scholarly journals Cytokines Polymorphisms and Relationship with Cytokine Expression in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4910-4910 ◽  
Author(s):  
Simone CO Gilli ◽  
Fernando V Pericole ◽  
Bruno Deltreggia Benites ◽  
Lilian Castilho ◽  
Marcelo Addas-Carvalho ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Rflp Analysis ◽  
Cell Disease ◽  
Genotype Frequencies ◽  
Number Of Patients ◽  
Chronic Inflammatory Condition

Abstract Sickle cell disease (SCD) is a chronic inflammatory condition, even in steady state, as indicated by elevated levels of inflammatory cytokines and increased Th17 responses, compared with healthy controls. These inflammatory pathways may be directly regulated by genetic polymorphisms and could be associated to different outcomes of the disease. High levels of a number of different circulating cytokines were found in SCD patients in several studies, and changes in the cytokine balance in SCD patients are an important risk factor for the occurrence of clinical events. Moreover, inter-patient variations in cytokine levels could be attributed to gene polymorphisms. To investigate cytokine polymorphisms and their association with cytokines expression we evaluated the IL4 intron3 VNTR (genotypes 1.1, 1.2, 2.2, 2.3), IL4T590C/T, IL6174G/C and TNFA308A/G polymorphisms and their correlation with TGFB, IL-4, IL-6 and IL-10 expression in steady-state SCD patients. Methods. Fourth-nine patients (24 male and 25 female; 39.8 ± 9.59 years) with SCD and 28 (22 male and 6 female; 35.5 ± 10.2 years) healthy blood donors were evaluated. The polymorphisms were performed by PCR-RFLP analysis described as [individuals (genotype frequencies)] and the expression of TGFB, IL-4, IL-6 and IL-10 by q-PCR expressed as [median (max-min)]. Results. A higher frequency of 1.2, 2.2 and 2.3 genotypes was found in SCD patients compared with normal controls [34(0.69) vs 12 (0.44), P=0.03]; higher expression of IL-4 was found in the ones carrying the 1.1 genotype [0.31 (2.53-0.01) vs 0.05 (0.95-0.0), P=0.047] and although no differences were found in the IL4T590C/T, IL6174G/C and TNFA308A/G polymorphism frequencies, a significantly greater expression of TGFB, IL6 and IL10 was observed in the patients cohort compared to normal individuals [1.55 (9.02-0.0) vs 0.97 (5.46-0.0), P=0.019]; [0.18 (45.45-0.0) vs 0.0 (8.14-0.0), P=0.03] and [0.98 (22.84-0.0) vs 0.0 (9.95-0.0), P<0.001, respectively]. All the genotype frequencies are consistent with Hardy-Weinberg equilibrium. Conclusion: A unique distribution of IL-4 genotypes was observed in our cohort of patients and controls, probably related to the miscellaneous ethnic background of our population. The highest prevalence of the IL4intron3 polymorphism in sickle cell patients suggests a less secretory phenotype associated with increased expression of inflammatory cytokines. IL-4 plays an important role in tissue adhesion and inflammation, including induction of adhesion molecules on vascular endothelial cells and could be responsible for a more “inflammatory” phenotype. Despite the small number of patients enrolled, our study brings insights and new data regarding the deregulation in immune system affecting SCD patients and this information must be investigated in larger cohorts, and may help to better characterize individual variations in immune responses and new markers for disease morbidity. Disclosures No relevant conflicts of interest to declare.

Implementation of a European Cohort to Follow Sickle Cell Children and Adults Treated with Hydroxycarbamide

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 564-564
Author(s):  
Mariane De Montalembert ◽  
Frédéric Galacteros ◽  
Jean Antoine Ribeil ◽  
Uwe Kordes ◽  
Jean Benoit Arlet ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Safety Profile ◽  
Conflicts Of Interest ◽  
Subcutaneous Tissue ◽  
Acute Chest Syndrome ◽  
Control Group ◽  
Cell Disease ◽  
Skin Reactions ◽  
Number Of Patients

Abstract Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is a multicenter prospective non interventional study implemented in Europe to collect more information about the safety profile of HU and morbi-mortality in SCD patients treated with HU. The study responds to EMA (European Medicines Agency) request and has been approved by the Ethical of Necker Enfants Malades Hospital (Paris, France).The ongoing study involves the largest number so far of patients with SCD treated with HU. Primary endpoints of ESCORT HU are to determine frequency of adverse events, and possible consequent changes of HU treatment. Secondary endpoints are to evaluate morbi-mortality of the disease although in the absence of control group. From June 2008 to June 2014, 483 patients (255 females; 228 males) were enrolled from 3 European countries, Greece (24%), Germany (19%), and France (56%). 67% patients were adults, median aged 37.35 yrs (17-83.5) and 33% were children, median aged 11.06 yrs (2.6-16.9). genotypes were HbS/HbS in 71.4% cases, and compound heterozygotous HbS/β-thalassemia in 22.8 % (Table 1). 137 (28.4%) patients experienced 421 events (Table 2). 132 (32.2%) of these events may be attributed to HU. The safety profile is roughly similar in children and adults. As expected the most frequent side effects were firstly blood disorders (n=86 events, 42.4%) such as neutropenia or thrombocytopenia. In all cases, these cytopenias were rapidly resolved with the transitory stop of HU. 71 events related to skin and subcutaneous tissue disorders were observed, mostly cutaneous dryness, skin reactions, alopecia and nails or skin pigmentation; 4 patients had a leg ulcer (34.8%). Most of these events are ongoing or stabilized despit the decrease of HU. No secondary cancer has been reported until now. Even if HU is an old drug with a relatively well-known safety profile, some uncertainties remain in terms of long-term safety as well as tolerance in the youngest people. The main interest of ESCORT HU is to offer the possibility of safety surveillance of hydroxycarbamide in European sickle cell patients. Table 1 Demographic data Adults Children < 17 years old Total Number of patients 322 (67%) 161 (33%) 483 Females/Males 183/139 72/89 255/228 Median age (yrs) (range) 37.35 (17-83.5) 11.06 (2.6-16.9) 28.58 Genotype SS 206 (64%) 139 (86.3%) 345 (71.4%) SC 1 (0.3%) 3 (1.86%) 4 (0.8%) Sβ0 51 (15.8%) 11 (6.8%) 62 (12.8%) Sβ+ 46 (14.2%) 2 (1.2%) 48 (9.9%) Other 18 (5.5%) 6 (3.7%) 24 (4.9%) Treatment with HU before enrollment in ESCORT HU No of pts 232 83 315 (65%) Median duration (range) of HU treatment before ESCORT HU 8.2 yrs (0.5 ans-24 yrs) 3. 1 yrs ( 71 days – 8.9 yrs) 6.85 (71 days-24 years)] HU ESCORT Daily mean dose (mg/kg/d) 16.11 ± 4.79 19.63 ± 4.69 17.32 ± 4.94 Abstract 564. Table 2 The most frequent events of hydroxycarbamide in the two populations of SCD patients ADULTS CHILDREN No ofGerman(%) No of adults No ofEpisodes(%) No of children Total(% /411) Events Related to HU treatment (Siklos®)(%**) Blood and lymphatic system disorders (%) 32 (17.7) 22 54 (31.03) 28 86 (20.9) 56 (65.1) Skin and subcutaneous tissue disorders (%) 42 (23.2) 28 29 (16.7) 19 71 (17.3) 46 (64.8) Nervous system disorders Headache (24), Dizziness/vertigo (14), 32 (17.7) 23 12(6.9) 10 44 (10.7) 11 (25) Gastrointestinal disorders Nausea (14), diarrhea (8), other (14) 20 (11) 17 23 (13.2) 16 43 (10.4) 7 (16.3) Metabolic and nutrition disorders: vit D deficiency (17), weight gain (5) 13 (7) 11 18 (18.3) 18 36 (8.75) 4 (11.1) Fever 11 (6) 10 12(6.9) 7 23 (5.6) 1 (4.3) Cardiac disorders (hypertension, bradycardia, chest pain, cardiomegaly) 4 4 2 2 6 1 (16.6) General disorders : fatigue 5 5 0 0 5 0 Hepatobiliary disorders 2 2 0 0 2 0 Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Harmatoma, benign vulvar sebaceous cyst 2 2 0 0 2 0 Renal & urinary disorders 2 2 0 0 2 0 Reproductive system and breast disorders 3 3 0 0 3 0 Other 13 13 21 14 34 6 (17.1%) 181 80 /181(24.8%) 174 57 / 174(35.4%) 411 132/411 (32.2%) ** compared to the total number of “system organ class” events Disclosures No relevant conflicts of interest to declare.

Maintaining High Level Of Care At Outreach Sickle Cell Clinics

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2976-2976 ◽  
Author(s):  
Jennifer Hamm ◽  
Lee Hilliard ◽  
Thomas H. Howard ◽  
Jeffrey D. Lebensburger
Keyword(s):  
Health Care ◽  
Sickle Cell Disease ◽  
Medical Care ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Attendance Rates ◽  
Cell Disease ◽  
Major Health ◽  
Cell Network ◽  
Number Of Patients

Introduction Parents of children with sickle cell disease often seek care at large, university based sickle cell clinics. A major health care barrier for children in Alabama involves the cost and time of travelling to and from university based clinics. To reduce this health care barrier, the University of Alabama at Birmingham (UAB) developed The Children and Youth Sickle Cell Network(®) (CYSN(®)). This network consists of the central sickle cell clinic located at UAB and four outreach sickle cell clinics located in Montgomery (100 miles south of UAB), Opelika (110 miles southeast of UAB), Huntsville (100 miles north of UAB), and Tuscaloosa (60 miles west of UAB). The goal for these clinics is to maintain a similar level of medical care while reducing the health care barrier of transportation. Objective To determine if the outreach clinics provide similar care to university based clinics, we evaluated three surrogate preventive care markers to compare access to care in central vs. outreach clinics: 1) attendance rates, 2) number of patients on hydroxyurea, and 3) percent of MRIs obtained for screening of silent infarct among eligible patients. Methods A retrospective review of all CYSN(r) clinic visits from June 2012 to June 2013 was performed to determine clinic attendance rates. All patients on hydroxyurea were categorized by clinic location. Every patient attending CYSN(r) clinic between ages of 6 and 15 years had their medical record reviewed for completion of a screening MRI/MRA. Results At the central Birmingham clinic, the appointment show rate was 59.8% as compared to the Montgomery, Opelika, Huntsville, and Tuscaloosa show rates which were 57.7%, 73.1%, 59.4%, and 70% respectively. At UAB, institutional guidelines were developed for offering hydroxyurea to patients based on clinical indications and applied to all clinics. The percentage of patients on hydroxyurea therapy in Birmingham is 22.2%, while the percentages in Montgomery, Opelika, Huntsville, and Tuscaloosa are 21.5%, 32%, 21.4% and 24.4%, respectively. Finally, screening MRI/MRA to evaluate for evidence of silent cerebral infarctions is performed in Birmingham but offered to children ages 6-15 years at all sickle cell clinics. In Birmingham, 63.6% of eligible patients completed MRI/MRA screening. This percentage is similar for patients in Montgomery, Opelika, and Tuscaloosa who were screened at 66.7%, 83.3%, and 67.7% respectively. Conclusions Our data suggests that outreach clinics can provide similar levels of medical care for children with sickle cell disease. Sickle cell centers treating patients that must travel long distances should consider developing outreach clinics to help reduce this major health care barrier. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evidence for Transient Acute Liver Injury in Mouse Models of Sickle Cell Disease during Steady State Health

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1373-1373 ◽  
Author(s):  
Nancy J. Wandersee ◽  
Sandra L. Holzhauer ◽  
Dawn M. Retherford ◽  
Thomas D. Foster ◽  
Cheryl A. Hillery
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Liver Injury ◽  
Mouse Models ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Organ Injury ◽  
State Health ◽  
Cell Disease ◽  
Over Time

Abstract Individuals with sickle cell disease experience episodes of acute vaso-occlusive complications interspersed by periods of feeling well and apparent health during “steady state”. It is likely that episodic and subclinical sickling and vaso-occlusion occur on an ongoing basis even during periods of steady state. In order to determine whether mice with sickle disease have acute vaso-occlusion sufficient for organ injury at apparent steady state health, we chose to study 2 mouse models of severe sickle cell disease with serial blood draws over time. Since we have shown in previous studies that the liver is highly susceptible to acute sickling/vaso-occlusion induced by hypoxia, we first examined serial ALT measurements in a total of 13 Berkeley sickle cell (BERK-SS) mice, initially from week-to-week and month-to-month, and then day-to-day time frames. Individual BERK-SS mice showed week-to-week and month-to-month variations of up to 5-fold over baseline ALT levels, followed by return to baseline levels in most mice. This suggests that BERK-SS mice, during steady state health, experience acute, yet transient, liver injury. Surprisingly, we also found day-to-day variations of up to 3-fold in ALT levels in BERK-SS mice. To determine if these changes in ALT levels were mirrored by changes in other biomarkers, we measured serum amyloid P (SAP) as a marker of acute inflammation (similar to CRP in humans) in the same plasma samples. We found up to 1.6-fold variation in SAP over baseline plasma levels over time. However, there was less overall variation in SAP levels in individual mice compared to the striking changes in ALT. In addition, we found that variations in SAP did not consistently precede, follow, or coincide with variations in ALT levels, suggesting that SAP is a marker of sickle cell-induced inflammation or vaso-occlusion independent of liver injury. We next sought to confirm our findings with daily serial ALT and SAP measurements from Townes sickle cell (TOWNES-SS) mice (n=8), a second commonly used mouse model of severe sickle cell disease. Our data showed that baseline ALT levels are higher and SAP levels are lower in TOWNES-SS as compared to BERK-SS mice, likely reflecting differences in strain background between the two models. However, we again found daily fluctuations in ALT and SAP levels in individual TOWNES-SS mice, similar to those seen in individual BERK-SS mice. We propose that these temporal variations indicate that both the Berkeley and Townes mouse models of sickle cell disease exhibit fluctuations in steady state health, similar to those seen in human individuals with sickle cell disease. In addition, the results suggest that studies in these mouse models should be designed and interpreted with these temporal fluctuations in mind. Disclosures No relevant conflicts of interest to declare.

scholarly journals Steady State Predictors of Mortality in Adults with Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1388-1388
Author(s):  
Susanna A Curtis ◽  
Neeraja Danda ◽  
Zipora Etzion ◽  
Hillel W Cohen ◽  
Henny H Billett
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Conflicts Of Interest ◽  
Treatment Modalities ◽  
Mortality Data ◽  
Cell Disease ◽  
Ed Visits ◽  
Over Time

Abstract Background: With improved treatment modalities, longevity for sickle cell disease (SCD) is increasing. Yet there is still a subgroup of adult patients whose survival rate has not improved. These patients, if well defined by evidence based decisions, might be those for whom more aggressive disease modifying therapy would be appropriate. Methods: We identified all patients with SS/Sβ0 seen at our medical center in 2002 whom we were still following in 2012 as well as those who had died between 2002 and 2012. Patients with SC and Sβ+ thalassemia were excluded. ED, clinic, and inpatient admissions over the entire years 2002 and 2012 were obtained. All 2002 and 2012 steady state parameters for a given laboratory test for a given patient were averaged. “Steady State” was defined as those values not within one day of an ED visit or within one week of a hospital admission. Data were assessed for normality; parametric and non-parametric bivariate tests were performed as appropriate. Data from 2002 and 2012 was compared with paired-T tests. Mortality data were analyzed using Kaplan-Meier curves and Cox proportional hazard models. Results: We identified 289 SS/Sβ0 patients in 2012 (ages 18-87, 54% female) who had been present in our system in 2002 (survival cohort). We also identified 70 patients present in 2002 (ages 19-88 at death, 47% female) who had died between 2002 and 2012, inclusive (mortality cohort). Average age at death was 42.1±14.0 years, median survival was 58.3 years (95% CI: 54.5 – 63.0). Survivors had, in 2002, higher HbF, Hb, higher MCHC, lower white blood cell (WBC) counts and creatinine (Cr) levels, and fewer admissions than those who did not survive past 2012 (Table 1). Absolute Reticulocyte count (Retic), MCV, LDH, liver function tests, ED and clinic use were not significantly different between survivor and mortality groups. Cox proportional hazards model showed increased hazard ratios with lower HbF, higher WBC, Cr and increased admissions. When the survivors from 2002 were compared to themselves in 2012, they were shown to decrease HbF, Hb, MCHC, WBC, alkphos, and total bilirubin over time and to increase admissions, ED visits, Retic, MCV, Cr, and weight. Clinic visits, direct bilirubin and LDH were not significantly different. Conclusions: As therapeutic alternatives increase, it may be important to tailor therapy, and the need for better prognostic markers becomes ever more important. We observed here that several known mortality predictors evolve over time. As the “survivor” population ages, they may begin to resemble those with a poorer prognosis with decreased Hb and HbF levels but increased admissions and ED visits. However in our sample, WBC, a recognized factor in mortality and morbidity, decreased further over time in those who survived. Similarly, absolute reticulocyte count increased further over time in the survivors, suggesting an ability of the marrow to respond to the increased anemia. Further studies should be done to distinguish which biomarkers, at what level and in what age groups, are truly predictive of severity in sickle cell disease. Abstract 1388. Table 1: Comparison of 2002 SCD cohort who survived until 2012 with those who did not (left panel) and of a subset of this survivor population with themselves in 2012 2002 All Patient Data Matched Data 2002&2012 Survivor 2002 Mortality 2002 Cox Hazard Survivor 2002 Survivor 2012 N 289 70 359 134 134 Hb (g/dL) 8.5±1.4 7.8±1.4* .82(.65-1.02) 1g/dL 8.4±1.4 8.1±1.5* MCHC (g/dL) 35.2±1.2 34.5±1.8* .85(.69-1.04)1g/dL 35.1±1.2 34.2±1.3# Retic (x10^9/L) 181.3(131.9/237.8) 183.4(128.5/218.2) 1.00(1.00-1.01) 1k/uL 185.9(144.0/236.8) 247.4(168.1/341.2)# WBC (x10^9/L) 11.6±3.6 12.4±4.5 1.11(1.02-1.21)* 1 k/Ul 11.6±3.5 10.8±4.1* Cr (mg/dL) 0.5(0.6/0.7) 0.8(0.6/1.5)# 1.25(1.00-1.55)* 1mg/dL 0.6(0.5/0.7) 0.7(0.6/0.9)# Alb (g/dL) 4.3±.3 4.1±.4# .72(.33-1.57) 1g/dL 4.3±.3 4.2±.5 AlkPhos (U/L) 103.0(86.8/159.8) 121.0(99.6/166.8) 1.3(.91-1.99) 100 U/KL 111.0(86.8/165.0) 91.3(70.0/125.1)# Weight (KG) 58.3±21.3 64.1±15.7* 1.00(.98-1.02) 1 KG 58.4±21.1 66.0±13.9# HbF (%) 15.7(8.4/20.1) 5.5(1.9/12.4)# .94(.90-.98)# 1% 15.9(7.4/20.5) 6.4(4.1/11.8)# ED (per year) 2.6±3.9 1.9±3.3 .96(.88-1.04) 1/year 2.6±3.9 5.2±10.7# Clinic (per year) 6.8±8.3 8.3±11.5 1.01(.99-1.04) 1/year 6.8±8.3 7.3±10.5 Admits (per year) 0.3±0.8 2±2.5# 1.28(1.18-1.38)# 1/year 0.3±0.8 2.1±3.2# *=p<.05, #=p<.01 Disclosures No relevant conflicts of interest to declare.

Determinants Of Heme-Oxygenase-1 Upregulation In Patients With Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2235-2235 ◽  
Author(s):  
Olufolake Adisa ◽  
Benjamin Yaw Owusu ◽  
Yijuan Hu ◽  
Samit Ghosh ◽  
Fang Tan ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Heme Oxygenase ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Dinucleotide Repeat ◽  
Acute Chest Syndrome ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
The Mean

Abstract Inflammation is a cardinal component of the pathogenesis of sickle cell disease (SCD). Increased plasma concentration of the inflammatory agonist hemin increases the odds of acute chest syndrome (ACS) in children with SCD (Adisa et al., Br. J Haematol, 2013). In addition, free hemin promotes the development of a lethal ACS-like disease in transgenic sickle mice (Ghosh et al., J Clin Invest, 2013). Hemin degradation is controlled by the rate-limiting enzyme heme oxygenase-1 (HO-1). Polymorphism of a (GT)n dinucleotide repeat in the HO-1 promoter, which enhances expression of the gene, is associated with lower rates of hospitalization for ACS in children. Over-expression of HO-1 reduces stasis in a mouse model of SCD vaso-occlusion. However, the role of plasma HO-1 in SCD patients is entirely unknown. In this study, we measured steady-state plasma HO-1 in two cohorts of patients. Cohort 1 in Atlanta (n=98) consisted of children with a mean age of 10.07±0.42 years (range 2-19 years) and cohort 2 from Accra (n=80) consisted of older patients (mean age 25.30±1.0 years, range 13-58 years). The mean plasma HO-1 of both cohorts was significantly higher compared to the mean value of age- and ethnic-matched individuals with normal adult Hb; Atlanta: 10.19±5.80 vs. 2.08± 1.16, p<0.0001 and Accra: 13.7±8.14 vs. 2.57± 0.82, p<0.0001. Plasma HO-1 varied by 25-fold in both cohorts and it correlated with the white blood cell count (Atlanta: r=0.3361, p<0.0001, Accra: r=0.25, p=0.02). Fifty-four percent (n=53) of subjects in the Atlanta cohort were on hydroxyurea. The mean plasma HO-1 of this subgroup was lower (8.1 ± 4.5) compared to the hydroxyurea naïve Accra cohort (p=<0.0001). Further studies of the Accra cohort revealed significant correlations between HO-1 and multiple markers of vascular inflammation; sICAM-1(r=0.2794, p=0.03, n=60), sE-selectin (r= 0.4209, p=0.0017, n=58) and sP-selectin (r=0.3855, p=0.0028, n=58). The number of the (GT)n dinucleotide in the HO-1 promoter ranged 17 to 45; the distribution was trimodal with peaks at 23, 30 and 41 repeats. The overwhelming majority of patients had medium and large size alleles that are generally hypo-response to induction. Plasma HO-1 level correlated with the length of the (GT)n dinucleotide repeat (p=0.003, n=80). In a multivariable regression model, WBC, sICAM-1, sE-selectin and sP-selectin accounted for 13.4% of the total variance of plasma HO-1 level, and the (GT)n polymorphism accounted for 9.8%. In conclusion, the concentration of plasma HO-1 is generally raised among SCD patients at steady-state. However, a large proportion of patients have a relatively modest level that is probably inadequate to counter the severity of inflammation typical of SCD, due in part to a hypo-responsive HO-1 promoter. Therapeutic strategies that complement induction of the endogenous HO-1 gene may be critical to ameliorate inflammation in SCD. Disclosures: No relevant conflicts of interest to declare.

Elevated Steady State WBC and Platelet Counts Are Associated with Frequent Emergency Room Use in Adults with Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Susanna A Curtis ◽  
Zipora Etzion ◽  
Neeraja Danda ◽  
Hillel W Cohen ◽  
Henny Heisler Billett
Keyword(s):  
Platelet Count ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Laboratory Tests ◽  
Conflicts Of Interest ◽  
Cell Disease ◽  
Platelet Counts ◽  
Ed Visits ◽  
Non Parametric

Abstract Patients with sickle cell disease (SS/Sβ0) often utilize the emergency department (ED) for treatment of painful vaso-occlusive crisis and other sequalae of their disease. However there is significant variation in use, with a minority of patients making up the majority of visits. We studied whether objective steady state laboratory parameters might be associated with frequent ED use and whether hydroxyurea use modified this relationship. Methods: We identified all patients with sickle cell disesase seen at our medical center in 2012. Patients were identified as having sickle cell disease if hemoglobin (Hb) electrophoresis demonstrated sickle hemoglobin (HbS), fetal hemoglobin (HbF) and HbA2 but no Hemoglobin A, C, or other detectable hemoglobinopathies. ED, clinic, and inpatient admissions over the entire year were calculated and ED use was categorized as either 0-1, 2-5, or >6 visits a year. Steady state laboratory tests were defined as those not within a day of an ED visit or a week of a hospital admission. All 2012 steady state parameters retrieved for a given laboratory test for a given patient were averaged. “Active” laboratory tests, defined as those within one day of an ED visit, were averaged separately. HbF and weight were not separated by activity. Data were analyzed for normality; parametric values were assessed by mean and SD, non-parametric values were assessed as medians and interquartile ranges. Parametric and non-parametric bivariate tests of association were used as appropriate. Results: 432 adult sickle cell patients were identified, ages 18-87yrs; 54% were female. 181 patients had 0-1 ED visits within the year, 143 had 2-5 visits in the year and 96 had >6 visits for a total of 2259 visits. Patients who had >6 visits accounted for 1750 (77%) of the total visits for the year. When steady state labs were examined, high WBC and platelet counts were most strongly associated with frequent admissions. Steady state WBC of >12.0 x10^9/L were significantly more likely to have >6 visits/year (OR 2.6; 95% CI: 1.6-4.2, p=.0004). Platelet counts of >420 x10^9/L were also strongly associated with >6 ED visits (OR 2.6, 95% CI:1.5-4.4, p=.0007). LDH and AST were also shown to correlate significantly with ED (p=0.02 and 0.005 respectively) use while Hb and albumin were negatively associated (p<0.001 and 0.02 respectively). Hydroxyurea scripts were associated with increased ED visits (p<0.001); 38.1% of the population had been given a script for hydroxyurea within the year; patients with frequent ED use were 2.8x more likely to have been given a script for hydroxyurea within the year. These patients had higher MCV and Hb levels and lower, but still elevated, WBC and platelet counts per ED visit cohort stratification, a suggestion that hydroxyurea was being taken, but despite this, had similar significant associations with ED visits as the non-hydroxyurea group. MCV, MCHC, absolute reticulocyte count, weight, and %HbF did not demonstrate an association with ED visit frequency. When “active” parameters were examined, leukocytosis was present in all categories and WBC count could no longer predict a predisposed cohort; Hb level, LDH and AST were also no longer significant. Albumin and platelet count remained associated with ED visits. When older patients >40 yrs (n=124) were compared with <40yrs (n=308 ), high WBC and platelet counts remained significantly associated with high (>6) ED visits in both cohorts. Conclusions: Our data suggest that baseline WBC and platelet count are strongly associated with frequent ED utilization and may be better predictors than Hb, HbF, and other red cell or hemolytic parameters. Hydroxyurea use was not associated with fewer ED visits but those patients with frequent ED use still have relatively higher WBC and platelet counts than those with less frequent ED use, suggesting that hydroxyurea under-dosing may be an important issue. To what extent objective steady state parameters can identify a population that needs more aggressive baseline care and to what extent maximization of therapy can decrease frequent ED visits needs further study. Disclosures No relevant conflicts of interest to declare.

Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition

2013 ◽  
Vol 24 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Bijan Keikhaei ◽  
Ali Reza Mohseni ◽  
Reza Norouzirad ◽  
Mastaneh Alinejadi ◽  
Somayeh Ghanbari ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Sickle Cell ◽  
State Condition ◽  
Cell Disease ◽  
Steady State Condition ◽  
Pro Inflammatory Cytokines

Heme Concentration As a Biomarker of Sickle Cell Disease Severity: Its Role in Steady-State and in Crisis Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 975-975 ◽  
Author(s):  
Magda Oliveira Seixas Carvalho ◽  
Larissa Carneiro Rocha ◽  
João Henrique Oliveira Reis ◽  
Théo de Araújo Santos ◽  
Valma Maria Lopes do Nascimento ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Clinical Manifestations ◽  
Healthy Individuals ◽  
Cell Disease ◽  
High Concentration ◽  
Significant Difference ◽  
Free Heme

Abstract Background: Sickle cell disease (SCD) is a heredity group of anemia characterized by hemolysis, chronic inflammation, and vaso-occlusive/painful crisis. The heme is a product of erythrocytes' lyses and is increased in hemolytic diseases. Objectives: To investigate associations between hematological/biochemistry biomarkers and total plasma heme levels between SCD patients groups (in crisis and in steady-state) and healthy controls. To identify molecules related to hemolysis, inflammation, hepatic dysfunction, renal and lipid metabolism. Methods: We evaluated a total of 125 SCD steady-state patients, 22 SCD in crisis patients, and 32 healthy individuals age- and sex-matched with patients groups. Hematological analyses were performed by automatic cell counter, and hemoglobin profile by HPLC. Biochemistry analyses of inflammatory and infection markers, as well as lipid, hepatic, and kidney metabolism markers were investigated by immunochemistry assays. Plasma concentration of total free heme was measured by QuantiChrom Heme Assay Kit. Results: SCD patients groups (steady state and crisis) had higher heme concentration when compared to healthy individuals (p < 0.0001). However, significant difference of heme level was not finding in the comparison between SCD in steady state and SCD crisis patients groups. Biomarkers analyses of steady-state SCD patients showed negative correlation between heme levels and: red blood cell (r = -0.36, p<0.0001); hematocrit (r = -0.38, p <0.0001); hemoglobin (r = -0.34, p <0.0001); and HDL-C (r = -0.42, p <0.0001). Heme level showed positive correlation with: platelets (r = 0.35, p <0.0001); lactic dehidrogenase (r = 0.40, p <0.0001); reticulocytes count (r = 0.19, p =0.04); monocytes count (r = 0.36, p <0.0001); HbS concentration (r = 0.54, p <0.0001); total proteins (r = 0.22, p =0.01); AST (r = 0.41, p <0.0001); ALT (r = 0.18, p= 0.04); serum iron (r =0.21, p =0.03); total cholesterol (r = 0.23, p =0.01); LDL-C (r = 0.22, p= 0.02); VLDL-C (r = 0.65, p <0.0001); and triglycerides (r = 0.63, p <0.0001). In steady state SCD patients there was no difference of clinical manifestations history and heme levels. Conclusions: The finding of similar heme concentration between steady state and crisis SCD patients may be explained by the hyperhemolysis phenomenon, showing that even in steady-state, these patients continue to have hemolysis and generate heme and reactive oxygen species. It was also shown that high concentration of free heme increases hemolytic and inflammatory biomarkers, such as LDH, bilirubin's, reticulocytes count, and lipids, contributing to a severe clinical modulation of SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Venous Thromboembolism (VTE) in Sickle Cell Disease (SCD) Is Associated with Neutrophilia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 791-791
Author(s):  
Jahnavi Gollamudi ◽  
Shashank Sarvepalli ◽  
Tara Alin ◽  
Animesh Vadaparti ◽  
Jane A. Little ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Neutrophil Count ◽  
Cell Disease ◽  
Number Of Patients ◽  
Venous Thromboembolic Events ◽  
Wbc Count

Introduction Venous thromboembolic events (VTE) are a frequent complication of patients with sickle cell disease (SCD). The estimated incidence of thrombosis is 25% and is associated with increased morbidity and mortality. Recent studies have implicated leukocytes and their subsets in development and propagation of VTE in malignancies and inflammatory diseases. However the role of leukocytes have not been elucidated in SCD. We conducted a retrospective study to precisely study the association of leukocytes and their subsets in VTE. Methods We accessed the medical records of patients with SCD who presented to University Hospitals Seidman Cancer Center from 2004 to 2018. Information collected included demographic characteristics, comorbidities, laboratory parameters as well as treatment details. Patient records were reviewed for VTE with radiographic confirmation. Cases were defined as patients with SCD with diagnosed VTE and controls were SCD patients without VTE. Cases and controls were matched for age, gender, red blood cell (RBC) genotype and treatment. We included twice as many controls as cases for the study. Inclusion criteria were age greater than 18 years and were followed up at the outpatient sickle cell clinic. Patients were excluded if they had infection, thrombophilia, neoplasm, pregnancy or arterial thrombosis. For cases, lab parameters at the time of the VTE were recorded. Since most patients with VTE were diagnosed during an admission, lab parameters for controls were also recorded during an admission for pain crises. For both cases and controls, steady state lab data 3 months prior to their admission was also recorded and compared. Data was analyzed using STATA SE 15 version. Mann-Whitney U test was used to analyze continuous variables and Fischer's exact test was used to analyze discrete variables. P-values less than 0.05 were considered significant. Results A total of 263 records were reviewed of which 97 patients were eligible for the study. There were 35 patients with VTE and 62 patients without VTE. Baseline characteristics are presented in Table 1. Compared to controls, patients with VTE had more comorbidities such as avascular necrosis (AVN; p = 0.0038), pulmonary hypertension or albuminuria (pHTN; p= 0.032), higher body mass index (BMI) (p = 0.038) and had more hospitalizations (p &lt; 0.001). Due to small number of patients, the comorbidities were analyzed as a group across all genotypes. A complete list of comparison of comorbidities is summarized in Table 2. When compared to controls, patients with VTE as a group had higher total white blood cell count (WBC) and neutrophil count (p=0.0032 and p = 0.0006 respectively) at the time of event. When RBC genotype was taken into account, patients with SC and SS genotype had a significantly elevated neutrophil count whereas only patients with SS genotype had a higher WBC count compared to controls (Please refer to Table 3). When compared to controls, cases as a group also had WBC and neutrophil count 3 months prior to the event (p=0.025 and p=0.020 respectively). Patients with SS and SC patients had a significantly higher WBC count 3 months prior compared to their non VTE counterparts (Please refer to Table 4) No other comorbidity or lab parameter was found to be significantly different between cases and controls. A multivariate analysis could not be performed due to small study numbers. Conclusion Our study is the first to show that VTE in SCD was associated with higher neutrophil counts 3 months prior to the event suggesting that patients with baseline or steady state leukocytosis and neutrophilia are at increased risk of thrombosis. Larger studies are needed to confirm this association. In addition, patients with VTE also had higher incidence of comorbidities such as AVN, pHTN or albuminuria and increased hospitalizations. Given the small number of patient, a multivariate analysis was not possible. While the association between pHTN and VTE is well documented; the association of AVN and higher BMI with VTE described here is novel and needs further exploration with larger studies. Disclosures Little: Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

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

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.

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