scholarly journals Kidney Iron Deposition By R2* Is Associated with Hemolysis and Urinary Iron

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3537-3537
Author(s):  
Christopher C Denton ◽  
Jon A Detterich ◽  
Thomas Coates ◽  
John C Wood
Keyword(s):  
Los Angeles ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Univariate Analysis ◽  
Iron Deposition ◽  
Specific Marker ◽  
Cell Disease ◽  
Plasma Hemoglobin ◽  
Urine Testing

Introduction Kidney iron deposition has been described in hemolytic disorders including mechanical valves, paroxysmal nocturnal hematuria, and sickle cell disease (Roberts & Morrow, Circulation 1966; Leonardi & Ruol, Blood 1960). Circulating plasma hemoglobin is filtered at the glomerulus and reabsorbed via the megalin cubulin system in the proximal and distal tubules (Gburek et al, J Am Soc Nephrol 2002). On MRI, this manifests as signal loss on gradient and spin echo sequences in the cortex of the kidney with complete sparing of the medulla (Jeong et al, Radiographics 2002). The signal darkening is quantified by the parameter R2*, which has been shown to be directly proportional to tissue iron in the liver and heart. Kidney R2* has previously been demonstrated to rise proportionally to lactate dehydrogenase (LDH) in chronically transfused sickle cell disease (SCD) patients (Wood et al, Br J Haematol 2016; Schein et al, J Magn Reson Imaging 2008), but LDH is not a specific marker of hemolysis, and chronically transfused patients could potentially deposit iron in the kidney through other mechanisms. Therefore, we characterized the relationship between kidney R2*, urinary iron and markers of hemolysis in non-transfused SCD patients. Methods Sixty-five non-transfused SCD patients were recruited to the study, which was approved by the Institutional Review Board of Children's Hospital Los Angeles. Following medical history and physical exam, subjects completed blood and urine testing, and then abdominal MRI for assessment of somatic iron stores. R2* measurements were collected using multiple gradient echo pulse sequences on 1.5 Tesla magnets. Statistical analysis was performed using JMP® Pro, Version 14.0.0 (SAS Institute Inc., Cary, NC, 2018). Results Subjects were generally adults with a mean age of 32 years. Nearly three quarters of subjects had homozygous sickle cell disease, while a quarter had SC disease or S-Beta thalassemia, and one subject had sickle cell trait. Most subjects were anemic, and all subjects had elevated markers of hemolysis. Fifty-four percent of subjects had an elevated kidney R2* level (≥34 Hz). On univariate analysis, kidney R2* was associated with urinary iron (R2=0.52, p<0.0001), LDH (R2=0.33, p<0.0001), plasma hemoglobin (R2=0.18, p=0.0007), and hemoglobin (R2=0.08, p=0.02), but it was not associated with reticulocyte count. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (Figure 1). No association was found between R2* values of the kidney, liver, and pancreas. Discussion Our study supports previous findings that kidney R2* is associated with intravascular hemolysis, as measured by plasma hemoglobin and LDH, and inversely by hemoglobin (Kato et al, Blood 2006). The stronger association with urinary iron reinforces the concept that kidney R2* reflects filtered iron, which is insufficiently reabsorbed due to proximal and distal tubular injury in iron overload (van Raaij et al, Am J Physiol Renal Physiol 2019). Urinary iron is also elevated in diabetic nephropathy (Van et al, J Am Soc Nephrol 2017) and nephrotic syndrome (Niel et al, Blood 2011). These data raise important questions regarding the possible role of iron in sickle related renal disease. Disclosures Coates: apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy.

scholarly journals Three Months of Human Haptoglobin Treatment Decreases Iron Deposition in the Kidneys of Townes Sickle Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2163-2163
Author(s):  
Patricia A Shi ◽  
Erika Choi ◽  
Julia Nguyen ◽  
Xinhua Guo ◽  
Narla Mohandas ◽  
...  
Keyword(s):  
Treatment Group ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Urine Osmolality ◽  
Organ Damage ◽  
Iron Deposition ◽  
P Value ◽  
Cell Disease ◽  
Old Mice

Abstract Introduction: Haptoglobin (Hp), the scavenger for hemoglobin, and hemopexin (Hx), the scavenger for heme, are depleted in most patients with sickle cell disease due to chronic hemolysis. There is mounting evidence of the crucial role of free hemoglobin and/or free heme in mediating inflammatory and oxidative damage in sickle cell disease, including vaso-occlusion and acute chest syndrome. Purified Hp has been used in Japan for a variety of hemolytic conditions and has been proposed as a potential treatment for sickle cell disease. Although infusions of Hp or Hx have been shown to ameliorate vaso-occlusion, acute lung injury, and heme toxicity in sickle cell mouse models, no prior studies have examined the utility of chronic Hp treatment for amelioration of organ damage. We therefore studied the effect of 3 months of chronic Hp treatment in the Townes sickle mouse model. Methods: Male and female Townes mice (Stock number 013071, The Jackson Laboratory) were used for all experiments, starting at 1 or 3 months of age. SS genotype was confirmed by PCR and HPLC. Organ damage in the spleen, liver, and kidneys as previously described was confirmed. Human Hp solution was a kind gift from Bio Product Laboratory (BPL, Hertfordshire, UK). Hp or equivalent volume PBS control was administered intraperitoneally (IP) in the first cohort of 5 mice and then subcutaneously (SC) in the next two cohorts of 7 and 12 mice on a 48-72 hr dosing schedule of Monday, Wednesday, Friday for a period of 3 months. At the end of 3 months treatment, mice were evaluated by the following studies (with concurrent blinding to treatment group for most studies): plasma Hp (ELISA), plasma heme (QuantiChrom heme assay), urine osmolality (osmometer), urine albumin (ELISA), CBC (Advia 120), WBC differential (Advia 120 and manual count), red blood cell ektacyometry (ektacyometer), organ mass (percent of body weight), and organ histology. Results: Mouse Hp levels in SS Townes mice were confirmed to be markedly low compared to Townes AA mice (mean ± SD: SS 2 ± 1 versus AA 39 ± 4 ug/mL). Dose-finding experiments determined that a dose of 200-400 mg/kg IP or SC in SS mice resulted in a 24 hr peak concentration that was 5-14X supraphysiologic, variably physiologic at 48 hr, and absent or almost absent at 72 hr. Chronic dosing at the 400 mg/kg IP in SA mice showed no CBC or organ toxicity. Three successive cohorts of SS mice were treated with Hp (or equivalent volume of PBS): 200 mg/kg IP in 3-month old mice, 400 mg/kg SC in 3-month old mice, and 400 mg/kg SC in 1-month old mice. At the 400 mg/kg dosing levels, there was a significant decrease in iron deposition in the kidneys of both 4-month and 6-month old mice (treatment started at 1-month and 3 months, respectively) (Table 1). There was also a trend towards decreased liver infarction in 6-month old mice (Table 2). Discussion: Functional binding of the administered human Hp to the human Hb of the Townes mice likely occurred, as evidenced by the decrease in iron deposition in the kidneys, suggesting that formation of the complex prevents filtration of Hb into the kidneys. Surprisingly, kidney function as measured by urine osmolality or albumin excretion was not improved, which may be explained by continued heme-laden red cell microparticle filtration (Camus SM, Blood 2015). Encouragingly, however, a trend towards decreased liver infarction in older mice was observed. The less-than-expected effect of Hp on mouse disease severity may also be explained by: 1) continuous physiologic Hp concentrations not being maintained with the dosing frequency while continued hemolysis releases Hb every minute of the day, and 2) CD163-mediated uptake in mice seems to only account for a part of the Hb clearance as opposed to in humans (Etzerodt A, Antioxid Redox Signal 2013). Despite the limitations of the SCD mouse model, the current study suggests haptogobin infusions could be beneficial in SCD patients. Acknowledgment: The authors are grateful to Sandra Suzuka for performing the HPLC. Table 1. Table 1. Kidney iron deposition (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 4.0 ± 1.4 1 ± 1.1 PBS 9.3 ± 0.6 5 ± 2.9 p-value 0.002 0.02 Table 2. Liver infarction (scale 1-10) Treatment group 6-month old SS 4-month old SS 400 mg/kg Hp 2.6 ± 2.0 3.7 ± 2.8 PBS 6.3 ± 2.4 3.8 ± 2.3 p-value 0.07 0.91 Disclosures Belcher: Biogen Idec: Research Funding; Seattle Genetics: Research Funding; CSL Behring: Research Funding. Vercellotti:CSL Behring: Research Funding; Seattle Genetics: Research Funding; Cydan: Research Funding; Biogen Idec: Research Funding.

Haptoglobin and Hemopexin Infusion Efficiently Activates the Nrf2/HO-1 Axis and Inhibits Inflammation and Vaso-Occlusion in Murine Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2477-2477 ◽  
Author(s):  
John D Belcher ◽  
Chunsheng Chen ◽  
Julia Nguyen ◽  
Fuad Abdulla ◽  
Phong Nguyen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Treatment Groups ◽  
Plasma Hemoglobin ◽  
Skin Fold ◽  
Chronic Hemolysis ◽  
Plasma Haptoglobin

Abstract Free hemoglobin and hemin, released by red blood cells during intravascular hemolysis, promote vasculopathy, inflammation, thrombosis, and renal injury. Plasma haptoglobin and hemopexin tightly bind free hemoglobin and hemin, respectively, thwarting these clinical sequelae. In sickle cell disease (SCD), chronic hemolysis can deplete plasma haptoglobin and hemopexin in humans and mice. To explore mechanisms mediating this protection and provide a basis for supplementation in SCD patients, dorsal skin fold chambers were implanted onto Townes-SS mice and microvascular stasis (% non-flowing venules) was measured in response to a hemoglobin challenge. Human haptoglobin, hemopexin, or albumin was co-infused with hemoglobin or 1 hour after hemoglobin at equimolar concentrations. Sickle mice co-infused with hemoglobin/haptoglobin, hemoglobin/hemopexin or hemoglobin/haptoglobin/hemopexin had less stasis 1 to 4 hours after infusion, compared to albumin- and saline-treated mice (*p<0.01, Figure A). Haptoglobin, hemopexin, or haptoglobin/hemopexin given to Townes-SS mice 1 hour after hemoglobin, decreased stasis 2 and 3 hours after supplementation, while the venules of mice treated with albumin remained static (*p<.01, Figure B). Plasma hemoglobin and heme levels in Townes-SS mice were not different between treatment groups 3 and 4 hours after supplementation. Haptoglobin or hemopexin infusion increased hepatic Nrf2 and HO-1 and decreased pro-inflammatory NF-ĸB phospho-p65 expression relative to albumin 3 and 4 hours after supplementation (p<.05). The combination of haptoglobin/hemopexin was similar to either scavenger alone. Inhibition of the enhanced HO-1 activity afforded by haptoglobin or hemopexin with tin protoporphyrin blocked the stasis protection, confirming the critical cytoprotective role of HO-1. Haptoglobin and hemopexin, but not albumin, are cytoprotective in part by efficiently delivering heme to CD163 and CD91 and activating the Nrf2/HO-1 axis. Figure Figure. Disclosures Belcher: CSL-Behring: Research Funding; Imara: Research Funding. Chen:Imara: Research Funding. Brinkman:CSL-Behring: Employment. Vercellotti:CSL-Behring: Research Funding; Imara: Research Funding.

scholarly journals Increased Iron Deposition Is Directly Associated With Myocardial Dysfunction in Patients With Sickle Cell Disease

2018 ◽  
Vol 11 (2) ◽  
pp. 279-280 ◽  
Author(s):  
Kana Fujikura ◽  
Anjani D. Golive ◽  
Tomo Ando ◽  
Francisco M. Corado ◽  
Sanyog G. Shitole ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Myocardial Dysfunction ◽  
Iron Deposition ◽  
Cell Disease

scholarly journals COVID Symptoms and COVID Anxiety in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Wally R Smith ◽  
Benjamin Jaworowski ◽  
Shirley Johnson ◽  
Thokozeni Lipato ◽  
Daniel M Sop
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Telephone Survey ◽  
Cell Disease ◽  
Weighted Mean ◽  
The Us ◽  
Associated Symptoms ◽  
At Home

Background Even before the US upswing of the current COVID pandemic, the number of sickle cell disease (SCD) patients coming to hospitals and EDs appeared to fall drastically. This happened despite SCD patients having often been heavy utilizers of the ED and hospital for their iconic vaso-occlusive crises (VOC). Though ambulatory SCD clinics quick converted largely to telehealth in order to comply with stay-at-home orders designed to suppress person-to-person transmission, some SCD patients appeared to avoid care, delay care, or refuse doctors' invitations for care. Presumably patients did so out of COVID fears, but this has not been confirmed in the literature. Further, whether these patients had COVID symptoms but stayed at home has not been studied. As part of quality improvement (QI) to conduct COVID surveillance in an adult sickle cell program, we sought to explain and predict SCD health care utilization patterns we were observing, as well as to determine urgent physical and mental health needs of patients who appeared to be avoiding care. Methods Fifteen staff in the Adult Sickle Cell Medical Home at Virginia Commonwealth University, a large urban academic medical center, conducted a telephone survey ("wellness check"was used when we talked to patients) of all known adults with SCD over 19 days in 2020. A staff member confirmed the patient had SCD, asked permission to proceed, then asked about symptoms consistent with COVID-19. At the end of the telephone survey, respondents wer invited to complete an email survey of sickle cell and COVID-19 utilization attitudes (19-33 items, depending on the response pattern, either drawn from the National Health Interview Survey, from the Adult Sickle Cell Quality of Life Measurement quality of care survey, or drafted by the authors), the Sickle Cell Stress Survey-Adult (SCSS-A, a 10-item previously validated survey), and anxiety and depression (PHQ9 of the PRIME-MD). Results Of 622 adults approached by phone call, 353 responded to the following yes/no screening questions regarding the prior 14 days: fever over 100 F 0/353 (0.00%); cough 3/353(0.01%); difficulty breathing 0/353(0.00%); unexplained shortness of breath 2/353(0.01%); sore throat 2/353 (0.01%); unexplained muscle soreness 2/353(0.01%);contact with anyone who tested positive for COVID-19 2/353(0.01%); testing for COVID 19 6/353(0.02%). For QI purposes, we set a threshold of three or more COVID-associated symptoms or the presence of fever as criteria requiring intense telephone or in-person staff monitoring for the following week. Only three patients met criteria. A total of 219/353 had email surveys sent. Of 63 patients (28.8%) who returned email surveys by June 10, 2020, 35.9% had already managed a "pain attack" at home 4 or more times in the prior 12 months, and 45.5% of these said their bad ER experiences were very or somewhat important in that decision. In the prior 14 days, although 30/64 reported a crisis for at least one day, only 4/64 had visited the Emergency Department for pain. On a 0-10 scale, 21/61 patients endorsed "0" for worry that they would be COVID-infected by going for medical care (weighted mean 3.9), but 18/59 endorsed "10" for worry they were more at risk of COVID because of SCD (weighted mean 6.31), and 22/60 endorsed "10" for worry they would fare worse than others if COVID infected (weighted mean 6.97). Many patients forwent "needed" care (16/62) or delayed "needed" care by at least a day (36/61). Eleven patients met criteria for moderately severe to severe depression on the PHQ-9, and 28/63 somewhat or strongly agreed with the statement "death is always on the back of my mind" on the SCSS-A. Conclusions In adolescents and adults with SCD, many were already reticent to come to the ED for pain, but a significant portion reported delays or avoidance of needed care during the early stages of the US COVID pandemic, and few reported using the ED despite over half reporting at least one crisis day in 14. Patients nonetheless reported very few COVID-associated symptoms. Fears of COVID infection/susceptibility may limit visits for needed sickle cell care among adults. Acknowledgements: Mica Ferlis RN, FNP, Caitlin McManus, RN, FNP, Emily Sushko, RN, FNP, Justin West, RN, Kate Osborne, RN, Stefani Vaughan-Sams, Marla Brannon, BS, Nakeiya Williams, BS Disclosures Smith: GlycoMimetics, Inc.: Consultancy; Emmaeus Pharmaceuticals, Inc.: Consultancy; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Shire, Inc.: Other: Investigator, Research Funding; NHLBI: Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; Health Resources and Services Administration: Other: Investigator, Research Funding; Incyte: Other: Investigator; Pfizer: Consultancy; Ironwood: Consultancy; Novo Nordisk: Consultancy; Imara: Research Funding; Shire: Research Funding.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value &lt; 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Victoria Brooks ◽  
Oluwalonimi Adebowale ◽  
Victor R. Gordeuk ◽  
Sergei Nekhai ◽  
James G. Taylor
Keyword(s):  
Risk Factors ◽  
Alkaline Phosphatase ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Severe Disease ◽  
Case Control ◽  
Red Cell ◽  
Cell Disease ◽  
History Of

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with &gt;10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

scholarly journals Cardiac Injury and Microvascular Ischemia in Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2286-2286
Author(s):  
Kiranveer Kaur ◽  
Ying Huang ◽  
Subha Raman ◽  
Eric H. Kraut ◽  
Payal Desai
Keyword(s):  
Sickle Cell Disease ◽  
Myocardial Perfusion ◽  
Sickle Cell ◽  
Cardiac Mri ◽  
Research Funding ◽  
Cardiac Injury ◽  
Microvascular Disease ◽  
Elevated Troponin ◽  
Cell Disease ◽  
Troponin Elevation

Introduction: Myocardial ischemic injury remains an under recognized problem in patients with sickle cell disease (SCD), for which the exact prevalence remains undefined. SCD patients are known to have microvascular disease, impaired myocardial perfusion reserve and lack of typical epicardial vessel involvement based on prior data. Previous study at our institution has demonstrated that 3/22(13%) patients with clinically stable sickle cell disease had impaired myocardial perfusion reserve but no epicardial coronary artery disease. In this study, we will aim to learn prevalence of cardiac injury and microvascular ischemic disease. We will also evaluate for impact of these findings on overall survival (OS) of SCD patients. Methods: We conducted a retrospective chart review of patients with SCD seen at OSU Wexner Medical Center from July 2005 to July 2015 to identify patients who had elevated troponin-I level or cardiac MRI performed for chest pain. Clinical and laboratory data around the time of cardiac MRI and troponin elevation was collected. Abnormal MRI was defined in three ways: 1) Microvascular disease was defined by presence of subendocardial or myocardial perfusion defects and myocardial scarring. 2) Myocardial disease otherwise includes other findings suggestive but not specific for myocardial ischemia including left ventricular dysfunction, midmyocardial fibrosis, inflammation and regional wall motion abnormalities. 3) Abnormal MRI includes patients described in either 1) or 2). Kaplan-Meier (KM) method was used to evaluate the impact of microvascular disease defined in all 3 ways on OS. Proportional hazards model was fit to estimate the association between troponin elevation and OS, where troponin elevation was treated as a time-dependent variable and OS was measured from time of birth. Results: Sixty-nine (51% male; genotype Hb SS 75%, SC 16%, and Sβ-thal 9%) of 373 SCD patients had either abnormal troponin and/or had cardiac MRI done. Median age was 34 years (range 19-67 years). Of 238 patients who had troponin-I measured over this period, 18 % (n=42) had elevated troponin. 24 of 47 patients with cardiac MRI showed abnormalities described above specific for microvascular disease (n=14, 30%) and myocardial disease otherwise (n=10, 21%). We identified 22 patients with troponin measurement within 30 days before cardiac MRI. Elevated troponin levels predicted MRI abnormalities with sensitivity of 71% (95% confidence interval (CI) 42-92%) and specificity of 63% (95% CI 24-91%). The degree of troponin elevation did not correlate with the MRI abnormality. Hazard ratio of death in patients with elevated troponin was 5.1 (95% CI 2.7-9.6; p<0.0001). While the KM survival curves show lower OS in patients in abnormal MRI (p=0.74) and microvascular disease (p=0.42; Figure 1) group compared with normal MRI, the comparisons were not statistically significant. There was no difference in OS for patients with nonspecific myocardial disease findings (p=0.59). Conclusion: Over a 10-year period, the prevalence of cardiac injury as measured by elevated troponin was 18% (42/238) in patients with atypical chest pain. Among 47 patients who had cardiac MRI performed, 51% were abnormal with 30% having findings specific for microvascular cardiac disease. Troponin elevation appears to significantly increase the risk of all-cause mortality. Patient with microvascular and myocardial ischemic disease tend to have lower OS, but it did not reach statistical significance. This could be one of the potential contributing factors to high early mortality and sudden deaths in SCD patients. Further studies will be needed to elaborate on disease modifying interventions that impact survival in these patients. Disclosures Desai: Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board.

scholarly journals Increased brain iron deposition in patients with sickle cell disease: an MRI quantitative susceptibility mapping study

Blood ◽  
2018 ◽  
Vol 132 (15) ◽  
pp. 1618-1621 ◽  
Author(s):  
Xin Miao ◽  
Soyoung Choi ◽  
Benita Tamrazi ◽  
Yaqiong Chai ◽  
Chau Vu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Susceptibility Mapping ◽  
Iron Deposition ◽  
Brain Iron ◽  
Cell Disease ◽  
Mapping Study ◽  
Quantitative Susceptibility Mapping ◽  
Brain Iron Deposition

Inflammation, Multiple Blood Transfusions and Osteoclast Activation in Sickle Cell Disease Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1534-1534
Author(s):  
Kevin Cheng ◽  
Mehdi Nouraie ◽  
Xiaomei Niu ◽  
Evadne Moore-King ◽  
Margaret F. Fadojutimi-Akinsi ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Bone Resorption ◽  
Sickle Cell ◽  
Research Funding ◽  
Blood Transfusions ◽  
Serum Concentrations ◽  
Cell Disease ◽  
Howard University ◽  
Tracp 5B ◽  
Multiple Blood

Abstract Abstract 1534 Poster Board I-557 Background Low bone mass density affects more than 65% of adult sickle cell disease patients and correlates with lower hemoglobin and higher ferritin concentrations (1). Increased iron supply promotes osteoclast differentiation and bone resorption (2). Proinflammatory cytokines also promote bone resorption (3). Tartrate resistant acid phosphatase isoform 5b (TRACP-5b) is produced only by activated osteoclasts and therefore serves as a marker of bone resorption (4). Sickle cell disease is a condition of chronic inflammation and patients often suffer from transfusional iron overload as well. In this study we aimed to determine the predictors of bone resorption in patients with sickle cell disease by measuring circulating levels of TRACP-5b. Methods Fifty-nine adult sickle cell disease patients and 22 apparently healthy controls were recruited at Howard University Hospital. Patients were at steady state with no crisis, hospitalization or blood transfusion in the last 3 weeks. Clinical and laboratory information was collected at the time of recruitment and TRACP-5b was measured in non-fasting serum samples using an enzyme immuno assay kit (Quidel, San Diego, CA). Serum concentrations of inflammatory cytokines and growth factors were measured by Multiplex assay (Bio-Rad, Hercules, CA).. Results Sickle cell disease patients had elevated concentrations of TRACP-5b compared to controls (median values of 4.4 vs. 2.4 U/l, P < 0.0001). Among the patients, TRACP-5b concentrations correlated positively with number of blood transfusions (r = 0.19) and serum concentrations of alkaline phosphatase (r=0.46), endothelin-1 (r=0.39), interleukin-8 (r= 0.38), and interleukin-6 (r=0.25). TRACP-5b correlated negatively with RANTES (r = -0.42) and PDGF (r = -0.31). It did not correlate significantly with serum ferritin (r = -0.03), LDH (r = 0.13) or hemoglobin concentration (r = 0.11). Interestingly, TRACP-5b correlated positively with tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure (r = 0.30). Conclusion Sickle cell patients have elevated steady-state osteoclast activity as reflected in serum TRACP-5b concentrations. Multiple blood transfusions and inflammation are associated findings. Among patients, higher TRACP-5b concentrations are associated with lower concentrations of RANTES and PDGF-BB, factors that influence function of osteoblasts. Further studies are needed to investigate whether common pathways may be involved in osteoclast activation and pulmonary changes in sickle cell disease. Supported by grants number 2 R25 HL003679-08 and 1 R01 HL079912-02 and 1U54HL090508-01 from NHLBI, by Howard University GCRC grant no 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program of the National Institutes of Health. Disclosures Gordeuk: Biomarin: Research Funding; TRF Pharma: Research Funding; Merck: Research Funding; Novartis: Speakers Bureau.

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