scholarly journals 525. Diminished End Organ Damage and Correction of Anemia in Sickle Cell Mice Treated with Non-Myeloablative Busulfan Conditioning and Y-Globin Lentiviral Vector Transduced HSCs

2010 ◽  
Vol 18 ◽  
pp. S202-S203
Keyword(s):  
Sickle Cell ◽  
Lentiviral Vector ◽  
Organ Damage ◽  
End Organ Damage

In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2224-2224
Author(s):  
Blair R Anderson ◽  
Erica E Davis ◽  
Marilyn J. Telen ◽  
Allison E Ashley-Koch
Keyword(s):  
At Risk ◽  
Sickle Cell Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Organ Damage ◽  
Strong Linkage Disequilibrium ◽  
Wild Type ◽  
Cell Disease ◽  
Gene Suppression ◽  
End Organ Damage

Abstract End-organ damage in patients with sickle cell disease (SCD) has become an emergent clinical priority over recent decades due to the increased lifespan of affected individuals. Renal failure (ESRD), which occurs in 4-12% of SCD patients and is strongly associated with early mortality, has become a particular concern. The detection of SCD nephropathy (SCDN) relies on relatively late markers of the disease process, namely proteinuria and reduced glomerular filtration rate (GFR). Therefore, at-risk SCD patients cannot be identified prior to end-organ damage. A genomic region on human chromosome 22 containing two genes, MYH9 and APOL1, has been associated with non-SCD nephropathy, although the primary gene responsible has remained elusive due to strong linkage disequilibrium in this region. Our group demonstrated that both MYH9 and APOL1 are strong, independent genetic predictors of risk for proteinuria in SCD and interact to affect GFR (Ashley-Koch et al., 2011). We have now used zebrafish as a model to study the contribution of each gene (myh9 and apol1) to kidney function and filtration. To test independent effects of the knockdown of myh9 or apol1, we injected morpholino (MO) antisense oligonucleotides in wild-type zebrafish embryos; this resulted in generalized edema (64% [myh9-MO] and 58% [apol1-MO], both significantly different compared to 3% of control embryos) and reduced glomerular filtration (as measured by quantitative dextran clearance; myh9-MO p=0.047 and apol1-MO p=0.042 when compared to control embryos) for both gene suppression models. Each morphant phenotype was rescued significantly by co-injection of each respective wild type human MYH9 (p=0.001) and APOL1 (p=0.043) mRNA. Importantly, co-injection of human mRNA corresponding to other APOL gene family members did not significantly rescue the observed apol1-MO phenotype, suggesting that apol1 is indeed the functional ortholog to the human gene. Next, we investigated the possibility of a genetic interaction between MYH9 and APOL1 by co-suppression of each of the zebrafish orthologous genes. We observed no additive or synergistic effects due to the co-suppression. Instead, the double morphants were indistinguishable from the myh9 morpholino alone, and neither single morpholino could be rescued by the human mRNA of the other gene. These data suggest that MYH9 and APOL1 may function independently but converge on the same biological process to affect risk of SCDN. In addition to evaluating the effects of candidate gene suppression in wild-type models, we have begun to utilize anemic zebrafish models described previously (Shah et al., 2012). Our preliminary work suggests that the myh9 knockdown phenotype is exacerbated under anemic stress. Ongoing efforts are aimed at identifying novel genetic contributions to SCDN through genome-wide association analysis and exome sequencing of extreme phenotypes in SCD patients, with functional evaluation of putative genetic candidates in our zebrafish model. By offering new insights into the contribution of genes that regulate renal function, these results further our understanding of the pathogenesis of SCDN and may provide genetic markers for the identification of at-risk SCD patients prior to the onset of kidney dysfunction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of Alloimmunization in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3251-3251
Author(s):  
Dipanjan Debnath ◽  
Hedy P Smith ◽  
Cathy Conry-Cantilena ◽  
Valentina Baez Sosa
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Health System ◽  
Sickle Cell ◽  
Organ Damage ◽  
Cell Disease ◽  
Academic Health ◽  
End Organ Damage ◽  
The Mean

Abstract INTRODUCTION Blood transfusion is an essential therapeutic and prophylactic component in the management of sickle cell disease (SCD) and associated complications. Prolonged transfusion therapy can lead to the development of antibodies to the donor's RBC antigens (alloimmunization), causing complications such as delayed hemolytic transfusion reactions, hyperhemolysis, worsening vaso-occlusive episodes, and end-organ damage. There have been only a few case series highlighting the impact of RBC alloimmunization on SCD morbidity and mortality, proposing a pathway involving RBC alloimmunization and decreased survival associated with hemolytic reactions or difficulty obtaining compatible blood when needed. However, apart from the consequences of iron overload, there is no long-term data for alloimmunization highlighting the clinical consequences, multiorgan damage, or associated morbidity in sickle cell patients. AIM The primary aim is to investigate the incidence of alloimmunization in SCD patients in an academic health system. The secondary aim is to elucidate the differences in demographics, frequency of vaso-occlusive crisis, end-organ damage, and inflammatory markers between alloimmunized and non-alloimmunized SCD patients. METHODS We conducted a retrospective multicentric descriptive study, including all sickle cell patients treated in an academic health system from January 1st, 2009, to December 31st, 2020, in Maryland, Virginia, and Washington, DC. An exemption from the Institutional Review Board for obtaining individual subjects' consent was procured. Patients included in the study were older than 18 years and diagnosed with sickle cell disease. Patients who did not have sickle cell disease were excluded from the study. Statistical analysis was reported using means for descriptive data, t-test for continuous variables, and chi-square for categorical variables. RESULTS A total of 94 patients with sickle cell disease were included in the study. Of these, 24 (25.5%) patients were found to have alloimmunization, whereas 70 (74.4%) patients did not. Of the alloimmunized patients, the average age, BMI and BSA were 30.15 years (p=0.037), 23.15 kg/m2 (p=0.040), and 1.65 m2 (p=0.003) compared to 37.07 years, 26.17 kg/m2 and, 1.84 m2 respectively among the non-alloimmunized group. 83% of the alloimmunized patients had sickle cell anemia (Hb SS), and 17% had a sickle thalassemia phenotype (p=0.005). A lower baseline hemoglobin (Hb) value of 8.01 g/dL was seen among alloimmunized patients compared to a higher Hb value of 9.63 g/dL (p=0.001) among the non-alloimmunized. Alloimmunized patients had an average of 5.55 alloantibodies. The average number of vaso-occlusive crises per year and related hospitalizations was statistically significantly higher in the alloimmunized group with 4.82 and 3.78, respectively, compared to 2.34 (p=0.035) 1.01 (p=0.0005) in the non-alloimmunized group. Similarly, the incidence of other sickle cell-related complications were higher among the alloimmunized patients, such as priapism (29% vs. 9%; p=0.0139), pulmonary hypertension (38% vs. 9%; p=0.0038) with no statistical difference in the iron overload (25% vs. 11%; p=0.150) or ferritin levels (. 83% of alloimmunized patients had a history of narcotic use vs. 34% among the non-alloimmunized (p=0.0001). Higher use of disease-modifying therapies including hydroxyurea (71% vs. 31%; p=0.0009) and voxelotor (13%vs0; p=0.0029), were also seen among alloimmunized patients. While no statistically significant difference was seen in the mean number of lifetime transfusions, there was a difference in the mean number of lifetime exchanges (3.67 vs. 0.0; p=0.0208). CONCLUSION The prevalence of alloimmunization in sickle cell patients in our study population (25.5%) was higher than in the literature (7- 59%) and the general population (2%). An increase in alloimmunization was associated with an increased number of exchanges but not with simple transfusions. Independent from the iron overload, alloimmunization was associated with increasing end-organ damage and sickle cell complications such as priapism, pulmonary hypertension. Strategies to decrease alloimmunization are needed to prevent these complications. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Single Institution Study of Chronic Erythrocytapheresis for Secondary Stroke Prevention in Children and Young Adults with Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4754-4754
Author(s):  
Nadia L Cheek ◽  
Robert L Saylors ◽  
Raghu Ramakrishnaiah ◽  
Suzanne Saccente ◽  
Xinyu Tang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Stroke Prevention ◽  
Organ Damage ◽  
Secondary Stroke Prevention ◽  
Cell Disease ◽  
End Organ Damage ◽  
Children And Young Adults ◽  
The Mean

Abstract Abstract 4754 Introduction: The current standard of care for secondary stroke prevention in children and young adults with sickle cell disease and cerebral infarction is chronic simple transfusion (ST). Published data indicate that at least 18% of patients treated with chronic ST will experience a second overt infarct and at least 28% will experience additional silent infarcts. Since 1996, we have used chronic erythrocytapheresis (RCE) instead of chronic ST in our hospital to treat all patients with either overt infarction or abnormal transcranial doppler (TCD) with silent infarction. Here we present clinical, radiographic, and laboratory data from this group of patients treated with chronic RCE for secondary stroke prevention. Methods: This was a retrospective study of all patients treated with chronic RCE for either overt infarction or for an abnormal TCD with silent infarction at Arkansas Children's Hospital from 1996 through 2011. We reviewed clinical records and serial MRI/MRA scans and determined the time to progression from the time of the initial diagnosis of an overt or silent infarct to the time of the second overt or silent infarct. Events were classified as overt infarcts if the MRI demonstrated acute cerebral ischemia, based on increased signal intensity on T2-weighted images and restricted diffusion on diffusion-weighted images, and abnormal neurologic findings correlated with the abnormalities identified on MRI. Events were classified as silent infarcts if the MRI demonstrated new lesions 3 mm or greater in a single dimension with increased signal intensity on T2-weighted images and there were no corresponding abnormal neurologic findings. We also studied the pre-procedure hemoglobin S concentration (%S), pre-procedure ferritin levels, volume of blood transfused per kilogram, necessity for chelation medication, and presence of end-organ damage. Results: We identified 24 patients, ranging in age from 2 to 18 years at the initiation of chronic RCE, who were treated with 2539 RCE procedures during the study period. These patients were treated with RCE every two to six weeks with the goal of maintaining their pre-RCE %S at less than 30%. Progressive cerebral infarcts occurred in 42% (10 of 24) of the patients while receiving chronic RCE (Figure 1): 3 were overt (13%) and 7 were silent (29%). There were no additional infarcts observed after patients had been on chronic RCE for greater than 5 years. Eight patients (33%) experienced increased vasculopathy and 3 patients (13%) had an improvement in vasculopathy while on therapy. The mean pre-procedure %S concentration was 29%. The mean pre-procedure ferritin was 1188 ng/ml but approximately 60% of the patients had ferritin levels under 1000 ng/ml and only three patients required chelation. Patients received a mean of 45.5 ml/kg of packed red blood cells per procedure. There was no evidence of end-organ damage secondary to iron overload. Discussion: We determined that children with sickle cell disease and cerebral infarction experience additional silent and overt strokes despite intensive treatment with chronic RCE. The proportion of patients developing new overt infarcts in our study (13%) was slightly lower than that in a recent multi-institution study (18%; Hulbert et al, Blood 117:772, 2011) but the proportion of patients developing new silent infarcts in our study (29%) was no different (28%). Although patients receiving RCE have increased blood product utilization as compared with patients receiving ST, only three patients required chelation medication and none experienced end-organ damage secondary to iron overload. We conclude that chronic RCE is no more effective than chronic ST for secondary stroke prevention, that chronic RCE prevents the iron overload and need for chelation that is common with chronic ST, and that other forms of therapy are needed to prevent the progressive accumulation of cerebral infarcts in these patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1844-1855 ◽  
Author(s):  
Paritha I. Arumugam ◽  
Eric S. Mullins ◽  
Shiva Kumar Shanmukhappa ◽  
Brett P. Monia ◽  
Anastacia Loberg ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Target ◽  
Organ Damage ◽  
Disease Outcome ◽  
Cell Disease ◽  
Spontaneous Bleeding ◽  
End Organ Damage ◽  
Key Points ◽  
Novel Therapeutic

Key PointsReduced prothrombin improves survival and ameliorates inflammation and end-organ damage without spontaneous bleeding in sickle cell mice. An individual procoagulant, prothrombin, represents a novel therapeutic target that can improve sickle cell disease outcome.

scholarly journals P-Selectin Deficiency Reduces Acute Vascular Complications but Not Chronic Organ Damage in Sickle Cell Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 187-187
Author(s):  
Erica Sparkenbaugh ◽  
Malgorzata Kasztan ◽  
Megan D Miller ◽  
Elizabeth A Binning ◽  
Christina M Abrams ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Research Funding ◽  
Thrombin Generation ◽  
Organ Damage ◽  
Heart Weight ◽  
Kidney Cortex ◽  
Elevated Plasma ◽  
Long Term Effects ◽  
End Organ Damage

Abstract P-selectin (Psel) is an adhesion molecule expressed on platelets and endothelial cells, which interacts with its ligand PSGL-1 on leukocytes and a PSGL-1-like molecule on sickle red blood cells (RBCs). Psel mediates the formation of the multicellular aggregates that promote vaso-occlusive crisis (VOC) and acute painful episodes in sickle cell disease (SCD). Crizanlizumab, a monoclonal antibody blocking Psel, reduces the frequency of VOC in SCD patients. In SCD mice, Psel contributes to heme-induced microvascular stasis, and thrombus and platelet-neutrophil aggregate formation in the lung and liver. Unexpectedly, Psel deficiency promotes liver senescence in a mouse model of SCD, suggesting a possible detrimental effect of Psel inhibition. In this study, we further investigated the long-term effects of Psel deficiency on thromboinflammation and end-organ damage in murine SCD. We used Townes wild type (AA) and sickle (SS) mice (n=12-27) that either express Psel (Psel +/+) or lack Psel (Psel -/-) at 11-12 months of age. Kidney damage was evaluated by histology and urine analysis. Heart function was determined using echocardiography. Complete blood counts and plasma biomarkers of thrombin generation (thrombin anti-thrombin [TAT] complexes) and inflammation (interleukin [IL]-6) were also analyzed. In addition, in a pilot experiment, we analyzed the effect of Psel deficiency on experimental venous thrombosis in SS mice. SS Psel +/+ mice exhibited renal damage, urinary concentrating defect, and reduced creatinine clearance, which was not improved in SS Psel -/- mice. Psel deficiency attenuated glomerular (GLM) congestion (0.17±0.05 vs 0.39±0.06, p<0.05) but failed to prevent GLM injury, as evidenced by similar extent of GLM sclerosis, hypertrophy and podocyte loss in SS mice. Interestingly, only SS P-sel -/- mice presented withdistinct differences in GLM structure, demonstrated by extensive hypercellularity, mesangial expansion and mesangiolysis. We also observed tubular injury concomitant with brush border loss and interstitial fibrosis in SS mice, regardless of Psel expression. Additionally, there was a significant reduction in CD3 + T cells (5.0±1.2 vs 9.5±1.6 cells/field; p<0.05) and macrophages (1.0±0.1 vs 1.6±0.2 % of area; p<0.05) infiltration in the kidney cortex of SS Psel -/- compared to SS Psel +/+ mice. This corresponded to a greater renal iron accumulation in SS Psel -/- mice (59.9±4.2 vs 48.2±3.2 Mpix/μm; p<0.05). We observed cardiac hypertrophy (elevated heart weight to tibia length ratio) in SS mice, regardless of Psel expression. Echocardiography of left ventricle (LV) revealed that SS mice had increased LV mass and LV internal diameter with no change in ejection fraction or fractional shortening compared to AA mice. None of these parameters were affected by Psel expression. Furthermore, hypertrophy observed in other organs (kidney, liver, lung and spleen) of SS Psel +/+ mice was also not affected by Psel deficiency. Consistent with previous studies, SS Psel +/+ mice had elevated plasma levels of TAT and IL-6 compared to AA Psel +/+ mice. Psel deficiency significantly reduced IL-6 (47±15 vs 20±10 ng/mL, P<0.05), but had no effect on elevated plasma TAT levels in SS mice. Despite the lack of effect of Psel deficiency on systemic thrombin generation in SS mice, femoral vein thrombi formed after electrolytic injury exhibited a strong trend in reduced fibrin and platelet content compared to SS Psel+/+ mice (n=5 per group). As expected, SS Psel +/+ mice exhibited anemia as shown by reduced RBC number, hemoglobin (Hb) and hematocrit (Hct) compared to AA Psel +/+ animals. Interestingly, these parameters were further decreased in SS Psel -/- mice (p<0.01 for all); RBC (5.6±0.2 vs 4.4±0.4 x 10 6/mL), Hg (6.7±0.2 vs 5.7±0.2 g/dL) and Hct (25.1±1.1 vs 19.7±1.1%). This was accompanied by a significant increase in mean corpuscular Hb concentration (26.9±0.5 vs 29.2±0.5 g/dL p< 0.01) but no changes in RBC mean corpuscular volume in SS Psel -/-mice compared to SS Psel +/+ mice. Our data suggest that despite improving acute vascular pathologies, including VOC and thromboinflammation, long term deficiency of Psel does not prevent end-organ damage. If fact, it may contribute to organ dysfunction and enhanced anemia. More mechanistic studies are needed to better understand the long-term effects of anti-Psel treatment in SCD patients. Disclosures Reeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Sundd: CSL Behring Inc: Research Funding; Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Effect of Sickle Cell Disease Type, Age and Gender On the Prevalence of Chronic Organ Damage in Adults with Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4607-4607
Author(s):  
Raymond U. Osarogiagbon ◽  
Syed N Haider ◽  
Jun Tang
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Brain Mri ◽  
Organ Damage ◽  
Categorical Variables ◽  
Acute Chest Syndrome ◽  
Continuous Variables ◽  
Cell Disease ◽  
End Organ Damage

Abstract Abstract 4607 Introduction The high mortality risk that sickle cell disease (SCD) patients experience from infancy is cumulative through adulthood, largely because of the effect of cumulative end organ damage, which is a more powerful predictor of early mortality than frequency of painful episodes. The latter, though, gets more attention from patients and caregivers. Any vascular territory is susceptible to damage. The most common target organs are the brain, lungs, kidneys, retina and joints. We examined the prevalence of the full spectrum of end organ damage in a cohort upon entry into our adult SCD program and compared the clinical and laboratory characteristics of patients based on age, gender and SCD type. Patients and Methods Retrospective review of prospectively collected data on 118 adults upon entry into our program between February 2005 and October 2008. All patients underwent a standardized battery of tests to evaluate hematological and biochemical parameters at entry. Historical presence of episodes of acute chest syndrome, pneumonia, stroke, avascular necrosis, osteomyelitis, leg ulcers, priapism, and cholecystectomy and hydroxurea therapy was quantified. Pulmonary hypertension (PHT) was defined as a tricuspid regurgitant jet velocity (TRJV) ≥2.5 m/s on Doppler echocardiography; sickle cell nephropathy (SCN) as glomerular filtration rate, (GFR) < 90ml/min. and/or 24-hour protein>300mg and/or urine protein/creatinine ratio>0.3); cerebrovascular disease (CVD) as evidence of previous ischemic and/or hemorrhagic infarct and/or aneurysm formation on brain MRI/MR angiography; and sickle cell retinopathy (SCR) as background to proliferative retinopathy) on fluorescent retinal angiography. Characteristics of patients were evaluated with t-test for continuous variables and chi-square test for the categorical variables. Results The relevant statistically significant correlative variables in these 3 comparisons are shown in the following tables. Conclusions Our study highlights the various differences in the prevalence of sickle cell disease-related end organ damage and morbidity among different age, gender and two major sickle cell disease categories. It shows the significant progression of organ damage with advancing age and the more severe nature of SS/Sβ0 phenotype. Further expansion of this assessment may help identify specific high risk groups that can be targeted as candidates for more intensive preventive interventions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Challenges in the Management of Sickle Cell Disease During SARS-CoV-2 Pandemic

2020 ◽  
Vol 26 ◽  
pp. 107602962095524
Author(s):  
Faisal Alsayegh ◽  
Shaker A. Mousa
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Case Series ◽  
Organ Damage ◽  
Cell Disease ◽  
End Organ Damage ◽  
Randomized Controlled Studies ◽  
Management Protocol ◽  
Prophylactic Anticoagulation

The management of sickle cell disease (SCD) and its complications in the COVID-19 era is very challenging. The recurrent sickling process in SCD causes tissue hypoxemia and micro-infarcts, resulting in end organ damage. Since the outbreak of SARS-CoV-2 pandemic, little data has been published about SCD concerning clinical presentation with COVID-19 and management. Hydroxyurea has been the cornerstone of management in children and adults with SCD, with evidence of its effect on controlling end organ damage. There are several anti-sickling drugs that have been approved recently that might have an additive value toward the management of SCD and its complications. The role of simple and exchange transfusions is well established and should always be considered in the management of various complications. The value of convalescent plasma has been demonstrated in small case series, but large randomized controlled studies are still awaited. Immunomodulatory agents may play a role in reducing the damaging effects of cytokines storm that contributes to the morbidity and mortality in advanced cases. Prophylactic anticoagulation should be considered in every management protocol because SCD and COVID-19 are thrombogenic conditions. Management proposals of different presentations of patients with SCD and COVID-19 are outlined.

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