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.

scholarly journals Higher Fetal Hemoglobin Following Escalation of Hydroxyurea to Maximum Tolerated Dose Provides Clinical Benefit to Children with Sickle Cell Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 85-85 ◽  
Author(s):  
Jeremie H. Estepp ◽  
Matthew P. Smeltzer ◽  
Guolian Kang ◽  
Banu Aygun ◽  
Russell E. Ware ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Clinical Data ◽  
Sickle Cell Anemia ◽  
Clinical Benefit ◽  
Research Funding ◽  
Fetal Hemoglobin ◽  
Long Term Effects ◽  
Clinical Benefits ◽  
Hydroxyurea Therapy

Abstract Background. Hydroxyurea has proven laboratory and clinical benefits for children with sickle cell anemia (SCA); however, the benefits of escalation to a maximum tolerated dosage (MTD) over a fixed or low-dose approach to therapy, remains controversial. Clinical trials utilizing hydroxyurea at MTD reported higher fetal hemoglobin (HbF) levels (~20% versus ~15%) compared to those with a fixed lower-dose (Ware, Blood 2010). The clinical benefits gained, if any, from increasing HbF levels from 15% to 20% has not been described. The Hydroxyurea Study of Long-Term Effects (HUSTLE) provides the opportunity to examine the relationship between the magnitude and duration of pharmacologically induced HbF and clinical outcomes, specifically the number of hospitalizations for vaso-occlusive complications such as acute chest syndrome (ACS) and vaso-occlusive events (VOE). Methods. The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) with a primary goal of describing the long-term effects of HU therapy in children with SCA, using serial and longitudinal collection of laboratory and clinical data. All children (≤18 years of age) who enrolled in HUSTLE and did not receive chronic blood transfusions are included in this analysis. All participants received hydroxyurea therapy escalated to a stable MTD, which was defined by moderate myelosuppression (typically ANC of 2,000-4,000 x 106/L) and no dose-limiting toxicities. Children were initially evaluated monthly but then every 2-3 months after achieving MTD. Neutropenia was defined as an ANC of <1,000 x 106/L. For this analysis, laboratory and clinical data were abstracted over twenty-seven months following enrollment onto HUSTLE, which constituted nine consecutive three month intervals. Hospitalizations for VOE and ACS were evaluated categorically for each three month time period, and %HbF levels at the beginning of each interval were used as the representative value for that period. To account for the correlated nature of the data, with potentially multiple hospitalizations per patient and time, a generalized estimating equation model was utilized. Results. A total of 162 children with SCA (148 HbSS, 14 HbSβ0thalassemia) at a mean (SD) age of 10.7 (4.3) years were analyzed. Children were hospitalized a total of 253 (52 ACS, 201 VOE) times during the first twenty-seven months following enrollment. The Figure illustrates the number of individuals hospitalized (yes versus no), stratified by HbF category, for each consecutive 3-month interval following HUSTLE enrollment. Compared to intervals when HbF levels were >20%, those with HbF levels of ≤20% had 2.2 (95% CI: 1.2-4.0; p=0.013) higher chance of hospitalization, and intervals with HbF levels <15% had 2.6 (95% CI: 1.3-5.1; p=0.021) times higher odds of hospitalization. For every 5% decrease in HbF, the odds of hospitalization due to VOE/ACS increased by 1.3 (95% CI: 1.1-1.5; p=0.014), correlating to a 30% increase. There was no statistically significant association between hydroxyurea dose (mg/kg) and hospitalization over time. Neutropenia occurred 39 times in 22 (13.6%) children; no episodes were associated with an invasive bacterial infection. Figure Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage. Figure. Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage. Discussion. In this pediatric cohort receiving hydroxyurea therapy escalated to MTD, higher %HbF levels conferred greater protection against hospitalization for severe vaso-occlusive pain or ACS. Escalation of hydroxyurea to MTD was rarely associated with neutropenia and had no clinical implications. These prospectively collected data from HUSTLE suggest that hydroxyurea dose escalation to MTD, designed to maximize %HbF levels, provides additional clinical benefit by reducing vaso-occlusive complications in children with SCA. Disclosures Estepp: Ely Lily: Research Funding; NIH: Research Funding. Off Label Use: Hydroxyurea in children with sickle cell anemia.

scholarly journals Economic Burden of End Organ Damage Among Patients with Sickle Cell Disease in the US

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3388-3388
Author(s):  
Xue Song ◽  
Andrew D. Campbell ◽  
Ze Cong ◽  
Irene Agodoa ◽  
Diane Martinez ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Economic Burden ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Index Date ◽  
Organ Damage ◽  
Cell Disease ◽  
End Organ Damage ◽  
Ibm Watson

Introduction Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin polymerization and red blood cell sickling, leading to chronic anemia, hemolysis, and episodic vaso-occlusion. Anemia affects the brain, kidneys and cardiovascular system, and is associated with neurocognitive dysfunction, silent cerebral infarction, stroke, renal dysfunction, pulmonary hypertension, and mortality. Limited research has been conducted to quantify the economic burden of end organ damage among patients with sickle cell disease in the US. Methods Patients with ≥3 nondiagnostic SCD ICD-9/ICD-10 codes within 5 years (Jan 1, 2013-Dec 31, 2017) were identified in the MarketScan® Medicaid claims databases. The first date of SCD diagnosis was the index date. At least three months of continuous enrollment with medical and pharmacy benefits prior to the index date, and at least 1 month of continuous enrollment following the index date were required to be included. Each patient's post-index period was divided into a series of 3-month intervals. For each 3-month interval, patients' entire available claims history (as early as 1/1/2008) was checked to identify four types of end organ damage experienced by SCD patients including stroke (within 1st year and >1 year after an acute stroke event), chronic kidney disease (CKD), end-stage renal disease (ESRD), and pulmonary hypertension (PH). Total healthcare costs (plan paid and patient out-of-pocket payment) and healthcare resource utilization (HRU) information were determined for each 3-month interval. Patient characteristics, HRU, and costs were summarized descriptively by type of end organ damage. Three multivariate generalized linear models with loglink function and gamma error distribution (assuming the cost follows an exponential relationship to the weighted average of covariates) were employed to estimate the relative cost ratios of patients with vs. without end organ damage, controlling for patients' demographic and clinical characteristics. Annualized costs for adult patients with each type of end organ damage were estimated based on the regression results. Results A total of 10,784 patients with SCD on Medicaid were identified. Patients were followed for 3.35 years on average, contributing 152,455 intervals (age ≥18: 42.7%; female: 54.6%; urban: 84.4%). Approximately 20% of the intervals had end organ damage. Patients with end organ damage had more days in hospital, ER visits, outpatient visits, lab tests, and outpatient pharmacy claims per month than patients without organ damage (Figure). The mean (SD) cost per hospitalization for acute stroke was $55,314 ($76, 847). In multivariate regression model 1 (accounting for end organ damage only), patients with any end organ damage had significantly higher costs than those without these conditions. After controlling for patient demographic characteristics (model 2) and additional clinical characteristics (model 3), the results were similar. The costs of SCD patients in the first year after stroke are 4.68 times as high as the costs of patients without any organ damage (2.08 times if >1 yr after stroke; 2.32 times for PH; 2.19 times for CKD; and 3.40 times for ESRD) (Table). The transitional age group (18-30 years) had significantly higher costs than other age groups. Having other SCD complications such as avascular necrosis, gallstones, cholelithiasis, cholecystitis, leg ulcers, osteomyelitis, or priapism also significantly increased the total costs. Based on model 3, after controlling for patient demographics and clinical characteristics, the predicted mean annual costs for adult patients with SCD in the first year after a stroke is $285,816; $127,393 if more than one year after a stroke; $148,174, $135,492, or $209,172 if the patient had PH, CKD or ESRD, respectively. Patients with multiple SCD complications had even higher costs. For example, the predicted mean annual cost for adult patients with CKD and avascular necrosis is $270,513. Conclusions Sickle cell disease is associated with substantial economic burden. When patients experience end organ damage such as stroke, renal dysfunction, or cardiopulmonary conditions, this economic burden is significantly elevated. SCD management strategies that can potentially reduce the risks of end organ damage offer both clinical and economic values to patients and society. Disclosures Song: Global Blood Therapeutics: Other: Xue Song is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Campbell:Cyclerion: Consultancy, Research Funding; Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Martinez:Global Blood Therapeutics: Other: Diane Martinez is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lew:Global Blood Therapeutics: Other: Carolyn Lew is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Black:Global Blood Therapeutics: Other: Danae Black is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Varker:Global Blood Therapeutics: Other: Helen Varker is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Chan:Global Blood Therapeutics: Other: Chris Chan is an employee of IBM Watson Health, which receives funding from Global Blood Therapeutics to conduct research. Lanzkron:Pfizer: Research Funding; Ironwood: Research Funding; Global Blood Therapeutics: Research Funding; HRSA: Research Funding; NIH: Research Funding; PCORI: Research Funding.

scholarly journals Real-World Clinical Burden of Sickle Cell Disease in the US Community-Practice Setting: A Single-Center Experience from the Foundation for Sickle Cell Disease Research

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5856-5856
Author(s):  
Lanetta Bronté-Hall ◽  
Matthew Parkin ◽  
Courtney Green ◽  
Elsa Tchouambou ◽  
Lynn Huynh ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Real World ◽  
Research Funding ◽  
Organ Damage ◽  
Community Practice ◽  
Cell Disease ◽  
End Organ Damage ◽  
The Mean

Background Sickle cell disease (SCD) is a progressively debilitating monogenic disease characterized by unpredictable, acute, life-threatening episodes and chronic complications such as hemolytic anemia and end-organ damage. It presents with a range of severity resulting in significant morbidity, poor quality of life, and early mortality. Real-world data on treatments and clinical outcomes for patients (pts) with SCD are limited, particularly in the community clinical care setting. The objectives of this retrospective real-world study were to characterize clinical manifestations and management of pts with SCD treated at the Foundation for Sickle Cell Disease Research (FSCDR). Methods A retrospective longitudinal analysis of an electronic health records (EHR) database from the FSCDR, which captured laboratory testing, treatments, and records on outpatient, emergency, and inpatient visits, was conducted. All unique pts with SCD assigned a medical record number in the EHR (N=172) were considered. Data from external records were manually entered into the EHR to supplement the EHR database. To address limitations of a real-world database, medical records for all pts included were manually reviewed and validation was performed on 10% of the sample. Pt demographics, clinical characteristics, hydroxyurea (HU) treatment (as captured by prescriptions and usage notes), administration of red blood cell transfusions, vaso-occlusive crisis (VOC) events and acute chest syndrome (ACS) (based on physician assessment) were described. Annual VOC rates were summarized by dividing the number of events by the total follow-up duration in years. Results In total, 122 pts with SCD were included. Twenty-three pts were excluded as they were not actively seeking care and/or had no relevant clinical data from 01/01/15-07/19/19. Data for 27 pts <22 years of age were unavailable at time of analysis (results of this cohort will be included in the presentation). Among all pts, 76 (62.3%) were female and 118 (96.7%) were Black or African American. The mean age at time of analysis was 39.1 (standard deviation [SD] 12.3) years with 9 (7.4%) 22-24 year-olds, 67 (54.9%) 25-40 year-olds, 35 (28.7%) 41-55 year-olds, and 11 (9.0%) ≥ 56 year-olds. The most common genotypes were HbSS (77.0%) and HbSC (17.2%). Over a mean follow-up period of 2.9 (interquartile range: 2.0, 4.4) years, 27 (22.1%) pts were treated with HU and 66 (54.1%) pts received transfusions, of which 1 (1.5%) pt chronically received episodic transfusions (i.e., continuous monthly transfusions for ≥ 6 months). The mean total hemoglobin (Hb) was 8.3 (SD 1.7) for HbSS pts and 10.9 (SD 1.5) for HbSC pts. Among pts who never received HU or transfusions during follow-up, mean Hb was 9.4 (SD 1.7) for HbSS pts and 11.4 (SD 1.6) for HbSC pts. Among pts who ever received HU or transfusions, mean Hb was 7.7 (SD 1.3) for HbSS pts and 10.3 (SD 1.1) for HbSC pts. Eleven (9.0%) pts had ≥ 1 ACS whereas 97 (79.5%) pts had ≥ 1 VOC event. ACS and VOC events occurred mostly in pts 25-55 years of age (ACS: 9 [81.8%] pts aged 25-40 years and 2 [18.2%] pts aged 41-55 years; VOC: 54 [55.7%] pts aged 25-40 years and 29 [29.9%] pts aged 41-55 years). Annual rates of VOC are described in Figure 1. Conclusions This is one of the first studies to describe clinical characteristics and management of pts with SCD in a community practice setting. Higher Hb levels among pts who never vs ever received HU or transfusions during follow-up may be a reflection of who were selected for treatment and additional studies to take into account timing of treatment and Hb assessments and confounding factors need to be conducted. The study found high VOC rates particularly among pts aged ≤ 40 years. Lower VOC rates among older pts do not necessarily indicate less severe disease. One potential reason for lower VOC rates among older pts with SCD is that cumulative exposure to ischemia-related tissue injury and resulting end organ damage may decrease VOC-related pain over time. Further investigation to elucidate the rate of VOC decline observed in older pts is needed, including looking at underlying health and end organ damage. While limitations are inherent in real-world studies, these findings underlie the ability to and importance of studying SCD management and clinical outcomes in community care settings. This study highlights the clinical burden of SCD and possibly higher than expected unmet need in this community setting. Disclosures Bronté-Hall: bluebird bio: Research Funding. Huynh:bluebird bio: Research Funding. Puri-Sharma:bluebird bio: Employment. Chang:bluebird bio: Research Funding. Chawla:bluebird bio: Employment. Signorovitch:bluebird bio: Research Funding.

scholarly journals High Molecular Weight Kininogen Contributes to End-Organ Damage and Mortality in a Mouse Model of Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 268-268 ◽  
Author(s):  
Erica Sparkenbaugh ◽  
Kathryn Wilson ◽  
Malgorzata Kasztan ◽  
David M. Pollock ◽  
Keith R. McCrae ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bone Marrow ◽  
Sickle Cell Disease ◽  
High Molecular Weight ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Organ Damage ◽  
High Molecular Weight Kininogen ◽  
Cell Disease

Abstract Introduction: Recent advances in preventive care, such as hydoxyurea and prophylactic antibiotics, have reduced the mortality of children with sickle cell disease (SCD) s in developed countries. Yet, the chronic hemolytic anemia and recurrent vaso-occlusive crises result in systemic inflammation and coagulopathy. Markers of coagulation activation correlate with painful crises, acute chest syndrome, stroke, venous thromboembolism, pulmonary hypertension, left ventricular diastolic heart disease, and sickle nephropathy. These complications result in end-organ failure that causes increased morbidity and mortality in adult SCD patients. We have shown that tissue factor (TF), the primary initiator of extrinsic coagulation, contributes to inflammation and coagulation in mouse models of SCD. (1,2). It has also been demonstrated that long-term reduction in thrombin protects from cardiopulmonary dysfunction and reduces mortality of sickle cell mice (3). Recent work from our laboratory demonstrates that high molecular weight kininogen (HK) promotes thrombin generation and inflammation in sickle mice. HK is proteolytically cleaved into bradykinin and cleaved HK fragments (HKf) by kallikrein and other proteases. HKf induces TF expression and activity on monocytes dependent on Mac-1 (CD11b/CD18). We found that Mac-1 inhibition attenuates thrombin generation and inflammation in sickle cell mice. Hypothesis: Long-term HK deficiency in sickle cell mice will attenuate TF-mediated coagulation and inflammation, and protect against end-organ damage and mortality. Methods and Results: To evaluate the effect of long-term HK deficiency on outcomes in sickle cell disease, we used bone marrow from Townes sickle (SS) and wild type (AA) mice to generate chimeras in lethally irradiated HK+/+ (WT) and HK-/- (KO) mice to create AA/WT, AA/KO, SS/WT, and SS/KO mice. Efficient reconstitution of bone marrow was confirmed by hemoglobin electrophoresis. Eight months after chimeras were generated, endpoints were assessed. SS/WT mice had early mortality (median survival 209 days, 6/23 mice survived to 250 days); HK deficiency significantly prolonged survival in SS mice (median survival 240 days, 24/29 mice survived to 250 days; p<0.01). Plasma levels of interleukin-6 were significantly higher in SS/WT mice compared to AA/WT controls (21 ± 3.7 ng/mL vs 6.6 ± 2.2 ng/mL in AA/WT, p<0.001); HK deficiency attenuated this increase (5.1 ± 1.2 ng/mL, p<0.001). The neutrophil-lymphocyte ratio was also elevated in SS/WT mice (0.47 ± 0.004 vs 0.3 ± 0.05 in AA/WT, p<0.05), yet not in the SS/KO group (0.25 ± 0.07, p<0.05), indicating that HK deficiency protects against inflammation in SS mice. Analysis of urine for renal injury markers revealed that SS/WT mice had elevated urine albumin/creatinine ratios (652 ± 34 mg albumin/g creatinine vs. 276 ± 54, p<0.01), which was significantly decreased in SS/KO mice (321 ± 49, p<0.01). Moreover, SS/WT mice had significantly reduced urine osmolality compared to AA/WT controls (2116 mOsm/kg vs 1208 mOsm/kg, p<0.05), which was reversed in SS/KO mice (1842 mOsm/kg, p<0.05). This suggests that HK deficiency protects against kidney injury and preserves urinary concentrating ability. We also observed increases in the relative left ventricle (LV+S/BW; 4.9 ± 0.2 vs 3.3 ± 0.1, p<0.05) and right ventricle (RV/BW; 1.4 ± 0.4 vs 0.99 ± 0.09, p<0.05) size in SS/WT mice compared to AA/WT controls, which was prevented in SS/KO mice (LV+S/BW: 4.0 ± 0.2, p<0.05 and RV/BW: 1.1 ± 0.06, p<0.05). Conclusions: These data indicate that HK deficiency attenuates chronic inflammation, kidney failure, and heart hypertrophy, and improves survival of sickle cell mice. Disclosures No relevant conflicts of interest to declare.

Priapism Associated with Sickle Cell Hemoglobinopathy in Children: Long-Term Effects on Potency

1996 ◽  
Vol 155 (4) ◽  
pp. 1419-1423 ◽  
Author(s):  
Amit Chakrabarty ◽  
J. Upadhyay ◽  
C.B. Dhabuwala ◽  
S. Sarnaik ◽  
A.D. Perlmutter ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Long Term Effects

scholarly journals Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

2020 ◽  
Vol 11 ◽  
pp. 204062072095500
Author(s):  
Ifeyinwa Osunkwo ◽  
Deepa Manwani ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Management Strategies ◽  
Organ Damage ◽  
Care Utilization ◽  
Cell Disease ◽  
High Resource ◽  
Emerging Treatments

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

scholarly journals The Effects of Hypertension on Cognitive Function in Children and Adolescents

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Stephen D. Cha ◽  
Hiren P. Patel ◽  
David S. Hains ◽  
John D. Mahan
Keyword(s):  
Children And Adolescents ◽  
Pediatric Population ◽  
Organ Damage ◽  
Future Research ◽  
Cognitive Effects ◽  
Long Term Outcomes ◽  
Future Studies ◽  
End Organ Damage ◽  
Anxiety Depression

Hypertension (HTN) is found in about 3-4% of the pediatric population with long-term risks of end organ damage if untreated or poorly controlled. Although children with HTN are being more frequently screened for end organ damage (i.e., LVH), the cognitive effects of HTN and methods to screen for cognitive dysfunction have not been extensively explored. In recent years, there have been a small number of studies that have provided important insights that can guide future research in this area. These studies show that HTN can be associated with headaches, restlessness, sleep disturbance, anxiety, depression, decreased attention, and also poor executive functioning. By increasing the utilization of cognitive tests in hypertensive children and adolescents, important cognitive defects secondary to HTN may be detected. More research is needed in the area, and the results of future studies could have far reaching implications for long-term outcomes in hypertensive children and adolescents.

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.

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