scholarly journals Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Renata Sesti-Costa ◽  
Marina Dorigatti Borges ◽  
Carolina Lanaro ◽  
Dulcinéia Martins de Albuquerque ◽  
Sara Terezinha Olalla Saad ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Sickle Cell ◽  
B Lymphocyte ◽  
Cytokine Production ◽  
Reticulocyte Count ◽  
Cell Disease ◽  
Main Component ◽  
Inflammatory Dendritic Cells

Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14+ DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14+ mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.

Human Sickle Cell Disease Increases Numbers and Activation Of Peripheral Blood Myeloid Dendritic Cells, Monocytes, and Neutrophils

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1033-1033
Author(s):  
Gene Lin ◽  
Jennifer C. Yu ◽  
Joshua J. Field ◽  
David G. Nathan ◽  
Joel Linden
Keyword(s):  
Dendritic Cells ◽  
Sickle Cell Disease ◽  
Adhesion Molecules ◽  
Inflammatory Cytokines ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Inkt Cells ◽  
Lipid Antigens

Abstract Sickle cell disease (SCD) is characterized by widespread vaso-occlusion in venules that is initiated by the polymerization of deoxy-hemoglobin in sickle RBCs and exacerbated by leukocyte activation and endothelial injury. In the course of the disease, episodic flare-ups result in painful vaso-occlusive crises (pVOC) and acute chest syndrome that over time result in chronic tissue injury. We have previously shown that pVOC in SCD is associated with activation of a small subset of CD1d restricted T lymphocytes known as invariant NKT (iNKT) cells that release large amounts of pro-inflammatory cytokines and propagate an inflammatory cascade. Antigen presenting cells (APCs) stimulate the activation of iNKT cells by presenting lipid antigens on CD1d and by releasing co-activating cytokines such as IL-12 and IL-18. Cytokines released by activated iNKT cells such as IFN-γ further propagate inflammation by stimulating chemotaxis of and activation of additonal leukocytes. In mice, the cytokines that are released by activated iNKT cells trans-activate monocytes and neutrophils. In this study we investigated for the first time the effect of pVOC in patients on the activation of myeloid (CD11c+/CD123-) dendritic cells (DCs) (CD45+/Lin1-/HLA-DR+), monocytes (CD3-/CD19-/CD15-/CD66b-/CD14+), and neutrophils (CD3-/CD19-/CD15+/CD66b+). Our findings indicate that like iNKT cells, myeloid DCs, monocytes, and neutrophils are increased in peripheral blood of SCD subjects relative to non-SCD controls. Plasmacytoid DCs (CD11c-/CD123+) were little affected. This increase in cell numbers is enhanced during pVOC except for myeloid DCs which decrease, possibly due to extravasation out of the blood stream. In addition, CD1d+ myeloid DCs from SCD individuals express higher levels of the activation marker, CD86, and this is further increased during pVOC. Similarly, neutrophils and monocyte subsets including classical monocytes (CD14+/CD16-) and patrolling monocytes (CD14dim/CD16+) express higher levels of activated adhesion molecules, LFA-1 (detected with KIM127 antibody) and Mac-1 (detected with CBRM1/5 antibody that recognizes active CD11b), in SCD subjects during pVOC as compared to controls and steady-state SCD patients. Taken together, these findings strongly suggest that the severity of vaso-occlusion during the clinical course of SCD correlates with an increased pro-inflammatory state reflected by increased circulating activated leukocytes. These findings are also consistent with previous murine studies showing that iNKT cells are necessary, but not sufficient for initiating and amplification of tissue inflammation and damage. The activation of CD1d+ APCs during pVOC is likely to facilitate iNKT cell activation due to the expression of co-stimulatory molecules (CD86), inflammatory cytokines, and possibly lipid antigens. Moreover, the activation of adhesion molecules on monocytes and neutrophils may enhance their propensity to contribute to vaso-occlusion. Disclosures: Field: NKT Therapeutics: Consultancy.

Low Erythrocytic Glutathione Peroxidase-1 Activity Correlates with Hemolytic Rate in Patients with Sickle Cell Disease and Is Elevated on Hydroxyurea.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2253-2253
Author(s):  
Gregory J. Kato ◽  
Chun Seok Cho ◽  
Seung Ha Yang ◽  
Sung Won Bae ◽  
Jong Seo Lee ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Glutathione Peroxidase ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Oxidant Stress ◽  
Fetal Hemoglobin ◽  
Cell Protein ◽  
Red Cell ◽  
Cell Disease ◽  
Glutathione Peroxidase 1

Abstract Background: Glutathione peroxidase-1 (GPX1) is the most significant catalytic antioxidant in the red cell. Congenital deficiency of GPX1 has been reported in association with hemolytic anemia due to oxidant stress. Hemolytic rate has been implicated in the development of sickle vasculopathy. Methods: Red cell pellets were collected from 32 patients with sickle cell disease and 17 healthy African American control subjects, and were stored frozen until assayed. A novel microplate immunoaffinity capture assay was used that measures both immunoreactive GPX1 protein and enzyme activity. Results: Patients with SCD had higher levels of red cell GPX1 activity than controls (2.42 ± 0.12 vs. 1.86 ± 0.15 units/mg red cell protein (mean ± SEM), p=0.006). GPX1 activity correlated with low reticulocyte count (r=−0.50, p=0.004)(Fig. 1A), low indirect bilirubin (r=–0.45, p=0.01) and high fetal hemoglobin expression (r=0.39, p=0.03). GPX1 activity in SCD patients on hydroxyurea was much higher than those not on hydroxyurea (2.75 ± 0.12, n=21 vs. 1.79 ± 0.13, n=11, p<0.001)(Fig. 1B), suggesting that hydroxyurea might induce GPX1 expression. In the patients off hydroxyurea, low GPX1 activity closely correlated with high serum lactate dehydrogenase level, a marker of high hemolytic rate (r=–0.85, p=0.002), suggesting that low GPX1 levels might contribute to rapid hemolytic rate. In a multivariate model, GPX1 was independently associated with reticulocyte count even when adjusted for fetal hemoglobin level. Conclusions: In addition to fetal hemoglobin, hydroxyurea may also induce expression of GPX1, a potent antioxidant that might have a role in decreasing hemolysis associated with the robust oxidant stress of SCD. This finding is consistent with previously published evidence of GPX1 induction by hydroxyurea in cancer cell lines, with increased antioxidant function. Additional studies are needed to confirm this phenomenon in a larger cohort of patients with SCD and to further evaluate the combined effect of fetal hemoglobin co-induction, but this finding suggests a potential mechanism by which hydroxyurea may produce clinical benefit in SCD even in the absence of significant fetal hemoglobin induction. Figure Figure

scholarly journals Hypersegmented Neutrophil Percentage Using Automated Digital Cell Morphology: A Simple Laboratory Parameter to Monitor Hydroxyurea Therapy in Sickle Cell Disease Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2188-2188
Author(s):  
Kleber Yotsumoto Fertrin ◽  
Elza Miyuki Kimura ◽  
Fernanda Madureira de Oliveira Araujo ◽  
Maria de Fatima Pereira Gilberti ◽  
Sara T.O. Saad ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Cell Morphology ◽  
Red Blood Cell ◽  
Half Life ◽  
Reticulocyte Count ◽  
Average Dose ◽  
Cell Disease ◽  
Long Term Treatment

Abstract Fetal hemoglobin (HbF) induction with hydroxyurea (HU) remains the only specific pharmacological treatment for sickle cell disease (SCD) patients. Compliance is key to achieve high HbF levels, but assessing patient adherence to long-term treatment is difficult. Since patient interviews are often unreliable, most hematologists rely on mean corpuscular volume (MCV) and HbF levels to monitor compliance, but red blood cell indices change slowly. Hypersegmented neutrophils (HN) have been for long recognized in patients taking HU, and automated digital cell morphology platforms allow routine peripheral blood smears to be conveniently photographed and stored for analysis. We have designed a protocol to determine the percentage of circulating HN and have studied how this parameter compares with others commonly used in clinical practice during HU therapy, such as HbF, MCV, and reticulocyte count. We collected blood samples from 38 patients with SCD in steady state, receiving an average dose of 20.5mg/kg/day of HU (range 10.2-33.3) at our Hematology outpatient clinic. Complete blood counts and HN percentage determinations were performed on a Sysmex XE-5000/Cellavision DM96 equipment. HbF levels were determined by HPLC (Bio-Rad). Statistical analysis was performed using GraphPad Prism 6.0 software. Standard protocol for image acquisition initially recorded 100 cells per smear and HN count was performed independently by two experienced laboratory personnel using the same image database, by counting cells with 5 or more nuclear segments. To increase precision due to the relatively low numbers of neutrophils in some samples, analysis was subsequently improved by acquiring 300 images per smear aiming to picture 100 neutrophils. Mean hemoglobin level in our population was 8.6±1.3g/dL (mean±SD), MCV 103.8±14.2fL, reticulocyte count 222,950±129,090/uL, and HbF was 13.1±7.8% (range 2.1-30.9%). HN percentage as determined with 100 images per smear displayed only borderline correlation with HbF levels (P =0.094), but acquisition of 300 images per smear yielded over 90 neutrophil images in 35/38 samples. Average HN percentage was 14,5% (range 2,0-45,0%) and correlated positively with HbF (r=0.4172, P =0.009) and MCV (r=0.4301, P =0.007). As expected, HbF also correlated with MCV (r=0.5777, P =0.0001) and reticulocyte count (r=-0.489, P =0.003). Despite our limited number of patients, ROC curve analysis showed that HN percentage had an area under curve of 0.7241 to detect patients with HbF>20% (P =0.047). Patients with more than 6 segments per neutrophil were also more likely to have higher HbF. Average daily HU dose did not correlate with HbF or any of the parameters analyzed. Lack of correlation between dose and HbF supports that medication adherence may indeed be suboptimal in the study population, but that may also be caused by individual differences in HU metabolism. While MCV still displayed the strongest correlation with HbF in our study, HN percentage performed similarly, with higher counts associated with higher HbF. Neutrophils have a much shorter half-life than erythrocytes, with an estimated half-life of hours rather than the 20 days calculated for sickle red blood cells. Therefore, digital cell morphology analysis enables clinical laboratories to determine HN counts that can change more quickly than HbF, MCV, or reticulocyte counts during HU therapy. Monitoring the number of HN may allow more timely assessment of compliance in patients starting HU or in those in need for HU in combination with sporadic blood transfusions, since neutrophil hypersegmentation should not be affected by changes in red blood cell mass. Further studies should investigate HN percentage as a potential surrogate marker of response to HU and of patient compliance. Financial support: FAPESP Disclosures No relevant conflicts of interest to declare.

scholarly journals Human red cell membrane adenylate cyclase in normal subjects and patients with hereditary spherocytosis, sickle cell disease and unidentified hemolytic anemias

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 963-968 ◽  
Author(s):  
JP Piau ◽  
J Delaunay ◽  
S Fischer ◽  
M Tortolero ◽  
G Schapira
Keyword(s):  
Sickle Cell Disease ◽  
Adenylate Cyclase ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Hereditary Spherocytosis ◽  
Reticulocyte Count ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Cell Disease

We have investigated adenylate cyclase in ghosts from normal and pathologic human red blood cells. Basic parameters such as specific activity, apparent Michaelis constant (KMapp), and response to effectors: sodium fluoride (NaF), 5′-guanylyl imidodiphosphate (Gpp (NH)p), isoproterenol, and PGE1 were investigated. Basal and NaF- stimulated activities were measured in ghosts from patients with hereditary spherocytosis, sickle cell disease, and various unidentified hemolytic anemias. Both activities were increased in any of these pathologic conditions as compared with those of normal red blood cells. Normal values were found in patients with hereditary spherocytosis after splenectomy and in patients with heterozygous sickle cell disease. There was a good correlation between the reticulocyte count and adenylate cyclase activity in hereditary spherocytosis and in sickle cell disease with reticulocyte count lower than 10%. The enzyme activity of the first group was about three times that of the second group. There was no correlation at all in sickle cell disease with higher reticulocytosis and in the group of unidentified hemolytic anemias. These results suggest that increased adenylate cyclase activities are not specific of any of these diseases. In the patients with hereditary spherocytosis, the adenylate cyclase activity seems to be essentially related to younger mean age of red blood cell population while in the patients with sickle cell disease and in others with unidentified hemolytic anemias some additional factors might interfere directly with the enzyme and alter its activity.

Predictors of Adverse Outcomes in Hospitalized Adult Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3197-3197
Author(s):  
Fahd Rahman ◽  
Roy N. Gay ◽  
Samir K. Ballas ◽  
Juan C. Zubieta ◽  
Zekarias Berhane ◽  
...  
Keyword(s):  
At Risk ◽  
Logistic Regression ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Acute Pain ◽  
Reticulocyte Count ◽  
Laboratory Data ◽  
Adverse Outcomes ◽  
Acute Chest Syndrome ◽  
Cell Disease

Abstract The identification of patients with sickle cell disease at risk of serious complications at the time of hospital admission can help stratify patients who will need aggressive management. We identified predictors associated with adverse outcomes such as frequent hospitalizations, acute pain crises and acute chest syndromes. To that end, we retrospectively reviewed medical records of 265 adult sickle cell disease patients, hospitalized between 1/1/98 and 2/3/05 at Mercy Catholic Medical Center, with complete clinical and laboratory data. 195/73.6% had HbSS and the rest had HbSC, HbSβ-thal0,HbS-βthal+or HbSOarab disease. 59 variables were considered including demographic, hematological, biochemical, clinical and treatment data. Logistic regression models were used to obtain associations between variables, and to adjust for confounding effects. Analysis showed that adverse events during admission included acute pain crises in 249/94%, acute chest syndromes in 25/9.4% and strokes in 5/1.9% patients. Other outcomes were a greater than 2 hospitalizations per year 82/31.9%, more than 2 pain crises per year 145/54.7%, transfusion required during admission 72/27.2%, length of hospital stay more than 5 days 105/39.6% and death during hospitalization 13/4.9%. Multivariate logistic regression analysis revealed 21 factors with statistically significant associations. A reticulocyte count greater than 1.5 (OR 3.98, CI 1.48–10.69, P.006) and employment status (OR .31, CI .13-.75, P.009) were associated with more admissions per year. History of acute chest syndrome (OR 5.33, CI 1.7–16.77, P.004), reticulocyte count greater than 1.5 (OR 3.46, CI .91–13.11, P.067) and care provided by a nonhematologist (OR 5.04, CI 1.7–14.95, P.0035) were linked with more pain crises per year. Pain crises during admission were associated with HbSS disease (OR 9.31, CI 2.17–39.9, P.01) and out patient folate therapy(OR 6.23, CI 1.45–26.84, P.003). Patients with leukocytosis (OR 3.41, CI 1.2–9.67, P.02) and a higher serum glucose level (OR 7.54, CI 2.6–21.86, P.0002) were linked to more acute chest syndromes. Females (OR .1, CI .03–.37, P.0004) were at lower risk of having acute chest syndromes. Outpatient folate therapy (OR .07, CI .007–.69, P.02) was associated with lower numbers of acute neurological events. Patients with initial hemoglobin levels less than 7 g/dL (OR 1.99, CI 1–4, P.0007) and prolonged hospitalization (OR 7.06, CI 3.63–13.74, P.0001) frequently required transfusions. Variant diseases (OR .28, CI .13–.58, P.05) required fewer transfusions. Deaths during hospitalization were lower with folate therapy (OR .18, CI .05–.63, P.007) and a transfusion requirement during admission (OR 5.07, CI 1.45–17.64, P.01) predicted more deaths. HbSS patients (OR 2.52, CI 1.1–5.8, P.03), substance abusers (OR 2.93, CI 1.21–7.08, P.01), those requiring antihistamines during admission (OR 3.33, CI 1.38–8.03, P.007), or requiring more than 2 hospitalizations per year (OR 2.62, CI 1.26–5.43, P.009) had hospital stays longer than 5 days while in females odds were low for this outcome (OR .30, CI .15–.59, P.0005). In conclusion, simple tools like a complete history, physical examination, demographic and laboratory data can help clinicians and health care providers to gauge severity of the illness and deliver tailored management protocols targeting these “at risk” sickle cell disease patients.

Tricuspid Regurgitant Jet Velocity Is Significantly Associated with Hemolysis in the Evaluation of Pulmonary Hypertension in Children and Young Adults with Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1211-1211
Author(s):  
Robert I. Liem ◽  
Nichele M. Willingham ◽  
Luciana T. Young ◽  
Alexis A. Thompson
Keyword(s):  
Pulmonary Hypertension ◽  
Young Adults ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Cell Disease ◽  
Significant Difference ◽  
Children And Young Adults ◽  
Jet Velocity ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Pulmonary hypertension (PHT) has emerged as a frequent cause of increased morbidity and mortality in adults with sickle cell disease (SCD). However, the incidence, prevalence and etiology of PHT in children with SCD are currently unknown. An elevated tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec on Doppler echocardiogram (ECHO) in adults may predict PHT usually diagnosed by traditional cardiac catheterization. We hypothesized that routinely measuring TRJV in children and young adults with SCD was feasible and that TRJV correlated with degree of baseline hemolysis. Methods Using a standard protocol, we prospectively measured steady state TRJV in a convenience, cross-sectional sample of 43 patients (mean age 14.2±2.8 years, range 10 to 20) with hemoglobin (Hb) SS, SC or S-β0 thalassemia at our institution as part of a PHT screening initiative beginning December 2005. Patients on chronic transfusions were excluded. The relationship between TRJV and same day laboratory studies and clinical data obtained from patient charts was examined. Results TRJV was not measurable in 5 of 43 (12%) patients, due presumably to normal pulmonary artery systolic pressures. Neither right ventricular hypertrophy nor decreased septal wall motion, both suggestive of PHT, was present when TRJV could not be determined. In the remaining 38 studies in which TRJV could be quantified (mean 2.34 m/sec±0.44), TRJV was ≥ 2.5 m/sec in 13 patients. Using Pearson’s correlation coefficient, we found a significant correlation between TRJV and LDH (r=0.54, p=0.01), with higher TRJV associated with higher LDH. There were also significant, though more modest, positive correlations between TRJV and WBC (r=0.37, p=0.05) and reticulocyte count (r=0.40, p=0.05) and a significant negative correlation between TRJV and Hb (r= -0.46, p=0.01). Using t-test for independent samples, we found a significant difference in mean LDH (458 IU/L±192 vs. 338 IU/L±144, p=0.037), Hb (8.7 g/dL±1.3 vs. 10.2 g/dL±1.6, p=0.008) and reticulocyte count (17.3%±10.3 vs. 10.7%±6.9, p=0.027) between patients with TRJV ≥ 2.5 and <2.5 m/sec. A difference approaching significance in total WBC (11.4 x103/μL±5.3 vs. 8.3 x103/μL ±3.2, p=0.075) was also observed between the two groups. We found neither a significant difference in mean values between the two groups nor significant relationships with TRJV when we examined platelet count, plasma free Hb, percent fetal Hb or total bilirubin. Using Fisher’s Exact Test, we did not demonstrate in our small cohort a difference in the proportion of patients with TRJV ≥ 2.5 or < 2.5 m/sec who had a history of hydroxyurea use, acute chest syndrome, frequent pain, asthma, splenectomy, gallstones, priapism, exchange transfusion, heart disease or tonsilloadenoidectomy. Conclusions We conclude that TRJV by ECHO is quantifiable in most children and young adults being evaluated for PHT and that a higher LDH and reticulocyte count and a lower Hb at baseline are observed more frequently with elevated TRJV. Larger cohort studies are needed to test the predictive value of one or more of these markers of hemolysis. Although long term outcomes associated with elevated TRJV, as an indication of PHT, in children with SCD remains unclear, decreasing hemolysis in this population may represent an early therapeutic target in the prevention of future clinically significant PHT.

Adding Hydroxyurea to Chronic Transfusion Therapy for Stroke in Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4620-4620
Author(s):  
Susan Claster ◽  
Keith C. Quirolo
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Conflicts Of Interest ◽  
Hematological Parameters ◽  
Fetal Hemoglobin ◽  
Venous Access ◽  
Time Frame ◽  
Cell Disease ◽  
Transfusion Therapy

Abstract Abstract 4620 Introduction Transfusions have clearly been shown to prevent stroke in patients with Sickle Cell Disease(SCD). The usual goal of transfusion therapy is to keep the percent sickle Hgb (%S) less than 30. %S greater than 30 has been associated with stroke reoccurance. Inability to transfuse adequately may result from poor vascular access or high hemolytic rate. Hydroxyurea, a drug which requires active erythropoeisis, is usually not given to patients who are chronically transfused. However, the presence of an elevated reticulocyte count in a transfused patient indicates ongoing sickle hematopoiesis. We added Hydroxyurea therapy to two patients who were unable to achieve %S levels less than 30 and who had elevated reticulocyte counts to assess whether this drug could improve their hematological parameters. Results We treated two post stroke patients, one receiving pheresis therapy, and the other on straight transfusion therapy who were unable to achieve 30% Hgb S despite regular transfusions. Patient 1, a 33 y/o female with Hgb SS had been on transfusions since childhood for multiple CVA's and resulting moya-moya. Her last stroke had occurred while she was being chronically transfused and had a % S of 40. Due to venous access issues the patient was receiving straight transfusion only and was unable to adequately suppress her marrow. In 8/07 her %S was greater than 40 and her reticulocyte count was 11.3 %. Hydroxyurea was started at 1500 mg daily(22 mg/kg). Over the next 24 months her Bilirubin dropped from 8.7mg/dl to 1.9 mg/dl, her reticulocyte count dropped to 4%(figure below) and her MCV increased to 104.6 from 90. Her Hgb F rose to 30%.Her %S has not changed. She has remained clinically stable with no new neurological findings. The second patient, a 17 y/o male had been on chronic transfusions since childhood for a stroke which resulted in a dense left hemiparesis. He has been on a pheresis program for 13 years. Despite this his % S remained greater than 40% and had been as high as 60% prepheresis. Hydroxyurea was added in 5/08 at a dose of 25mg/kg. Within 6 months his pretransfusion %S had dropped to 22-27%. No increase in fetal Hgb was detected, possibly due to the exchange transfusion process. His bilirubin, which had been running between 12-16 mg/dl dropped to 7.6-8.9 mg/dl and his reticulocyte count went from an average of 19.6% to 11.2% in the same time frame. He has also remained stable. Discussion These two patients demonstrate that the addition of Hydroxyurea to patients on chronic transfusion can be useful in decreasing hemolytic rate and improving the efficacy of transfusions by decreasing sickle erythropoiesis and increasing fetal hemoglobin synthesis. Further studies of the combination of these two modalities may be warranted in those patients who cannot achieve adequate suppression of sickle erythropoeisis. Disclosures: No relevant conflicts of interest to declare.

Monthly Laboratory Monitoring May Not Be Necessary for Patients with Sickle Cell Disease On Hydroxyurea

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3231-3231
Author(s):  
John J Nevin ◽  
Leann Myers ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Data Collection ◽  
Sickle Cell ◽  
Pediatric Patients ◽  
Reticulocyte Count ◽  
Significant Risk ◽  
Standard Of Care ◽  
Laboratory Monitoring ◽  
Cell Disease ◽  
Monitoring Protocols

Abstract Abstract 3231 Background: Hydroxyurea is the only FDA-approved disease modifying agent for sickle cell disease. However, despite its efficacy proven in multi-centered, randomized, placebo-controlled studies, it remains highly under-utilized. This study aimed to determine the necessity for routine laboratory testing through a retrospective chart review of compliant, pediatric patients. Study Design: Charts were reviewed on all of the pediatric patients receiving treatment with HU at a single institution. 16 pediatric patients with HbSS disease were chosen to be included since they had attended >80% of monthly clinic visits over the designated 12-month period. Age range was 2–18 years (mean age of 11.8 years) and included 10 girls and 6 boys. All patients followed in this study also reported adherence to their HU regimens (missed <10% medication) during their clinic appointments. As per the standard of care protocol, a complete blood count and reticulocyte count were performed at each monthly appointment, and the Hemoglobin (HGB), Reticulocyte count (Retic), Absolute Neutrophil Count (ANC), White Blood Cell Count (WBC), and Mean Corpuscular Volume (MCV) were recorded. During the time of data collection, patients were on a range of 13–25mg/kg (median 18.6mg/kg) of HU and 4 patients underwent a dose increase during this 12 month period. Prior to the index point (first point of data collection), included patients had already been taking HU an average of 29.44 months (range 0–64 months). The coefficient of variation (a standardized measure of variability) was calculated as both a monthly and quarterly assessment for each variable. Results: The coefficients of variation (Cv) was computed for each of five target variables including Hgb, Retic, ANC, WBC, and MCV (see table 1). The Cv was computed both quarterly (CVq) and monthly (CVm) for each patient. Finally, each measure was also compared to critical laboratory values to assess if patients were considered neutropenic (ANC<1500), reticulocytopenic (absolute reticulocyte count <80 × 109/L unless hemoglobin concentration was 9.0 g/dL or higher), or thrombocytopenic (platelet count <80,000) at any point. Hgb and MCV were very stable. ANC was highly variable; however, it was never <1000, thus there was no significant risk of infection from neutropenia. There was only one moderately concerning value observed in which a patient had an ANC of 1,500 exactly (HU dose was not changed). At no time during the 12 months did a laboratory value detected on routine monthly screening trigger a dose reduction or result in a hospitalization. Discussion: Hydroxyurea is currently the only FDA approved medication for patients with SCD and is proven to decrease the overall frequency of vaso-occlusive crisis, decrease hospitalization rate, and improve overall quality of life. Despite these impressive results, the medication remains severely underutilized in part due to the stringent laboratory monitoring considered standard of care when treating patients with this medication. Current laboratory monitoring protocols were developed due to the potential risk of neutropenia, neutropenic infections, reticulocytopenia, or thrombocytopenia. These results in this limited study demonstrate that quarterly assessment would have been sufficient to obtain the necessary information without missing critical nadirs or complications. Decreasing the stringency of the requirements for laboratory monitoring for patients being treated with Hydroxyurea may lead to improved use. To confirm these results, outcomes including both laboratory and hospital utilization should be prospectively studied in a randomized fashion of patients undergoing monthly vs quarterly laboratory assessments. Disclosures: Off Label Use: Hydroxyurea is not currently FDA approved for use in pediatrics. It is presented for use in this abstract for treatment of sickle cell disease as per National guidelines.

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