGF). After seven days, the plugs were removed and Matrigel hemoglobin content measured, using Drabkin's method. The positive control group (VEGF) presented extensive neovascularization of the Matrigel, as shown by the red color distributed in the whole plug. In contrast, Matrigel implants treated with both VEGF and HU demonstrated a strong inhibition of vascular development (67.53 ± 6.68% reduction in neovascularization; N=6, P<0.05) that was similar to that of negative controls (Matrigel not treated with VEGF). Data presented herein show that important features of the angiogenic process, endothelial cell invasion and proliferation, can be upregulated by plasma from SCD patients, confirming the apparent proangiogenic status of these individuals. In contrast, plasma from patients treated with HU exerted antiangiogenic effects by inhibiting the same angiogenic steps. Furthermore, HU was found to have direct antiangiogenic effects in in vivo assays. To our knowledge, this is the first report of the antiangiogenic activity of HU in a mouse model. Balancing angiogenesis is essential for SCD individuals, as enhanced angiogenesis may increase the incidence of manifestations such as proliferative retinopathy and pulmonary hypertension. On the other hand, angiogenesis is essential for mechanisms such as ulcer recovery, neovascularization of ischemic tissues and tissue regeneration and it may be that HU therapy may retard such processes. In conclusion, this study finds further evidence for a proangiogenic state in SCD. HU inhibits key steps in angiogenic mechanisms, demonstrating a possible use for this drug in the treatment of pathological angiogenesis in this and other diseases. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Differentially Expressed Genes and Pathways in Endothelial Cells Exposed to Hemin or Plasma from Patients with Sickle Cell Disease: A Meta-Analysis of Gene Expression Studies

Blood ◽

10.1182/blood.v124.21.4018.4018 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4018-4018

Author(s):

Maiara M L Fiusa ◽

Marina Pereira Colella ◽

Joyce M Annichino-Bizzacchi ◽

Loredana Nilkenes ◽

Bidossessi W Hounpke ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Steady State ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Meta Analysis ◽

P Value ◽

Cell Disease ◽

Expression Studies ◽

Gene Expression Studies

Abstract Introduction: Vaso-occlusion and chronic hemolysis are recognized as the most important pathogenic mechanisms of sickle cell disease (SCD), feeding a vicious circle that leads to acute and chronic complications. Although phenotypic aspects of this pro-inflammatory state have been described in detail, much less is known about the upstream pathways that activate and perpetuate inflammation in SCD. It has been known for more than 50 years that patients with SCD present higher plasma concentrations of heme. More recently, the role of heme as a mediator of inflammation in SCD has been confirmed in relevant models, suggesting that free heme can be a trigger for both microvascular occlusion and acute chest syndrome (ACS). In the past, microarray-based gene expression experiments have been used to study the effects of heme on endothelial cells (EC), as well as gene expression signatures of SCD. These studies can be analyzed in combination, since original raw data are now collected in public archives. In fact, it has been shown that by analyzing data from multiple experiments by meta-analysis, biases and artifacts between datasets can be cancelled out, potentially allowing true relationships to stand out. In order to gain insights into the cellular and molecular pathways activated by heme in endothelial cells (EC), as well as about their potential relevance in SCD, we performed a meta-analysis of microarray-based gene expression studies involving heme, EC and SCD. Material and methods: Microarray data were identified by searching two public databases (GEO and Array-Express) using the following search criteria: (“sickle cell disease” and “homo sapiens”). Eleven studies were identified, of which two were selected for our meta-analysis (GSE1849; GSE25014). One study evaluated the effect of heme 5µM in human primary pulmonary artery (PAECs) and microvascular EC (PMVECs) (12 samples), while the other study evaluated the effect of plasma from SCD patients (9 patients in steady state and 12 patients during ACS) in PAECs. To perform the meta-analysis we used INMEX, an integrative web-based tool for meta-analysis of expression data. For the meta-analysis, we applied a combining rank orders method based in the RankProd package. Genes with expression fold-changes (FC) in the same direction (either up or down) of 1.4 in at least one study were selected as candidates for differentially expressed (cDE) genes. Selected genes were ranked based on p value, and a p value ≤0.05 was considered statistically significant. To further understand functions of the subset of genes that were cDE in both studies, we performed gene ontology enrichment analysis. The functional analysis was undertaken using INMEX, and confirmed in other three gene set analysis tools (Pathway Commons, WikiPathways and KEGG). Only pathways that were identified in more than one tool were considered in the analysis. Results: Two different meta-analysis were performed. Gene expression data from heme-stimulated EC was compared to: (i) data from EC stimulated by plasma from SCD patients at steady-state; or (ii) data from EC stimulated by plasma obtained during ACS. In the first (heme x steady-state) and second (heme x ACS) analysis, 799 and 786 genes were consistently up- or down-regulated in both studies. The up- and down-regulated genes with the lowest p values were C2CD4A (C2 calcium-dependent domain containing 4A), and KLHL23 (kelch-like family member 23), respectively. In addition, genes associated with depletion of reactive oxygen species and coagulation activation were also identified. The most significant pathways identified in the gene set analysis were “IL5-mediated signaling events” (heme x steady-state; p= 0.0012) and “MAPK signaling pathway” (heme x ACS; p= 0.0073512) respectively. Results and conclusion: Genes and pathways that are DE both in EC stimulated by heme or by plasma from SCD patients could be relevant elements in the pathogenesis of inflammation in SCD. Heme has been shown to increase the generation of ROS and to induce the expression of inflammatory and pro-coagulant proteins by EC. The results of our meta-analysis are consistent with these effects. Therefore, the comprehensive list of genes and pathways identified in our study could help the generation new hypothesis about the mechanisms involved in heme-induced activation and perpetuation of inflammation in SCD. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Increased Inflammatory State and Metabolic Activation in Neutrophils from Patients with Sickle Cell Disease: Comparison of Neutrophil Gene Expression Profiles with Controls.

Blood ◽

10.1182/blood.v104.11.3571.3571 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3571-3571

Author(s):

Sule Bakanay ◽

Ferdane Kutlar ◽

Joshi Ratanmani ◽

Betsy Clair ◽

Leigh Wells ◽

...

Keyword(s):

Gene Expression ◽

Steady State ◽

Sickle Cell Disease ◽

Disease Severity ◽

Sickle Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Disease ◽

Expression Of Genes ◽

Inflammatory State

Abstract Chronic inflammation is a well-established feature of sickle cell disease (SCD) even at steady state, and the degree of inflammation tends to correlate with disease severity. Elevated neutrophil count, as a reflection of the overall inflammatory state, has emerged as an indicator of poor prognosis and has been associated with adverse outcomes including stroke and early mortality. To further delineate the role of neutrophils in the pathogenesis of various complications and in overall disease severity in SCD, we analyzed the gene expression profiles of neutrophils from 5 patients with "severe" disease (>3 vaso-occlusive episodes [VOE] per year), 5 patients with "mild" disease (<3 VOE/year) and compared these to each other and to the gene expression profiles of neutrophils from 5 age and sex matched, healthy, non-sickle cell, African-American individuals. Granulocytes were separated from freshly collected venous blood using Histopaque (Sigma diagnostic) density gradient separation. Total RNA was extracted immediately after cell separation by using Rneasy Mini Kit (Qiagen). 2 micrograms of total RNA was converted to double stranded cDNA (ds-cDNA) by using SuperScript Choice System (Invitrogen). In vitro transcription was performed on the ds-cDNA using Enzo RNA transcript labelling kit. After the fragmentation, labeled RNA was hybridized to a set of oligonucleotide arrays (HG U133A, Affymetrix, Santa Clara, CA) and the data was analysed with the Microarray suite 5.0 software (Affymetrix). Out of the differentially expressed genes (314 genes for severe vs. control, 718 genes for mild vs control), those with greater than two fold expression were analysed with the geneMAPP software for localization into biological pathways. In general, a larger number of genes were differentially expressed between "mild" patients vs. control, compared to that between "severe" vs "mild" patients. Genes related to cellular proliferation, growth and maintenance, DNA repair, DNA replication, and cell cycle progression were expressed at significantly higher levels in SCD patients compared to controls. The most impressive finding was the significantly higher expression of genes leading to NFkB activation and inhibition of apoptosis: IAP-1 (increased 6.7 fold and 4.7 fold in mild and severe patients respectively), IkB (decreased 0.14 fold and 0.3 fold), Apaf-1 (decreased 0.4 fold in mild), and c-jun (decreased 0.4 fold in severe); Traf-2 (TNF receptor associated factor-2; increased 3.5 fold and 2 fold); genes in the MAPK signalling pathway: ERK-2 (increased 3.5 fold and 2-fold), MAP2K3 (increased 3.5 fold and 2 fold). These data show that neutrophils in SCD patients are activated with higher expression of genes in the TNF, MAPK, and NFkB pathways consistent with an inflammatory state. Delayed or inhibited apoptosis of neutrophils further maintains this inflammatory state even during the so-called "steady state" of the disease. We conclude that the analyses of gene expression in neutrophils can be a useful tool in identifying pathways and genes that distinguish SCD patients from controls and in differentiating mild and severe phenotypes.

Download Full-text

Low Molecular Weight Heparin Reduces sVCAM-1 and Lung Congestion In a Murine Model of Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.1635.1635 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1635-1635 ◽

Cited By ~ 3

Author(s):

YiHe H. Guo ◽

Joshua Field ◽

Thomas D. Foster ◽

J. Paul Scott ◽

Nancy Wandersee ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Mouse Model ◽

Tissue Factor ◽

Sickle Cell ◽

Pulmonary Arteries ◽

Endothelial Injury ◽

Organ Injury ◽

Bleeding Complications ◽

Cell Disease

Abstract Abstract 1635 There is evidence for increased levels of procoagulant proteins, thrombin generation and tissue factor activity in individuals with sickle cell disease. Both thrombin and tissue factor also have potent proinflammatory effects that likely further contribute to the vascular dysfunction and organ injury observed in sickle cell disease. In this study, we examine the effect of the LMW heparin, enoxaparin, on markers of vascular injury and inflammation in the Berkeley mouse model of severe sickle cell disease (HbSS mice). HbSS mice or control HbAA mice (that exclusively express normal human HbA) were treated with continuous subcutaneous infusion of enoxaparin (10 mg/kg/day) or saline for 14 days using a surgically implanted Alzet pump (n=12-14 mice per group). Blood was collected at baseline and following 14 days enoxaparin therapy. Anesthetized animals were perfused with PBS at constant physiologic pressure (80 mmg Hg) and lung and liver collected for pathologic analyses. Enoxaparin-treated mice had steady state LMW heparin levels of 0.45 ± 0.17 anti-Xa U/mL compared to <0.1 anti-Xa U/mL in saline treated animals. Enoxaparin reduced d-dimer levels by approximately 35% in both HbSS and HbAA mice compared to saline-treated mice (p=0.03 and p=0.02, respectively), showing a functional reduction in coagulation and fibrinolytic activity. The hemoglobin level did not change and no obvious hemorrhage was noted in enoxaparin-treated mice suggesting no major bleeding complications. sVCAM-1 is a measure of endothelial injury and is increased at baseline in HbSS mice compared to HbAA mice (p<0.001). sVCAM-1 levels were reduced in HbSS mice after 14 days of enoxaparin therapy (1424 ± 83 ng/mL baseline, 1314 ± 85 ng/mL post enoxaparin, p=0.02), but not in saline treated HbSS mice (1462 ± 69 ng/mL baseline, 1392 ± 85 ng/mL post saline, p=0.3). Furthermore, the sVCAM-1 level negatively correlated with the steady state heparin level (r=-0.48, p=0.02) suggesting a modest dose-dependent effect of heparin on sVCAM-1 level. There was no effect of enoxaparin or saline therapy on sVCAM-1 levels in control HbAA mice. Preliminary histological analysis revealed a reduced number of congested pulmonary arteries in enoxaparin-treated HbSS mice compared to saline treated HbSS mice (p=0.01). These data suggest that enoxaparin therapy may improve endothelial injury as measured by sVCAM-1 and pulmonary vascular congestion in a mouse model of severe sickle cell disease. The data also suggest that heparin-based anticoagulant therapy may be a novel therapeutic approach to improve vascular health in individuals who suffer from sickle cell disease. Disclosures: Field: Novartis: Honoraria.

Download Full-text

Hemopexin Metabolism in Sickle-Cell Disease, Porphyrias and Control Subjects — Effects of Heme Injection

New England Journal of Medicine ◽

10.1056/nejm197404112901503 ◽

1974 ◽

Vol 290 (15) ◽

pp. 822-826 ◽

Cited By ~ 26

Author(s):

R. Dean Wochner ◽

Isaias Spilberg ◽

Atsushi Iio ◽

Ham Heng Liem ◽

Ursula Muller-Eberhard

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Disease ◽

Control Subjects ◽

And Control

Download Full-text

Neutrophil gelatinase–associated lipocalin as a biomarker of nephropathy in sickle cell disease

Annals of Hematology ◽

10.1007/s00277-021-04500-4 ◽

2021 ◽

Author(s):

Rajaa Marouf ◽

Adekunle D. Adekile ◽

Hadeel El-Muzaini ◽

Rasha Abdulla ◽

Olusegun A. Mojiminiyi

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Roc Curve ◽

Screening Tests ◽

Cell Disease ◽

Urine Ngal ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Plasma Ngal ◽

Neutrophil Gelatinase

AbstractSickle cell nephropathy (SCN) develops via altered hemodynamics and acute kidney injury, but conventional screening tests remain normal until advanced stages. Early diagnostic biomarkers are needed so that preventive measures can be taken. This study evaluates the role of neutrophil gelatinase–associated lipocalin (NGAL) as a biomarker of SCN in steady state and vaso-occlusive crisis (VOC). In this case-control study, 74 sickle cell disease (SCD) patients (37 in steady state and 37 in VOC) and 53 control subjects had hematological and biochemical measurements including plasma and urine NGAL. Univariate and logistic regression analyses were used to find the associations between variables. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance characteristics of plasma and urine NGAL for detection of VOC. Plasma and urine NGAL, urine microalbumin:creatinine ratio, and urine protein:creatinine ratio were significantly higher in VOC. Microalbuminuria was present in 17.1% steady state and 32.0% VOC patients. Microalbuminuria showed significant correlations with age, plasma NGAL, WBC, and hemolytic parameters. Area under the ROC curve for plasma NGAL was 0.69 (95%CI = 0.567–0.813; p = 0.006) and 0.86 (95%CI = 0.756–0.954; p < 0.001) for urine NGAL. Urine NGAL cut-off value of 12.0 ng/mL had 95% sensitivity and 65% specificity. These results confirm the presence of nephropathy during VOC and suggest that plasma and urine NGAL would be useful in the identification of SCN. Urine NGAL should be used as the screening biomarker, and patients with VOC and urine NGAL > 12.0 ng/mL should be selected for aggressive management to prevent progression of renal damage.

Download Full-text

Effects of Genotypes and Treatment on Oxygenscan Parameters in Sickle Cell Disease

Cells ◽

10.3390/cells10040811 ◽

2021 ◽

Vol 10 (4) ◽

pp. 811

Author(s):

Camille Boisson ◽

Minke A. E. Rab ◽

Elie Nader ◽

Céline Renoux ◽

Celeste Kanne ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Blood Cell ◽

Sickle Cell ◽

Red Blood Cell ◽

Cell Disease ◽

Oxygen Gradient ◽

Acute Complication ◽

Adults And Children ◽

The Difference

(1) Background: The aim of the present study was to compare oxygen gradient ektacytometry parameters between sickle cell patients of different genotypes (SS, SC, and S/β+) or under different treatments (hydroxyurea or chronic red blood cell exchange). (2) Methods: Oxygen gradient ektacytometry was performed in 167 adults and children at steady state. In addition, five SS patients had oxygenscan measurements at steady state and during an acute complication requiring hospitalization. (3) Results: Red blood cell (RBC) deformability upon deoxygenation (EImin) and in normoxia (EImax) was increased, and the susceptibility of RBC to sickle upon deoxygenation was decreased in SC patients when compared to untreated SS patients older than 5 years old. SS patients under chronic red blood cell exchange had higher EImin and EImax and lower susceptibility of RBC to sickle upon deoxygenation compared to untreated SS patients, SS patients younger than 5 years old, and hydroxyurea-treated SS and SC patients. The susceptibility of RBC to sickle upon deoxygenation was increased in the five SS patients during acute complication compared to steady state, although the difference between steady state and acute complication was variable from one patient to another. (4) Conclusions: The present study demonstrates that oxygen gradient ektacytometry parameters are affected by sickle cell disease (SCD) genotype and treatment.

Download Full-text

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

Blood ◽

10.1182/blood.v71.3.597.597 ◽

1988 ◽

Vol 71 (3) ◽

pp. 597-602 ◽

Cited By ~ 18

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.

Download Full-text