Interleukin 8 Level, Reticulocyte Counting and aPTT Ratio in Brazilian Sickle Cell Anemia Patients with Leg Ulcers

Abstract Abstract 4835 Background: Sickle cell anemia (SCA) is characterized by a chronic inflammatory state in which oxidative stress, particularly in the endothelium, exerts a strong influence on the pathogenesis of vaso-occlusion and may be implicated in patients' clinical heterogeneity and survival. It has been suggested that the cytokine production profile of cells involved in the immune response may vary among patients with SCA. Leg ulcers (LU) represent a severe complication in these patients, and this condition has been associated with specific end-organ damage and an increase in morbidity and mortality. Recent studies have shown that venous obstruction, endothelial dysfunction, coagulopathy and infections are implicated in the complex pathogenesis of LU. Aims: To determine IL-1β, IL-6 and IL-8 plasma levels and gene expression rates as well as hematological and coagulation parameters and correlate these with the history of LU in adult SCA patients followed up at HEMOPE, in the state of Pernambuco, northeastern Brazil. Methods: Peripheral blood samples from 92 patients (median age 27 years; 42 female; 52 male; all Afro-descendants) in the steady state who had been diagnosed with SCA (HbSS), had not received a transfusion and were not using hydroxyurea were analyzed. Plasma levels of cytokines were determined by ELISA, and the gene expression rates by qRT-PCR. The patients' clinical and laboratorial characteristics were obtained from their medical charts. Statistical analysis was performed using the SAS System for Windows version 9.2. Results: Median age was higher in patients with a history of LU than in those without a history (33.1 vs. 28.4; p = 0.04). Although no statistically significant (p = 0.5) differences in IL-8 gene expression rates were observed, IL-8 plasma levels were significantly higher in patients with a history of LU than in patients without a history (23.8 vs. 7.7; p = 0.01) (Figure 1). Thus, patients with high levels of IL-8 had an increased risk for the occurrence of leg ulcers (OR = 1.01; 95% CI = 1.00–1.02). The ROC curve showed that IL-8 levels higher than 8.55 pg/mL could indicate the presence of LU (accuracy = 71.6%; sensitivity = 73.7%; specificity = 68.5%). The laboratory tests revealed reticulocyte counts and activated partial thromboplastin time (aPTT) ratios (R) that were significantly higher in patients with a history of LU than in those without a history (11.8 vs. 8.4, p = 0.01; 1.1 vs. 0.9, p = 0.04, respectively). Both the higher reticulocyte counts and R values were associated with increased risk for the occurrence of leg ulcers in these patients (OR = 1.12, 95% CI = 1.02 – 1.20; OR = 24.28, 95% CI = 1.20 – 486.09, respectively). Conclusion: In this study, patients who had had LU at some time in their lives showed significantly higher IL-8 levels, reticulocyte counts and R values than patients who had never had LU. Our results therefore suggest a relationship between the parameters described above and LU in patients with SCA. These parameters could perhaps be used, in association with different genetic modulators that may contribute to different clinical phenotypes observed in this disease, as markers of this clinical manifestation of SCA or of a propensity to develop it. Financial Support: CAPES (Brazil)/FAPESP/CNPq/INCTS Disclosures: No relevant conflicts of interest to declare.

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Association of MBL2 polymorphism with Leg Ulcers Development in Sickle Cell Anemia Patients

Blood ◽

10.1182/blood.v124.21.4912.4912 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4912-4912

Author(s):

Marcos André Cavalcanti Bezerra ◽

Isabela Cristina Farias ◽

Diego Arruda Falcão ◽

Igor de Farias Domingos ◽

Luana Laranjeira Prado ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Clinical Manifestations ◽

Monogenic Disease ◽

Prior History ◽

Leg Ulcers ◽

Immune Disorder ◽

History Of ◽

Mbl Deficiency

Abstract Leg ulcers are the most common clinical manifestations of sickle cell anemia (SCA), a monogenic disease with huge clinical diversity among patients. They affect 8% to 10% of SCA patients, reaching a percentage greater than 50% in patients residing in tropical areas. These ulcers occur due to vascular occlusion, tissue hypoxia, hemolysis and genetic factors, presenting a slow healing, high recurrence rate and huge susceptibility to infection. Recently, some studies have shown a positive relationship between the complement system and the development of some vascular diseases and injuries such as leg ulcers in non-SCA patients. Mannan-binding lectin (MBL) is an important component of the humoral innate immune system, and MBL possesses several characteristics indicating that it may play an essential role in wound healing; modulating inflammation and contributing to the clearance of microorganisms and apoptotic cells. In a recent study of chronic leg and foot ulcer patients, serum MBL levels were significantly different between wounds of different etiologies, with chronic venous leg ulcers patients having a higher frequency of MBL deficiency. Polymorphisms in the MBL2 are associated with a reduction in the MBL protein serum levels, increasing risk of developing leg ulcers and also the maintenance of these wounds, compromising the integrity of the immune defence and its response to potential invading pathogens. Here, we aimed to determine the frequency of polymorphisms in the promoter region -221 (Y / X) and -550 (H / L) and exon 1 of the MBL2 and assess the clinical impact of these variants in a northeastern Brazilian SCA population who presented leg ulcers. Two-hundred seventy-five unrelated SCA patients were included. According the leg ulcers presence, the total cohort was classified in patients presenting current or prior history of leg ulcers (n=100) and SCA patients above 18 years with no history of leg ulcers (n=175). Molecular analysis was performed by qPCR. Our population was in Hardy-Weinberg equilibrium. The allelic frequency of haplotypes associated with high MBL production (HYA, LYA) was 54.5% for cases and 62.9% in controls. The genotypes related to low MBL production (HYO, LYO) in cases and controls was 27.5% and 18.6%, respectively. The frequency of genotype related to intermediate MBL production (LXA) was 18% in cases and 18.5% in controls. We had no statistically significant results when we analyzed only the polymorphisms (P>0.05). However, the phenotypic analysis between high and low MBL production revealed that patients with leg ulcers have lower MBL protein levels (P=0.019). We focused specifically on a possible role of MBL deficiency on healing complications, based on the facts that MBL deficiency is the most common immune disorder, and that a common causality for prolonged healing of these ulcers is infection or colonization by bacteria. In our study, MBL deficiency appears to increase the risk of developing leg ulcers in SCA patients. Disclosures No relevant conflicts of interest to declare.

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Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia

Blood ◽

10.1182/blood.v99.7.2297 ◽

2002 ◽

Vol 99 (7) ◽

pp. 2297-2303 ◽

Cited By ~ 58

Author(s):

Malika Benkerrou ◽

Charlotte Delarche ◽

Lamia Brahimi ◽

Michèle Fay ◽

Etienne Vilmer ◽

...

Keyword(s):

Adhesion Molecules ◽

Sickle Cell ◽

Adhesion Molecule ◽

Sickle Cell Anemia ◽

Plasma Levels ◽

Polymorphonuclear Neutrophil ◽

H2o2 Production ◽

Soluble Adhesion Molecules ◽

Hydroxyurea Treatment ◽

History Of

Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n = 15); (2) patients with a history of vasoocclusive events (n = 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n = 9). Unstimulated PMNs showed decreased L selectin expression and increased H2O2 production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H2O2 production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H2O2 production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H2O2 production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug.

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Absolute Reticulocyte Count Is Negatively Correlated with Fetal Hemoglobin during Infancy and Early Childhood in Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood.v124.21.4081.4081 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4081-4081

Author(s):

Emily R. Meier ◽

Colleen Byrnes ◽

Y. Terry Lee ◽

Maxine Weissman ◽

Jeffery L. Miller

Keyword(s):

Steady State ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Fetal Hemoglobin ◽

Convenience Sample ◽

Risk Of Death ◽

Increased Risk ◽

F Cells ◽

Analytical Approaches

Abstract Hemoglobin switching is largely complete in healthy infants by 6 months of age. In infants with sickle cell anemia (HbSS, SCA), reticulocytosis begins early in life as fetal hemoglobin (HbF) is replaced by sickle hemoglobin (HbS). Previous studies demonstrated that patients with an ARC greater than 200 K/uL during early infancy (60-196 days of age) were at the highest risk for SCA-associated events. 1,2 The objective of this study was to determine if ARC is related to HbF levels in a cohort of pediatric SCA patients. A convenience sample of 106 children with SCA between the ages of 1 month and 20 years who were not receiving hydroxyurea or monthly blood transfusions were enrolled in this observational study [42 (39.6%) less than 1 year of age (28-362 days old), 46 (43.4%) between the ages of 1 and 10 years, and 18 (17.0%) between 10 and 20 years old]. After consent and assent were provided, discarded peripheral blood was obtained during routine clinic visits at steady state and analyzed within 48 hours of collection and storage at 40C. Steady state was defined as a sample drawn at least 30 days following an acute event and at least 60 days following a blood transfusion. Hematologic data, including ARC and HbF levels, were measured using CLIA approved methods. F-cells were enumerated by flow cytometry following intracellular staining with a fluorescent antibody directed against HbF. Correlations were calculated to determine the relationships of ARC with HbF, F-cells, and other hematologic data, while two-tailed t tests were used to compare means. Initial studies compared groups based upon ARC greater than or equal to 200 K/uL (ARC≥200) during infancy because of the previously reported utility of this threshold as a predictive marker for SCA severity.1 Over one third of the infants less than 1 year of age (n=16) had an ARC≥200. Mean HbF and F-cell levels were significantly lower in the ARC≥200 group when compared to the ARC<200 group (HbF: 29.9±10.9% vs. 53.5±17.6%, respectively, p=2.2E-05; F-cells: 83.5±13.2% vs. 96.6±5.7%, p=6.2E-05). Mean hemoglobin levels were also lower in the ARC≥200 group [8.1±1.4 g/dL vs. 9.5±1.6 g/dL (ARC<200), p=0.005]. Of the 22 (52.4%) infants who had a HbF level greater than 40%, only 2 (9.1%) had an ARC greater than 200K/uL. Enrolled patients were also grouped according to age and comparisons were made between ARC and HbF or F-cell levels. HbF and F-cell levels were negatively correlated to ARC in the infant subgroup (r=-0.696, p=3.1E-07 and r=-0.795, p=0.000, respectively). HbF and F-cell levels from children between the ages of 1 and 10 years were inversely related to the ARC, but the correlation was less significant (r=-0.626, p=3.3E-06 and r=-0.538, p=1.2E-04, respectively). The inverse relationship was no longer present in the oldest group of patients (HbF vs. ARC r=-0.203, p=0.420 and F-cells vs. ARC, r=-0.258, p=0.302). According to both analytical approaches described here, increased ARC is associated with decreased HbF and F-cell levels in infants with SCA. Less robust negative correlations are maintained through age 10 years, but no significant correlation was identified in adolescence and young adulthood. Overall, the data suggest that increased ARC levels may identify SCA infants who manifest a more rapid or greater loss of fetal hemoglobin during the later stages of the HbF-to-HbS switching phenomenon. Meier ER, Byrnes C, Lee YT, et al. Increased reticulocytosis during infancy is associated with increased hospitalizations in sickle cell anemia patients during the first three years of life. PLoS One 2013; 8(8):e70794. doi: 10.1371/journal.pone.0070794.Meier ER, Wright EC, Miller JL. Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease. Am J Hematol 2014 May 31; doi: 10.1002/ajh.23777. [Epub ahead of print] Disclosures No relevant conflicts of interest to declare.

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ID: 139: PROGRESSIVE GLOMERULAR DAMAGE IN SICKLE CELL TRAIT AND SICKLE CELL ANEMIA MOUSE MODELS

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.95 ◽

2016 ◽

Vol 64 (4) ◽

pp. 957.2-958

Author(s):

SL Saraf ◽

JR Sysol ◽

JA Arruda ◽

RF Machado ◽

VR Gordeuk ◽

...

Keyword(s):

Gene Expression ◽

African Americans ◽

Kidney Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Sickle Cell Trait ◽

Linear Trend ◽

Mesangial Expansion ◽

Urine Protein ◽

Increased Risk

The hemoglobin S mutation, a glutamic acid to valine substitution in the β-globin chain, results in hemoglobin polymerization under hypoxic conditions and leads to vaso-occlusion and hemolysis. Homozygous inheritance (Hb SS; sickle cell anemia) affects 1 in 500 African Americans and is consistently associated with an increased risk for kidney disease which may be due to cell-free hemoglobin toxicity, ischemic injury, or hyperfiltration-mediated damage to the kidney. Heterozygous inheritance (Hb AS; sickle cell trait) affects 1 in 8 African Americans and has also been associated with an increased risk for kidney disease, although not in all cohorts and the mechanisms are not well understood.We investigated whether inheritance of the Hb S mutation resulted in incremental kidney damage in Hb AS and Hb SS mice compared to Hb AA mice by histology, proteinuria, and candidate gene expression using transgenic sickle mice ≥6 months of age (Townes model, Jackson Laboratory). Values are presented as mean±standard error and analyses are adjusted for age.Using Masson trichrome stained sections of the kidney, progressive patterns of mesangial expansion were observed in age-matched Hb AS and Hb SS mice versus Hb AA mice by renal pathologists blinded to the hemoglobin genotype (figure 1). Hb AS mice had diffuse (>50% of the glomeruli per slide being involved) mesangial expansion while Hb SS mice had diffuse and global (>50% of the individual glomerulus being involved) mesangial expansion. Glomerular perimeters were measured using NanoZoomer Whole Slide Imaging in 26 randomly selected glomeruli from 2 age-matched mice per genotype. Using the upper quartile as the definition for an enlarged glomerulus, the proportion of enlarged glomeruli progressively increased from Hb AA (15%) to Hb AS (31%) to Hb SS mice (58%) (Cochran's test of linear trend, P=0.001) (figure 2). Progressively higher kidney weights were also observed from Hb AA (429±28 mg, n=8) to Hb AS (446±27 mg, n=18) to Hb SS (567±19 mg, n=5) mice (Test for linear trend, P=0.047). We then measured urine protein and urine creatinine concentrations using the Bio-Rad dye method and Jaffé reaction, respectively. Progressively higher urine protein-to-creatinine ratios were observed from Hb AA to Hb AS to Hb SS mice (figure 3) (Test for linear trend, P=0.09). Gene expression of candidate genes (TGFB1, IL6, MMP9, Klotho, HMOX1, and SHROOM3) was determined by rt-PCR from kidneys of age-matched, female Hb AA and Hb AS mice (n=5). Increased expression of Klotho (P=0.09) was observed in Hb AS mice (figure 4). Klotho is a β-glucoronidase that is highly expressed in the kidney and acts as a cofactor that increases the affinity of the FGF23 ligand for the FGF receptor.In conclusion, we observed progressive glomerular injury, determined by mesangial expansion, proportion of enlarged glomeruli, and urine protein concentrations in Hb AS and Hb SS mice compared to Hb AA mice. Klotho was upregulated in Hb AS mice and may play a role in the pathophysiology of kidney damage in Hb AS which will require further investigation.Abstract ID: 139 Figure 1

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Targeted Education after an Emergency Department Visit Increases Hydroxyurea Initiation in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v130.suppl_1.868.868 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 868-868

Author(s):

Sarah Kappa ◽

Lydia Pecker ◽

Deepika S. Darbari ◽

Robert Nickel

Keyword(s):

Emergency Department ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

National Health System ◽

Clinic Visit ◽

Acute Chest Syndrome ◽

Hemoglobin F ◽

History Of ◽

One Year

Abstract Introduction: Hydroxyurea decreases many complications of sickle cell anemia (SCA) but is underused in treatment-eligible patients. Barriers to hydroxyurea initiation occur on the health care system, provider, and patient level. Novel strategies to increase hydroxyurea use in patients with SCA are needed. To address this challenge at our center, we implemented the Quick Start Hydroxyurea Initiation Project (Q-SHIP). Methods: Patients with SCA were eligible to participate in Q-SHIP if they presented to the Children's National Health System (CNHS) emergency department (ED) for pain or acute chest syndrome and were not taking hydroxyurea. Patients <9 months old, on chronic transfusions, pregnant, or not followed by CNHS hematology were excluded. Eligible patients were referred to a weekly Q-SHIP clinic visit focused on hydroxyurea education and were offered initiating treatment at the visit's conclusion. Participants completed a pre-session questionnaire, discussed hydroxyurea with a hematologist using a handbook developed by CNHS, and watched videos featuring patients and parents of children with SCA sharing their experience with hydroxyurea. Subjects were classified as starting hydroxyurea if they had a clinic visit for hydroxyurea monitoring within 3 months of participation in a Q-SHIP session. Results: Over 13 months (2/1/2016 - 3/31/2017) 65 eligible patients participated in Q-SHIP a median of 5 days (IQR 2, 20 days) after ED or hospital discharge. Although 44% (28/64) of participants reported no previous hydroxyurea offer, provider clinic documentation indicated that 61% (17/28) of these families had declined a previous hydroxyurea offer. After Q-SHIP, 55% (36/65) of participants started hydroxyurea. Subjects who started hydroxyurea after Q-SHIP were similar to those who did not, except subjects who started were more likely have a history of an intensive care unit admission (Table 1). After a median follow-up of 11 months, 81% (29/36) of participants who started hydroxyurea after Q-SHIP continued on therapy. Among Q-SHIP participants continuing treatment, mean corpuscular volume increased by a median of 8.6 fL (IQR +5.4, +17.7, p<0.0001) and hemoglobin F increased by a median of 5.8% (IQR +3.0, +11.3, p<0.001). One year after implementation of Q-SHIP, the proportion of treatment-eligible patients with SCA who presented to the ED with pain or ACS who were receiving hydroxyurea increased; February 2016: 56% (32/57) vs. February 2017: 73% (43/59), p=0.059. Conclusion: Addressing indications for hydroxyurea therapy in a clinic encounter exclusively for this purpose soon after a SCA complication is a meaningful time to meet with families of children with SCA to initiate treatment. Disclosures No relevant conflicts of interest to declare.

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TCD in Infants: A Report from the BABY HUG Trial.

Blood ◽

10.1182/blood.v106.11.952.952 ◽

2005 ◽

Vol 106 (11) ◽

pp. 952-952 ◽

Cited By ~ 2

Author(s):

Robert J. Adams ◽

Julio Barredo ◽

Duane R. Bonds ◽

Clark Brown ◽

James Casella ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Maximum Flow ◽

Organ Damage ◽

Sample Volume ◽

Phase Iii ◽

Mean Velocity ◽

Increased Risk ◽

The Mean ◽

The Right

Abstract Transcranial Doppler (TCD) is useful in children with sickle cell anemia (SCA) to detect increased risk of stroke. The use of TCD in infants less than 2 years of age is less well established, but has previously been shown to be feasible. As a secondary endpoint in the BABY HUG Trial, TCD is expected to provide useful information on the possible effects of hydroxyurea (HU) in babies with SCA. BABY HUG is an NHLBI-NICHD sponsored phase III clinical trial to compare hydroxyurea to placebo to ascertain effectiveness in preventing end organ damage of the spleen and kidney. Eligible subjects underwent a baseline TCD using the Nicolet Companion (EME) 2-MHz pulsed Doppler. All infants were 8–18 months of age at enrollment, had no history of stroke and were not receiving chronic blood transfusions. Blood flow velocities were recorded using the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol with the exception of reducing the standard sample volume to 4 mm. No sedation was used. The time averaged maximum mean was measured to determine the highest velocity on either side to categorize the study as normal (all recordings <170 cm/sec), conditional (170–199cm/sec) or abnormal (≥200 cm/sec). Recordings of the middle cerebral artery (MCA) and internal carotid artery (ICA) bifurcation defined an adequate TCD. TCD was not required for study entry but subjects with an abnormal exam were not eligible for randomization and treatment. TCD exams were read by blinded reviewers at the Medical College of Georgia. TCD results were transmitted to Clinical Trials & Surveys Corporation (C-TASC) for statistical analysis. As of June 24, 2005, 70 TCD exams had been attempted. Two exams were unsuccessful (no data) because of the children’s irritability and 1 was interpreted as inadequate. Of the remaining 67 TCD exams, 66 were normal and one baby had a high conditional TCD (190 cm/sec). No subjects were found ineligible for the study due to TCD results. The mean velocity of the left MCA was 117 cm/sec ±22.9 and that of the right MCA was 114 cm/sec ±24.9. Regression analyses were performed to examine the relationship of maximum flow velocity (VMAX) to age and total hemoglobin (Hb). VMAX was inversely correlated to Hb (left p=<0.0001, right=<0.0014) and directly associated with age (left p=<.0005, right p=<0.0022). When the mean MCA velocity was regressed against age and Hb, both age (p=0.0285) and Hb (p=.0024) were significant. Adequate baseline TCD evaluation was obtained on 67 out of 70 babies. As expected, baseline TCD velocities varied inversely with the degree of anemia and directly with age; all but one was normal by childhood sickle cell disease standards. These studies provide valuable normative data for infants with SCA, and for further assessment of the effect of HU on TCD in infants with SCA as the study progresses.

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The Hyperhemolysis Phenotype in Sickle Cell Anemia: Increased Risk of Leg Ulcers, Priapism, Pulmonary Hypertension and Death with Decreased Risk of Vasoocclusive Events.

Blood ◽

10.1182/blood.v108.11.787.787 ◽

2006 ◽

Vol 108 (11) ◽

pp. 787-787 ◽

Cited By ~ 1

Author(s):

James G. Taylor ◽

Vikki G. Nolan ◽

Gregory J. Kato ◽

Mark Gladwin ◽

Martin H. Steinberg

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Phenotypic Expression ◽

Vascular Complications ◽

Clinical Variable ◽

Leg Ulcers ◽

Risk Of Death ◽

Arginase 1 ◽

Increased Risk

Abstract Polymerization of hemoglobin in sickle cell anemia (HbSS) results in red blood cell damage, vasoocclusive disease and hemolytic anemia. Plasma hemoglobin and arginase released during hemolysis produce endothelial dysfunction and lead to vascular complications such as leg ulceration, priapism, pulmonary hypertension and increased risk of death. Examination of 2 independent patient groups from the NIH and CSSCD revealed considerable heterogeneity in the rates of hemolysis as estimated by LDH. We therefore hypothesized that inter-individual variation in hemolytic rate influences the phenotypic expression of HbSS. To test this hypothesis, we have defined a hemolysis phenotype as a clinical variable in our 2 HbSS groups. At NIH, LDH was analyzed as a quantitative trait in 166 adults to define a subgroup above the 75th percentile suggestive of exaggerated hemolysis (n= 42, mean LDH 645). When compared with 42 cases in the lowest LDH quartile (mean 230), the hyperhemolysis group had significantly lower hemoglobin and higher AST, bilirubin, and absolute reticulocyte levels supporting this phenotypic classification. HbF, arginine:ornithine ratios and arginase 1 activity were also significantly different. Clinically, the hyperhemolysis group had an increased prevalence of leg ulcers (OR 5.10; P=0.007), priapism (OR 3.67; P=0.16), and pulmonary hypertension (TRV > 3.0 m/s; OR 12.00; P<0.001). In addition, these patients have fewer severe vasoocclusive pain crises (3.1 ER visits/yr. with high LDH vs. 9.1/yr. with low LDH; P=0.004), supported by a lower prescription rate for hydroxyurea (37% with high LDH vs. 61% with low LDH; P=0.06). To validate these findings, we repeated the LDH phenotypic assignment analysis using 451 comparable CSSCD adults greater than 30 years of age. An identical pattern of laboratory results was seen when comparing high and low LDH quartiles. Hyperhemolysis was defined by anemia, elevated total bilirubin and AST and lower HbF. The most striking observations for this group were the significantly higher proportion of males (55% vs. 27% with low LDH; P<0.001), occurrence of leg ulcers (OR 3.44; P<0.001), and frequent death (33% vs. 16% with low LDH; P=0.003). There were also trends towards more prevalent priapism and stroke in the hemolysis group. After adjustment for HbF and gender, the associations between hyperhemolysis and risk of leg ulceration and risk of death remained significant in the CSSCD. Together, these findings suggest that excessive hemolysis results in a vascular HbSS phenotype characterized by leg ulcers, priapism, pulmonary hypertension, possibly stroke, and death. The lack of an association between excess hemolysis and pain/ACS suggests this phenotype is distinct from vasoocclusion/hyperviscosity. The consistent association of hyperhemolysis with this spectrum of symptoms, even after HbF correction, indicates the existence of unknown determinants for hemolysis. Future environmental and genetic studies of hyperhemolysis may provide novel mechanistic insights into the pathogenesis and treatment of HbSS vascular complications. From a clinical standpoint, these data further support the use of LDH as a simple biomarker for identifying a sub-set of HbSS patients at high risk for hemolysis-driven complications and death, who may otherwise be overlooked by clinicians because of infrequent vasoocclusive pain events.

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Efficacy of Hydroxyurea To Prevent Organ Damage in Young Children with Sickle Cell Anemia.

Blood ◽

10.1182/blood.v110.11.3386.3386 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3386-3386 ◽

Cited By ~ 3

Author(s):

Courtney D. Thornburg ◽

Natalia Dixon ◽

Shelly Burgett ◽

Nicole A. Mortier ◽

Sherri A. Zimmerman ◽

...

Keyword(s):

Young Children ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Brain Mri ◽

Organ Damage ◽

Study Entry ◽

Acute Chest Syndrome ◽

Time Interval ◽

Splenic Sequestration ◽

Increased Risk

Abstract Hydroxyurea (HU) prevents many acute complications of sickle cell anemia (SCA) in adults and children, but its potential to delay or prevent chronic organ damage has not been defined. The objectives of this prospective IRB-approved study were to assess the safety and efficacy of HU in young children with SCA (age 18 mon–5 years) and to determine whether 2 years of therapy preserves renal function, reduces transcranial doppler ultrasound (TCD) values, and prevents development of brain ischemia as evidenced by magnetic resonance imaging/angiography (MRI/MRA). Fourteen children with SCA (11 male, 3 female; mean age 35±11 mon) enrolled and underwent evaluation including blood counts, %HbF measurement, determination of the glomerular filtration rate (GFR) by radionuclide DTPA clearance and Schwartz estimate, TCD mean cerebral artery (MCA) velocities, and brain MRI/MRA. HU was started at 20 mg/kg/day and escalated by 5mg/kg/day every 8 weeks to a maximum tolerated dose (MTD) or 30 mg/kg/day (mean dose 28±4 mg/kg). Children were evaluated initially every 4 weeks. All baseline tests were repeated at study exit (mean time 25±3 months). HU was tolerated well by all children. Hematological changes occurred as expected, with significant increases observed in hemoglobin concentration, MCV, and %HbF and significant decreases in reticulocytes, WBC, and neutrophils. The average GFR value did not rise as expected in this age range; the DTPA GFR decreased by 5.1 mL/min/1.73 m2 (p=0.26) with only 3 of 11 exit studies exceeding 150 mL/min/1.73 m2 and the Schwartz estimate increased by 16.5 mL/min/1.73 m2 (p=0.17). During HU therapy, the average TCD values significantly decreased with a mean decrease of 26±28 cm/sec in the right MCA (p<.01) and mean decrease of 27±33 in the left MCA (p<.05). At study entry, 3 children had conditional TCD velocities, but all were normal at study exit. One child had mild small vessel ischemic changes on MRI at study entry that were unchanged at study exit. Two children had mild MRA changes that were stable or improved at the end of the study. All children had normal or improved rates of growth and development during therapy. Two children required PRBC transfusion for acute events (acute chest syndrome and hypoplastic anemia during a viral illness). There was one episode of Moraxella catarrhalis bacteremia that was unrelated to myelosuppression and responded to antibiotic therapy. One child was removed from study at week 82 due to the development of thrombocytopenia and hypersplenism, another had acute splenic sequestration but continued HU without recurrence, and a third child with previous acute splenic sequestration did not have recurrence during the study. In conclusion, HU therapy appears to be well tolerated in young children with SCA. In addition to providing beneficial changes in hematological parameters, HU has salutary effects on both the kidney and brain. HU therapy was associated with a stable GFR value during a time interval when hyperfiltration develops, and led to significant decreases in TCD velocities. However, preservation of splenic tissue could lead to an increased risk of splenic complications. Follow-up studies are warranted to determine if long-term HU therapy can preserve or restore organ function in this patient population.

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Renal Iron Load in Sickle Cell Anemia Patients - a Brazilian Study

Blood ◽

10.1182/blood.v128.22.3658.3658 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3658-3658

Author(s):

Flavia Pegado Junqueira ◽

Sandra Regina Loggetto ◽

Viviani L R Pessoa ◽

Juliano Lara Fernandes

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Signal Intensity ◽

Conflicts Of Interest ◽

Interventricular Septum ◽

Organ Damage ◽

Iron Deposition ◽

Rank Test ◽

Medical Systems ◽

Iron Load

Abstract Background and Objectives: Sickle cell anemia (SCA) is characterized by chronic haemolysis and frequent painful vaso-occlusive episodes, eventually leading to multiple organ damage, including the kidneys. Chronic haemolysis is frequent in SCA patients receiving regular transfusions. Not all renal disease in patients with SCA is due to sickle cell nephropathy (SCN), but the incidence of renal failure increases as patient survival improves. Since Magnetic Resonance Image can provide a unique evaluation of the abdomen in a single exam, the aim of this study was to assess renal iron deposits in patients with SCA, correlating these values with transfusion burden, liver and heart T2* and blood LDH levels. Material and methods: Twenty patients with SCA older than 20 years of age and transfusion burden were studied in a 1.5T scanner (Avanto, Siemens Medical Systems, Erlangen, Germany) using T2* technique and compared to age- and sex-matched normal controls. For liver T2* analysis, regions of interest (ROI) were manually drawn in the liver, using Viewing software (Leonardo - Siemens) avoiding all major visible vessels. For heart T2* analysis, a full-thickness ROI was manually defined in the interventricular septum (routinely chosen to avoid T2* artifacts from the cardiac veins, liver, and lungs). For renal T2* analysis, ROI were manually drawn in the cortex, using Viewing software (Leonardo - Siemens) avoiding the medullary region. All parameters are presented as mean ± standard deviation. Spearman's rank test was used to assess the correlation between renal T2* and blood LDH levels. The Ethics Committee for Research approved this trial. Results: Mean renal T2* was significantly lower (p < 0.001) in the SCA patients [16.4 ± 11.8 ms] compared with healthy controls (47.9 ± 11.1 ms). However there was no correlation between renal T2* and heart (p = 0.500) and liver T2* (p= 0.578). Median liver and myocardial T2* in this population was 3.96 ± 3.58 ms and 36.87 ± 8.06 ms. Cortico-medullary signal differences in renal iron loading were observed. Low signal intensity in the cortex relative to the medulla was observed in thirteen patients (65%). SCA patients who showed no cortico-medullary difference in signal intensity had a mean T2* of 30.9 ± 6.5 ms, which was significantly lower (p < 0.001) than that of the group of patients showing a hypointense cortical signal (8.6 ± 2.8 ms). We investigated the relationship between cortico-medullary differences and haemolysis using LDH values as a marker of haemolysis. Renal T2* showed a significant correlation with LDH values. Mean LDH values were significantly different between patients with and without cortico-medullary differences (p = 0.004), being 470.6 ± 123.1 IU/L for those with no cortico-medullary differences, and 1313.0 ± 788.6 IU/L for those with hypointense cortex. The seven highest LDH values in this cohort of 20 patients corresponded to seven patients with cortico-medullary signal intensity differences. Conclusion: Our study in SCA shows that iron deposition in the kidney is not related to systemic iron overload, but to haemolysis. There appears to be a clear localization of iron deposition within the kidney, with the deposits being found in the cortex and not in the medulla, as found by T1 and T2-weighted MRI. Our results suggest that haemolysis is a major determinant of renal iron load in SCA patiests. Disclosures No relevant conflicts of interest to declare.

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Sickle Cell Disease

10.1093/med/9780190678333.003.0033 ◽

2018 ◽

Author(s):

Ann Ng ◽

Erin S. Williams

Keyword(s):

African American ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Sickle Cell Trait ◽

Organ Damage ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Systemic Involvement ◽

History Of

Sickle cell anemia (sickle cell disease) is a common hemoglobinopathy with anywhere from 90,000 to 100,000 Americans affected. This chronic condition has a predominance in populations of African descent, occurring in approximately 1 out of 365 African American births, compared to 1 out of 16,300 Hispanic births. The sickle cell trait can be detected in 1 of 13 African American births. One of the most common complications associated with sickle cell anemia, vaso-occlusive crises by sickled cells, results in severe pain. Other issues associated with this condition include acute chest syndrome, lung infections, end organ damage, and stroke. With improvements in the management and prevention of pain crises, infection, and other systemic involvement, these patients are living longer, thus increasing the potential for surgical needs. Whether it is for routine surgeries or surgeries that are due to the natural history of the disease; the pediatric anesthesiologist must be knowledgeable of the management of these patients in order to prevent morbidity and mortality.

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