scholarly journals The First Two Years of Life in Sickle Cell Anemia Infants: Results of a Comprehensive Longitudinal Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 688-688
Author(s):  
Valentine Brousse ◽  
Sara El Hoss ◽  
Naim Bouazza ◽  
Cecile Arnaud ◽  
Francoise Bernaudin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Disease Severity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Neonatal Screening ◽  
Research Funding ◽  
Clinical Event ◽  
Acute Chest Syndrome ◽  
Hbf Level

Abstract Background and hypothesis: Infancy is a critical time during which the first complications of sickle cell anemia (SCA) emerge. Very early prognostic factors of severity are needed to select high-risk children to offer precisely tailored therapy. Our hypothesis was that clinical, biological or genetic parameters measurable soon after birth (3 to 6 months of age) could predict severe outcomes in the first two years of life in SCA infants. Methods: Infants with SCA were offered to participate in a prospective study (ClinicalTrials.gov: NCT01207037) that included clinical and laboratory assessment at enrollment (3-6 months) and at 12, 18 and 24 months of age. The prognostic performance of conventional and SCA-specific biomarkers (notably erythroid adhesion markers, dense cells, ektacytometry indices) on disease severity was assessed using Cox's proportional hazard regression models. The disease severity was defined as time to first occurrence of either acute splenic sequestration (ASS), vaso occlusive (VOC) event requiring hospitalization, transfusion, conditional or abnormal Trans Cranial Doppler, acute chest syndrome and death. Hazard ratios (HRs) were calculated with 95% Cis. Results: Fifty-seven infants (55 SS; 2 Sβ°; 54.4% males), diagnosed through neonatal screening, were included in the study at a mean age of 4.4 ± 1 months and longitudinally assessed with a median follow-up of 19.4 months (range 3.1-23.2). Only 1 of 57 infants had experienced a SCA-related event prior to enrolment (dactilytis). At inclusion, clinical examinations were unremarkable except for pallor found in 15 (26,3%) and none of the infants had an enlarged or palpable spleen. Growth parameters were normal. Main biological characteristics were a mild hemolytic anemia (Hb 9.3 ±1.3 g/dL; reticulocytes count: 151.2 ±76 x 109/L), increased HbF level (3.8 ±1.3 g/dL. or 41.4 ±11.7%) and presence of dense red cells (23.1 % ±10.8). Genetic analysis showed one alpha globin deletion in 18 (32.1%) and a balanced distribution of beta globin haplotypes: 16 (30.8%), 18 (34.6%) and 18 (34.6%) in the favorable (SEN/SEN, BEN/SEN, CAM/SEN or SEN/ATYP), unfavorable (CAR/CAR, CAM/CAR, CAR/ATYP or BEN/CAR) and intermediate category (other) respectively. During the 2 years duration of the study, 44 of 57 (77%) infants required 157 hospital admissions, median (range): 2 (1-12) per patient. Infection was a leading cause of hospitalization although no serious adverse event related to pneumococcal infection was noted. Eight (14%) children experienced an episode of ASS at a median (range) age of 13.4 months (7.8- 15.9) while 13 infants (22.8%) experienced at least one VOC event at a median age of 12.7 months (7-22.5), with 6 experiencing ≥ 2 episodes. Nineteen infants (33.3%) required at least one transfusion with 10 (17.6%) requiring more than 2. Altogether, 22 (38.6%) infants of this cohort experienced a SCA-related severe clinical event by 24 months of age. The Kaplan Meier estimate of the 24-month event-free rate was 54.4% (95% CI, 39.7 to 74.5%) (Figure). Univariate analysis of potential prognostic markers at inclusion showed that higher HbF % and concentration were the strongest protective parameters for ASS in particular and for all severe outcomes, except for VOC (p < 0.001). Unfavorable haplotypes were also associated with severe outcome (HR (95% CI) 4.73 (1.31-17.01), p=0.017). Protective factors for VOC were higher Hb level (threshold > 8 g/dL) and low % of circulating dense cells (p=0.04 and 0.02, respectively). In a multivariate analysis, Hb level ≥ 8 g/dL and HbF ≥ 2.8 g/dL proved to be two independent prognostic factors of a SCA-related severe event (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43) respectively). Interestingly, absolute neutrophil or reticulocyte counts, level of expression of known potentially pathogenic erythroid adhesion markers (CD36, Lu/B-CAM, ICAM-4/LW), % of red dense cell, or deformability parameters failed to be prognostic factors of specific complications or overall severity in this very young cohort. Conclusion: HbF and Hb levels measured between 3 and 6 months of age in SCA infants predict the risk of subsequent severe clinical outcome in the next 2 years. These events are frequent even in a high-income setting where neonatal screening is implemented. These findings further support the early use of HbF inducers such as hydroxyurea in high-risk infants to sustain a protective HbF level. Figure 1 Figure 1. Disclosures Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding.

Severity of Sickle Cell Disease: Modeling Interrelationships among Hemolysis, Pulmonary Hypertension and Risk of Death.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 786-786
Author(s):  
Paola Sebastiani ◽  
Vikki G. Nolan ◽  
Clinton T. Baldwin ◽  
Maria M. Abad-Grau ◽  
Ling Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Disease Severity ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Clinical Severity ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Risk Of Death

Abstract A single point mutation in the β hemoglobin gene causes sickle cell disease (SCD), but patients have extremely variable phenotypes. Hemolysis-related complications include pulmonary hypertension (PHT), priapism, stroke and leg ulceration; blood viscosity and sickle vasoocclusion are associated with painful episodes, acute chest syndrome and osteonecrosis. Predicting who is at highest risk of death would be useful therapeutically and prognostically. Applying Bayesian network modeling that describes complex interactions among many variables by factorizing their joint probability distribution into modules, to data from 3380 SCD patients, we constructed a disease severity score (DSS: 0, least severe; 1, most severe), defining severity as risk of death within 5 years. A network of 24 variables described complex associations among clinical and laboratory complications of SCD. The analysis was validated in 140 patients whose SCD severity was assessed by expert clinicians and 210 adults where severity was also assessed by the echocardiographic diagnosis of PHT and death. Information about PHT allowed a comparison of the DSS with the tricuspid regurgitant jet velocity (TRJV), an objective marker of PHT and an independent risk factor for death. DSS and three indices of clinical severity (severity ranking of individuals by expert clinicians; objective measurement of the presence and severity of PHT; risk of prospective death) were correlated. Among living subjects, the median score was 0.57 in 135 patients without PHT, 0.64 in 40 patients with mild PHT and 0.86 in 15 patients with severe PHT. The difference in average score between living patients with and without PHT is significant. The same increasing trend was noticeable in the subjects who died during follow-up: 0.60 in subjects without PHT; 0.68 in subjects with mild PHT; 0.79 in subjects with severe PHT. The utility of the DSS is also supported by the ability to assign a score to subjects for whom the TRJV cannot be measured. Surprisingly, besides known risk factors like renal insufficiency and leukocytosis, we identified the intensity of hemolytic anemia and clinical events associated with hemolytic anemia as contributing to risk for death. Priapism, an excellent reflection of the hemolytic anemia-related complications of SCD, is associated with PHT and its association with death was unexpected. Laboratory variables predictive of disease severity included LDH and reticulocytes that reflect the intensity of hemolytic anemia. Elevated systolic blood pressure increased the odds of death by 3.4, consistent with hypertension as a marker of early death in SCD. Subjects with sickle cell anemia are at greatest risk compared with subjects with sickle cell anemia-α thalassemia and with subjects with HbSC disease. Our model suggests that the intensity of hemolytic anemia, estimated by LDH, reticulocyte count and AST, and shown previously to be associated with PHT, priapism, leg ulceration and possibly stroke, is an important contributor to death. This model can be used to compute a personalized measure of disease severity that might be useful for guiding therapeutic decisions and designing clinical trials.

scholarly journals Regulatory Genetic Variation at the S100B Gene Associates with Vaso-Occlusive Manifestations in Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1063-1063 ◽  
Author(s):  
Xu Zhang ◽  
Wei Zhang ◽  
Santosh L. Saraf ◽  
Sergei Nekhai ◽  
Mark T Gladwin ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Genetic Regulation ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Thrombotic Risk ◽  
Increased Risk

Abstract In sickle cell disease (SCD) polymerization of hemoglobin S under deoxygenated conditions causes vaso-occlusion, which can manifest as acute pain crisis and progressive bone/organ damage. Molecular studies have attributed vaso-occlusion to elevated vascular adhesion and inflammatory responses, whereas the genetic regulation has only recently been assessed. Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) was hybridized to Illumina Human 610-Quad SNP array for the PUSH and Walk-PHaSST cohorts and to Affrymetrix SNP 6.0 array for the Howard SCD expression cohort. Single nucleotide polymorphisms (SNPs) for 381 PUSH, 525 Walk-PHaSST, and 55 Howard patients were imputed to 1000 genomes project phase 3 data. Messenger RNA from PBMCs was profiled using Affymetrix Human Exon 1.0 ST Array for the Howard expression cohort and Affymetrix Human gene 2.0 ST array for the UIC expression cohort. Patients within the PUSH and Walk-PHaSST cohorts were classified to four groups according to a cumulative pain score, calculated based on pain frequency and questionnaire description of pain intensity. Pain grouping was examined for correlation with other SCD complications using Cochran Armitage test. History of acute chest syndrome (ACS, PUSH P=3.8×10-9, Walk-PHaSST P=2.4×10-5) and avascular necrosis (AVN, PUSH P=4.1×10-4, Walk-PHaSST P=3.7×10-5) were the most significant clinical manifestations that consistently associated with pain in the two cohorts. To investigate the genetic control of vaso-occlusive manifestations with appropriate power, we leveraged genetic association of pain, ACS, and AVN with genetic regulation of disease-specific gene expression. We mapped expression quantitative trait loci (eQTL) in the Howard expression cohort for SNPs<1 Mb away from gene ends per expression trait. At a permutation based false discovery rate of 5%, 1004 independent eQTL (linkage disequilibrium r2 ≤0.3 per trait) were identified for 880 genes. Focusing on 129 genes whose expression was altered in PBMCs in sickle cell anemia by at least 1.5-fold [1], we identified six eQTL for five differential genes (up-regulated: OSBP2, SLC14A1, RNF182, CCRL2; down-regulated: S100B). The six eQTL were assessed for association with pain, ACS, and AVN, using the Walk-PHaSST cohort for discovery and the PUSH cohort for validation. At a significance of Bonferroni corrected P=0.05 (nominal P=0.0083), an eQTL of S100B (rs2154586) significantly associated with AVN in the Walk-PHaSST cohort (OR=1.8, P=0.00061) and the association was replicated in the PUSH cohort (OR=2.7, P=0.0052). The A allele of the eQTL (frequency=0.18) associated with increased risk for AVN and increased expression level of S100B in the Howard expression cohort (β=0.40, P=1.6 ×10-6). In an additional 64 sickle cell anemia patients without hydroxyurea treatment from the UIC expression cohort, expression levels of S100B were significantly elevated in the individuals with AVN (β=0.28, P=0.029). The 24 SNPs in linkage disequilibrium with the eQTL (r2 >0.7) constituted the third most significant peak in a meta-analysis of genome-wide association of AVN in the PUSH and Walk-PHaSST cohorts. To test the hypothesis that genes involved in vaso-occlusion in SCD may affect thrombotic risk in non SCD individuals, we examined the association of the locus with venous thromboembolism (VTE) in the ARIC, JHS and CHS cohorts from dbGaP. The locus was imputed in African Americans and VTE was defined as being told by a doctor to have a blood clot in the leg or lung as answered in questionnaires during medical exams. The SNPs were associated with VTE using logistic linear regression adjusting for age, gender, enrollment site, and the first 15 principal components per cohort. The risk allele of the leading SNP for AVN consistently associated with increased risk of VTE across the cohorts, with a combined P=0.0041 and OR=1.4. S100B encodes a calcium sensor that appears to intervene in a variety of biological functions. S100B can mediate the inflammatory effects of damage-associated molecular pattern molecules (DAMPs) produced by erythrocyte hemolysis [2, 3]. Serum concentration of S100B correlates with LDH and with TCD-determined peak velocity of the left middle cerebral artery in thalassemia patients[4]. Polymorphisms of S100B that lead to increased serum levels are associated with increased risk of ischemic stroke in the Chinese population[5]. Disclosures Nekhai: NIMHD, NIH: Research Funding; NHLBI, NIH: Research Funding; NIAID, NIH: Research Funding.

A Repertoire of Genes Modifying the Risk of Death in Sickle Cell Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 150-150
Author(s):  
Paola Sebastiani ◽  
Ling Wang ◽  
Thomas Perls ◽  
Dellara F. Terry ◽  
Monty Montano ◽  
...  
Keyword(s):  
Disease Severity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Severity Score ◽  
Association Studies ◽  
Acute Chest Syndrome ◽  
Risk Of Death ◽  
Genome Wide ◽  
Laboratory Variables ◽  
Individual Disease

Abstract Phenotypic heterogeneity is a well known characteristic of sickle cell anemia. Patients have different rates of hemolysis-related complications, like pulmonary hypertension, priapism and leg ulceration, and viscosity/vasoocclusion-related complications, like painful episodes, acute chest syndrome and osteonecrosis; they also have variation in levels of HbF and hematocrit. To integrate individual disease variables into a global measure of severity, we developed a Bayesian network model that described the complex associations of 25 clinical and laboratory variables, deriving a score that we used to define disease severity (0, least severe to 1, most severe) as the risk of death within 5 years (Sebastiani et al, Blood 2007). This initial network, validated in 2 unrelated patient populations, did not incorporate the genetic heterogeneity that is likely to modulate its components. Accordingly, we studied the association of single nucleotide polymorphisms (964 SNPs) in candidate genes (315 genes) using a Bayesian beta regression model of the severity score in 741 HBB glu6val homozygotes, aged more than 18 years. Forty-three SNPs in about 25 genes were associated with disease severity. Some associated SNPs tag genes that affect nitric oxide and oxidative biology and the endothelium, such as NOS1, ASS, KL, HMOX1, ECE1, KDR, FLT1. Homozygosity for an intronic SNP in ECE1 is associated with a increase of severity (OR=3.5). As expected, some associations were consistent with our previous findings. For example, the same SNP in ECE1 and TGFBR3, that was highly predictive of severity, was also strongly associated with sickle cell stroke (Sebastiani et al, Nature Genet 2005). Also, the association with severity of genes in the TGF-beta signaling pathway, including BMP6 and TGFBR3, were also associated with individual disease complications. Other associated genes play a less obvious role in the pathobiology of disease, e.g., HAO2, but are very strongly associated with the phenotype of severity (probability of a chance association, for HAO2, 10−6). Several of the genes associated with severity, including KL, PRKCA, FLT1 and MET have been related to aging, as suggested by gene expression profiling and studies in model organisms for aging. In genome-wide studies of the genetic basis of exceptional longevity, we found associations with some of the same genes that were associated with severity in sickle cell anemia. Perhaps increased oxidative stress, and the relentless progression of vasculopathy in sickle cell anemia, cause accelerated tissue damage that is modulated by a set of genes similar to those involved in the normal aging process. We suggest that the disease severity score can be used as a phenotype integrating many features of the disease, for genetic association studies. As we add the results of unbiased genome-wide association studies to capture polymorphisms not included in candidate gene studies, we can develop a predictive network with even greater reliability than one using only clinical and laboratory variables. Such networks might also identify pathways that could be targeted to alter the course of disease.

An Analysis Of The Pediatric Sub-Group From The Phase 2 Study Of GMI 1070 – A Novel Agent For The Vaso-Occlusive Crisis Of Sickle Cell Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2206-2206
Author(s):  
Timothy L. McCavit ◽  
Lakshmanan Krishnamurti ◽  
Lewis L. Hsu ◽  
Charles T. Quinn ◽  
Isaac Odame ◽  
...  
Keyword(s):  
Median Time ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Study Drug ◽  
Acute Chest Syndrome ◽  
Phase 2 ◽  
Opioid Use ◽  
Advisory Committees ◽  
Secondary Outcomes

Abstract Introduction Vaso-occlusive crisis (VOC) is the hallmark of sickle cell anemia (SCA), yet VOC treatment has not improved in decades. Recently the role of adhesive interactions between leukocytes, erythrocytes, and the vascular endothelium has been recognized in VOC. GMI 1070, a pan-selectin inhibitor, was designed to decrease the contribution of leukocyte adhesion to VOC. Herein, we report a sub-analysis of the pediatric patients enrolled in a study of GMI 1070 with the aims of determining the efficacy and toxicities in this subgroup and comparing pediatric to adult patients. Methods This multi-center, randomized, double-blind, placebo-controlled phase 2 trial enrolled afebrile patients ≥ 12 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Subjects had no organ dysfunction or other acute SCA complications. GMI 1070 was administered IV as a loading dose, then in up to 14 q12 h maintenance doses. Following a pre-specified interim PK analysis including 1 pediatric and 10 adult subjects, the loading and maintenance doses were doubled. Other management was at the discretion of the treating physician. Pain intensity was measured with a 10 cm visual analog scale. The primary outcome was time to resolution of VOC, defined as either a sustained 1.5 cm decrease in the pain score and cessation of IV analgesics; readiness for discharge; or hospital discharge. Secondary outcomes included time to discharge, time to transition from IV to oral analgesics, opioid usage, and safety profile. Median time-to-event was compared between arms using the Kaplan-Meier (KM) method. Analysis of covariance was used to compare the mean hourly opioid use, by hospital day. Results Seven sites enrolled 20 pediatric subjects: GMI 1070 - 13 vs placebo - 7. The median age was 14 years, and 40% were female. Time to 1st dose of study drug was a mean of 15 h from initial medical evaluation. Median length of stay was 105 h. The GMI 1070 arm had a 60.7 h reduction in the median time to resolution of VOC compared to placebo (Fig. 1a). Similarly, the median difference in time to transition to oral opioids and time to discharge were clinically significant between GMI 1070 and placebo at 87.8 h and 96 h, respectively (Fig. 1b & 1c). Mean hourly opioid use was lower with GMI 1070 than placebo in the first 24 h, but the trajectory thereafter did not differ (Fig. 1d). The effect of GMI 1070 on the primary and secondary outcomes was similar for pediatric and adult subjects (Table 1). Differences between pediatric and adult subjects included which opioid was used (pediatrics – 80% morphine vs adults – 80% hydromorphone). Also more pediatric subjects received IV antibiotics (Table 1), particularly in the first 24 hrs of study drug (pediatrics – 35% vs adults – 14%). The proportion of pediatric subjects experiencing a serious adverse event (SAE) was similar between arms (GMI 1070 – 31% vs placebo – 43%). Most SAE's were VOC recurrence; 1 SAE was an episode of acute chest syndrome (ACS) in the GMI 1070 arm (0 in the placebo arm). Of 4 total ACS events (1 SAE, 3 AE), 3 occurred within 24 h of 1st study drug, 1 required red blood cell transfusion and 0 required intensive care. No severe or unusual infections occurred in either arm. Conclusions GMI 1070 is a promising agent for reducing duration of VOC in SCA. Compared to adults, pediatric subjects demonstrated similar efficacy and safety. The ACS cases in the GMI 1070 arm are noteworthy but are not definitively associated with study drug. The strong efficacy signal in adolescents, along with minimal safety concerns, warrants inclusion of younger children in a subsequent phase 3 clinical trial of GMI 1070. Disclosures: McCavit: Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Quinn:Glycomimetics: Research Funding; Eli Lilly: Research Funding; MAST Therapeutics: Research Funding; American Society of Hematology: Advisory Committees, Advisory Committees Other, Honoraria. Odame:Glycomimetics: Research Funding. Alvarez:Glycomimetics: Research Funding. Driscoll:Glycomimetics: Research Funding. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. Telen:GlycoMimetics, Inc.: Research Funding; Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

scholarly journals Maximum Tolerated Dose Versus Fixed Low-Dose Hydroxyurea for Treatment of Adults with Sickle Cell Anemia - Retrospective Comparison of Two Studies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3656-3656
Author(s):  
Titilola S. Akingbola ◽  
Bamidele Tayo ◽  
Chinedu A Ezekekwu ◽  
Omowunmi Sonubi ◽  
Santosh L. Saraf ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Multicenter Study ◽  
Research Funding ◽  
Low Dose ◽  
Primary Care Providers ◽  
Maximum Tolerated Dose ◽  
Acute Chest Syndrome ◽  
Care Providers ◽  
Hemoglobin F

Abstract Background. Despite a large body of evidence that hydroxyurea is effective for sickle cell anemia (SCA), utilization with the "maximum tolerated dose" regimen has been low.1 Hydroxyurea therapy for SCA increases hemoglobin F, reduces pain crises, acute chest syndrome and blood transfusions, and possibly increases survival.2 The increase in hemoglobin F with hydroxyurea is related to the plasma level achieved, which depends on the dose.3 Hydroxyurea is typically initiated at 15 mg/kg/day followed by dose escalations up to 35 mg/kg/day if tolerated - the "maximum tolerated dose" approach used in the seminal Multicenter Study of Hydroxyurea (MSH) in the 1990's.4 With this approach, neutropenia and thrombocytopenia are limitations to achieving maximal dose and frequent blood count monitoring is required.These considerations limit the use of hydroxyurea in areas of the world where frequent blood monitoring is not feasible, and they also cause primary care providers in the US to hesitate to prescribe the medication. Methods. We recently reported a trial of hydroxyurea (500 mg/day orally) in 48 adults with SCA in Ibadan, Nigeria - a "fixed low-dose" approach.5 In the present report, we compare hematologic responses in 38 per protocol patients from the Ibadan study (received at least five of the planned six 4-weekly supplies of hydroxyurea)5 to the responses in 152 patients in the MSH study.6 Results. Baseline hematologic values for the two studies are shown in Table 1. Over the first 12 to 14 weeks of hydroxyurea, responses in hemoglobin, mean corpuscular volume (MCV), and platelets were similar in the two studies (Figure 1). At end-of-study (24 weeks Ibadan and 104 weeks MSH) responses in hemoglobin F and complete blood count were similar, except that the decline in neutrophil count in the Ibadan cohort was significantly less than the decline in MSH after the Bonferroni correction for multiple comparisons (Table 1and Figure 2). At this time the median (range) dose of hydroxyurea per body weight was 10 (7-14) mg/kg per day in the 38 Ibadan patients versus 20 (2.5-35) mg/kg per day in the 119 patients who remained on hydroxyurea in the MSH study.6 We performed a review of the medical records in the Ibadan patients. There were seven acute non-infectious complications in the 38 patients while taking fixed low-dose hydroxyurea for 24 weeks (admission for pain or acute chest syndrome) versus 17 while being observed off hydroxyurea for 24 weeks (pain, acute chest syndrome, need for blood transfusion, heart failure or death) (Table 2). Incidence of infections was similar during 24 weeks of fixed low-dose hydroxyurea and during 24 weeks of observation off hydroxyurea (Table 2). Discussion. These findings suggest that a "fixed low-dose" regimen may have substantial clinical benefit. Such a regimen would have a low chance of inducing cytopenias, would be straightforward for primary care providers to prescribe and would be ideal to test in combination therapy regimens for SCA. It would also be cost-efficient and affordable, especially for patients in low and middle-income countries where access to health insurance is lacking. We propose that the clinical efficacy of "fixed low-dose" hydroxyurea for SCA should be investigated further. We believe that a randomized comparison of the efficacy and safety of the "fixed low-dose" and "maximum tolerated dose" regimens should be a high priority. References Stettler N, McKiernan CM, Melin CQ, Adejoro OO, Walczak NB. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015;313:1671-2. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008;358:1362-9. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555-65. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-22. Tayo BO, Akingbola TS, Saraf SL, et al. Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. Am J Hematol 2018. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. Disclosures Hsu: Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy.

scholarly journals Prognostic factors of disease severity in infants with sickle cell anemia: A comprehensive longitudinal cohort study

2018 ◽  
Vol 93 (11) ◽  
pp. 1411-1419 ◽  
Author(s):  
Valentine Brousse ◽  
Sara El Hoss ◽  
Naïm Bouazza ◽  
Cécile Arnaud ◽  
Francoise Bernaudin ◽  
...  
Keyword(s):  
Cohort Study ◽  
Prognostic Factors ◽  
Disease Severity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Longitudinal Cohort Study ◽  
Longitudinal Cohort

scholarly journals Erythroid Adhesion Molecule Expression Profile in Sickle Cell Anemia Infants

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1368-1368
Author(s):  
Valentine Brousse ◽  
Yves Colin ◽  
Catia Pereira ◽  
Arnaud Cecile ◽  
Marie-Helene Odievre ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Disease Severity ◽  
Sickle Cell ◽  
Expression Profile ◽  
Adhesion Molecule ◽  
Sickle Cell Anemia ◽  
Reticulocyte Count ◽  
Adhesion Molecule Expression ◽  
Risk Of Death ◽  
Hbf Level

Abstract Introduction: In normal conditions, circulating red blood cells (RBCs) are not supposed to adhere. Some erythroid adhesion molecules expressed on young reticulocytes are therefore lost upon maturation. Conversely, abnormal RBC adhesiveness in sickle cell anemia (SCA) through activation, sustained or increased expression of adhesion molecules are considered central in vaso occlusive crisis (VOC), the hallmark of SCA. SCA is seldom symptomatic in the first six months of life. One main explanation lies in the sustained level of fetal hemoglobin (HbF) and F cells during this period preventing HbS polymerization. However, infra clinical vaso occlusion, particularly in the spleen, has been demonstrated to be present and the absolute reticulocyte count is paradoxically elevated in the first semester of life, evidencing the very early onset of hemolysis. Our objectives were to analyze the profile of erythroid adhesion molecules in SCA and non-SCA infants in combination with HbF level, in order to evidence significant differences specifically attributable to SCA, informative on very early pathophysiology and disease severity. Patients and methods: Infants were enrolled in a longitudinal multi center prospective study on prognostic factors in SCA between September 2010 and March 2013. Blood sampling was performed at enrolment (3-6 months) at steady state, in asymptomatic infants. In parallel, blood samples from infants with no hemoglobinopathy were collected. Flow cytometer analysis (BD FACSCanto II) was performed using murine monoclonal antibodies against CD36, CD44, CD47, CD49d, CD58, CD99, CD147, CD239 and CD242. Statistical analysis was performed with Graphpad software, Prism 6. Differences in the percentage of positive cells and the level of expression of molecules between groups were calculated with Mann Whitney test. Results were considered statistically significant at an a-risk level of 5%. Results: Fifty-four SCA infants were included and compared to 17 non-SCA infants. Median age in the two groups was not statistically different (144 days, range 81-196 versus 128, range 68-621, p=0,84). Mean HbF level was, as previously described, statistically increased in SCA compared to non-SCA infants (41.2% +/-11.2 versus 10,4 % +/- 1,8; p<0,0001). Median reticulocyte count tended to be more elevated in SCA infants (2.6 % range 0,5-10) compared to non-SCA infants (2 range 1-3,1) without reaching statistical significance (p=0,052). Reticulocytes from SCA infants display a distinct surface molecule expression profile, with a statistically increased percentage of reticulocytes expressing the following adhesion molecules: CD239 (Lu/BCAM), CD242 (ICAM-4), CD47, CD99, CD58, CD147 and CD44 (Figure 1). Furthermore the mean intensity of fluorescence is statistically increased concerning CD239, CD58 and CD242 (data not shown). Surprisingly, known adhesion markers demonstrated to play an important role in SCA pathogeny i.e. CD36 and CD49d (α4β1/Very Late Antigen-4) are not significantly increased in SCA infants (Figure 1) No significant difference of expression profile was found on mature or total RBCs between SCA and non-SCA infants (data not shown). Figure 1 Figure 1. Discussion: Recent publications have pointed to the significance of reticulocytosis associated with an increased risk of death or stroke during childhood. Our results further demonstrate that this early rise of reticulocyte count in SCA infants, despite elevated HbF level, include reticulocytes with a specific adhesion molecule expression profile. This numerically small subpopulation of red cells may play in fact a major role in this complex disease. An interesting hypothesis may be that the spleen, as long as its function is preserved, prevents VOC by trapping this subpopulation in very young infants. As spleen function decreases, proadhesive reticulocytes remain in the circulation, which may, in combination with the decline of HbF, subsequently favor extra splenic VOC. Ongoing analysis will confirm if this idiosyncratic erythroid adhesion molecule profile in infants indeed correlates with HbF level and, importantly, correlates with functional activation, in order to serve as a readily available biomarker of disease severity. Disclosures De Montalembert: Novartis: Speakers Bureau. Le Van Kim:SHIRE: Research Funding.

scholarly journals Children with Sickle Cell Anemia and APOL1 Gene Variants Develop Albuminuria Early in Life

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2377-2377
Author(s):  
Rima Zahr ◽  
Jeffrey Lebensburger ◽  
Evadnie Rampersaud ◽  
Jane S. Hankins ◽  
Jeremie H. Estepp
Keyword(s):  
High Risk ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Intervention Program ◽  
Clinical Care ◽  
Whole Genome Sequence ◽  
Individual Risk ◽  
Gene Variants ◽  
Risk Alleles

Abstract Introduction: Gene variants in the apolipoprotein L-1 (APOL1) gene are strong modifiers for the development of chronic kidney disease in individuals of African descent and are associated with progression of renal disease and albuminuria in cross-sectional studies of individuals with sickle cell anemia (SCA). While the association of APOL1 with albuminuria in older SCA patients is established, it is unclear whether participants with APOL1 G1 (rs73885319/ rs6090145) and G2 (rs71785313) variants (Ashley-Koch Br J Hematol 2011; Kormann Br J Haematol 2017) are more likely to develop albuminuria early in life. We hypothesized that individuals with SCA with the APOL1 G1 and G2 variants experience albuminuria at a higher rate and at a younger age than individuals without these APOL1 mutations. Methods: APOL1 G1 (rs73885319/ rs6090145) and G2 (rs71785313) variants were identified from whole genome sequence (WGS) data for individuals with SCA (HbSS or HbSβ0 thalassemia) enrolled in the longitudinal Sickle Cell Clinical Research and Intervention Program (SCCRIP; NCT02098863) (Hankins et al, Pediatr Blood Cancer 2018). WGS data were generated by aligning paired-end 150 bp reads to the GRCh38 human reference using the Burrows-Wheeler Aligner (BWA-ALN v0.7.12) and the GATK best-practices workflow implemented in GATK v3.4.0. We modeled the time to first albuminuria diagnosis defined by abnormal urine albumin:creatinine ratio (>30mg/g). Covariates included age, sex, and hydroxyurea therapy. We considered two risk models. Model 1 defined high risk APOL1 mutation as either APOL1 G1 homozygotes or G2 homozygotes or G1/G2 double heterozygotes. Model 2 was defined additively wherein G1 or G2 homozygotes were assumed to confer more risk compared to G1/G2 double heterozygotes. Results: In 285 individuals with SCA, 93% (n=266) with HbSS and 7% (n=19) with HbSβ0 thalassemia, 14% (n=41) experienced albuminuria at a mean age of 11.4 (±3.3) years. In total, 11% (n=32) of this SCA cohort had an APOL1 mutation; 6% (n=17) were G1/G2 double heterozygote, 4% (n=11) were G1 homozygotes, and 1% (n=4) were G2 homozygotes. Among the 32 participants with an APOL1 mutation, 40% (n=13) had albuminuria as compared to 11% (n=28) of the 253 participants without an APOL1 mutation (OR: 9.85, 95% CI 3.84-25.25). There was also a significant association with albuminuria based on the additive genetic model (OR: 4.38, 95% CI 2.39 -8.02) (Table). In a survival analysis, participants with an APOL1 mutation had a hazard ratio (HR) of 3.75 (95% CI: 1.93-7.29, p<0.0001) associated with time to diagnosis of albuminuria compared with individuals with other non-risk APOL1 genotypes. The mean age for individuals having albuminuria with APOL1 G1/G2 risk alleles was 9.8 (±3.2) years, roughly 2 years younger than those without the risk alleles (11.8 ±4.7 years) (Satterthwaite t value=3.10, p=0.003). APOL1 G1 alleles also contributed individual risk of albuminuria (HR=1.66, p=0.0374). Summary: Our analyses found that pediatric individuals with SCA who have APOL1 two risk alleles are at high risk of developing albuminuria which many will experience early in childhood. This important finding has significant implications for clinical care. First, using a genetic screening program for all patients with SCAC can identify individuals with APOL1 mutations. Second, individuals with SCA and an APOL1 mutation should be screened for albuminuria during childhood. Finally, early initiation of therapeutic strategies to ameliorate renal dysfunction needs to be evaluated in the presence of APOL1 mutations. Figure. Figure. Disclosures Hankins: Global Blood Therapeutics: Research Funding; Novartis: Research Funding; NCQA: Consultancy; bluebird bio: Consultancy. Estepp:ASH Scholar: Research Funding; Daiichi Sankyo: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding.

scholarly journals FOETAL HAEMOGLOBIN AND DISEASE SEVERITY IN NIGERIAN CHILDREN WITH SICKLE CELL ANAEMIA.

2017 ◽  
Vol 9 (1) ◽  
pp. e2017063 ◽  
Author(s):  
Oluwagbemiga Adeodu ◽  
Morenike Akinlosotu ◽  
Samuel Adegoke ◽  
Saheed Oseni
Keyword(s):  
Disease Severity ◽  
Sickle Cell ◽  
Clinical Severity ◽  
Acute Chest Syndrome ◽  
Foetal Haemoglobin ◽  
Nigerian Children ◽  
Moderate Disease ◽  
History Of ◽  
The Mean ◽  
Hbf Level

Background: Foetal haemoglobin (HbF) is a major modifying factor influencing sickle cell disease (SCD) severity. Despite this, HbF estimation is not routinely done in Nigeria. Relationship between HbF and SCD severity among affected children is also poorly studied.Methods: In this descriptive cross-sectional study, we determined the relationship between steady state HbF levels and disease severity of Nigerian children aged 1 – 15 years with homozygous SCD. For each child, the socio-demographic characteristics and SCD clinical severity were determined. The latter was assessed based on the frequency of significant painful episodes, blood transfusion, and hospitalization in the preceding 12 months; lifetime cummulative incidence of SCD-related complications; degree of splenic and hepatic enlargement; current haematocrit and leucocyte count, as previously described. Foetal haemoglobin levels were quantified with high performance liquid chromatography.Results: The mean HbF level of the 105 children with SCA was 9.9 ± 6.0%. Male had significantly lower mean HbF levels than females, 8.0 ± 5.6% vs. 12.2 ± 5.8% (p < 0.001). None of the children had severe disease. However, those with moderate disease had significantly lower mean foetal haemoglobin levels than those with mild disease (7.7 ± 5.6% vs. 10.8 ± 6.0% respectively). The mean HbF level was also significantly lower in children who had history of acute chest syndrome and stroke compared to those without these complications,   p = 0.002 and 0.010 respectively.Conclusion: Children with SCA who had moderate disease and those with history of life threatening complications such as stroke and acute chest syndrome had significantly low HbF. Therefore it is recommended that facilities for early quantification of foetal haemoglobin and HbF inducement be made available in order to reduce the morbidity and mortality among these children.

scholarly journals The Oxygenscan: A Rapid and Reproducible Test to Determine Patient-Specific, Clinically Relevant Biomarkers of Disease Severity in Sickle Cell Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2360-2360
Author(s):  
Minke A.E, Rab ◽  
Celeste K Kanne ◽  
Brigitte A. van Oirschot ◽  
Jennifer F. Bos ◽  
Maite Elizabeth Houwing ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Disease Severity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Patient Specific ◽  
Advisory Committees ◽  
Laboratory Parameters ◽  
Oxygen Concentrations ◽  
Rbc Deformability

Abstract Background: In sickle cell anemia (SCA), hemoglobin S (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These deoxygenated RBCs have strongly reduced deformability, which contributes to the etiology of vaso-occlusive crises and chronic hemolytic anemia. There are no widely available clinical laboratory tests to directly monitor effects of disease modifying therapies (i.e. hydroxyurea) on RBC deformability. RBC deformability can be measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, the Netherlands), which measures RBC deformability over a range of osmolalities. Recently, a new module was added which consists of a method to measure RBC deformability, expressed as Elongation Index (EI), during controlled deoxygenation. This test, termed oxygenscan, has 3 key read out parameters: 1) EImax, which represents RBC deformability at normoxia; 2) EImin represents deformability upon deoxygenation; and 3) the point of sickling (PoS), the point at which a >5% decrease in EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1). In this study, we correlated laboratory parameters associated with SCA disease severity with oxygenscan parameters to establish the clinical utility of this test. Methods: The discovery cohort consisted of 15 SCA patients (median age 22.0 years, 33.3% on hydroxyurea (HU)) enrolled at University Medical Center Utrecht (UMCU). The validation cohort consisted of 21 patients with SCA (median age 12.5 years, 76.2% on HU) from Texas Children's Hematology Center (TCHC). Oxygenscans were carried out in duplicates at both sites. Percentage dense RBC (%DRBC) were measured using an ADVIA hematology analyzer (Siemens) at TCHC only. In this study, we used Pearson's correlation to test for linear correlations between oxygenscan parameters EImax, EImin and PoS and clinically relevant laboratory parameters: total hemoglobin (Hb), absolute reticulocyte count (ARC), %HbS and %HbF, and %DRBC. Results: In both cohorts PoS significantly positively correlated with ARC (Figure 2A-B). In the UMCU cohort, total Hb levels also significantly positively correlated with EImax (Figure 2C), which was validated in the TCHC cohort (Figure 2D). HbF positively correlated with the EImin in both cohorts (Figure 2E-F). EImin also significantly negatively correlated with HbS (r=-0.828 p=<0.001 in the UMCU cohort, r=-0.936, p=<0.001 in the TCHC cohort data not shown). EImax showed a strong negative correlation with the %DRBC (Figure 2G) in the TCHC cohort. Individual test results were highly reproducible at both sites, with a median coefficient of variability of all tested parameters below 3%. Conclusion: The oxygenscan is a semi-automated, inexpensive, highly reproducible, and rapid test to fully characterize patient-specific RBC deformability under a range of oxygen concentrations. Key oxygenscan measurements- PoS, EImin, and EImax- correlated with known measures of SCA disease severity, namely ARC, HbF, HbS, total Hb and %DRBC. Patients with higher reticulocyte counts showed a clinically unfavorable increase of oxygen concentration at which RBCs start to sickle (termed PoS), than patients with lower ARC. Patients with higher HbF had more deformable RBCs even at the lowest oxygen concentrations, or EImin, while patients with higher HbS had lower EImin (low values indicate poor deformability under deoxygenated conditions). Patients with high %DRBC had lower EImax, indicating poor RBC deformability at normoxic conditions. Conversely, patients with high total Hb had high EImax. The very strong correlations of key oxygenscan measurements with different measures of SCA disease severity suggest that these parameters could be exploited as useful biomarkers of clinical severity and in the follow-up and treatment of SCA patients and warrant further investigation. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Roche: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; Shire: Research Funding; Pfizer: Research Funding. Schutgens:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding; Novo Nordisk: Research Funding; Baxalta/Shire: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding. van Beers:RR Mechatronics: Research Funding; Bayer: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document