scholarly journals Biomarkers of Cardiopulmonary, Renal, and Liver Dysfunction in an Adult Sickle Cell Disease Cohort

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3574-3574
Author(s):  
Xu Zhang ◽  
Binal N. Shah ◽  
Roberto Machado ◽  
Santosh L. Saraf ◽  
Victor R Gordeuk
Keyword(s):  
Iron Overload ◽  
Sickle Cell ◽  
Left Atrial ◽  
Research Funding ◽  
Left Heart ◽  
Cell Disease ◽  
Liver Mass ◽  
Left Atrial Diameter ◽  
Marker Analysis ◽  
Marker Regression

Introduction In sickle cell disease (SCD), chronic anemia, hypoxia, and NO scavenging related to intravascular hemolysis contribute to diastolic dysfunction and pulmonary hypertension. Free hemoglobin and heme released during hemolysis cause oxidative stress and exacerbate vascular inflammation. Iron overload from frequent blood transfusions provokes reactive oxygen species and consequently cellular damage. We examined correlation of biomarkers reflecting major aspects of SCD patho-physiology (hemolysis, anemia, hypoxia, inflammation, and iron overload) with cardiopulmonary, renal, and liver dysfunction in an adult SCD cohort. The study provides observational evidence for etiologies of sickle cell organ damage by assessing the relative strength of outcome association for these biomarkers. Methods The study included 442 SCD patients with median age of 31 years, 77% with severe β hemoglobin mutation genotypes (HbSS, HbSβ0-thalassemia, HbSOarab) and 58% female. Biomarkers were identified for the SCD etiological conditions listed in Table 1. Primary cardiopulmonary outcomes were left heart enlargement (left atrial and ventricular diameter) and elevated systolic pulmonary artery pressure measured by tricuspid regurgitation peak velocity (TRV). The primary renal outcome was elevated urine albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Primary hepatic outcomes were hepatocyte integrity estimated as the first principal component (PC) of alanine transaminase (ALT) and aspartate aminotransferase (AST), cholestasis estimated as the first PC of alkaline phosphatase (ALP) and direct bilirubin, and functioning liver mass measured by serum albumin1. Clinical associations between biomarkers and primary outcomes first applied single marker regression with covariates of age, gender, and severity of β hemoglobin genotype. Significant biomarkers representative of the major SCD etiological conditions were then analyzed by multi-marker regression and model selection. Results Left atrial diameter showed significant associations with biomarkers of hemolysis (LDH, percent reticulocytes, AST, total bilirubin), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), and inflammation (WBC) (Table 1). Left ventricular diameter had a profile of biomarker associations similar to left atrial diameter. TRV showed significant associations with biomarkers of hemolysis (LDH, percent reticulocytes, AST), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), inflammation (WBC), and iron overload (ferritin) (Table 1). In multi-marker analysis, anemia and hypoxia (low HCT, low O2 saturation) associated with greater left atrial diameter and with high TRV (Figure 1). Urine ACR significantly associated with biomarkers of hemolysis (LDH, AST, percent reticulocytes), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), inflammation (WBC, serum albumin), and iron overload (ferritin) (Table 1). Impaired kidney function based on eGFR <60 mL/min/1.73m2 had a profile of biomarker associations similar to ACR. In multi-marker analysis, hemolysis (high LDH), anemia (low HCT), and iron overload (high ferritin) associated with increased ACR that indicates renal damage (Figure 2). Hepatocyte integrity significantly associated with biomarkers of hemolysis (percent reticulocytes), anemia (HCT, HGB), hypoxia (HCT, HGB, O2 saturation), inflammation (WBC, serum albumin), and iron overload (ferritin) (Table 2). Cholestasis had a profile of biomarker associations similar to decreased hepatocyte integrity (Table 2). Functioning liver mass showed significant association with hemolysis (percent reticulocyte), anemia (HGB, HCT), and iron overload (ferritin) (Table 2). In multi-marker analysis, hemolysis (high percent reticulocyte) and iron overload (high ferritin) associated with decreased hepatocyte integrity (Figure 3A, 3B), whereas anemia (low HCT) and iron overload (high ferritin) associated with cholestasis (Figure 3C, 3D) and with low functioning liver mass (Figure 3E, 3F). Conclusion Our study indicated significant correlations of anemia and hypoxia with both left heart enlargement and elevated pulmonary arterial systolic pressure. Our study also underscores a significant impact of iron overload on renal and liver damages. Acknowledgement We thank CSL Behring Biotherapies for Life™ for their support of this study. Disclosures Saraf: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Gordeuk:Pfizer: Research Funding; Inctye: Research Funding; Imara: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria.

scholarly journals Assessment of Iron Overload Impact on QTc Interval in Patients with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3673-3673
Author(s):  
Gilbert Bader ◽  
Gregory J. Kato ◽  
Suvankar Majumdar ◽  
James Pollard ◽  
Jarrod Knudson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Research Funding ◽  
Iron Toxicity ◽  
Conduction Delay ◽  
P Value ◽  
Qtc Interval ◽  
Cell Disease ◽  
Qtc Prolongation

Abstract Ischemic injuries and subsequent degenerative myocardial and conduction system abnormalities occur in patients with sickle cell disease (SCD). This may lead to conduction and repolarization delays reflected as QTc prolongation. Patients with SCD have increased risk of cardiac death, the basis of which remains uncertain. QTc prolongation may be a contributing factor. We decided to examine factors that can potentiate QTc prolongation in this population. In particular, we studied effect of iron overload estimated by serum Ferritin level on QTc. We performed a cross-sectional study in SCD patients older than 18 years, in steady state, followed in our clinic. Patients with acute illness or vaso-occlusive crisis in prior 2 weeks, patients with bundle branch block, pacemaker or arrhythmia and patients unable to give consent were excluded. Prolonged QTC was defined as >450 and >460 ms in men and women respectively. Patients were divided into 3 groups corresponding to mild, moderate and severe iron overload with Ferritin < 1000, between 1000 and 3000 and > 3000 ng/mL respectively. QTc was prolonged in 25/177 patients (14%). Those were older (p=0.041), had lower hemoglobin (Hb) (p<0.001) and higher Ferritin (p=0.019). Their mean age was 33.8 years, Hb 8.26 g/dL and Ferritin 3167 ng/mL compared to 29.2, 9.58 and 1735 respectively in patients with normal QTc. Twenty eight % of patients with prolonged QTc had comorbidities compared to 9% of patients with normal QTc (p=0.004). There was no difference between the 2 groups regarding gender, weight, blood pressure, Lactate dehydrogenase, electrolytes, Reticulocytes count or use of medications known to prolong QTc. Mean QTC was 429, 438 and 440 ms in groups 1,2 and 3 respectively (p=0.013). Linear regression analysis showed that QTc is expected to be longer in groups 2 and 3 compared to group 1. We also estimated QTc prolongation corresponding to 500 unit increment in Ferritin. QTc is expected to get prolonged by 0.83 ms for each 500 unit increment of Ferritin with p value of 0.028 in unadjusted model and by 0.79 ms with p value of 0.035 and 0.67 ms with p value of 0.085 in models where age and comorbidities were adjusted for respectively. Hb was found to be inversely correlated with Ferritin. Correlation coefficient was -0.39 with p value < 0.001. Although there was no significant correlation between Ferritin and JTc, analysis showed that QRS is expected to increase by 0.33 ms for each 500 unit increment in Ferritin with p value of 0.022. Comorbidities including diabetes mellitus, kidney and heart disease are known independent factors that can cause QTC prolongation. QTc increases with age. However, this mainly applies to people older than 50 years (J Geriatric Cardiol 2016 Sep;13(9):740-8). We don't believe age is an independent QTc prolonging factor in our patients especially that mean age of patients with prolonged QTc was 33.87 years. Probably older patients had longer exposure to iron toxicity which may be the true contributing factor to QTc prolongation. Patients with prolonged QTc had lower Hb. However, no correlation was found between Hb and QTc in patients with anemia caused by conditions other than SCD (Chin Med J 2015 Dec 20;128(24):3385-6). In addition, major cause of tissue injury in SCD patients is intracellular polymerization of HbS. However, there is no correlation between Hb concentration and intracellular HbS polymer content (Blood 1998 Mar 1;91(5):1777-83). Thus, we don't think Hb is an independent QTc prolonging factor. Probably patients with lower Hb received more transfusions and subsequently had more pronounced iron overload which may be the direct contributing factor to QTc prolongation. The negative correlation between Hb and Ferritin supports our hypothesis. Thus, we think that the model where just comorbidities were adjusted for is the best to reflect the association between Ferritin and QTc. Iron overload reduces overshoot ( Circulation 1999 Aug 10;100(6):675-83) which will compromise propagation of cardiac impulse and result in conduction delay. Iron also leads to production of free radicals. That will cause chronic inflammation and fibrosis. We showed that QRS is expected to get prolonged with iron overload in SCD patients which is consistent with the physiology of iron toxicity. QTc prolongation seems to be associated with iron overload in SCD patients. Conduction delay manifested by prolonged QRS may be the main contributor rather than repolarization delay. Disclosures Bader: NIMHD: Research Funding. Majumdar:NIMHD: Research Funding. Maher:NIMHD: Research Funding.

scholarly journals Iron Overload Is Under-Recognized and Under-Treated in SCD: A Report from the Grndad Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 158-158
Author(s):  
Matthew Sears ◽  
Sophie Lanzkron ◽  
Carolyn Hoppe ◽  
Joshua J. Field ◽  
Payal C Desai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Research Funding ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Research Network ◽  
Cell Disease ◽  
Liver Iron ◽  
High Iron

Abstract Background: Chronic transfusion therapy (CTT) is a mainstay of prophylactic management and treatment for adults and children with high risk Sickle Cell Disease (SCD). We estimate that 10-20% of all adults with SCD managed at our centers, especially those with homozygous HbSS disease, are on CTT, for long-term management of cerebral vasculopathy, significant end organ damage, or chronic pain. Iron overload is a common complication of CTT and for patients receiving intermittent transfusion to treat acute complications. Each unit of transfused blood introduces approximately 250 mg of iron into the bloodstream, and with it, increased oxidative stress (A. Remacha, et al., "Guidelines on haemovigilance of post-transfusional iron overload," Blood Transfusion, vol. 11, no. 1, pp. 128-139, 2013). High iron levels in the blood cumulatively lead to systemic iron deposition, particularly in the liver and heart, and untreated may lead to organ dysfunction or death. Patients with high iron levels should be put on iron chelation. Recent NHLBI guidelines suggest that patients on CTT be monitored for iron accumulation with quarterly ferritin levels, and annual or semiannual liver iron scans to assess hepatic iron burden, though the optimal frequency of these scans has not been established (B. P. Yawn, et al., "Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members," JAMA, vol. 10, no. 312, pp. 1033-1048, 2014). We examined iron overload, its frequency, severity, and management, in a modern population of adults with SCD enrolled in the multi-center prospective sickle cell registry, Globin Research Network of Data and Discovery (GRNDaD). Methods: GRNDaD is a multi-site registry of both adult and pediatric SCD patients, currently accruing at 5 urban sickle cell centers, in Baltimore MD, Cleveland OH, Milwaukee WI, Columbus OH, and Oakland CA. It currently contains prospective baseline and annual update information on nearly 500 people with SCD. Additionally, approximately 150 more patients have consented, with data entry pending. The dataset comprises demographics as well as baseline and yearly lab values, complications, procedures, treatment, and vaccination history for each patient. Among these data are ferritin levels, liver iron scan results, and chelation therapy information. We analyzed ferritin levels in people with SCD, relative to genotype, age, gender, treatment type, liver iron scan results, and chelation therapy history. Results: There were 402 adults (age≥18 years) in GRNDaD who had a non-crisis ferritin level from a routine follow-up visit. This included people with phenotypic homozygous SCD (HbSS, n=255 and Sβ0 thalassemia, N=13), variant SCD (HbSC, n=80, or Sβ+ thalassemia, n=37), and other or unknown genotypes (n=17, Table 1). Nearly 3 in 10 of all patients with SCD (n=118, 29.3%) had a ferritin level at baseline ≥1500 mg/dL, which is an accepted threshold above which to initiate chelation. Most people with an elevated ferritin had phenotypic SCA (homozygous Hb S) (n=111, or 94%). Over half of all SCD patients with a critically elevated ferritin were on CTT (n=64, 54%), and a similar number of people with SCD and critical ferritin levels were on chelation (n=64, 54%). Less than 1 in 4 had had a liver iron scan within 3 years (n=27, 23%). More than 1 in 3 patients with critical ferritin levels and no chelation therapy remained on CTT (n=21, not shown). Conclusions: Our multi-site registry, GRNDaD, prospectively surveyed a sizable population of adults with SCD, including data about iron overload. Of the adults in the GRNDaD registry with iron overload, we identified an unacceptably high fraction, nearly half, who were not on chelation. Most of these patients were people with phenotypic homozygous SCD. We are systematically addressing this deficiency with educational tools through GRNDaD. Since GRNDaD sites are academic centers across the country which focus on the management of SCD, we speculate that the problem of undertreated iron overload nationally is probably both widespread and under-recognized. We anticipate that, as GRNDaD continues to add additional sites, it will evolve as a robust resource through which to highlight important opportunities for clinical quality improvement in the expanding young adult population with SCD. GRNDaD may be a model for identifying and addressing deficiencies in current clinical practices for management of SCD. Disclosures Lanzkron: selexys: Research Funding; Ironwood: Research Funding; PCORI: Research Funding; HRSA: Research Funding; Pfizer: Research Funding; NHLBI: Research Funding; GBT: Research Funding; Prolong: Research Funding. Field:Incyte: Research Funding; Prolong: Research Funding; Ironwood: Consultancy, Research Funding. Desai:University of Pittsburgh: Research Funding; Selexy/Novartis: Research Funding; NIH: Research Funding; Ironwood: Other: Adjudication Committee; FDA: Research Funding; Pfizer: Research Funding. Little:PCORI: Research Funding; NHLBI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.

scholarly journals Biomarker Association with Hypertension in Mild Versus Severe Sickle Cell Disease Genotypes of a Single Center Cohort, in Comparison with African Americans from the Nhanes Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2051-2051
Author(s):  
Franklin Njoku ◽  
Xu Zhang ◽  
Binal N. Shah ◽  
Faiz Ahmed Hussain ◽  
Jin Han ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Advisory Committees ◽  
Blood Pressures ◽  
Laboratory Variables ◽  
Marker Regression

Abstract Introduction: Previous studies have reported that patients with sickle cell disease (SCD) have lower systemic blood pressures when compared with age-, sex-, and race-matched controls. We compared systolic and diastolic blood pressure (SBP and DBP) measurements in an SCD patient cohort followed at our clinical center with values obtained from background population using African Americans from the National Health and Nutrition Examination Survey (NHANES) study. Furthermore, we evaluated the association of SBP and DBP with clinical and laboratory variables in our patient cohort in comparison to NHANES. Methods: We cross-sectionally analyzed 442 adult SCD patients receiving medical care at the University of Illinois at Chicago (UIC) between 2009-2018, categorized as severe (HbSS/Sβ 0-thalassemia; n=342) or mild (HbSC/Sβ +-thalassemia; n=100) genotypes. 884 African American from the NHANES were age-, sex-, and race- matched as control in a 2:1 ratio. We evaluated associations between systolic and diastolic BP and 32 clinical and laboratory variables. Evaluation of medians, interquartile range (IQR), Wilcoxon rank sum and the χ2 test, were performed on covariates. Clinical associations between biomarkers and primary outcomes of SBP, DBP, were determined by first applying single marker regression with covariates. Significant biomarkers were then analyzed by multi-marker regression and model selection to predict the relative strength of outcome association for these biomarkers. All variables included were normally distributed or transformed to normal distribution. Results: The median age of participants ranged from 31-38 years for both SCD cohorts and NHANES control. 16%, 21% and 8% of the mild genotype patients, severe genotype patients and NHANES controls, respectively were on at least one antihypertensive medication for either hypertension or proteinuria. The median (IQR) for systolic and diastolic BP for the patients with mild genotype were 122 mm Hg (112-130) and 78mmHg (70-84); severe genotype 119 mmHg (110-128) and 70 mmHg (64-75); NHANES 118(110-128) and 70 mmHg (62-78). Systolic blood pressures did not differ among the SCD groups versus NHANES, but diastolic blood pressures were higher in the mild SCD genotype patients than severe SCD patients (P&lt;0.0001) or NHANES (P&lt;0.0001), regardless of antihypertensive therapy. After controlling for covariates, in the severe genotype patients SBP associated significantly with gender and prior diagnosis of hypertension, but SBP associated only with hemoglobin level in the mild genotype patients. In contrast diastolic BP associated with gender and hemoglobin in the mild genotype but had no significant association in the severe genotype patients. In the NHANES controls, we observed that SBP was significantly associated with age, gender, BMI, prior hypertension, LDH, total bilirubin, urine albumin-creatinine ratio; and DBP associated with age, BMI, WBC count (Table 1). Discussion: Our SCD patient cohorts demonstrate a much higher median SBP, and for the mild genotype patients, higher DBP than was described for their age group in the cooperative study of sickle cell disease (Pegelow et al 1997). When compared with a contemporary NHANES cohort, we failed to observe a lower SBP or DBP as was expected. Higher systolic blood pressure has been reported as risk factor for the development of silent cerebral infarct in HbSS children (DeBaun et al 2014). Our study also shows that BP changes in SCD may be less influenced by traditional anthropometric measures and clinical markers. Figure 1 Figure 1. Disclosures Saraf: 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; Pfizer: Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

Non Transferrin Bound Labile Plasma Iron and Iron Overload in Sickle Cell Disease: a Comparative Study Between Sickle Cell Disease and β Thalassemic Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4625-4625
Author(s):  
Ariel Koren ◽  
Daniel Fink ◽  
Osnat Admoni ◽  
Yardena Tennenbaum-Rakover ◽  
Carina Levin
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Research Funding ◽  
Iron Status ◽  
Blood Transfusions ◽  
Grey Zone ◽  
Cell Disease ◽  
Plasma Iron ◽  
Oncology Research

Abstract Abstract 4625 BACKGROUND Blood transfusions are the standard of care in β thalassemia and transfusions are also indicated in Sickle Cell Disease (SCD) patients with hypersplenism, recurrent vaso-occlusive crises and for stroke prevention. Iron overload caused by blood transfusions in thalassemia and in SCD may affect morbidity and mortality. Recent studies of iron overload in SCD suggest that the biologic features of SCD and the chronic inflammatory state may protect SCD patients from iron damage. DESIGNS AND METHODS In view of the controversy regarding the effect of iron overload in patients with SCD we studied the iron status, including non transferrin bound iron (NTBI) and labile plasma iron (LPI) levels in a cohort of thirty six SCD patients and compare the results with 43 thalassemia patients. RESULTS Our results indicate that none of the SCD patients had clinical symptoms of iron overload. Only two SCD patients had NTBI values in the grey zone (0.4 units) and none had positive values. By contrast, 14 patients with Thalassemia Major and 3 with Thalassemia Intermedia had NTBI values above 0.6, level that are in the positive pathological range. Similarly, four thalassemia patients, but only one SCD patient had positive LPI levels. CONCLUSIONS The parameters of iron status in SCD patients, even after frequent transfusions are different when compared to patients with thalassemia. The low NTBI and LPI levels found in patients with SCD are in keeping with the absence of clinical signs of iron overload in this disease. Disclosures: Koren: Novartis Oncology: Research Funding. Levin:Novartis Oncology: Research Funding.

Iron Trafficking and Distribution in Transfusional Overload: Insights From Comparing Diamond Blackfan Anemia with Sickle Cell Disease and Thalassemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 995-995 ◽  
Author(s):  
John B. Porter ◽  
Patrick B Walter ◽  
Lynne D Neumayr ◽  
Patricia Evans ◽  
Marcela G Weyhmiller ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Research Funding ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Cell Disease ◽  
Ineffective Erythropoiesis ◽  
Iron Distribution ◽  
Diamond Blackfan Anemia

Abstract Abstract 995 Background: β-thalassemia major (TM) is the paradigm for chronic transfusional iron overload, in which the extra-hepatic organ failure is best described. In Sickle Cell Disease (SCD), these consequences appear later and at a lower frequency. In chronically transfused Diamond Blackfan Anemia (DBA), extra-hepatic iron overload, although less well documented, appears to occur early and at high frequency. A Multicenter Study of Iron Overload (MCSIO) aims to explore how key candidate factors affect iron distribution; including inflammation, ineffective erythropoiesis, level of iron overload, and hepcidin synthesis. Plasma non-transferrin bound iron (NTBI) could be a key mechanism by which iron is delivered to tissues and may determine the propensity for extra-hepatic iron distribution. Here we focus on how markers of ineffective erythropoiesis (IE) and erythron expansion impact iron distribution, with particular reference to NTBI and iron distribution determined by MRI. Methods: Iron-overloaded patients (5 TM, 5 SCD, and 5 DBA) with ferritin > 1500 g/dl or LIC > 7 mg/g dry wt, age ≥16, age 0 to 9 at initiation of transfusion and 10 to 20 years of transfusion exposure were enrolled from 3 sites in the US and Europe. 5 non-transfused healthy controls were also enrolled. A detailed medical, transfusion and chelation history were obtained with standardized MRI evaluations for hepatic, cardiac, and pituitary iron deposition. Fasting, early morning blood samples were obtained one day prior to transfusion. Chelation was held for 72 hours prior to each sample. Results: Results are shown in the table as median values. DBA patients had the highest NTBI prior to transfusion despite having the lowest ferritin and LIC levels. GDF15 levels were highest in TM, with similar levels in SCD and DBA. EPO levels were nearly two orders of magnitude higher in DBA than TM or SCD. DBA patients also had the highest median cardiac R2*; two patients showing values above the control range. Whereas the median pituitary R2 in DBA was not above control, two of the patients had the highest R2 values, suggesting heavy iron deposition. EPO values in DBA are nearly two orders of magnitude higher that in SCD or TM despite similar pre-transfusion Hb values. GDF15 values are approximately three times controls, while soluble transferrin receptors (sTfR) values are almost undetectable. With SCD, no patients had increased cardiac iron loading, despite median SF and LIC being the highest in this group. Surprisingly all SCD patients had pituitary R2 values above the upper limit of normal. 1 TM patient had increased cardiac R2* whereas three had increased pituitary iron. In TM, NTBI was strongly correlated with GDF15 (Pearson's Rho=0.93) but in DBA, GDF15 was inversely correlated with NTBI (-.95). Conclusions: High GDF15 levels have been reported in conditions associated with IE, such as TM, but not in DBA. GDF15 reputedly suppresses hepcidin synthesis, thereby increasing iron absorption and potentially NTBI levels. The increased GDF15 in DBA, while sTfr remain less than controls, suggests that erythropoietic precursors do not reach the stage where sTfr are expressed and that this occurs at a later differentiation stage than GDF15. Increasing NTBI in TM with increasing GDF15 is consistent with IE contributing to NTBI formation, but the lack of this relationship in DBA suggest another mechanism for high NTBI. As the erythron is destroyed at a pre-hemoglobinised stage in DBA, IE would not contribute directly to NTBI formation. However, the extremely high EPO levels in DBA may inhibit hepcidin synthesis, as in other conditions, thereby increasing NTBI. This in turn may account for the extra-hepatic iron distribution demonstrated by MRI in DBA. The increased pituitary iron without cardiac loading in the heavily loaded SCD patients suggests that with prolonged exposure to heavy iron overload, the pituitary iron loading may be the first indicator of extra-hepatic deposition. Disclosures: Porter: Novartis: Consultancy, Research Funding. Walter:Novartis: Research Funding. Harmatz:Novartis: Research Funding; Ferrokin: Research Funding. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding.

Growth differentiation factor-15 in young sickle cell disease patients: Relation to hemolysis, iron overload and vascular complications

2014 ◽  
Vol 53 (4) ◽  
pp. 189-193 ◽  
Author(s):  
Azza Abdel Gawad Tantawy ◽  
Amira Abdel Moneam Adly ◽  
Eman Abdel Rahman Ismail ◽  
Yasser Wagih Darwish ◽  
Marwa Ali Zedan
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Vascular Complications ◽  
Cell Disease ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

scholarly journals Serum ferritin and total units transfused for assessing iron overload in adults with sickle cell disease

2012 ◽  
Vol 157 (5) ◽  
pp. 645-647 ◽  
Author(s):  
Emma Drasar ◽  
Nisha Vasavda ◽  
Norris Igbineweka ◽  
Moji Awogbade ◽  
Marlene Allman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
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.

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